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  • American Association for Cancer Research (AACR)  (5)
  • 1
    In: Cancer Immunology Research, American Association for Cancer Research (AACR), Vol. 4, No. 11 ( 2016-11-01), p. 936-947
    Abstract: The major histocompatibility complex I (MHC-1) presents antigenic peptides to tumor-specific CD8+ T cells. The regulation of MHC-I by kinases is largely unstudied, even though many patients with cancer are receiving therapeutic kinase inhibitors. Regulators of cell-surface HLA amounts were discovered using a pooled human kinome shRNA interference–based approach. Hits scoring highly were subsequently validated by additional RNAi and pharmacologic inhibitors. MAP2K1 (MEK), EGFR, and RET were validated as negative regulators of MHC-I expression and antigen presentation machinery in multiple cancer types, acting through an ERK output–dependent mechanism; the pathways responsible for increased MHC-I upon kinase inhibition were mapped. Activated MAPK signaling in mouse tumors in vivo suppressed components of MHC-I and the antigen presentation machinery. Pharmacologic inhibition of MAPK signaling also led to improved peptide/MHC target recognition and killing by T cells and TCR-mimic antibodies. Druggable kinases may thus serve as immediately applicable targets for modulating immunotherapy for many diseases. Cancer Immunol Res; 4(11); 936–47. ©2016 AACR.
    Type of Medium: Online Resource
    ISSN: 2326-6066 , 2326-6074
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2016
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  • 2
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 70, No. 8_Supplement ( 2010-04-15), p. 387-387
    Abstract: Anti angiogenic agents that target the VEGF pathway (bevacizumab, sorafenib and sunitinib (SU)) have demonstrated improved clinical benefit as single agents or in combination with chemotherapy in a variety of solid tumor types. Although this class of agents has provided an improved treatment option to certain tumor types, it is evident that some patients do not respond to therapy or will relapse despite an initial response to treatment due to an acquired resistance. To better understand this mode of acquired resistance to this class of agents, a model of Renal Cell Carcinoma (RCC) which has shown regression, eventually developed evasive resistance during long term administration of the single agent sunitinib (a small-molecule inhibitor of the VEGF-1, 2, 3, PDGF-α,β, KIT, CSF-1R and FLT-3 receptor tyrosine kinases). Despite the observation that resistant tumors under continuous treatment with sunitinib (60 mg/kg PO, QD) demonstrated a gross phenotypic reduction of micro-vascular density (MVD), they continued to show a progressive increase in size. Because the observed low MVD phenotype was suggestive of an ability of resistant tumor cells to survive in an increasingly hypoxic environment with a reduced functional vasculature, emphasis was placed on identifying tumor cell derived resistance factors. Gene expression and/or proteomic profiling studies accompanied by confirmatory immunoblotting indicated a subset of differentially expressed genes and/or proteins in resistant vs. sensitive treated tumors. Although profiling studies did not clearly elucidate definitive resistance mechanisms, the dysregulation of EGFR, FGFR1, & TGFB1 pathways and downstream signaling through PI3K and MEK were potentially implicated. Comparative genomic hybridization studies did not identify any resistance mechanisms at the cytogenetic level. Sunitinib combination studies designed to target pathways potentially involved in resistance (SU + a PI3K/mTOR inhibitor; SU + a MEK inhibitor) demonstrated the ability to restore sensitivity in the sunitinib resistance model. The ability to identify and characterize resistance mechanisms and circumvent resistance through combination approaches may have utility in developing future combination regimens for anti angiogenic therapies. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 387.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
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    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2010
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  • 3
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 70, No. 24 ( 2010-12-15), p. 10090-10100
    Abstract: Molecular and cellular mechanisms underlying resistance/low responsiveness to antiangiogenic compounds are under extensive investigations. Both populations of tumor and stroma (nontumor compartment) seem to contribute in inherent/acquired resistance to antiangiogenic therapy. Here, investigating in vivo efficacy of sunitinib in experimental models resulted in the identification of tumors that were resistant/sensitive to the therapy. Analysis of tumor protein lysates indicated a greater concentration of hepatocyte growth factor (HGF) in resistant tumors than in sensitive ones. In addition, using flow cytometry, c-Met expression was found to be significantly higher in endothelial cells than in tumor cells, suggesting that HGF might target the vascular endothelial cells in resistant tumors. Combination of sunitinib and a selective c-Met inhibitor significantly inhibited tumor growth compared with sunitinib or c-Met inhibitor alone in resistant tumors. Histology and in vitro analyses suggested that combination treatment mainly targeted the vasculature in the resistant tumors. Conversely, systemic injection of HGF in the sensitive tumor models conferred resistance to sunitinib through maintenance of tumor angiogenesis. In conclusion, our study indicates a role for HGF/c-Met pathway in development of resistance to antiangiogenic therapy and suggests a potential strategy to circumvent resistance to vascular endothelial growth factor receptor tyrosine kinase inhