. _:b546868438 "6"^^ . _:b546868889 . _:b546868840 . _:b546868473 . . _:b546868888 . _:b546868439 "6"^^ . . _:b546868882 . _:b546869493 . . _:b546869369 . _:b546868436 "6"^^ . _:b546868891 . . _:b546868437 "6"^^ . _:b546868890 . _:b29429167 . _:b546868593 . _:b546868434 "6"^^ . _:b546868901 . _:b546869045 . . _:b546868900 . _:b546868435 "6"^^ . . _:b546868920 . _:b546868903 . _:b546868432 "7"^^ . _:b546868823 . . _:b546868902 . _:b546868433 "6"^^ . _:b546868905 . . . _:b29429188 "Furthermore, elevated plasma TGF\u03B2 levels correlate with advanced tumor stage, metastases, and poor survival [>>15<<]\u2013[17]. Given its integral role in the progression of cancer, TGF\u03B2 is an attractive therapeutic target." . _:b546868897 . _:b546868446 "6"^^ . _:b29429172 . _:b546868447 "6"^^ . _:b546868896 . . _:b29429173 . . _:b546868444 "6"^^ . _:b546868899 . . _:b29429174 . _:b546869196 . _:b546868445 "6"^^ . _:b546868898 . _:b29429175 . _:b546868794 . . _:b546869261 . _:b546868909 . _:b546868442 "6"^^ . _:b29429168 . _:b29429202 _:b29429228 . _:b29429202 _:b29429229 . _:b546868443 "6"^^ . _:b546868908 . _:b29429202 _:b29429230 . _:b29429202 _:b29429231 . _:b29429212 "Interestingly, KAs and SCCs have been reported in patients receiving sorafenib, B-RAF inhibitors, and anti-tumor necrosis factor (TNF) \u03B1-directed therapies [33], [38], [>>39<<], and recent data with vemurafemib have implicated RAS pathway mutations and signaling through the mitogen-activated protein kinase pathway in the development of these lesions [40]." . _:b29429169 . _:b29429202 _:b29429224 . . _:b29429202 _:b29429225 . _:b546868440 "6"^^ . _:b546868911 . _:b29429202 _:b29429226 . . _:b29429202 _:b29429227 . _:b29429170 . _:b29429202 _:b29429220 . _:b29429202 _:b29429221 . . _:b546868910 . _:b29429202 _:b29429222 . _:b546868441 "6"^^ . _:b546868469 . _:b29429171 . _:b29429202 _:b29429223 . . _:b29429202 _:b29429216 . _:b29429202 _:b29429217 . _:b29429202 _:b29429218 . _:b546869258 . _:b546869117 . _:b546868905 . . _:b29429180 . _:b29429202 _:b29429219 . . _:b546869468 . _:b546868453 "5"^^ . . _:b546868904 . _:b546868992 . _:b29429181 . _:b546868452 "6"^^ . _:b546868907 . _:b29429182 . _:b546868455 "5"^^ . _:b546868906 . _:b546869451 . _:b29429183 . _:b29429202 _:b29429232 . _:b546868454 "5"^^ . _:b29429202 _:b29429233 . _:b546868450 "6"^^ . _:b546868917 . _:b29429202 _:b29429234 . . _:b29429176 . _:b29429202 _:b29429235 . . _:b546869495 . . _:b546868451 "6"^^ . _:b546869016 . _:b546868916 . _:b546869242 . _:b29429177 . _:b546869321 . _:b546869524 . _:b546868448 "6"^^ . _:b546868919 . _:b29429178 . _:b546868449 "6"^^ . _:b546868918 . _:b29429179 . . _:b546868913 . _:b29429188 . _:b29429202 _:b29429212 . _:b546868461 "5"^^ . _:b29429202 _:b29429213 . _:b29429202 _:b29429214 . _:b546868912 . _:b29429202 _:b29429215 . _:b29429189 . _:b546868812 . _:b29429202 _:b29429208 . _:b546868460 "5"^^ . _:b29429202 _:b29429209 . _:b29429202 _:b29429210 . _:b546868915 . _:b29429202 _:b29429211 . _:b29429190 . _:b29429202 _:b29429204 . _:b546868463 "5"^^ . _:b29429202 _:b29429205 . _:b29429202 _:b29429206 . _:b546868914 . _:b29429202 _:b29429207 . _:b29429191 . _:b546868462 "5"^^ . _:b546868925 . . _:b29429184 . _:b29429202 _:b29429203 . . _:b546868457 "5"^^ . _:b546869470 . _:b546868924 . _:b29429185 . _:b546868456 "5"^^ . _:b546868909 . _:b546868927 . _:b546868648 . _:b29429186 . . _:b546868459 "5"^^ . _:b546868926 . _:b29429181 "growth factor (VEGF) and angiogenesis, dysregulated lymphangiogenesis, increased extracellular matrix deposition, and production of factors such as parathyroid hormone-related peptide (PTHrP) that increase osteoclastic activity [4], [>>8<<]\u2013[10]. TGF\u03B2 also attenuates host antitumor immune responses." . _:b29429187 . _:b546868458 "5"^^ . _:b29429214 "in the combined 10 and 15 mg/kg cohorts was 7.2 weeks (range, 4.1\u201320.1 weeks, mean 8.9 weeks), which is consistent with the median TTP/PFS of 1.3 to 2 months reported for patients with MM treated with dacarbazine or other chemotherapy [>>33<<], [34]. Based on this, there appears to be no negative impact of higher doses of GC1008 on clinical outcome." . _:b546868736 . _:b546868921 . _:b546869000 . _:b29429196 . . _:b546868469 "5"^^ . _:b546868920 . _:b29429197 . _:b546868468 "5"^^ . _:b546868923 . . _:b29429198 . . _:b546868471 "5"^^ . . _:b546869110 . _:b546868922 . _:b546868501 . . _:b29429199 . _:b546868991 . _:b546868470 "5"^^ . _:b546868933 . _:b546869410 . _:b546869007 . _:b29429192 . . _:b546869476 . _:b546868861 . _:b546868465 "5"^^ . _:b546868932 . _:b546869243 . _:b29429193 . . _:b546868464 "5"^^ . _:b546868935 . _:b29429194 . . _:b546868467 "5"^^ . . . _:b546868934 . _:b546868771 . _:b29429195 . _:b546869424 . . _:b546868466 "5"^^ . . _:b546868929 . _:b29429204 . _:b546868477 "5"^^ . _:b546868595 . _:b546868928 . _:b29429205 . . _:b546868653 . _:b546868476 "5"^^ . _:b546868931 . _:b29429206 . _:b546868479 "5"^^ . _:b546868930 . _:b29429207 . _:b546868478 "5"^^ . _:b546868941 . _:b29429200 . _:b546869459 . _:b546868473 "5"^^ . . _:b546868940 . _:b546868452 . . _:b29429201 . . _:b546868805 . . . _:b546868472 "5"^^ . _:b546868943 . . _:b546869479 . _:b29429202 . . _:b546869268 . _:b546868475 "5"^^ . _:b546868942 . . _:b29429203 . _:b546868474 "5"^^ . . _:b546868937 . . _:b29429212 . _:b546868485 "5"^^ . _:b546869042 . _:b546868936 . . _:b29429213 . _:b546869049 . _:b546868484 "5"^^ . _:b546869475 . _:b546868939 . _:b546869273 . _:b29429182 "factor (VEGF) and angiogenesis, dysregulated lymphangiogenesis, increased extracellular matrix deposition, and production of factors such as parathyroid hormone-related peptide (PTHrP) that increase osteoclastic activity [4], [8]\u2013[>>10<<]. TGF\u03B2 also attenuates host antitumor immune responses." . _:b29429214 . _:b29429192 "In a number of preclinical models, neutralizing antibodies or soluble receptors that bind TGF\u03B2 have demonstrated antitumor activity [10], [18]\u2013[>>23<<]. In murine metastatic breast cancer models, a survival benefit and a reduction in the incidence and size of lytic bone lesions and lung metastases were observed in animals receiving anti-TGF\u03B2 antibody therapy alone [20], [24] as well as" . _:b546868487 "5"^^ . _:b546868785 . _:b546868938 . _:b546868765 . _:b29429215 . _:b546868835 . _:b546869231 . _:b546868486 "5"^^ . _:b546868949 . _:b29429208 . _:b546868481 "5"^^ . _:b546868690 . _:b546868948 . . _:b29429209 . _:b546868480 "5"^^ . _:b546868951 . _:b29429210 . _:b546868483 "5"^^ . . _:b546868950 . _:b29429211 . _:b546868482 "5"^^ . _:b546868945 . _:b546868447 . _:b29429220 . . _:b546868493 "4"^^ . _:b546868944 . . _:b29429221 . _:b546868833 . . _:b546868492 "4"^^ . . . _:b546868947 . _:b546868787 . _:b29429222 . _:b546868495 "4"^^ . _:b546868946 . _:b29429223 . _:b546868494 "4"^^ . _:b546868957 . _:b29429216 . _:b546868489 "5"^^ . _:b546868956 . _:b546869083 . _:b29429217 . _:b546868488 "5"^^ . _:b546868959 . _:b29429218 . _:b546868491 "4"^^ . _:b546868958 . _:b546868570 . _:b29429219 . _:b546868490 "5"^^ . _:b546869267 . _:b546868953 . _:b29429228 . _:b546868501 "4"^^ . . _:b546868952 . _:b29429229 . _:b546868500 "4"^^ . . _:b546868955 . . _:b29429230 . _:b546868503 "4"^^ . _:b29429193 . _:b546868954 . _:b546869142 . _:b29429231 . _:b546868502 "4"^^ . _:b546868965 . _:b29429224 . _:b546868497 "4"^^ . . . _:b29429228 . _:b546868964 . _:b546868896 . . _:b29429225 . _:b546868496 "4"^^ . . _:b546869503 . _:b546868967 . _:b29429226 . _:b546868499 "4"^^ . _:b546868966 . _:b546868767 . _:b29429227 . _:b29429222 . _:b546868498 "4"^^ . . _:b546868961 . . _:b546869491 . . _:b546868509 "4"^^ . _:b546868579 . . _:b546868960 . _:b546868508 "4"^^ . _:b546868963 . . _:b546868511 "4"^^ . . . _:b546868962 . _:b546868811 . _:b546868749 . . _:b546868510 "4"^^ . _:b546868606 . _:b546869205 . _:b546868973 . _:b29429232 . _:b546868505 "4"^^ . . _:b546868972 . _:b29429233 . _:b546868504 "4"^^ . . _:b546869466 . _:b546868975 . _:b546868391 . _:b29429234 . _:b546868507 "4"^^ . _:b546868974 . . _:b29429235 . _:b546868506 "4"^^ . _:b546869070 . _:b546868969 . _:b546868517 "4"^^ . _:b29429219 "A variety of anti-TGF\u03B2 agents combined with chemotherapy, radiation, biologics, immunotherapeutics and vaccines have demonstrated enhanced antitumor effects in preclinical models [11], [21], [22], [25], [28]\u2013[>>30<<], [41]\u2013[44]." . _:b546868778 . . _:b546868568 . _:b546868968 . _:b546868718 . _:b546868470 . . _:b546868516 "4"^^ . . . _:b546868971 . _:b546868519 "4"^^ . _:b546868936 . _:b546868970 . _:b546868518 "4"^^ . _:b546869455 . _:b546868707 . _:b546868981 . . _:b546868513 "4"^^ . _:b546868980 . _:b546869306 . _:b546868512 "4"^^ . _:b546869170 . _:b546868983 . _:b546869136 . _:b546868530 . . _:b546868515 "4"^^ . _:b546868982 . . _:b546868514 "4"^^ . _:b546868977 . . _:b546868525 "4"^^ . . _:b546868976 . . . _:b546868524 "4"^^ . _:b546868979 . _:b546868563 . _:b546868527 "4"^^ . . _:b546868978 . _:b546868526 "4"^^ . . _:b546868989 . _:b546869211 . _:b546868481 . _:b546868521 "4"^^ . _:b546869304 . . _:b546868988 . _:b546868520 "4"^^ . _:b546868808 . _:b546868991 . . _:b546869005 . _:b546868523 "4"^^ . _:b546868990 . . _:b546868522 "4"^^ . _:b546868939 . _:b546868996 . _:b546868985 . _:b546869138 . _:b546869217 . _:b546868533 "4"^^ . _:b29429167 _:b29429192 . _:b29429167 _:b29429193 . _:b546868946 . . _:b29429167 _:b29429194 . _:b546868984 . _:b29429167 _:b29429195 . _:b546868532 "4"^^ . _:b29429202 . . _:b29429167 _:b29429196 . _:b29429167 _:b29429197 . _:b29429167 _:b29429198 . _:b546868987 . _:b546868535 "4"^^ . _:b546868829 . _:b546868664 . _:b29429167 _:b29429184 . _:b29429167 _:b29429185 . _:b546869190 . _:b546868709 . _:b29429167 _:b29429186 . _:b546868986 . _:b29429167 _:b29429187 . _:b546868534 "4"^^ . _:b546868813 . _:b29429167 _:b29429188 . _:b29429167 _:b29429189 . _:b29429167 _:b29429190 . _:b546868485 . _:b29429167 _:b29429191 . _:b546869515 . . _:b546868529 "4"^^ . _:b546868484 . _:b546868864 . . _:b546868528 "4"^^ . . . _:b546868487 . _:b546868531 "4"^^ . _:b29429199 . . _:b546868821 . _:b546868486 . _:b546869253 . _:b546868530 "4"^^ . _:b546868481 . _:b546868541 "4"^^ . . _:b546868553 . . _:b546868480 . . _:b546868540 "4"^^ . _:b546868483 . _:b546868961 . _:b546868543 "4"^^ . _:b546868510 . _:b546868482 . _:b546868542 "4"^^ . _:b546868678 . _:b546868507 . _:b546868493 . . _:b546868537 "4"^^ . . _:b546868492 . . _:b546868536 "4"^^ . _:b546868900 . . . _:b546868495 . _:b546868657 . _:b546868539 "4"^^ . . _:b29429167 . _:b546868494 . _:b546868538 "4"^^ . _:b546868489 . _:b546868964 . . . _:b29429207 "KAs can be a diagnostic challenge and are difficult to distinguish from well-differentiated cutaneous SCCs [35], [>>36<<]. KA/SCCs developed in 4 patients as multiple waxing and waning lesions (Figure S1). The development of KA/SCCs and cutaneous hyperkeratosis appeared to be associated with greater GC1008 exposure, occurring in patients treated at higher" . _:b546868549 "4"^^ . _:b546868488 . . _:b29429226 "include increased diffusion of chemotherapy and payload-containing particles such as liposomes into tumor masses [45], [46], reversal of chemotherapy resistance [29], [41], inhibition of DNA repair by blockade of \u03B3H2AX foci formation [>>28<<] and reversal of TGF\u03B2-induced accumulation of tumor cells in G0/G1 [21], [44]." . _:b546868548 "4"^^ . . _:b546868491 . _:b546868551 "4"^^ . _:b29429194 "In murine metastatic breast cancer models, a survival benefit and a reduction in the incidence and size of lytic bone lesions and lung metastases were observed in animals receiving anti-TGF\u03B2 antibody therapy alone [20], [>>24<<] as well as when combined with chemotherapy [25]." . _:b546868490 . . _:b546868550 "4"^^ . . _:b546868501 . _:b546869056 . _:b546868397 . _:b546868545 "4"^^ . _:b29429167 _:b29429176 . _:b29429167 _:b29429177 . _:b29429167 _:b29429178 . _:b546868500 . _:b29429167 _:b29429179 . _:b546868544 "4"^^ . _:b29429167 _:b29429180 . _:b29429167 _:b29429181 . _:b29429167 _:b29429182 . _:b546868503 . _:b29429167 _:b29429183 . _:b546868547 "4"^^ . _:b546868965 . _:b29429167 _:b29429168 . . _:b29429167 _:b29429169 . _:b546869118 . _:b29429167 _:b29429170 . _:b546868425 . _:b546868502 . _:b29429167 _:b29429171 . _:b546869132 . _:b546868546 "4"^^ . _:b29429167 _:b29429172 . . _:b29429167 _:b29429173 . _:b29429167 _:b29429174 . _:b546868497 . _:b29429167 _:b29429175 . . _:b546868557 "4"^^ . _:b546868496 . _:b546868556 "4"^^ . _:b546868499 . _:b546868888 . _:b546868559 "4"^^ . _:b546869028 . _:b546868498 . _:b546869511 . . _:b546868995 . . _:b546868558 "4"^^ . _:b546868509 . _:b546868553 "4"^^ . _:b546868441 . . _:b546868508 . _:b546868883 . _:b29429196 . _:b546868552 "4"^^ . _:b546868511 . _:b546868670 . _:b546868571 . _:b546868555 "4"^^ . _:b546868779 . _:b546868510 . _:b546868554 "4"^^ . . _:b546868505 . _:b546869234 . _:b546868565 "4"^^ . . _:b546868504 . _:b546868564 "4"^^ . _:b546868507 . _:b29429195 . _:b546868567 "4"^^ . . . _:b546868506 . _:b546868566 "4"^^ . _:b546868517 . _:b546868561 "4"^^ . . . _:b546868516 . _:b546869288 . _:b546869378 . _:b546868560 "4"^^ . _:b546868519 . _:b546868563 "4"^^ . _:b546868518 . _:b546868619 . _:b546868562 "4"^^ . _:b546868513 . _:b546869361 . _:b546868573 "3"^^ . _:b546869010 . _:b546868512 . . _:b546868572 "4"^^ . . _:b546868515 . _:b546868575 "3"^^ . _:b546868541 . _:b546868514 . _:b546869071 . _:b546868574 "3"^^ . _:b546868525 . _:b546868569 "4"^^ . . _:b546868524 . _:b546868568 "4"^^ . . _:b546868558 . _:b546868683 . _:b546868527 . _:b546868571 "4"^^ . _:b546868526 . _:b546868795 . _:b546868570 "4"^^ . _:b546869294 . . _:b546868521 . _:b546868581 "3"^^ . _:b546868520 . _:b546868580 "3"^^ . _:b546869146 . _:b546868845 . _:b546868523 . . _:b546868583 "3"^^ . _:b546868781 . . _:b546868522 . . _:b546868582 "3"^^ . _:b546868533 . _:b546868577 "3"^^ . . _:b546868532 . _:b29429180 . _:b546869099 . _:b546868576 "3"^^ . . _:b546868486 . . _:b546868535 . . . _:b546868579 "3"^^ . _:b546868844 . _:b546869074 . _:b546868534 . . _:b546868578 "3"^^ . . . _:b29429223 . _:b546868529 . _:b29429177 . _:b546868589 "3"^^ . _:b546869326 . . . _:b546868478 . _:b546868528 . _:b546868588 "3"^^ . _:b29429197 "Additive effects of anti-TGF\u03B2 combined with various chemotherapies, radiation or biologics including vaccines have been reported to improve the treatment of both primary and metastatic disease [21], [25], [27]\u2013[>>30<<]." . _:b546868993 . . _:b29429186 . _:b546868531 . _:b546869165 . _:b546868591 "3"^^ . . _:b546868530 . _:b546868590 "3"^^ . . _:b546868714 . _:b546868541 . _:b29429173 . _:b546869521 . _:b546868585 "3"^^ . _:b546868540 . _:b546868584 "3"^^ . . _:b546868543 . . _:b546868587 "3"^^ . _:b546868542 . _:b546868827 . _:b546868557 . _:b546868586 "3"^^ . _:b546869241 . _:b546868537 . _:b546868597 "3"^^ . _:b546868536 . . _:b546868596 "3"^^ . . _:b546868455 . _:b546868539 . _:b29429171 . _:b546868599 "3"^^ . _:b546869414 . _:b546868538 . _:b546868598 "3"^^ . _:b546868866 . _:b546868549 . _:b546868593 "3"^^ . . _:b546868548 . _:b546868592 "3"^^ . _:b546868551 . . _:b546868595 "3"^^ . _:b546868854 . _:b546869130 . _:b546868550 . . _:b546868594 "3"^^ . . _:b546868545 . _:b546868605 "3"^^ . _:b29429207 . _:b546868544 . _:b29429221 "A variety of anti-TGF\u03B2 agents combined with chemotherapy, radiation, biologics, immunotherapeutics and vaccines have demonstrated enhanced antitumor effects in preclinical models [11], [21], [22], [25], [28]\u2013[30], [41]\u2013[>>44<<]. Several mechanisms have been proposed to explain the improved efficacy with cytotoxic agents and include increased diffusion of chemotherapy and payload-containing particles such as liposomes into tumor masses [45], [46], reversal of" . _:b546868777 . . _:b546868604 "3"^^ . . _:b546868547 . _:b546868607 "3"^^ . . _:b29429208 "Ferguson-Smith disease is an autosomal-dominant skin disorder characterized by multiple, locally invasive SCC\u2013like skin tumors that grow rapidly for a few weeks before spontaneously regressing [>>35<<]. A recent genomic analysis of patients with this disease indicated a correlation between loss-of-function mutations of the TGF\u03B2R1 receptor and the development of KAs [37]. The lesions observed in patients receiving GC1008 are similar to" . _:b29429201 "GC1008 levels were measured by ELISA-based assay [>>31<<] from blood samples collected on days 0, 1, 3, 7, 14, 28, 42, 56, 63, 70, 84, 112, 140 and every three months during follow up." . _:b546868546 . _:b546868606 "3"^^ . . _:b546869270 . _:b546868830 . . _:b546868557 . _:b546868601 "3"^^ . _:b546869427 . _:b546868556 . _:b29429169 "Transforming growth factor-beta (TGF\u03B2) is a pleiotropic cytokine that is a member of a superfamily of ligands that includes bone morphogenetic proteins and activins [1], [>>2<<]. Under normal conditions, TGF\u03B2 helps to maintain homeostasis and limit the growth of epithelial, endothelial, neuronal, and hematopoietic cell lineages through anti-proliferative and apoptotic responses." . _:b546868739 . . _:b546868600 "3"^^ . _:b546868637 . _:b546869145 . _:b546868559 . . _:b546868603 "3"^^ . . _:b546868558 . _:b546868602 "3"^^ . . _:b546868553 . . _:b546868613 "3"^^ . . _:b546868552 . . _:b546868612 "3"^^ . _:b546869330 . _:b546868555 . _:b546868630 . _:b546868615 "3"^^ . _:b546869391 . _:b546868554 . . . _:b546868614 "3"^^ . _:b29429185 . _:b546868565 . _:b546868609 "3"^^ . . . _:b546868902 . _:b546868564 . . _:b546868608 "3"^^ . _:b546868567 . _:b546868611 "3"^^ . . . _:b546868958 . _:b546868566 . . _:b546868610 "3"^^ . _:b546868561 . _:b546869486 . _:b546869037 . . _:b546868621 "3"^^ . . . _:b546868560 . _:b546868620 "3"^^ . _:b546868563 . . _:b546868623 "3"^^ . _:b546868562 . _:b546868622 "3"^^ . _:b546869295 . _:b546869124 . _:b546868573 . _:b546868617 "3"^^ . _:b546868572 . _:b546868616 "3"^^ . . _:b546869161 . _:b546869075 . . . _:b546868575 . _:b546868619 "3"^^ . . . _:b546868574 . _:b546869334 . . _:b546868618 "3"^^ . . . _:b546868569 . . _:b546868629 "3"^^ . _:b546868549 . . . _:b29429220 "A variety of anti-TGF\u03B2 agents combined with chemotherapy, radiation, biologics, immunotherapeutics and vaccines have demonstrated enhanced antitumor effects in preclinical models [11], [21], [22], [25], [28]\u2013[30], [>>41<<]\u2013[44]. Several mechanisms have been proposed to explain the improved efficacy with cytotoxic agents and include increased diffusion of chemotherapy and payload-containing particles such as liposomes into tumor masses [45], [46], reversal" . _:b546868568 . . _:b546868628 "3"^^ . . _:b546868571 . _:b546868433 . _:b546868631 "3"^^ . _:b546869308 . _:b546868570 . . _:b546868630 "3"^^ . . _:b546868875 . _:b546868581 . . _:b546868625 "3"^^ . _:b546868580 . _:b546868624 "3"^^ . _:b546869236 . _:b546868522 . _:b546868583 . _:b546868627 "3"^^ . _:b546868758 . _:b546868582 . _:b546868626 "3"^^ . _:b546868577 . _:b546868679 . _:b546868637 "3"^^ . _:b29429193 "In murine metastatic breast cancer models, a survival benefit and a reduction in the incidence and size of lytic bone lesions and lung metastases were observed in animals receiving anti-TGF\u03B2 antibody therapy alone [>>20<<], [24] as well as when combined with chemotherapy [25]." . . _:b29429224 "been proposed to explain the improved efficacy with cytotoxic agents and include increased diffusion of chemotherapy and payload-containing particles such as liposomes into tumor masses [45], [46], reversal of chemotherapy resistance [>>29<<], [41], inhibition of DNA repair by blockade of \u03B3H2AX foci formation [28] and reversal of TGF\u03B2-induced accumulation of tumor cells in G0/G1 [21], [44]." . _:b546868576 . _:b546868636 "3"^^ . . _:b546868579 . _:b546868639 "3"^^ . _:b546869498 . . _:b546869399 . _:b546868578 . _:b546868638 "3"^^ . . _:b546868589 . . _:b546868633 "3"^^ . . . _:b546868393 . _:b29429198 "GC1008 is being investigated as a treatment for cancer and fibrotic diseases [>>31<<]. Herein, we report our results on the safety and antitumor activity of repeated doses of GC1008 administered to patients with advanced malignant melanoma (MM) and renal cell carcinoma (RCC)." . _:b546868588 . . _:b546868632 "3"^^ . _:b546868562 . _:b546868591 . _:b546868635 "3"^^ . . _:b546868590 . _:b546868634 "3"^^ . . _:b546868585 . _:b546868645 "3"^^ . _:b546868853 . . _:b546869253 . _:b546868584 . _:b546868644 "3"^^ . . _:b546869123 . _:b546868587 . _:b546869252 . _:b546868647 "3"^^ . _:b546869289 . . _:b29429201 . _:b546868586 . _:b546869255 . _:b546868646 "3"^^ . _:b546868871 . _:b546868597 . _:b546869254 . _:b546868641 "3"^^ . _:b546868800 . _:b546868596 . _:b546869249 . _:b546868640 "3"^^ . _:b546868842 . _:b546868796 . _:b546868599 . _:b546869248 . _:b546868643 "3"^^ . . . _:b546868598 . _:b546869251 . _:b546868642 "3"^^ . _:b546868593 . _:b546869250 . . _:b546868653 "3"^^ . . _:b546868931 . _:b546868592 . _:b546869261 . _:b546868652 "3"^^ . _:b546869237 . _:b546868595 . _:b546869260 . _:b546868655 "3"^^ . _:b546868594 . _:b546869263 . _:b546868654 "3"^^ . . . . _:b546869262 . _:b546869076 . _:b546868605 . _:b546868649 "3"^^ . . _:b546869257 . _:b546868604 . _:b546868648 "3"^^ . _:b546868417 . _:b546869384 . _:b546868607 . _:b546869256 . _:b546868885 . . _:b546868651 "3"^^ . _:b546868606 . _:b546869259 . _:b546868650 "3"^^ . _:b546869478 . . _:b546869258 . _:b546869173 . _:b546868601 . _:b546868403 . . _:b546868838 . _:b546868661 "3"^^ . . _:b546868600 . _:b546869269 . _:b546868660 "3"^^ . . . _:b546868603 . _:b546869268 . _:b546868663 "3"^^ . _:b546868602 . _:b546869271 . _:b546868662 "3"^^ . _:b546868719 . _:b546868613 . _:b29429227 "such as liposomes into tumor masses [45], [46], reversal of chemotherapy resistance [29], [41], inhibition of DNA repair by blockade of \u03B3H2AX foci formation [28] and reversal of TGF\u03B2-induced accumulation of tumor cells in G0/G1 [21], [>>44<<]. In addition, novel anti-TGF\u03B2 activity such as inhibition of angiogenesis, fibrosis, metastases, and immune suppression may be additive to other treatments [4], [10], [30]." . _:b546869270 . _:b546868657 "3"^^ . . _:b546868601 . _:b546868612 . _:b546869265 . _:b546869066 . _:b546868525 . _:b546868957 . _:b546868656 "3"^^ . . . . _:b546869264 . _:b546868615 . . _:b546869301 . _:b546868659 "3"^^ . _:b546868614 . _:b546869267 . _:b546868658 "3"^^ . _:b29429198 . _:b546868609 . _:b546869266 . _:b546868669 "3"^^ . _:b546869510 . . . _:b546869277 . _:b546868608 . _:b546868457 . _:b546868668 "3"^^ . _:b546868611 . _:b546869276 . _:b546869235 . . _:b546868671 "3"^^ . _:b546868610 . _:b546869279 . _:b546868670 "3"^^ . _:b546868621 . _:b546869278 . . _:b546868665 "3"^^ . _:b546869178 . . _:b546869273 . _:b546868620 . _:b546868528 . _:b546868664 "3"^^ . _:b546868617 . . _:b546869272 . _:b546868623 . . _:b546868667 "3"^^ . . . . _:b546868622 . _:b546869275 . _:b546868666 "3"^^ . _:b546869437 . . _:b546868617 . _:b546869274 . _:b546868398 . _:b546868677 "3"^^ . . _:b546869285 . _:b546868616 . _:b546868676 "3"^^ . _:b546868863 . _:b546868619 . _:b546869284 . . _:b546868679 "3"^^ . _:b546868618 . _:b546869287 . _:b546868495 . _:b546868678 "3"^^ . . _:b546868629 . _:b546869286 . _:b546868673 "3"^^ . _:b546868708 . _:b546869154 . _:b546869446 . _:b546868422 . _:b546868628 . _:b546869281 . . _:b546868672 "3"^^ . . _:b546868631 . _:b546869280 . . _:b546868675 "3"^^ . _:b546868630 . _:b546869283 . _:b546868674 "3"^^ . _:b546869357 . _:b546868625 . _:b546869282 . _:b546868685 "3"^^ . _:b546868873 . . _:b546869293 . _:b546868624 . . _:b546868684 "3"^^ . _:b546868627 . _:b546869292 . _:b546868687 "3"^^ . . . _:b29429213 . _:b546868535 . _:b546869295 . _:b546868626 . _:b546868686 "3"^^ . . _:b546868637 . _:b29429174 "Instead, TGF\u03B2 will directly promote tumor growth and metastases [2], [4], [>>5<<]. Chronic exposure of transformed mouse keratinocytes to TGF\u03B2 causes a change in morphology and engenders these cells with the ability to form spindle cell carcinomas when transplanted into mice [6]." . _:b546869294 . _:b546868681 "3"^^ . . _:b546869289 . _:b546868636 . _:b546868680 "3"^^ . _:b546868639 . _:b546869288 . _:b546868683 "3"^^ . _:b546868638 . _:b546869291 . _:b546868682 "3"^^ . . _:b546869290 . _:b546868633 . . _:b546868693 "3"^^ . _:b546868924 . _:b546868632 . _:b546869316 . _:b546869301 . _:b546868692 "3"^^ . _:b546869135 . _:b546868635 . _:b546869300 . _:b546868695 "3"^^ . _:b546868634 . _:b546869303 . _:b546868694 "3"^^ . . _:b546868645 . _:b546869346 . _:b546869302 . . _:b546868858 . _:b546868689 "3"^^ . _:b546868644 . _:b546869297 . _:b546868688 "3"^^ . _:b546868944 . . . _:b546869296 . _:b546868647 . _:b546868691 "3"^^ . . _:b546869299 . _:b546868646 . . _:b546868690 "3"^^ . . _:b546869078 . _:b546868962 . _:b546868641 . _:b546869298 . _:b546868701 "3"^^ . _:b546868723 . _:b546868640 . _:b546869309 . _:b546868700 "3"^^ . _:b546869256 . _:b546868643 . _:b546869308 . _:b546868703 "3"^^ . . _:b546869276 . _:b546868642 . _:b546869311 . _:b546869008 . _:b546868702 "3"^^ . . _:b546868653 . _:b546869310 . _:b546868697 "3"^^ . _:b546868652 . _:b546869305 . _:b546868696 "3"^^ . _:b546869011 . _:b546869133 . . _:b546868655 . _:b546869383 . _:b546869304 . . _:b546869444 . _:b546869397 . _:b546869328 . _:b546868699 "3"^^ . _:b546868497 . _:b546869244 . _:b546868654 . _:b546869307 . _:b546868698 "3"^^ . . _:b29429168 . . _:b546868649 . _:b546869306 . _:b546868709 "3"^^ . _:b546868648 . _:b546869317 . _:b546868708 "3"^^ . . . _:b546868651 . _:b546869354 . _:b546869316 . _:b546868711 "3"^^ . . _:b546869362 . _:b546868392 . _:b546869319 . _:b546868650 . . _:b546868710 "3"^^ . _:b546868661 . _:b546869318 . _:b546868705 "3"^^ . . _:b546868660 . _:b546869313 . _:b546868704 "3"^^ . _:b546869226 . . _:b546868663 . _:b546869312 . _:b546868707 "3"^^ . _:b546869144 . _:b546868662 . _:b546869315 . _:b546868602 . _:b546868706 "3"^^ . _:b546868869 . _:b546868657 . _:b546869314 . _:b546868717 "3"^^ . . _:b546869325 . _:b546868677 . _:b546868656 . _:b546868716 "3"^^ . _:b546868503 . . _:b546869324 . _:b546868659 . _:b546868719 "3"^^ . _:b546868658 . _:b546869327 . _:b546868718 "3"^^ . _:b546869425 . _:b546868669 . _:b546869326 . . _:b546868713 "3"^^ . . . . _:b546869321 . _:b546868668 . _:b546868712 "3"^^ . _:b546869514 . _:b546868671 . _:b546869320 . _:b546869065 . _:b546868715 "3"^^ . . . _:b546868670 . _:b546869323 . _:b546868714 "3"^^ . _:b546868665 . _:b546869322 . _:b546868725 "3"^^ . _:b546868837 . _:b546869219 . _:b546868664 . _:b546869333 . _:b546868724 "3"^^ . . _:b546868667 . _:b546869332 . _:b546868727 "3"^^ . . _:b546869335 . _:b546868666 . _:b546868726 "3"^^ . _:b546868654 . _:b546868677 . _:b546869334 . _:b546868721 "3"^^ . _:b546868581 . _:b29429174 . . _:b546868676 . _:b546869329 . _:b546868720 "3"^^ . . . _:b546868679 . _:b546869328 . _:b546868723 "3"^^ . _:b546869507 . . _:b546868678 . _:b546869331 . _:b546868722 "3"^^ . _:b546868673 . _:b546869330 . _:b546868756 . _:b546868733 "3"^^ . _:b546868587 . _:b546868672 . _:b546869341 . _:b546869320 . _:b546868732 "3"^^ . _:b546868761 . _:b546868675 . _:b546869340 . _:b546868735 "3"^^ . _:b546868674 . _:b546869343 . _:b546868734 "3"^^ . . _:b546868685 . _:b546869342 . _:b546868729 "3"^^ . _:b546868717 . _:b546868684 . _:b546869337 . _:b546868728 "3"^^ . _:b546868687 . _:b546869336 . _:b546868731 "3"^^ . . _:b546868686 . _:b546869339 . . _:b546868730 "3"^^ . _:b546868681 . _:b546869338 . . _:b546868680 . _:b546869349 . _:b546869227 . . . _:b546868446 . . _:b546869348 . _:b546868683 . _:b546868697 . _:b546869152 . _:b546868682 . _:b546869351 . _:b546868542 . _:b546869487 . . _:b546868693 . _:b546869350 . . _:b546868516 . _:b546868673 . _:b546869477 . _:b546868692 . _:b546869345 . . _:b546868695 . _:b546869344 . _:b546868489 . . _:b546869347 . _:b546868694 . _:b546869101 . _:b546868689 . _:b546869346 . _:b546868688 . _:b546869357 . _:b546869050 . _:b546869407 . _:b546868691 . _:b546869356 . _:b546868735 . _:b546868690 . _:b546869359 . _:b546868701 . _:b546869358 . _:b546868769 . _:b546868468 . _:b546869353 . _:b546868700 . . _:b546868720 . _:b546868655 . _:b546869352 . _:b546868703 . _:b546869513 . _:b546868702 . _:b546869355 . _:b546868697 . _:b546869354 . . _:b546868696 . _:b546869365 . . _:b546869364 . _:b546868699 . _:b546869183 . _:b546868698 . _:b546869367 . _:b546868584 . _:b546868709 . _:b546869366 . . _:b546869361 . _:b546868708 . _:b546868711 . _:b546869360 . _:b29429189 "Furthermore, elevated plasma TGF\u03B2 levels correlate with advanced tumor stage, metastases, and poor survival [15]\u2013[>>17<<]. Given its integral role in the progression of cancer, TGF\u03B2 is an attractive therapeutic target." . _:b546868710 . _:b546869363 . . . _:b546868705 . _:b546869362 . _:b546868987 . _:b546868704 . _:b546869373 . _:b546868505 . _:b546869255 . _:b546869412 . _:b546869372 . _:b546868707 . _:b546868597 . _:b546869413 . _:b546869414 . _:b546869415 . _:b546868762 . _:b546869408 . _:b546869375 . _:b546868706 . . _:b546869297 . _:b546869409 . _:b546868533 . _:b546869410 . _:b546869411 . _:b546868589 . . _:b546869374 . _:b546868717 . _:b546869420 . _:b546869421 . _:b546869422 . _:b546869423 . _:b546868676 . _:b546869416 . _:b546869369 . _:b546868716 . _:b546869417 . _:b546869418 . _:b546869419 . _:b546869291 . _:b546869428 . _:b546869368 . _:b546868719 . . _:b546869429 . _:b546869430 . _:b546869313 . _:b546869431 . _:b546869424 . _:b546869371 . _:b546869086 . _:b546868718 . _:b546869425 . . . _:b546869426 . _:b546869427 . _:b546869436 . _:b546869370 . _:b546868713 . _:b546868396 . _:b546869437 . . _:b546868849 . _:b546869438 . _:b546869439 . _:b546869387 . . _:b546869381 . _:b546868712 . _:b546869432 . _:b546869433 . _:b546869434 . . _:b29429205 "KAs are epidermal tumors characterized by initially rapid growth typically followed by spontaneous resolution [>>35<<]. KAs can be a diagnostic challenge and are difficult to distinguish from well-differentiated cutaneous SCCs [35], [36]. KA/SCCs developed in 4 patients as multiple waxing and waning lesions (Figure S1). The development of KA/SCCs and" . _:b546869435 . _:b546869380 . _:b546869380 . _:b546868715 . _:b546869381 . _:b546869044 . _:b546868459 . _:b546869382 . _:b546869383 . . _:b546869383 . _:b546868714 . _:b546869376 . _:b546869377 . _:b546869300 . _:b546868731 . _:b546869378 . _:b546869379 . . _:b546869388 . _:b546869382 . _:b546868725 . . _:b546869389 . _:b546869390 . _:b546869391 . _:b546869384 . _:b546869377 . _:b546868724 . _:b546869385 . . _:b546869386 . _:b546869387 . . _:b546869376 . _:b546868727 . _:b546869396 . _:b546869397 . _:b546869398 . _:b546869399 . . _:b546869379 . _:b546868726 . _:b546869392 . . _:b546869393 . _:b546869394 . _:b546868532 . _:b546869395 . _:b546869404 . _:b546869378 . _:b546868721 . . _:b546869405 . _:b546868467 . _:b546869406 . _:b546869407 . _:b546869271 . _:b546869014 . _:b546869400 . _:b546869389 . _:b546869168 . _:b546868720 . _:b546869401 . _:b546869402 . _:b546869403 . _:b546868650 . _:b546869476 . _:b546869388 . _:b546868803 . _:b546868723 . _:b546869477 . _:b29429178 "which is characterized by a morphological change to a spindle cell shape, down-regulation of E-cadherin and cytokeratin expression, loss of cell-cell junctions, remodeling of the cytoskeleton, and increased cell motility [2], [4], [>>7<<]. TGF\u03B2-induced cellular changes have been described in many different tumor models and appear to be important for inducing cell migration and promoting metastases [7]." . . _:b546869478 . _:b546869479 . _:b546869472 . _:b546869391 . _:b546868722 . . . _:b546869473 . _:b546869474 . _:b546869475 . _:b546869484 . _:b546869390 . _:b546868733 . . _:b546869088 . _:b546869485 . . _:b546869486 . _:b546869487 . _:b546869480 . _:b546869385 . _:b546868732 . _:b546869481 . _:b546869482 . . _:b546869483 . _:b546869492 . _:b546869384 . _:b546868759 . _:b546868735 . . . _:b546869493 . _:b546869494 . _:b546869495 . _:b546869488 . _:b546869387 . _:b546868734 . _:b546869489 . . _:b546869490 . . _:b546869491 . _:b546869500 . _:b546869386 . _:b546868729 . _:b546868545 . _:b546869501 . _:b546869502 . . _:b546869503 . _:b546869496 . _:b546869429 . _:b546869397 . _:b546868728 . _:b546869497 . _:b546869498 . _:b546868950 . _:b546869499 . _:b546869355 . _:b546869444 . _:b546869396 . _:b546868731 . _:b546868519 . _:b546869348 . _:b546869445 . _:b546869446 . _:b546869447 . _:b546869440 . _:b546869399 . _:b546868730 . . _:b546869104 . _:b546869441 . _:b546869442 . _:b546869443 . . _:b29429233 . _:b546869398 . _:b546869452 . _:b546869453 . _:b546869454 . . _:b546869455 . _:b546869448 . _:b546869393 . _:b546869206 . _:b546869449 . . _:b546869450 . _:b546869009 . _:b546869451 . _:b29429211 . _:b546869460 . _:b546869392 . _:b546869461 . _:b546869523 . . _:b546869462 . . _:b546869463 . _:b546869456 . _:b29429234 . _:b546869395 . _:b546869457 . _:b546869458 . . _:b546869459 . _:b546869468 . _:b546869394 . _:b546869469 . . _:b546869470 . _:b546869471 . _:b546869464 . _:b546869405 . _:b546869465 . _:b546869466 . _:b546869467 . _:b546869284 . _:b546869404 . _:b546869285 . _:b546869286 . _:b546869287 . _:b546869280 . _:b546869407 . . _:b546869281 . _:b546868410 . . _:b546869282 . _:b546868537 . _:b546869283 . _:b546869292 . _:b546869406 . _:b546869293 . _:b546869294 . _:b546869295 . _:b546869288 . _:b546869401 . . _:b546869289 . _:b546869290 . _:b546868480 . _:b546869291 . _:b546869300 . _:b546869400 . _:b546869301 . . _:b546869085 . _:b546869302 . _:b546869303 . _:b546869296 . _:b546869403 . _:b546869297 . _:b546869298 . _:b546869299 . . _:b546869402 . _:b546869308 . _:b546869309 . _:b546869310 . . _:b546869311 . _:b546869304 . _:b546869413 . _:b546869305 . _:b546869306 . _:b546869307 . _:b546869062 . _:b546868680 . _:b546869252 . _:b546869412 . _:b546869253 . _:b546869254 . _:b546869255 . _:b546869248 . _:b546869415 . _:b546869249 . _:b546869250 . _:b546869251 . . _:b546869414 . _:b546869260 . . _:b546869261 . _:b546869262 . _:b546869263 . _:b546869256 . _:b546869409 . _:b546869257 . . _:b546869258 . . _:b546869259 . . _:b546869268 . _:b546869408 . _:b546869269 . _:b546869270 . . _:b29429172 "Instead, TGF\u03B2 will directly promote tumor growth and metastases [>>2<<], [4], [5]. Chronic exposure of transformed mouse keratinocytes to TGF\u03B2 causes a change in morphology and engenders these cells with the ability to form spindle cell carcinomas when transplanted into mice [6]." . _:b546869271 . _:b546869264 . _:b546869411 . _:b546869265 . _:b546869266 . _:b546869267 . . _:b546869276 . _:b546869410 . . _:b546869277 . _:b546869278 . _:b546869279 . _:b546868647 . . _:b546869421 . _:b546869272 . _:b546869273 . . _:b546869274 . _:b546869253 "2"^^ . _:b546869275 . _:b546869348 . _:b546869420 . _:b546869349 . _:b546869350 . _:b546869252 "2"^^ . _:b546869351 . . _:b546869423 . _:b546869344 . _:b546869345 . . _:b546869346 . _:b546869255 "2"^^ . _:b546869347 . _:b546869356 . _:b546869422 . _:b546869084 . _:b546869357 . _:b546869358 . _:b546869254 "2"^^ . _:b546869359 . _:b546869352 . _:b546869417 . _:b546868623 . _:b546869353 . _:b546869354 . _:b546869249 "2"^^ . _:b546869355 . _:b546869364 . _:b546869416 . _:b546869365 . _:b546869366 . _:b546869248 "2"^^ . . _:b546869310 . _:b546869367 . _:b546869360 . _:b546869419 . . _:b546869361 . . _:b546869251 "2"^^ . _:b546869362 . _:b546869363 . . _:b546869418 . _:b546869372 . _:b546869373 . _:b546869374 . _:b546869250 "2"^^ . _:b546869375 . _:b546869368 . _:b546869429 . _:b546869203 . _:b546869369 . . _:b546869261 "2"^^ . _:b546869370 . _:b546869371 . _:b546869316 . _:b546869428 . _:b546869317 . _:b546869318 . _:b546869260 "2"^^ . _:b546869185 . _:b546869319 . _:b546869312 . _:b546869431 . _:b546869313 . _:b546869314 . _:b546869263 "2"^^ . _:b546869315 . . _:b546869430 . . _:b546869324 . _:b546868565 . _:b546869325 . . _:b546869262 "2"^^ . _:b546869326 . . _:b546869327 . _:b546869320 . _:b546869425 . _:b546869321 . _:b546869322 . _:b546869257 "2"^^ . . _:b546869323 . _:b546869332 . _:b546869424 . _:b546869193 . _:b546869333 . _:b546869334 . _:b546869256 "2"^^ . _:b546869335 . _:b546869328 . _:b546869427 . _:b546869329 . . _:b546869259 "2"^^ . _:b546869330 . _:b546869331 . _:b546869340 . _:b546869426 . _:b546868841 . _:b546869341 . _:b546869342 . _:b546869258 "2"^^ . _:b546869343 . _:b546869102 . . _:b546869437 . _:b546869336 . . _:b29429194 . _:b546869337 . _:b546869338 . _:b546869269 "2"^^ . _:b546869339 . . _:b546869436 . _:b546869268 "2"^^ . _:b546868511 . . _:b546869439 . _:b546869336 . . _:b546869271 "2"^^ . _:b546868976 . . _:b546869439 . _:b546869438 . _:b546869270 "2"^^ . . _:b546869433 . . _:b546868750 . _:b546869265 "2"^^ . _:b546869225 . _:b546869432 . _:b546869264 "2"^^ . _:b546869435 . _:b546869267 "2"^^ . _:b546868634 . _:b546869434 . _:b546868408 . _:b546869266 "2"^^ . _:b546868988 . _:b546869445 . _:b546868772 . _:b546869277 "2"^^ . _:b546869191 . _:b546869444 . _:b546869276 "2"^^ . _:b546869469 . _:b546868454 . _:b546869447 . _:b546869030 . _:b546869279 "2"^^ . _:b546869446 . _:b546869278 "2"^^ . _:b546869441 . . _:b546868499 . _:b546869273 "2"^^ . . _:b546869440 . . _:b546869272 "2"^^ . _:b546869151 . _:b546869443 . _:b546869275 "2"^^ . _:b546869442 . _:b546868737 . _:b546869274 "2"^^ . . _:b546869040 . _:b546869453 . _:b546869285 "2"^^ . _:b546869452 . . _:b546869284 "2"^^ . . . _:b546869455 . _:b546869194 . _:b546869287 "2"^^ . _:b546869454 . . _:b546869286 "2"^^ . _:b546868973 . _:b546869449 . _:b546869281 "2"^^ . . _:b546869277 . _:b546869448 . . _:b546869198 . _:b546869280 "2"^^ . _:b546869451 . . _:b546869283 "2"^^ . _:b546869450 . _:b546869282 "2"^^ . _:b546869461 . _:b546869293 "2"^^ . _:b546868940 . _:b546869460 . _:b546869292 "2"^^ . . _:b546869463 . . _:b546869295 "2"^^ . _:b546869462 . . _:b546869294 "2"^^ . _:b29429185 "killer (NK) cells, T cells including T regulatory cells, NKT cells, monocytes/macrophages, and dendritic cells, TGF\u03B2 can down-regulate both primary and secondary immune responses and suppress antitumor effector cells [3], [11], [>>12<<]." . . _:b546869457 . . _:b546869289 "2"^^ . _:b546869200 . _:b546869456 . . _:b546869288 "2"^^ . _:b546868484 . _:b546869459 . . . _:b546869494 . _:b546869291 "2"^^ . _:b546869290 . . _:b546869458 . _:b546869290 "2"^^ . . _:b29429231 . _:b546869469 . _:b546868547 . _:b546869301 "2"^^ . _:b546869468 . _:b546869232 . _:b546869300 "2"^^ . _:b546868443 . _:b29429223 "Several mechanisms have been proposed to explain the improved efficacy with cytotoxic agents and include increased diffusion of chemotherapy and payload-containing particles such as liposomes into tumor masses [45], [>>46<<], reversal of chemotherapy resistance [29], [41], inhibition of DNA repair by blockade of \u03B3H2AX foci formation [28] and reversal of TGF\u03B2-induced accumulation of tumor cells in G0/G1 [21], [44]." . _:b546869471 . _:b546869021 . _:b546869303 "2"^^ . _:b546868921 . _:b546868500 . _:b546869470 . _:b546869302 "2"^^ . _:b546869465 . _:b546868477 . _:b546869411 . . _:b546869297 "2"^^ . . _:b546869464 . _:b546869296 "2"^^ . _:b546869006 . _:b546869467 . _:b546869299 "2"^^ . . _:b29429192 . _:b546869466 . . _:b546869298 "2"^^ . _:b546868776 . _:b546869477 . . _:b546869309 "2"^^ . _:b546869508 . _:b546869476 . _:b546869209 . _:b546869509 . . _:b546869308 "2"^^ . _:b546869510 . _:b546869511 . . _:b546869479 . _:b546869504 . _:b546869505 . _:b546869506 . _:b546869311 "2"^^ . _:b546869507 . _:b546869516 . _:b546869478 . _:b546869139 . . _:b546869517 . . _:b546869310 "2"^^ . _:b546869518 . . _:b546868971 . _:b546869519 . _:b546869512 . _:b546869473 . _:b546868666 . _:b546869513 . _:b546869048 . . _:b29429200 "Response was assessed using RECIST criteria [>>32<<] evaluated by physical exam and imaging studies that included CT or MRI, radionuclide bone scan and positron emission tomography (PET)." . _:b546869305 "2"^^ . _:b546869514 . _:b546869515 . _:b546869169 . _:b546869524 . _:b546869472 . _:b546869525 . _:b546869148 . . _:b546869304 "2"^^ . _:b546869526 . . . _:b546869520 . _:b546869475 . _:b546869521 . . _:b546869307 "2"^^ . _:b546869522 . _:b546869523 . . _:b546869474 . . _:b546869306 "2"^^ . . _:b546869485 . _:b546868710 . _:b546869317 "2"^^ . _:b546869484 . _:b546869311 . _:b546869496 . _:b546868569 . _:b546869316 "2"^^ . _:b546869487 . _:b29429199 "materials and methods" . . _:b546869319 "2"^^ . _:b546869486 . _:b546868960 . _:b546869318 "2"^^ . _:b546869481 . _:b546869313 "2"^^ . . . _:b546869480 . . . . _:b546869312 "2"^^ . _:b546869483 . . _:b546869315 "2"^^ . _:b546868551 . _:b546869482 . _:b546869314 "2"^^ . _:b546869329 . _:b546869322 . _:b546869281 . _:b546869493 . _:b546869325 "2"^^ . _:b546869492 . _:b546869324 "2"^^ . _:b546869495 . _:b546869327 "2"^^ . . _:b546869494 . . . _:b546869326 "2"^^ . _:b546869489 . _:b546869321 "2"^^ . . . _:b546869488 . _:b546869320 "2"^^ . . _:b546868974 . _:b546869491 . _:b546869323 "2"^^ . _:b546869502 . _:b546869490 . _:b546869322 "2"^^ . _:b546869401 . _:b546868640 . _:b29429204 . _:b546869501 . _:b546869186 . _:b546868404 . . _:b546869333 "2"^^ . _:b546869500 . _:b546869332 "2"^^ . _:b546869388 . _:b546869503 . _:b546869335 "2"^^ . _:b546869431 . . _:b546869041 . . _:b546869502 . . . . _:b546869334 "2"^^ . . _:b546869497 . _:b29429202 "discussion" . . _:b546869329 "2"^^ . _:b546869496 . _:b546869328 "2"^^ . _:b546869499 . . _:b546869331 "2"^^ . _:b546868865 . . . _:b546869498 . _:b29429215 . _:b546869330 "2"^^ . _:b546869517 . . _:b546869341 "2"^^ . . _:b546869340 "2"^^ . _:b546868672 . _:b546869343 "2"^^ . . _:b546869094 . _:b546868984 . _:b546869342 "2"^^ . . . . _:b546869337 "2"^^ . _:b546869278 . _:b546869350 . _:b29429179 . _:b546869356 . _:b546868722 . _:b546869336 "2"^^ . _:b546868482 . _:b29429178 . . . _:b546869339 "2"^^ . _:b546868614 . . _:b546869338 "2"^^ . _:b546869034 . . _:b546869349 "2"^^ . _:b546869221 . . _:b546869348 "2"^^ . _:b29429184 "in natural killer (NK) cells, T cells including T regulatory cells, NKT cells, monocytes/macrophages, and dendritic cells, TGF\u03B2 can down-regulate both primary and secondary immune responses and suppress antitumor effector cells [3], [>>11<<], [12]." . _:b546869351 "2"^^ . . _:b546869350 "2"^^ . _:b546868884 . _:b546869345 "2"^^ . . . _:b546868600 . _:b546869344 "2"^^ . _:b546869024 . _:b546868878 . _:b546869432 . _:b546869347 "2"^^ . _:b546869312 . . _:b546869163 . _:b546869346 "2"^^ . _:b546868518 . _:b546869357 "2"^^ . _:b546868555 . _:b546869303 . . _:b546869356 "2"^^ . _:b546868793 . _:b546869347 . _:b546869359 "2"^^ . _:b546868685 . _:b546869358 "2"^^ . . _:b546868784 . _:b29429221 . _:b546869089 . _:b546869353 "2"^^ . _:b546868927 . . . _:b546869352 "2"^^ . _:b546869093 . _:b546869355 "2"^^ . . _:b546869354 "2"^^ . . _:b546869365 "2"^^ . . . _:b546869364 "2"^^ . _:b29429227 . _:b546869367 "2"^^ . _:b546869526 . _:b546869366 "2"^^ . . _:b546869239 . _:b546869430 . _:b546869361 "2"^^ . _:b546869360 "2"^^ . . _:b546869363 "2"^^ . . _:b546869362 "2"^^ . . _:b546869373 "2"^^ . _:b29429170 "In addition, TGF\u03B2 exerts potent effects that influence immune function, differentiation, adhesion, extracellular matrix production, cell motility, angiogenesis, and cytokine production [>>3<<], [4]." . . _:b546869372 "2"^^ . . . _:b546869375 "2"^^ . _:b546869460 . _:b546869374 "2"^^ . _:b546868782 . _:b546869436 . . _:b546869025 . _:b546869369 "2"^^ . _:b546869368 "2"^^ . _:b546868566 . _:b546868985 . _:b546869371 "2"^^ . . _:b546868870 . _:b546869370 "2"^^ . _:b29429186 "reported in many different malignancies including prostate, breast, lung, pancreatic, renal cell, liver, colon, gastric, esophageal, ovarian, cervical, bladder, thyroid, head and neck cancers, melanoma, gliomas, and multiple myeloma [>>13<<], [14]. Furthermore, elevated plasma TGF\u03B2 levels correlate with advanced tumor stage, metastases, and poor survival [15]\u2013[17]." . _:b546869381 "2"^^ . . _:b546869019 . _:b546869223 . _:b546869380 "2"^^ . . _:b546869383 "2"^^ . . _:b546869382 "2"^^ . _:b546868515 . . _:b546869377 "2"^^ . . _:b546869364 . _:b546869376 "2"^^ . . . _:b546869379 "2"^^ . _:b546869378 "2"^^ . _:b546868423 . _:b546868464 . _:b546869389 "2"^^ . _:b546868625 . _:b546868818 . . _:b546869215 . . _:b546869388 "2"^^ . _:b546868937 . _:b546868411 . _:b546869391 "2"^^ . _:b546868389 . _:b546869435 . _:b546868980 . _:b546869390 "2"^^ . . _:b546868436 . _:b546868388 . _:b546869213 . _:b546869385 "2"^^ . _:b546868391 . _:b546868645 . _:b546869384 "2"^^ . _:b546868390 . . _:b546869387 "2"^^ . _:b546868943 . _:b546869386 "2"^^ . . . . _:b546869397 "2"^^ . _:b546869349 . . _:b29429233 "Gene expression analyses of metastatic and aggressive cancers have identified elevated expression of TGF\u03B2-associated genes, especially those involved with epithelial-to-mesenchymal transition [>>50<<]. Significant overlap of the TGF\u03B2 response gene signature, lung metastasis signature, and basal cell breast subtype exist [50]. Recently, targeted therapies directed against B-RAF and other genes have been used successfully to treat" . _:b546869073 . _:b546868432 . _:b546869396 "2"^^ . _:b546868741 "3"^^ . _:b546869399 "2"^^ . _:b546868831 . _:b546868397 . _:b546868740 "3"^^ . _:b546869398 "2"^^ . _:b546868608 . _:b546868396 . _:b546869067 . _:b546868847 . . _:b546869393 "2"^^ . _:b546868743 "3"^^ . _:b546868461 . _:b546868399 . _:b546868667 . _:b546869392 "2"^^ . _:b546868862 . _:b546868742 "3"^^ . . . _:b546868911 . _:b546868398 . . _:b546869450 . _:b546868737 "3"^^ . _:b546869395 "2"^^ . _:b546868393 . _:b546868701 . _:b546869029 . _:b546868736 "3"^^ . _:b546869394 "2"^^ . _:b546868914 . _:b546868392 . _:b546868739 "3"^^ . _:b546869405 "2"^^ . _:b546868740 . _:b546868395 . . _:b546869404 "2"^^ . _:b546868738 "3"^^ . . . _:b546868394 . _:b546868749 "3"^^ . _:b546869407 "2"^^ . _:b546868405 . _:b546868748 "3"^^ . _:b546869406 "2"^^ . _:b546869012 . _:b546868404 . . _:b546868751 "3"^^ . _:b546869401 "2"^^ . . _:b546868407 . _:b546868907 . _:b546868750 "3"^^ . _:b546869400 "2"^^ . _:b546868978 . _:b546868406 . . _:b546868721 . _:b546869403 "2"^^ . _:b546868745 "3"^^ . . _:b546868401 . _:b546868744 "3"^^ . _:b546869402 "2"^^ . _:b546869064 . _:b546868400 . _:b546868747 "3"^^ . _:b546869413 "2"^^ . _:b546869305 . _:b546868403 . _:b29429228 "In addition, novel anti-TGF\u03B2 activity such as inhibition of angiogenesis, fibrosis, metastases, and immune suppression may be additive to other treatments [>>4<<], [10], [30]." . _:b546868746 "3"^^ . _:b546869412 "2"^^ . _:b546868402 . _:b29429187 "in many different malignancies including prostate, breast, lung, pancreatic, renal cell, liver, colon, gastric, esophageal, ovarian, cervical, bladder, thyroid, head and neck cancers, melanoma, gliomas, and multiple myeloma [13], [>>14<<]. Furthermore, elevated plasma TGF\u03B2 levels correlate with advanced tumor stage, metastases, and poor survival [15]\u2013[17]." . _:b546868757 "3"^^ . _:b546869421 . _:b546869415 "2"^^ . _:b546868413 . _:b546868756 "3"^^ . _:b546869414 "2"^^ . _:b546868412 . . _:b546869345 . _:b546868759 "3"^^ . _:b546869409 "2"^^ . _:b546869337 . _:b546868415 . _:b546869426 . _:b546868758 "3"^^ . _:b546869408 "2"^^ . _:b546868414 . _:b546868390 . _:b546868753 "3"^^ . _:b546869411 "2"^^ . _:b546868409 . . _:b546869410 "2"^^ . _:b546868752 "3"^^ . . _:b546868408 . . . _:b546869421 "2"^^ . _:b546868755 "3"^^ . . _:b546868411 . . _:b546868754 "3"^^ . _:b546869420 "2"^^ . _:b546868410 . _:b546868611 . _:b546868765 "2"^^ . . _:b546869423 "2"^^ . . _:b546868421 . _:b546868764 "2"^^ . . _:b546869422 "2"^^ . _:b546868658 . _:b546868420 . _:b546868583 . . _:b546868792 . _:b546868767 "2"^^ . _:b546869417 "2"^^ . . _:b546868423 . _:b546868766 "2"^^ . _:b546869416 "2"^^ . _:b546868422 . _:b546868761 "2"^^ . _:b546868925 . _:b546869419 "2"^^ . _:b546868417 . . . _:b546868760 "3"^^ . _:b546869418 "2"^^ . _:b546868416 . . _:b546868763 "2"^^ . . _:b546869429 "2"^^ . _:b546869001 . _:b546868419 . _:b546868524 . _:b546868388 . _:b546868762 "2"^^ . . _:b546869428 "2"^^ . . _:b546868418 . . _:b546868773 "2"^^ . . _:b546869431 "2"^^ . _:b546868429 . _:b546868772 "2"^^ . _:b546869430 "2"^^ . . _:b29429230 . _:b546868428 . _:b546868674 . _:b546868775 "2"^^ . _:b546869425 "2"^^ . _:b546868431 . _:b546868774 "2"^^ . _:b546869172 . _:b546868986 . _:b546869424 "2"^^ . . _:b546868430 . _:b546868769 "2"^^ . _:b546869105 . _:b546869427 "2"^^ . _:b546868425 . . _:b546868768 "2"^^ . _:b546869426 "2"^^ . _:b546868424 . . . _:b546868771 "2"^^ . . _:b546869437 "2"^^ . _:b29429219 . _:b546868427 . _:b546868476 . _:b546868770 "2"^^ . _:b546869436 "2"^^ . _:b546868426 . _:b546868904 . _:b546868781 "2"^^ . _:b546869439 "2"^^ . _:b546868437 . _:b546868780 "2"^^ . _:b546869058 . _:b546869438 "2"^^ . _:b29429182 . _:b546868436 . _:b546868783 "2"^^ . _:b546869433 "2"^^ . _:b546868439 . _:b546868782 "2"^^ . _:b546869432 "2"^^ . _:b546868438 . _:b546868777 "2"^^ . _:b546869435 "2"^^ . . _:b546868433 . _:b546868776 "2"^^ . _:b546869434 "2"^^ . _:b546868432 . _:b546868779 "2"^^ . _:b546869445 "2"^^ . _:b546868435 . . _:b546868778 "2"^^ . _:b546869444 "2"^^ . _:b546868434 . _:b546868789 "2"^^ . _:b546869254 . _:b546869447 "2"^^ . _:b546868445 . . _:b546869367 . _:b546868788 "2"^^ . . _:b546869446 "2"^^ . _:b546868444 . _:b546868450 . _:b546868791 "2"^^ . _:b546868790 . _:b546869293 . _:b546869441 "2"^^ . _:b546868447 . . _:b546868790 "2"^^ . _:b546869440 "2"^^ . _:b546868446 . _:b546868785 "2"^^ . . _:b546869443 "2"^^ . _:b546869167 . _:b546868441 . . _:b546868784 "2"^^ . . _:b546869442 "2"^^ . _:b546868440 . _:b546869492 . _:b546868787 "2"^^ . _:b546869453 "2"^^ . _:b546868443 . _:b546868554 . _:b546868786 "2"^^ . . _:b546869452 "2"^^ . _:b546869127 . _:b546868442 . . . _:b546868797 "2"^^ . _:b546869455 "2"^^ . _:b546868453 . _:b546868796 "2"^^ . _:b546869454 "2"^^ . _:b546868452 . _:b546868799 "2"^^ . _:b546869449 "2"^^ . _:b546868455 . _:b546868798 "2"^^ . _:b546869448 "2"^^ . _:b546868454 . _:b546868668 . _:b546869166 . _:b546868793 "2"^^ . _:b546869451 "2"^^ . _:b546868449 . _:b546869506 . _:b546868434 . _:b546868604 . _:b546868792 "2"^^ . . _:b546869450 "2"^^ . . _:b546868448 . _:b546868795 "2"^^ . _:b546869461 "2"^^ . . _:b546868451 . _:b546868794 "2"^^ . _:b546869309 . . _:b546869460 "2"^^ . . _:b546868450 . _:b546868805 "2"^^ . _:b546869463 "2"^^ . _:b29429197 . _:b546868461 . . _:b546868804 "2"^^ . _:b546869462 "2"^^ . _:b546868460 . _:b546868807 "2"^^ . _:b546869457 "2"^^ . _:b546868463 . . _:b546868972 . _:b546868806 "2"^^ . _:b546868599 . . _:b546869456 "2"^^ . _:b546868514 . _:b546869113 . _:b546868462 . . _:b546868801 "2"^^ . . _:b546869459 "2"^^ . . . . _:b29429169 . _:b546869248 . _:b546868457 . _:b546868800 "2"^^ . _:b546869485 . _:b546869458 "2"^^ . _:b546868456 . _:b546868641 . _:b546868803 "2"^^ . _:b546869469 "2"^^ . _:b546868459 . . _:b546868802 "2"^^ . _:b546869468 "2"^^ . _:b546868458 . _:b546868813 "2"^^ . _:b546869471 "2"^^ . _:b546869377 . _:b546868469 . . . _:b546868812 "2"^^ . _:b546869470 "2"^^ . . _:b546868468 . _:b29429172 . _:b546868815 "2"^^ . _:b546869465 "2"^^ . _:b29429211 "Interestingly, KAs and SCCs have been reported in patients receiving sorafenib, B-RAF inhibitors, and anti-tumor necrosis factor (TNF) \u03B1-directed therapies [33], [>>38<<], [39], and recent data with vemurafemib have implicated RAS pathway mutations and signaling through the mitogen-activated protein kinase pathway in the development of these lesions [40]." . _:b546868453 . _:b546868471 . _:b546868814 "2"^^ . _:b546869464 "2"^^ . _:b546869220 . _:b546868470 . . _:b546868809 "2"^^ . . _:b546869467 "2"^^ . _:b546869379 . _:b546868460 . _:b546868465 . _:b546868808 "2"^^ . _:b546869466 "2"^^ . _:b546868605 . _:b546868464 . _:b29429176 . _:b546868811 "2"^^ . _:b546869477 "2"^^ . _:b546868467 . _:b546868810 "2"^^ . _:b546869476 "2"^^ . _:b546868466 . . . _:b546868821 "2"^^ . . _:b546869479 "2"^^ . . _:b546868477 . _:b546868820 "2"^^ . _:b546869478 "2"^^ . _:b29429190 . . _:b546868476 . _:b546869257 . . . _:b29429222 "Several mechanisms have been proposed to explain the improved efficacy with cytotoxic agents and include increased diffusion of chemotherapy and payload-containing particles such as liposomes into tumor masses [>>45<<], [46], reversal of chemotherapy resistance [29], [41], inhibition of DNA repair by blockade of \u03B3H2AX foci formation [28] and reversal of TGF\u03B2-induced accumulation of tumor cells in G0/G1 [21], [44]." . _:b546868823 "2"^^ . _:b546869473 "2"^^ . . _:b546868479 . _:b546868822 "2"^^ . _:b546869472 "2"^^ . _:b546868478 . _:b546868817 "2"^^ . _:b546868889 . _:b546869475 "2"^^ . _:b546868473 . _:b546868816 "2"^^ . _:b546869474 "2"^^ . _:b546868472 . . . _:b546868819 "2"^^ . _:b546869485 "2"^^ . . _:b546868475 . _:b546868818 "2"^^ . . _:b546869484 "2"^^ . _:b546868474 . _:b546869051 . _:b546868768 . _:b546868527 . _:b546868829 "2"^^ . _:b546869487 "2"^^ . . . _:b546868409 . . . _:b546868828 "2"^^ . _:b546869486 "2"^^ . _:b546868831 "2"^^ . _:b546869481 "2"^^ . _:b546868830 "2"^^ . _:b546868741 . _:b546869480 "2"^^ . _:b546868399 . _:b546868825 "2"^^ . _:b546869483 "2"^^ . _:b546868802 . _:b546868824 "2"^^ . _:b546869482 "2"^^ . . . _:b546868827 "2"^^ . . _:b546869493 "2"^^ . _:b546868559 . . _:b546869282 . _:b546868826 "2"^^ . . . _:b546869492 "2"^^ . _:b546868456 . _:b546868837 "2"^^ . _:b546869495 "2"^^ . . _:b546868543 . _:b546868836 "2"^^ . _:b546868874 . _:b546869494 "2"^^ . . _:b546868839 "2"^^ . _:b546869489 "2"^^ . _:b546868642 . _:b546868838 "2"^^ . _:b546869488 "2"^^ . _:b546869360 . _:b546868833 "2"^^ . _:b546869043 . _:b546869491 "2"^^ . _:b546869483 . _:b546868651 . _:b546868832 "2"^^ . . _:b546869490 "2"^^ . _:b546868791 . . _:b546868835 "2"^^ . _:b546869501 "2"^^ . . . _:b546868834 "2"^^ . _:b546869208 . _:b546869500 "2"^^ . _:b546869508 . . _:b546868845 "2"^^ . _:b546869503 "2"^^ . _:b546869458 . _:b546868844 "2"^^ . _:b546869413 . _:b546869502 "2"^^ . . _:b546869204 . . _:b546868847 "2"^^ . _:b546869497 "2"^^ . _:b546868846 "2"^^ . . _:b546869496 "2"^^ . . _:b546869490 . _:b546868841 "2"^^ . _:b546869499 "2"^^ . . . _:b546869063 . _:b29429168 "Transforming growth factor-beta (TGF\u03B2) is a pleiotropic cytokine that is a member of a superfamily of ligands that includes bone morphogenetic proteins and activins [>>1<<], [2]. Under normal conditions, TGF\u03B2 helps to maintain homeostasis and limit the growth of epithelial, endothelial, neuronal, and hematopoietic cell lineages through anti-proliferative and apoptotic responses." . _:b546869179 . _:b546869171 . _:b546868752 . _:b546868840 "2"^^ . _:b546869498 "2"^^ . _:b546869108 . . _:b546868915 . _:b546868843 "2"^^ . _:b546869509 "2"^^ . _:b546868898 . _:b546868842 "2"^^ . _:b546869423 . _:b546869508 "2"^^ . . _:b546868853 "2"^^ . _:b546869275 . _:b546868773 . _:b546869511 "2"^^ . . _:b546868852 "2"^^ . _:b546869510 "2"^^ . . _:b546868855 "2"^^ . . _:b546869505 "2"^^ . . _:b546868854 "2"^^ . _:b546869302 . _:b546869504 "2"^^ . . . _:b546868849 "2"^^ . _:b546869507 "2"^^ . _:b546868649 . _:b546868848 "2"^^ . . _:b546869506 "2"^^ . . _:b546868851 "2"^^ . _:b546869517 "2"^^ . . _:b546868850 "2"^^ . _:b546869516 "2"^^ . . _:b29429176 "transition, which is characterized by a morphological change to a spindle cell shape, down-regulation of E-cadherin and cytokeratin expression, loss of cell-cell junctions, remodeling of the cytoskeleton, and increased cell motility [>>2<<], [4], [7]. TGF\u03B2-induced cellular changes have been described in many different tumor models and appear to be important for inducing cell migration and promoting metastases [7]." . _:b546868861 "2"^^ . . _:b546869519 "2"^^ . _:b546869332 . _:b29429196 "Additive effects of anti-TGF\u03B2 combined with various chemotherapies, radiation or biologics including vaccines have been reported to improve the treatment of both primary and metastatic disease [21], [25], [>>27<<]\u2013[30]." . _:b546868860 "2"^^ . _:b546869518 "2"^^ . _:b546868868 . _:b546868863 "2"^^ . _:b546868919 . _:b29429229 . _:b546869513 "2"^^ . . _:b546869149 . . _:b546868862 "2"^^ . . _:b546869512 "2"^^ . _:b546868857 "2"^^ . . _:b546869515 "2"^^ . . _:b546868856 "2"^^ . _:b546869514 "2"^^ . . . . _:b546868859 "2"^^ . . _:b546869525 "2"^^ . . . . _:b546868858 "2"^^ . _:b546869524 "2"^^ . . _:b546868665 . . _:b546868869 "2"^^ . _:b546868421 . . _:b546868868 "2"^^ . _:b546869526 "2"^^ . _:b546868871 "2"^^ . . _:b546869521 "2"^^ . _:b546868706 . _:b546868870 "2"^^ . _:b546869520 "2"^^ . _:b546868491 . _:b546869318 . . _:b546868865 "2"^^ . . _:b546869523 "2"^^ . _:b546868644 . _:b546868864 "2"^^ . _:b546869137 . _:b546869522 "2"^^ . _:b546868726 . . _:b546868867 "2"^^ . . . . _:b546868866 "2"^^ . _:b546869230 . _:b546869315 . _:b546868877 "2"^^ . _:b546868876 "2"^^ . _:b546869519 . _:b546868394 . _:b546868879 "2"^^ . _:b546868878 "2"^^ . _:b546869245 . . . _:b546868873 "2"^^ . . _:b546868872 "2"^^ . . _:b546868804 . _:b546868875 "2"^^ . . . _:b546868874 "2"^^ . _:b546868763 . . _:b546868774 . _:b546868639 . _:b546868885 "2"^^ . _:b546869081 . . . _:b546868590 . _:b546868884 "2"^^ . . _:b29429180 "growth factor (VEGF) and angiogenesis, dysregulated lymphangiogenesis, increased extracellular matrix deposition, and production of factors such as parathyroid hormone-related peptide (PTHrP) that increase osteoclastic activity [>>4<<], [8]\u2013[10]. TGF\u03B2 also attenuates host antitumor immune responses." . _:b546868887 "2"^^ . _:b546868431 . _:b546868886 "2"^^ . _:b546868591 . _:b546868881 "2"^^ . . . _:b546868880 "2"^^ . _:b29429213 "necrosis factor (TNF) \u03B1-directed therapies [33], [38], [39], and recent data with vemurafemib have implicated RAS pathway mutations and signaling through the mitogen-activated protein kinase pathway in the development of these lesions [>>40<<]. The exact link between these drugs and the effects of GC1008 are unknown." . _:b546868883 "2"^^ . _:b546869380 . _:b546868536 . . _:b546868882 "2"^^ . . . _:b546869020 . _:b546869192 . _:b546868893 "2"^^ . _:b546868892 "2"^^ . _:b546869222 . . _:b546868895 "2"^^ . _:b546869035 . . _:b546868894 "2"^^ . _:b546868889 "2"^^ . . _:b29429226 . _:b546868407 . _:b546868888 "2"^^ . . _:b546868891 "2"^^ . . _:b546868890 "2"^^ . _:b546868700 . _:b546868463 . . _:b546868901 "2"^^ . . _:b546868900 "2"^^ . _:b546868405 . _:b546868573 . _:b546868903 "2"^^ . _:b546868902 "2"^^ . . _:b546868681 . _:b546868897 "2"^^ . . _:b29429218 . _:b546869128 . _:b546868638 . _:b546868896 "2"^^ . . . . _:b546868899 "2"^^ . . _:b546869150 . . . _:b546868898 "2"^^ . . _:b546868909 "2"^^ . _:b29429188 . . _:b546868580 . . . _:b546868908 "2"^^ . _:b546868911 "2"^^ . . . . _:b29429234 "Significant overlap of the TGF\u03B2 response gene signature, lung metastasis signature, and basal cell breast subtype exist [>>50<<]. Recently, targeted therapies directed against B-RAF and other genes have been used successfully to treat patients with MM [33]. Studies of these genes and associated mutations were under investigation and no results were available when" . _:b546868814 . _:b546868910 "2"^^ . _:b546869177 . _:b546868905 "2"^^ . . . _:b546868904 "2"^^ . _:b546868945 . _:b546869296 . _:b546868879 . _:b546868907 "2"^^ . _:b546869520 . . _:b546868906 "2"^^ . _:b546868886 . _:b546868917 "2"^^ . . _:b546868626 . _:b546868916 "2"^^ . . _:b546869174 . _:b546868913 . . _:b546868919 "2"^^ . . _:b546868977 . . _:b546868918 "2"^^ . _:b546868732 . _:b546868913 "2"^^ . _:b546869298 . _:b546868912 "2"^^ . . _:b546868915 "2"^^ . _:b546868705 . . . _:b546868914 "2"^^ . . "PMC0" . _:b546868925 "2"^^ . _:b546868924 "2"^^ . _:b546869307 . _:b546869341 . _:b546869359 . _:b546868927 "2"^^ . . _:b29429173 "Instead, TGF\u03B2 will directly promote tumor growth and metastases [2], [>>4<<], [5]. Chronic exposure of transformed mouse keratinocytes to TGF\u03B2 causes a change in morphology and engenders these cells with the ability to form spindle cell carcinomas when transplanted into mice [6]." . _:b546868926 "2"^^ . . _:b546868921 "2"^^ . . _:b546868729 . . _:b546868521 . _:b546868920 "2"^^ . _:b546869004 . _:b546868923 "2"^^ . _:b29429175 "Chronic exposure of transformed mouse keratinocytes to TGF\u03B2 causes a change in morphology and engenders these cells with the ability to form spindle cell carcinomas when transplanted into mice [>>6<<]. TGF\u03B2 induces epithelial-to-mesenchymal transition, which is characterized by a morphological change to a spindle cell shape, down-regulation of E-cadherin and cytokeratin expression, loss of cell-cell junctions, remodeling of the" . _:b546868922 "2"^^ . . . _:b546869156 . . _:b546869462 . _:b546868933 "2"^^ . _:b546868880 . . . _:b546869022 . _:b546869269 . _:b546868646 . _:b29429191 . _:b546868932 "2"^^ . _:b546868564 . _:b546868661 . _:b29429232 "Control of these effects may be critical in the development of effective anti-cancer therapies. Norton and Massague [48], [>>49<<] have proposed that cancer cell migration and \u201Cre-seeding\u201D of the primary tumor with cells primed for metastatic growth leads to a tumor with heterogenous subpopulations of aggressive, rapidly growing cancer cells that may become resistant" . . . . _:b546868935 "2"^^ . _:b546868671 . _:b546868934 "2"^^ . _:b546868815 . _:b546868949 . _:b546868520 . _:b546868517 . _:b546868929 "2"^^ . . _:b546868928 "2"^^ . _:b546868414 . _:b546868931 "2"^^ . _:b546869054 . _:b546868663 . . _:b546868930 "2"^^ . . _:b546868941 "2"^^ . _:b546869454 . . _:b546868724 . _:b546868935 . _:b546868940 "2"^^ . _:b546869366 . _:b546868998 . _:b546868943 "2"^^ . _:b546868942 "2"^^ . . _:b546869195 . _:b546868937 "2"^^ . _:b546869452 . _:b546868508 . . _:b546868936 "2"^^ . . . _:b546868933 . _:b546869155 . _:b546868939 "2"^^ . _:b546868938 "2"^^ . _:b546868529 . _:b546869418 . . _:b546868949 "2"^^ . . . _:b546868948 "2"^^ . . . _:b546869106 . _:b546868951 "2"^^ . . . _:b546868950 "2"^^ . _:b546868427 . _:b546868945 "2"^^ . . _:b29429216 "A variety of anti-TGF\u03B2 agents combined with chemotherapy, radiation, biologics, immunotherapeutics and vaccines have demonstrated enhanced antitumor effects in preclinical models [>>11<<], [21], [22], [25], [28]\u2013[30], [41]\u2013[44]." . . _:b546868944 "2"^^ . _:b546869182 . _:b546869488 . . . _:b546868947 "2"^^ . _:b546869463 . . _:b546868946 "2"^^ . _:b546868957 "2"^^ . _:b546868881 . _:b546868956 "2"^^ . _:b546868959 "2"^^ . _:b546869201 . _:b546868958 "2"^^ . _:b546868798 . . _:b546868953 "2"^^ . . _:b546868704 . _:b546868952 "2"^^ . . . . _:b546868955 "2"^^ . . . . _:b546868954 "2"^^ . _:b546869405 . _:b546868965 "2"^^ . . . _:b546868728 . . _:b546868964 "2"^^ . _:b546868967 "2"^^ . . _:b546868966 "2"^^ . . _:b546868961 "2"^^ . . . _:b546868960 "2"^^ . _:b546868825 . _:b546869059 . _:b546868963 "2"^^ . _:b546869153 . _:b546868620 . _:b29429225 . _:b546868962 "2"^^ . _:b546868901 . _:b546869375 . . _:b546868973 "2"^^ . . _:b546869246 . _:b546868972 "2"^^ . _:b546869224 . _:b29429220 . . . _:b546868509 . . _:b546868975 "2"^^ . _:b546868578 . _:b546868974 "2"^^ . _:b546868903 . . _:b546868969 "2"^^ . _:b546868968 "2"^^ . . _:b546869055 . . _:b546868971 "2"^^ . . _:b546868970 "2"^^ . _:b546869216 . _:b546869120 . _:b546868891 . _:b546868846 . _:b546869408 . _:b546868981 "2"^^ . _:b546869176 . _:b546868980 "2"^^ . _:b546869158 . _:b546868586 . _:b546868983 "2"^^ . _:b546869189 . "10.1371%2Fjournal.pone.0090353" . . _:b546868982 "2"^^ . . . . _:b546868977 "2"^^ . _:b546868976 "2"^^ . _:b546869181 . _:b546868979 "2"^^ . . . _:b546868978 "2"^^ . _:b546869442 . _:b546868867 . _:b546868999 . _:b546868989 "2"^^ . _:b546868988 "2"^^ . _:b546869480 . _:b29429235 "Recently, targeted therapies directed against B-RAF and other genes have been used successfully to treat patients with MM [>>33<<]. Studies of these genes and associated mutations were under investigation and no results were available when this trial of GC1008 was initiated. Therefore, analyses of tumor samples for these defects were not performed in this trial. In" . _:b546868797 . _:b546868991 "2"^^ . _:b546868809 . _:b546868947 . _:b546868990 "2"^^ . . _:b546869441 . . _:b546868872 . . . _:b546868985 "2"^^ . . _:b546868984 "2"^^ . . _:b546868970 . _:b546868987 "2"^^ . . . . _:b546868986 "2"^^ . . _:b546868556 . _:b546868539 . _:b546868997 "2"^^ . _:b546868982 . _:b546868981 . _:b546868996 "2"^^ . _:b546869090 . _:b546869371 . _:b546868999 "2"^^ . . . . _:b546868998 "2"^^ . _:b29429208 . _:b546868418 . _:b546868993 "2"^^ . . _:b29429177 "which is characterized by a morphological change to a spindle cell shape, down-regulation of E-cadherin and cytokeratin expression, loss of cell-cell junctions, remodeling of the cytoskeleton, and increased cell motility [2], [>>4<<], [7]. TGF\u03B2-induced cellular changes have been described in many different tumor models and appear to be important for inducing cell migration and promoting metastases [7]." . _:b546868992 "2"^^ . . . _:b546868995 "2"^^ . . . _:b546869068 . _:b546868994 "2"^^ . _:b546868451 . _:b546869032 . _:b546868548 . . _:b546869005 "2"^^ . . . . _:b546869004 "2"^^ . . . _:b546869015 . _:b546869007 "2"^^ . _:b546869428 . _:b546869264 . _:b29429218 "A variety of anti-TGF\u03B2 agents combined with chemotherapy, radiation, biologics, immunotherapeutics and vaccines have demonstrated enhanced antitumor effects in preclinical models [11], [21], [22], [25], [>>28<<]\u2013[30], [41]\u2013[44]." . _:b546869006 "2"^^ . . _:b546868687 . . _:b546869001 "2"^^ . _:b546868415 . _:b29429217 . _:b546868806 . _:b546869000 "2"^^ . _:b546869474 . . _:b546869003 "2"^^ . _:b29429205 . _:b546868699 . _:b546869002 "2"^^ . _:b546868444 . _:b546868748 . _:b546868448 . _:b546869013 "2"^^ . _:b546869012 "2"^^ . _:b29429206 . . _:b546869015 "2"^^ . _:b546869014 "2"^^ . _:b546869009 "2"^^ . _:b546869279 . _:b546868856 . _:b546869233 . _:b546869008 "2"^^ . _:b546869011 "2"^^ . . _:b546869010 "2"^^ . _:b546869210 . . . _:b546869021 "2"^^ . _:b546869522 . . _:b546869020 "2"^^ . . . _:b546868839 . _:b546868388 . _:b546869023 "2"^^ . . _:b546868389 . _:b546868390 . _:b546868391 . _:b546868908 . _:b546869022 "2"^^ . . _:b546869017 "2"^^ . _:b546868396 . _:b546868397 . _:b546868398 . _:b546868399 . _:b546868392 . _:b546869016 "2"^^ . _:b546868393 . _:b546868394 . _:b546868395 . . . _:b546868404 . _:b546869019 "2"^^ . _:b546868405 . _:b546868406 . _:b546868407 . . . _:b546868400 . _:b546869018 "2"^^ . _:b546868401 . _:b546869143 . _:b546868402 . _:b546868403 . _:b546869047 . _:b546868412 . _:b546869029 "2"^^ . . _:b546868413 . _:b546868414 . _:b546868415 . _:b546868408 . _:b546869028 "2"^^ . _:b546868409 . _:b546868410 . _:b546869373 . . _:b546868411 . . . _:b546869031 "2"^^ . _:b546869030 "2"^^ . _:b546868631 . _:b546869025 "2"^^ . _:b546868684 . _:b546869024 "2"^^ . _:b546869027 "2"^^ . _:b29429179 "TGF\u03B2-induced cellular changes have been described in many different tumor models and appear to be important for inducing cell migration and promoting metastases [>>7<<]." . . _:b29429204 "number of patients was small, the median PFS for all 29 patients was 11.1 weeks, which was comparable to the median TTP/PFS of 1.3 to 2 months reported for patients with advanced MM treated with dacarbazine or other chemotherapy [33], [>>34<<]." . . _:b546869026 "2"^^ . _:b546869504 . . _:b546869037 "2"^^ . _:b546869052 . _:b546869036 "2"^^ . _:b546869449 . . . _:b546869039 "2"^^ . _:b546868452 . _:b546868453 . . _:b546868916 . _:b546868454 . _:b546868455 . _:b546868448 . _:b546869038 "2"^^ . . _:b546868449 . _:b546868413 . _:b546869409 . . _:b546868450 . _:b546868451 . _:b546868460 . _:b546869033 "2"^^ . . _:b546868461 . _:b546868462 . _:b546868463 . _:b546868456 . _:b546869032 "2"^^ . _:b546868457 . _:b546868458 . . _:b546868459 . . _:b546869035 "2"^^ . _:b546868468 . _:b546868469 . _:b546869098 . _:b546868470 . . _:b546868471 . . _:b546868464 . _:b546869034 "2"^^ . _:b546868435 . . _:b546869079 . _:b546868465 . _:b546868466 . _:b546868467 . . _:b546869045 "2"^^ . . _:b546868476 . _:b546868477 . _:b546868552 . . _:b546868478 . _:b546868479 . _:b546868472 . _:b546869044 "2"^^ . _:b546868952 . _:b546868473 . _:b546868474 . _:b546868475 . . _:b546868420 . _:b546869047 "2"^^ . _:b546868421 . _:b546868951 . . _:b546868422 . . _:b546868423 . _:b546868416 . _:b546869046 "2"^^ . . _:b546868417 . _:b546868418 . _:b546869358 . _:b546868941 . _:b546868419 . _:b546868428 . _:b546869041 "2"^^ . _:b546868997 . . _:b546869484 . _:b546868429 . _:b546868430 . . _:b546868431 . . _:b546869040 "2"^^ . _:b546868996 . . _:b546868424 . _:b546868425 . _:b546869319 . _:b546868691 . _:b546868426 . _:b546868427 . _:b546868967 . _:b546868436 . _:b546869043 "2"^^ . _:b546868999 . _:b546868753 . _:b546868437 . _:b546869499 . _:b546868438 . _:b546868439 . _:b546868432 . _:b546869042 "2"^^ . _:b546868998 . _:b546868433 . _:b546868434 . _:b546868526 . _:b546869443 . _:b546868435 . _:b546868444 . _:b546869053 "2"^^ . _:b546868993 . _:b546868445 . . _:b546868446 . _:b546868447 . _:b546868440 . _:b546869052 "2"^^ . _:b546868992 . . _:b546868441 . _:b546868442 . _:b546868443 . _:b546868995 . _:b546869055 "2"^^ . _:b546868994 . _:b546869054 "2"^^ . _:b546869229 . _:b546869473 . _:b546869005 . _:b546869049 "2"^^ . . _:b29429230 "In addition, novel anti-TGF\u03B2 activity such as inhibition of angiogenesis, fibrosis, metastases, and immune suppression may be additive to other treatments [4], [10], [>>30<<]. The potential to inhibit suppressive immune cells, cytokines and enzymes was recognized by the National Cancer Institute (NCI) Immune Response Modifier Pathway Prioritization Working Group, who recommended anti-TGF\u03B2 agents be" . _:b546869004 . _:b546869048 "2"^^ . . . _:b546869007 . _:b29429214 . _:b546869051 "2"^^ . _:b546869006 . _:b546869050 "2"^^ . . _:b546869001 . _:b546869061 "2"^^ . _:b546868892 . . _:b546869060 "2"^^ . _:b546869000 . _:b546868789 . . _:b546869003 . _:b29429210 . _:b546869063 "2"^^ . . _:b546868401 . _:b546869002 . _:b546869062 "2"^^ . _:b546868465 . _:b546869013 . _:b546869057 "2"^^ . _:b546868725 . _:b546869012 . _:b546869056 "2"^^ . _:b546868513 . _:b546869015 . _:b546869263 . _:b546869059 "2"^^ . _:b546869014 . _:b546869058 "2"^^ . _:b546868656 . _:b546869009 . _:b546869069 "2"^^ . _:b546868426 . _:b546869287 . . _:b546869008 . _:b29429203 . _:b546869068 "2"^^ . _:b546869011 . _:b546869071 "2"^^ . _:b546869403 . _:b546869010 . _:b546869070 "2"^^ . . . _:b546869021 . _:b546869065 "2"^^ . . _:b546869285 . _:b546869020 . _:b546869077 . _:b546869064 "2"^^ . _:b546869187 . _:b546869415 . _:b546869023 . _:b546869333 . _:b546869067 "2"^^ . . . _:b546869066 "2"^^ . _:b546869022 . _:b546869017 . _:b546869077 "2"^^ . . _:b546869016 . _:b546869392 . _:b546869076 "2"^^ . _:b546868855 . _:b546868494 . . _:b29429195 "Similarly, in B16 murine melanoma, anti-TGF\u03B2 therapy alone [26] or in combination with interleukin-2 reduced the number of lung metastases [>>27<<]. Additive effects of anti-TGF\u03B2 combined with various chemotherapies, radiation or biologics including vaccines have been reported to improve the treatment of both primary and metastatic disease [21], [25], [27]\u2013[30]." . _:b546869079 "2"^^ . _:b546869019 . _:b546868954 . . _:b546869078 "2"^^ . _:b546869018 . . . _:b546869029 . _:b546869073 "2"^^ . . _:b546869072 "2"^^ . _:b546869028 . _:b546868742 . . _:b546869031 . _:b546869075 "2"^^ . _:b546869030 . _:b546869074 "2"^^ . . _:b546869025 . _:b546869085 "2"^^ . . . _:b546868572 . _:b546869084 "2"^^ . _:b546869024 . _:b546869018 . _:b546868607 . _:b546868644 . _:b546869087 "2"^^ . _:b546869027 . _:b546868645 . _:b546868646 . _:b546868647 . _:b546868640 . _:b546869086 "2"^^ . _:b546869026 . _:b546868923 . . _:b546868504 . _:b546868641 . _:b546868642 . _:b546868643 . _:b546868652 . _:b546869081 "2"^^ . _:b546869037 . _:b546868653 . . _:b546868654 . _:b546868655 . _:b546868648 . _:b546869080 "2"^^ . _:b546869036 . . . _:b546868649 . _:b546868650 . . _:b546868651 . _:b546868660 . _:b546869331 . _:b546869083 "2"^^ . _:b546869039 . _:b546868661 . _:b546868662 . _:b546868663 . _:b546868656 . _:b546869160 . _:b546869082 "2"^^ . _:b546869038 . _:b546868657 . . _:b546868658 . _:b546868659 . _:b546868969 . _:b546868487 . . _:b546868668 . _:b546869093 "2"^^ . _:b546869033 . _:b546868669 . . _:b546868828 . _:b546868670 . _:b546868671 . _:b546868664 . _:b546869092 "2"^^ . _:b546869032 . _:b546868665 . _:b546868666 . _:b546868955 . _:b546868667 . . _:b546869095 "2"^^ . _:b546869035 . _:b546868612 . _:b546868523 . _:b546869353 . _:b546868613 . _:b546868614 . _:b546868615 . . _:b546869094 "2"^^ . _:b546869034 . _:b546868608 . . _:b546868609 . . _:b546868610 . _:b546868611 . _:b546869340 . _:b546868620 . _:b546869089 "2"^^ . _:b546869045 . _:b546868621 . _:b546868622 . _:b546868623 . _:b546868616 . _:b546869088 "2"^^ . _:b546869044 . _:b546868617 . _:b546868618 . _:b546868619 . _:b546868628 . _:b546869091 "2"^^ . _:b546869047 . . _:b546869247 . _:b546868629 . _:b546868630 . _:b546868631 . _:b546869180 . _:b546868624 . _:b546869090 "2"^^ . _:b546869046 . _:b546868625 . _:b546868626 . _:b546868627 . _:b546868636 . _:b546869101 "2"^^ . _:b546869041 . _:b546868637 . _:b546868638 . _:b546868639 . _:b546868632 . _:b29429235 . _:b546869100 "2"^^ . _:b546869040 . _:b546868633 . _:b546868634 . _:b546869109 . _:b546868635 . _:b546868770 . _:b546868708 . _:b546869103 "2"^^ . _:b546869043 . _:b546868709 . _:b546868975 . _:b546868710 . _:b546868711 . _:b546868704 . _:b546869102 "2"^^ . _:b546869042 . _:b546868860 . _:b546868705 . _:b546868706 . _:b546868707 . _:b546868716 . _:b546869097 "2"^^ . _:b546869053 . _:b546868912 . . _:b546868717 . . _:b546868718 . _:b546868719 . _:b546868712 . _:b546869096 "2"^^ . _:b546869052 . _:b546868437 . _:b546868713 . _:b546868714 . _:b546868715 . _:b546868724 . _:b546869099 "2"^^ . _:b546869055 . _:b546868725 . _:b546868726 . _:b546869386 . . _:b546868727 . _:b546868720 . _:b546869098 "2"^^ . _:b546869054 . _:b546868610 . _:b546868721 . _:b546868722 . _:b546868723 . _:b29429232 . _:b546868732 . _:b546869109 "2"^^ . _:b546869049 . _:b546868733 . _:b546868412 . _:b546868734 . _:b546868735 . . _:b546869108 "2"^^ . _:b546869048 . _:b546868728 . _:b546868729 . _:b546868475 . _:b546868730 . _:b546868731 . _:b546868764 . _:b546868676 . _:b546869111 "2"^^ . _:b546869051 . _:b546868677 . _:b546868678 . _:b546868679 . _:b546868672 . _:b546869110 "2"^^ . _:b546869050 . _:b546868673 . _:b546868674 . _:b546868675 . _:b546868684 . _:b546869105 "2"^^ . _:b546869087 . _:b546869061 . _:b546868685 . _:b546868686 . . _:b546868687 . _:b546868680 . _:b546869368 . _:b546869104 "2"^^ . _:b546869060 . _:b546868681 . _:b546868682 . . _:b546868683 . _:b546868994 . . _:b546868692 . _:b546869107 "2"^^ . _:b546869063 . _:b546868693 . _:b546868694 . _:b546869249 . _:b546869003 . _:b546868695 . _:b546868688 . _:b546869106 "2"^^ . _:b546869062 . _:b546868689 . _:b546868690 . . _:b546868691 . . _:b546868700 . _:b546869117 "2"^^ . _:b546869057 . . _:b546868701 . _:b546868702 . . _:b546869365 . _:b546868703 . . _:b546869453 . _:b546869116 "2"^^ . _:b546869056 . _:b546868696 . _:b546868697 . _:b546868698 . _:b546868699 . _:b546868516 . _:b546869119 "2"^^ . _:b546869059 . _:b546868517 . _:b546868518 . _:b546868519 . _:b546868512 . _:b546869118 "2"^^ . _:b546869058 . . _:b546868513 . . _:b546868817 . _:b546868514 . _:b546868515 . _:b546868524 . _:b546869113 "2"^^ . _:b546869069 . . _:b546868525 . _:b546868526 . . _:b546868527 . _:b546868520 . _:b546869112 "2"^^ . _:b546869068 . _:b546868521 . _:b546868522 . _:b546868523 . _:b546868532 . _:b546869115 "2"^^ . _:b546869071 . _:b546868533 . . _:b546868534 . _:b546868535 . _:b546868512 . _:b546869114 "2"^^ . _:b546869070 . _:b546868528 . _:b546868529 . . _:b546868659 . . _:b546868530 . . _:b29429224 . _:b546868531 . _:b546868540 . _:b546869125 "2"^^ . _:b546869065 . . _:b546868541 . _:b546868542 . . _:b546868543 . _:b546868536 . _:b546869124 "2"^^ . _:b546869064 . _:b546868537 . _:b546868754 . _:b546868538 . _:b546868539 . _:b546868484 . _:b546869127 "2"^^ . _:b546869067 . _:b546868485 . _:b546868486 . _:b546869394 . _:b546868487 . _:b546868480 . _:b546869126 "2"^^ . _:b546869066 . _:b546868481 . _:b546869207 . _:b546868482 . _:b546868948 . _:b546868483 . _:b546868492 . _:b546869121 "2"^^ . _:b546869077 . . _:b546869456 . _:b546868493 . . _:b546868494 . . _:b546868495 . _:b546868488 . _:b546869120 "2"^^ . _:b546869076 . _:b546868489 . _:b546868490 . _:b546868491 . _:b546868500 . _:b546869123 "2"^^ . _:b546869119 . _:b546869079 . _:b546868501 . _:b546868502 . _:b546868503 . _:b546868496 . _:b546869122 "2"^^ . _:b546869078 . _:b546868497 . _:b546868498 . _:b546868499 . _:b546868508 . _:b546869133 "2"^^ . _:b546869073 . _:b546868509 . _:b546868510 . _:b29429191 "In a number of preclinical models, neutralizing antibodies or soluble receptors that bind TGF\u03B2 have demonstrated antitumor activity [10], [>>18<<]\u2013[23]. In murine metastatic breast cancer models, a survival benefit and a reduction in the incidence and size of lytic bone lesions and lung metastases were observed in animals receiving anti-TGF\u03B2 antibody therapy alone [20], [24] as well" . _:b546868511 . _:b546868504 . _:b546869132 "2"^^ . _:b546869072 . . _:b546868505 . _:b546868506 . _:b546868507 . _:b546868395 . . _:b546869135 "2"^^ . _:b546869075 . _:b546868580 . _:b546868581 . . _:b546868582 . _:b546868583 . . _:b546868406 . _:b546869134 "2"^^ . _:b546869074 . _:b546868968 . _:b546868576 . _:b546868577 . _:b546868578 . _:b546868579 . . _:b546869382 . _:b546869129 "2"^^ . _:b546869085 . . _:b546868588 . _:b546868589 . . _:b546868590 . . _:b546868591 . _:b546868584 . _:b546869128 "2"^^ . _:b546869084 . _:b546868585 . _:b546868586 . _:b546868479 . _:b546868587 . _:b546868596 . _:b546869131 "2"^^ . _:b546869087 . . _:b546869283 . _:b546868597 . . _:b546868598 . _:b546868599 . _:b546868592 . _:b546869130 "2"^^ . _:b546869086 . _:b546868593 . . _:b546868594 . _:b546868595 . _:b546868604 . _:b546869141 "2"^^ . _:b546869081 . _:b546868605 . _:b546868606 . _:b546868607 . _:b546869033 . _:b546868600 . _:b546869140 "2"^^ . _:b546869080 . _:b546868601 . . _:b546868602 . _:b546868466 . _:b546868603 . _:b546868548 . _:b546869143 "2"^^ . _:b546869083 . _:b546868549 . _:b546868550 . _:b546869481 . _:b546868551 . _:b546868544 . _:b546869323 . _:b546869142 "2"^^ . _:b546869082 . _:b546868490 . _:b546868545 . . _:b546868546 . _:b546868547 . _:b546868556 . _:b546869137 "2"^^ . _:b546869093 . _:b546868557 . _:b546868558 . _:b546868559 . _:b546868552 . _:b546869136 "2"^^ . _:b546869092 . _:b546868553 . _:b546868554 . _:b546868555 . . _:b546869139 "2"^^ . _:b546869095 . _:b546868564 . _:b546868565 . _:b546869335 . _:b546868887 . _:b546868566 . _:b546868567 . . _:b546869138 "2"^^ . _:b546869094 . _:b546868560 . _:b546868561 . _:b546868562 . _:b546868563 . _:b546868572 . _:b546869149 "2"^^ . _:b546869089 . _:b546868573 . _:b546868574 . _:b546868890 . . _:b546868575 . _:b546868568 . _:b546869148 "2"^^ . _:b546869088 . . _:b546868569 . _:b546868570 . _:b546868571 . _:b546868900 . _:b546869151 "2"^^ . _:b546869091 . _:b546868901 . . _:b546868902 . _:b546868903 . _:b546869157 . _:b546868896 . _:b546869150 "2"^^ . _:b546869090 . _:b546868897 . _:b546868898 . _:b546868899 . _:b546868908 . _:b546869145 "2"^^ . _:b546869101 . _:b546868909 . . _:b546869363 . _:b546868910 . . _:b546868911 . _:b546868904 . _:b546869144 "2"^^ . _:b546869100 . _:b546869023 . _:b546868966 . _:b546868905 . _:b546868906 . _:b546868907 . _:b546868916 . _:b546869147 "2"^^ . _:b546869103 . _:b546868746 . _:b546868917 . _:b546868918 . _:b546868897 . _:b546868919 . _:b546868912 . _:b546869146 "2"^^ . _:b546869102 . _:b546868913 . _:b546868914 . _:b546868915 . _:b546869129 . . _:b546869157 "2"^^ . _:b546869097 . _:b546868669 . _:b546868924 . _:b546868925 . . _:b546868926 . _:b546868927 . _:b546868920 . _:b546869156 "2"^^ . _:b546869096 . _:b546868538 . . _:b546868921 . _:b546868922 . _:b546868923 . _:b546868429 . _:b546869525 . _:b546869370 . _:b546869159 "2"^^ . _:b546869099 . _:b546868868 . _:b546868869 . _:b546868870 . . _:b546868871 . _:b546868864 . _:b546869158 "2"^^ . _:b546869098 . _:b546868865 . _:b546868866 . _:b546868867 . _:b546868876 . _:b546869325 . _:b546869153 "2"^^ . _:b546869109 . _:b546868877 . _:b546868878 . . _:b546868879 . _:b546868872 . _:b546869152 "2"^^ . _:b546869108 . _:b546868873 . _:b546868874 . _:b546869501 . . _:b546868875 . _:b546868884 . _:b546869155 "2"^^ . _:b546869111 . _:b546868885 . _:b546868886 . _:b546868887 . . _:b546868880 . _:b546869154 "2"^^ . _:b546869110 . _:b546868881 . _:b546868882 . _:b546868419 . _:b546868883 . _:b546868892 . _:b546869422 . _:b546869165 "2"^^ . _:b546869105 . _:b546868893 . _:b546869438 . _:b546868894 . _:b546868895 . _:b546868888 . _:b546869164 "2"^^ . _:b546869104 . _:b546868889 . _:b546868890 . _:b546868891 . _:b546868964 . _:b546869167 "2"^^ . _:b546869107 . _:b546868965 . _:b546868932 . _:b546868966 . _:b546868967 . _:b546869184 . _:b546868960 . _:b546869166 "2"^^ . _:b546869106 . _:b546868961 . _:b546869376 . _:b546868962 . _:b546868963 . _:b546868972 . _:b546869161 "2"^^ . _:b546869117 . _:b546868973 . _:b546868974 . _:b546868975 . _:b546868485 . _:b546869160 "2"^^ . _:b546869116 . _:b546868968 . _:b546868969 . _:b546869147 . _:b546868970 . . _:b546868826 . _:b546868971 . . _:b546869163 "2"^^ . _:b546869119 . _:b546868980 . . _:b546868981 . _:b546868979 . _:b546868982 . _:b546869352 . _:b546868816 . _:b546868983 . _:b29429217 "A variety of anti-TGF\u03B2 agents combined with chemotherapy, radiation, biologics, immunotherapeutics and vaccines have demonstrated enhanced antitumor effects in preclinical models [11], [21], [>>22<<], [25], [28]\u2013[30], [41]\u2013[44]." . . _:b546869162 "2"^^ . _:b546869118 . . _:b546868976 . _:b546868977 . _:b546868978 . _:b546868979 . _:b546868506 . _:b546869173 "2"^^ . _:b546869113 . _:b546868988 . . _:b546868989 . . . _:b546868990 . _:b546868991 . _:b546868984 . _:b546869172 "2"^^ . _:b546869112 . _:b546868985 . . _:b546868986 . _:b546868987 . _:b546868932 . _:b546869175 "2"^^ . _:b546869115 . . _:b546868933 . _:b546868934 . _:b546868935 . _:b546869420 . _:b546868928 . _:b546869174 "2"^^ . _:b546869114 . _:b546868692 . _:b546868929 . _:b546868930 . _:b546868931 . _:b546868940 . _:b546869169 "2"^^ . _:b546869125 . _:b546868922 . _:b546868941 . _:b546869374 . . _:b546868942 . _:b546868943 . _:b546868934 . _:b546868936 . _:b546869168 "2"^^ . _:b546869124 . _:b546868937 . . _:b546868730 . _:b546868938 . _:b546868939 . _:b546868603 . _:b546868948 . _:b546869171 "2"^^ . _:b546869127 . _:b546868949 . _:b546868950 . _:b546868951 . . _:b546869344 . _:b546869170 "2"^^ . _:b546869126 . _:b546868628 . _:b546868944 . _:b546868945 . _:b546869057 . _:b546868946 . _:b546868622 . _:b546868947 . _:b546868956 . _:b546869181 "2"^^ . _:b546869121 . . _:b546868957 . _:b546868958 . _:b546869292 . _:b546868959 . _:b546868952 . _:b546869180 "2"^^ . _:b546869120 . _:b546868474 . _:b546869400 . _:b546868953 . _:b546868954 . _:b546868955 . _:b546868567 . _:b546869183 "2"^^ . _:b546869123 . _:b546868772 . _:b546868773 . _:b546869396 . _:b546868774 . _:b546868775 . _:b546869417 . _:b546868768 . _:b546869182 "2"^^ . _:b546869122 . _:b546868769 . _:b546869046 . _:b546868770 . _:b546869238 . _:b546868771 . _:b546868780 . _:b29429212 . _:b546869177 "2"^^ . _:b546869133 . _:b546868929 . . _:b546868781 . _:b546868782 . _:b546868783 . . _:b546869176 "2"^^ . _:b546869132 . _:b546868776 . _:b546868777 . . _:b546868778 . . _:b546868779 . . _:b546869179 "2"^^ . _:b546869135 . _:b546868788 . _:b546868789 . _:b546868790 . _:b546868791 . _:b546868696 . . . _:b546869404 . _:b546869178 "2"^^ . _:b546869134 . _:b546868784 . _:b546868785 . _:b546868786 . _:b546868787 . _:b546868796 . _:b546869189 "2"^^ . _:b546869129 . _:b546868797 . _:b546868798 . . _:b546868757 . _:b546868799 . _:b546868792 . _:b546869188 "2"^^ . _:b546869128 . _:b546868793 . _:b546868794 . _:b546868795 . _:b546868740 . _:b546869191 "2"^^ . _:b546869131 . . _:b546868741 . _:b546868742 . _:b546868743 . _:b546868736 . _:b29429175 . _:b546869190 "2"^^ . _:b546869130 . _:b546868737 . _:b546868738 . _:b546868739 . _:b546869280 . _:b546868748 . _:b546869185 "2"^^ . _:b546869141 . _:b546868749 . . _:b546868750 . . _:b546868751 . _:b546868744 . _:b546869184 "2"^^ . _:b546869140 . _:b546868745 . _:b546868746 . _:b546868747 . . _:b546869187 "2"^^ . _:b546869143 . _:b546868756 . . _:b546868757 . _:b546868758 . . _:b546868759 . . _:b546869186 "2"^^ . _:b546869142 . . _:b546868752 . _:b546868753 . _:b546868754 . _:b546868755 . . _:b546869197 "2"^^ . _:b546869137 . _:b546868764 . _:b546868765 . _:b546869343 . _:b546869121 . _:b546868766 . _:b546869164 . . _:b546868767 . _:b546868760 . _:b546869196 "2"^^ . _:b546869136 . _:b546868761 . . _:b546868762 . _:b546868763 . _:b546869342 . _:b546868836 . _:b546869199 "2"^^ . _:b546869139 . _:b546868837 . _:b546868838 . _:b546868851 . _:b546868839 . _:b546868832 . _:b546869198 "2"^^ . _:b546869138 . . _:b546868833 . _:b546868834 . _:b546868835 . . _:b29429210 "Interestingly, KAs and SCCs have been reported in patients receiving sorafenib, B-RAF inhibitors, and anti-tumor necrosis factor (TNF) \u03B1-directed therapies [>>33<<], [38], [39], and recent data with vemurafemib have implicated RAS pathway mutations and signaling through the mitogen-activated protein kinase pathway in the development of these lesions [40]." . _:b546869193 "2"^^ . _:b546869149 . _:b546868844 . _:b546868845 . _:b546868846 . _:b546868847 . . _:b546869192 "2"^^ . _:b546869148 . _:b546868840 . . _:b546868841 . . . _:b546869351 . _:b546869175 . _:b546868842 . _:b546868492 . . _:b546869072 . _:b546868843 . . _:b546869195 "2"^^ . _:b546869151 . _:b546868733 . _:b546868852 . _:b546868577 . _:b546868853 . . _:b546868854 . _:b546869199 . _:b546868855 . . _:b546869372 . _:b546869194 "2"^^ . _:b546869150 . _:b546868848 . . _:b546869122 . _:b546869097 . _:b546868849 . . _:b546868850 . . _:b546869017 . _:b546868851 . _:b546868860 . _:b546869205 "2"^^ . _:b546869145 . . _:b546868861 . _:b546868862 . _:b546868863 . . _:b546869204 "2"^^ . _:b546869144 . _:b546868856 . _:b546868857 . _:b546868858 . _:b546868801 . _:b546868859 . _:b546869500 . . _:b546869489 . _:b546869207 "2"^^ . _:b546869147 . _:b546868804 . _:b546868805 . _:b546868806 . _:b546868807 . _:b546868800 . _:b546869206 "2"^^ . _:b546869146 . _:b546868801 . _:b546868802 . _:b546868803 . _:b546868812 . _:b546869201 "2"^^ . _:b546869157 . _:b546868813 . _:b546868820 . _:b546868814 . _:b546868815 . . _:b29429231 "Control of these effects may be critical in the development of effective anti-cancer therapies. Norton and Massague [>>48<<], [49] have proposed that cancer cell migration and \u201Cre-seeding\u201D of the primary tumor with cells primed for metastatic growth leads to a tumor with heterogenous subpopulations of aggressive, rapidly growing cancer cells that may become" . _:b546869200 "2"^^ . _:b546869156 . _:b546868439 . _:b546868808 . _:b546868809 . . _:b546868810 . _:b546868811 . _:b546868820 . _:b546869203 "2"^^ . _:b546869159 . . . _:b546868821 . _:b546868822 . _:b546868823 . _:b546868816 . _:b546869202 "2"^^ . _:b546869158 . _:b546868817 . _:b546868818 . _:b546868819 . . _:b546869213 "2"^^ . _:b546869153 . _:b546868828 . _:b546868829 . _:b546868830 . . _:b546868831 . . _:b546869212 "2"^^ . _:b546869152 . _:b546868824 . _:b546868825 . _:b546868826 . _:b546868827 . _:b546869156 . _:b546869215 "2"^^ . _:b546869155 . _:b546868989 . _:b546869157 . . _:b546869158 . . . _:b546868822 . _:b546869159 . _:b546869152 . _:b546869214 "2"^^ . _:b546869154 . . _:b546869153 . . _:b546869154 . . _:b546869155 . _:b546869164 . _:b546869265 . _:b546869209 "2"^^ . _:b546869165 . . _:b546868745 . _:b546869165 . _:b546869166 . _:b546869167 . _:b546869160 . _:b546869208 "2"^^ . _:b546869164 . _:b546869161 . _:b546869162 . _:b546869445 . _:b546868715 . _:b546869163 . _:b546869172 . _:b546869211 "2"^^ . _:b546869167 . _:b546869173 . _:b546869174 . . _:b546869175 . _:b546869168 . _:b546869210 "2"^^ . _:b546869166 . . _:b546869169 . _:b546869170 . _:b546869171 . _:b546868693 . _:b546869180 . _:b546869221 "2"^^ . _:b546869161 . . _:b546869181 . . . _:b546869182 . _:b546869183 . _:b546869176 . _:b546869220 "2"^^ . _:b546869160 . _:b546869177 . _:b546869178 . _:b546868596 . _:b546869179 . _:b546868575 . _:b546869124 . _:b546869223 "2"^^ . _:b546869163 . _:b546869111 . _:b546869125 . . _:b546868615 . _:b546869126 . _:b546869127 . _:b546869286 . . _:b546869222 "2"^^ . _:b546869162 . _:b546869069 . _:b546869120 . _:b546869121 . _:b546868917 . _:b546869122 . _:b546869457 . _:b546869123 . _:b546869131 . _:b546869132 . _:b546869217 "2"^^ . _:b546869173 . _:b546869133 . . _:b546869134 . _:b546869135 . . _:b546869216 "2"^^ . _:b546869172 . _:b546869128 . _:b546869129 . _:b546869130 . _:b546869131 . . _:b546869219 "2"^^ . _:b546869175 . . _:b546869140 . _:b546868534 . _:b546869141 . . _:b546869142 . _:b546869143 . _:b546869136 . _:b546869218 "2"^^ . _:b546869174 . . _:b546869137 . _:b546869138 . _:b29429229 "In addition, novel anti-TGF\u03B2 activity such as inhibition of angiogenesis, fibrosis, metastases, and immune suppression may be additive to other treatments [4], [>>10<<], [30]. The potential to inhibit suppressive immune cells, cytokines and enzymes was recognized by the National Cancer Institute (NCI) Immune Response Modifier Pathway Prioritization Working Group, who recommended anti-TGF\u03B2 agents be" . _:b546869139 . _:b546869148 . _:b546869229 "2"^^ . _:b546869169 . _:b546869149 . _:b546869150 . _:b546869151 . . _:b546869228 "2"^^ . _:b546869168 . _:b546869144 . . _:b546869145 . _:b546869146 . . _:b546869147 . _:b546869220 . _:b546869231 "2"^^ . _:b546869171 . _:b546869221 . _:b546869222 . _:b546869223 . . _:b546869230 "2"^^ . _:b546869170 . _:b546869216 . _:b546869217 . _:b546869218 . _:b546868498 . _:b546869219 . _:b546869228 . _:b546869225 "2"^^ . _:b546869181 . . _:b546869229 . _:b546869230 . _:b546869115 . _:b546869080 . _:b546869231 . . _:b546869224 . _:b546869224 "2"^^ . _:b546869180 . . . _:b546869225 . _:b546868458 . _:b546869226 . _:b546869227 . _:b546869236 . _:b546869227 "2"^^ . _:b546869183 . _:b546869237 . _:b546869238 . _:b546869239 . . _:b546869226 "2"^^ . _:b546869182 . _:b546869232 . _:b546869233 . _:b546869234 . . _:b546868594 . _:b546869235 . . _:b546869237 "2"^^ . _:b546869177 . _:b546869244 . _:b546869245 . _:b546868493 . _:b546869246 . _:b546869247 . _:b546869240 . _:b546869236 "2"^^ . _:b546869176 . . _:b546869241 . _:b546869242 . _:b546868550 . _:b29429209 "A recent genomic analysis of patients with this disease indicated a correlation between loss-of-function mutations of the TGF\u03B2R1 receptor and the development of KAs [>>37<<]. The lesions observed in patients receiving GC1008 are similar to those described in this disorder. Therefore, the development of KAs is suggestive of an on-target effect of GC1008 where neutralization of TGF\u03B2 by GC1008 appears to mimic" . _:b546869243 . _:b546869188 . _:b546869239 "2"^^ . _:b546869179 . _:b546868688 . _:b546869189 . _:b546869190 . _:b546869191 . _:b546869184 . _:b546869238 "2"^^ . _:b546869178 . _:b546869185 . . . _:b546869186 . _:b546869187 . _:b546869250 . _:b546869196 . _:b546869233 "2"^^ . _:b546869189 . _:b546869197 . _:b546869198 . _:b546868877 . _:b546869199 . _:b546869103 . . _:b546869232 "2"^^ . _:b546869188 . _:b546868824 . _:b546869192 . _:b546869193 . _:b546869194 . _:b546869195 . _:b546869204 . _:b546869235 "2"^^ . _:b546869191 . . _:b546869205 . _:b546868502 . _:b546869206 . . _:b546868442 . _:b546868561 . _:b546869207 . _:b546869200 . _:b546869234 "2"^^ . _:b546869190 . . _:b546869201 . . . . _:b546869202 . . _:b546869203 . _:b546869212 . _:b546869245 "2"^^ . _:b546869185 . _:b546869213 . _:b546869214 . _:b546869215 . . _:b546869244 "2"^^ . _:b546869184 . _:b546869208 . _:b546869209 . _:b546869210 . _:b546868930 . _:b546869211 . _:b546869028 . _:b546869247 "2"^^ . _:b546869187 . . _:b546869029 . _:b546869030 . . _:b546869031 . _:b546869024 . _:b546869246 "2"^^ . _:b546869186 . _:b546869025 . _:b546869026 . _:b546869027 . _:b546869036 . _:b546869241 "2"^^ . _:b546869197 . . _:b546869037 . . _:b546869038 . . . _:b546869039 . _:b546869032 . _:b546869240 "2"^^ . _:b546869196 . _:b546869033 . _:b546869034 . _:b546868560 . _:b546869035 . _:b546869044 . _:b546869243 "2"^^ . _:b546869199 . _:b546869045 . _:b546869046 . _:b546869047 . _:b546869040 . _:b546869242 "2"^^ . _:b546869198 . _:b546869041 . _:b546869042 . _:b546869043 . _:b546869467 . _:b546869052 . _:b546869193 . _:b546869053 . _:b546869054 . _:b546869055 . _:b546868713 . _:b546869048 . _:b546869192 . _:b546869049 . . _:b546869050 . _:b546869051 . _:b546868996 . _:b546869195 . _:b546868997 . . _:b546868998 . _:b546868999 . _:b546868992 . _:b546869194 . _:b546868993 . _:b546869381 . _:b546868994 . _:b546868995 . _:b546869004 . _:b546869205 . _:b546869005 . _:b546869006 . _:b546869007 . _:b546869162 . . _:b546869204 . _:b546869000 . _:b546869001 . _:b546869002 . _:b546869003 . _:b546869012 . _:b546869207 . _:b546869036 . _:b546869013 . _:b546868738 . _:b546869014 . _:b546869015 . . _:b546869206 . _:b546869008 . . _:b546869009 . . _:b546869010 . _:b546868624 . _:b546869011 . _:b546869020 . _:b546869201 . . _:b546869021 . . _:b546868689 . _:b546869022 . _:b546869023 . _:b546869416 . _:b546869016 . _:b546869200 . . _:b546869017 . _:b546869018 . _:b546869398 . _:b546869019 . _:b546869092 . _:b546869203 . _:b546869093 . _:b546869094 . _:b546869095 . _:b546869114 . _:b546869088 . _:b546869202 . _:b546869089 . _:b546869090 . _:b546869091 . _:b546869038 . . _:b546869464 . _:b546869213 . _:b546869100 . . _:b546869101 . _:b546869102 . _:b546869103 . _:b546869096 . _:b546869212 . _:b546869097 . _:b546869098 . _:b546868531 . _:b546869099 . _:b546869108 . _:b546869215 . . _:b546868734 . _:b546869109 . _:b546869110 . _:b546869111 . _:b546869104 . _:b546869214 . _:b546869105 . . _:b546869106 . _:b546869107 . _:b546869284 . _:b546869116 . _:b546869209 . _:b546869117 . _:b546869118 . _:b546869119 . _:b546869112 . _:b546869208 . _:b546869113 . _:b546869114 . . _:b546869115 . _:b546869060 . _:b546869211 . . _:b546869061 . _:b546869062 . _:b546869505 . _:b546869095 . _:b546869063 . . _:b546869210 . _:b546869056 . _:b546869057 . . _:b546869058 . _:b546869059 . . _:b546869221 . _:b546868686 . _:b546869068 . . _:b546869069 . _:b546869070 . _:b546869390 . _:b546869071 . _:b546868744 . _:b546869064 . _:b546869220 . _:b546869065 . . _:b546869066 . _:b546869067 . . _:b546869223 . _:b546869076 . . _:b546869077 . . _:b546869078 . _:b546869079 . _:b546869072 . _:b546869222 . . _:b546869073 . _:b546869074 . _:b546869075 . . _:b546869217 . _:b546869084 . . _:b546869085 . _:b546869086 . _:b546869087 . . _:b546869216 . _:b546869080 . . _:b546869081 . _:b546869082 . _:b546868582 . _:b546869083 . _:b546869126 . _:b546869219 . _:b29429215 "combined 10 and 15 mg/kg cohorts was 7.2 weeks (range, 4.1\u201320.1 weeks, mean 8.9 weeks), which is consistent with the median TTP/PFS of 1.3 to 2 months reported for patients with MM treated with dacarbazine or other chemotherapy [33], [>>34<<]. Based on this, there appears to be no negative impact of higher doses of GC1008 on clinical outcome." . _:b546869218 . . _:b546868633 . _:b546869229 . _:b546868716 . _:b546868660 . _:b546869228 . _:b546869231 . _:b29429181 . _:b546869461 . _:b546869393 . _:b546869230 . _:b546869060 . _:b29429216 . _:b546869225 . _:b546868942 . . _:b546869224 . . . _:b546869227 . . _:b546869226 . _:b546869237 . _:b546868702 . _:b29429189 . _:b546869236 . . . _:b546869239 . _:b546868918 . _:b546869238 . . _:b546869233 . . . _:b546869027 . _:b546869232 . _:b546868990 . _:b546869338 . . _:b546869235 . . _:b546869448 . . _:b546869465 . _:b546869234 . _:b546869202 . _:b546869245 . . . _:b546869244 . . _:b546869247 . _:b546869246 . _:b546869419 . . . _:b546869241 . . _:b546868440 . . _:b546869240 . _:b546868698 . . _:b546869243 . . _:b546868712 . _:b546869242 . _:b546868741 . . _:b546868416 . _:b546869272 . _:b546868810 . . . _:b546868740 . _:b546868743 . _:b29429206 "KAs can be a diagnostic challenge and are difficult to distinguish from well-differentiated cutaneous SCCs [>>35<<], [36]. KA/SCCs developed in 4 patients as multiple waxing and waning lesions (Figure S1). The development of KA/SCCs and cutaneous hyperkeratosis appeared to be associated with greater GC1008 exposure, occurring in patients treated at" . . _:b546868742 . . _:b546868621 . _:b546868737 . . . _:b546869002 . _:b546868736 . _:b546869518 . _:b546868739 . . _:b546868738 . _:b546868749 . . . . _:b546868748 . _:b546869228 . _:b546869053 . _:b546869412 . _:b546868751 . . _:b546868938 . _:b546869266 . _:b546868750 . _:b546868745 . _:b29429184 . . _:b546868744 . . _:b546868703 . _:b546868747 . . _:b546868746 . _:b546868757 . _:b546869497 . _:b546868756 . _:b546868496 . . . _:b546868963 . _:b546868759 . . _:b546868544 . _:b546868758 . _:b546869262 . _:b546868859 . _:b546868753 . _:b546868483 . _:b546868752 . . _:b546868850 . . . _:b546868755 . . . _:b546868754 . . _:b546868424 . _:b546868765 . . . _:b546869317 . _:b546868764 . _:b546868767 . . _:b546868766 . _:b546869141 . _:b546868761 . _:b546868959 . . _:b546868760 . _:b546869440 . _:b546868763 . . _:b546869509 . _:b546868836 . _:b546868762 . _:b546868773 . _:b546869389 . . _:b546868775 . _:b546868772 . _:b29429183 "in natural killer (NK) cells, T cells including T regulatory cells, NKT cells, monocytes/macrophages, and dendritic cells, TGF\u03B2 can down-regulate both primary and secondary immune responses and suppress antitumor effector cells [>>3<<], [11], [12]." . _:b546868775 . . _:b546868400 . _:b546868774 . _:b546868471 . . _:b546868769 . _:b29429183 . _:b546868768 . _:b546868428 . _:b546868771 . . _:b546868636 . _:b546868770 . . _:b546868781 . _:b546868574 . _:b546868783 . _:b546868780 . _:b546868780 . _:b546868783 . . _:b546868782 . . _:b546869471 . . _:b546868777 . . _:b546868776 . _:b546868546 . _:b546868779 . . . _:b546868778 . _:b546869482 . _:b29429170 . _:b546869082 . . _:b546868789 . _:b546868420 . . _:b546869324 . _:b546868788 . . _:b546868791 . . _:b546868790 . _:b546869092 . _:b546868612 . _:b546868785 . . _:b546868784 . _:b546868852 . _:b546868956 . _:b29429190 "In a number of preclinical models, neutralizing antibodies or soluble receptors that bind TGF\u03B2 have demonstrated antitumor activity [>>10<<], [18]\u2013[23]." . _:b546868787 . . _:b546869197 . . _:b546868786 . _:b546868662 . . _:b546868462 . _:b546868797 . _:b546868796 . _:b546868627 . . . . _:b546868488 . _:b546868799 . . _:b546868798 . _:b546869402 . _:b546868694 . _:b546869214 . . _:b546868793 . _:b546868389 . _:b29429200 . . . _:b546868792 . . _:b546868795 . . _:b546868794 . _:b546868805 . _:b546869134 . _:b546868747 . _:b546868804 . _:b546868711 . _:b546868807 . . _:b546868799 . _:b546868806 . . . _:b546868801 . _:b546868800 . _:b546869260 . . _:b546868803 . _:b546868588 . _:b546868906 . . _:b546868802 . _:b546869512 . _:b546868928 . . _:b546868813 . . . _:b546869240 . _:b546868812 . _:b546868449 . _:b546868815 . . . . _:b546869395 . _:b546868814 . _:b546868809 . _:b546868618 . _:b29429209 . _:b546868808 . _:b546868760 . _:b546869406 . _:b546868643 . _:b546868811 . . _:b546868832 . _:b546868438 . _:b546868810 . _:b546869013 . _:b546868821 . . _:b546868592 . _:b546868820 . _:b546868895 . _:b546868823 . _:b29429167 "introduction" . _:b546868822 . . _:b546868817 . _:b546868682 . _:b546868816 . _:b546869107 . _:b546868635 . _:b546868819 . _:b546869299 . . _:b546868818 . _:b546868997 . _:b546869140 . _:b29429171 "In addition, TGF\u03B2 exerts potent effects that influence immune function, differentiation, adhesion, extracellular matrix production, cell motility, angiogenesis, and cytokine production [3], [>>4<<]." . . _:b546868829 . . . . _:b546868828 . _:b546868834 . _:b546868831 . _:b546868830 . _:b546869385 . . _:b546868825 . . _:b546868824 . . _:b546868827 . . _:b546868826 . _:b546868953 . _:b546868755 . _:b546868837 . . _:b546868836 . . _:b546868983 . _:b546868576 . _:b546869100 . _:b546868540 . _:b546868839 . . _:b546868838 . _:b546869472 . _:b546868727 . _:b546868833 . _:b546868743 . _:b29429225 "proposed to explain the improved efficacy with cytotoxic agents and include increased diffusion of chemotherapy and payload-containing particles such as liposomes into tumor masses [45], [46], reversal of chemotherapy resistance [29], [>>41<<], inhibition of DNA repair by blockade of \u03B3H2AX foci formation [28] and reversal of TGF\u03B2-induced accumulation of tumor cells in G0/G1 [21], [44]." . _:b546869188 . _:b546868832 . _:b546868876 . _:b546868430 . _:b546868835 . . _:b546868834 . _:b546868843 . _:b546868609 . _:b546868845 . . . _:b546868910 . . _:b546868844 . _:b546869125 . . _:b546869091 . _:b546868847 . _:b546869026 . . . _:b546868846 . . . _:b546868841 . _:b546868445 . _:b546869218 . _:b546868840 . _:b546869509 . . _:b546869516 . . _:b546868843 . _:b546869508 . _:b546868807 . _:b546868842 . _:b546869511 . _:b546868853 . _:b546869510 . _:b546868819 . . _:b546869505 . _:b546868852 . . _:b546869274 . _:b546868388 "20"^^ . _:b546868389 "17"^^ . _:b546868629 . _:b546868855 . _:b546869504 . _:b546869447 . _:b546868390 "16"^^ . . _:b546868788 . _:b546868854 . _:b546869507 . _:b546868391 "15"^^ . . . _:b546868849 . _:b546869506 . _:b546869159 . _:b546868399 "11"^^ . _:b546869061 . _:b546868392 "15"^^ . . _:b546868848 . _:b546869517 . _:b546868398 "11"^^ . _:b546868393 "15"^^ . _:b546869434 . . _:b546869516 . _:b546868851 . _:b546868394 "14"^^ . . _:b546869259 . _:b546868848 . _:b546868397 "11"^^ . . _:b546868632 . _:b546868850 . _:b546869519 . . _:b546868396 "12"^^ . _:b546868861 . _:b546869518 . _:b546868598 . _:b546868395 "12"^^ . _:b546868860 . _:b546869513 . . _:b29429187 . _:b546869512 . _:b546868863 . . . . _:b546868862 . _:b546869515 . _:b546868472 . . _:b546869252 . _:b546868857 . _:b546869514 . . _:b546868406 "9"^^ . . _:b546869525 . _:b546869327 . _:b546869116 . _:b546868856 . . _:b546868766 . _:b546868407 "9"^^ . _:b546868859 . _:b546869524 . _:b546869096 . _:b546868404 "10"^^ . _:b546868858 . _:b546868926 . _:b546868405 "9"^^ . _:b546868616 . _:b546868403 "10"^^ . _:b546869526 . _:b546868869 . . _:b546868868 . _:b546869521 . _:b546868893 . _:b546868402 "11"^^ . _:b546868585 . _:b546868857 . _:b546869251 . _:b546868871 . _:b546869520 . _:b546868401 "11"^^ . _:b546869339 . . _:b546869523 . _:b546868870 . . _:b546868400 "11"^^ . _:b546868652 . _:b546868865 . _:b546869522 . _:b546869039 . _:b546868414 "8"^^ . _:b546868675 . _:b546868864 . . _:b546868415 "8"^^ . _:b546868867 . _:b546868412 "8"^^ . _:b546868695 . . _:b546868866 . _:b546869031 . . . _:b546868413 "8"^^ . . _:b546868786 . . _:b546868877 . _:b546868410 "9"^^ . _:b546868876 . . _:b546868411 "8"^^ . . _:b546868879 . _:b546868402 . . _:b546868408 "9"^^ . _:b546869212 . _:b546868878 . _:b546868409 "9"^^ . . _:b546868873 . . _:b546868422 "7"^^ . _:b546868872 . _:b546868423 "7"^^ . _:b546868875 . _:b546868420 "7"^^ . _:b546869433 . _:b546868874 . _:b546868421 "7"^^ . . _:b546868885 . _:b546868418 "7"^^ . . _:b546868613 . . _:b546868884 . _:b546868419 "7"^^ . . _:b546868887 . _:b546868899 . _:b546868416 "8"^^ . _:b546868886 . . _:b546868751 . _:b546868417 "7"^^ . _:b546868881 . _:b546868430 "7"^^ . . _:b29429203 "the number of patients was small, the median PFS for all 29 patients was 11.1 weeks, which was comparable to the median TTP/PFS of 1.3 to 2 months reported for patients with advanced MM treated with dacarbazine or other chemotherapy [>>33<<], [34]." . . . _:b546868880 . _:b546868431 "7"^^ . . . _:b546868883 . _:b546868428 "7"^^ . _:b546868882 . _:b546868429 "7"^^ . _:b546868893 . _:b546868426 "7"^^ . _:b546868892 . _:b546868894 . . _:b546868427 "7"^^ . . . _:b546868895 . _:b546868424 "7"^^ . _:b546869314 . _:b29429199 _:b29429200 . _:b29429199 _:b29429201 . _:b546869112 . . _:b546868894 . _:b546868425 "7"^^ .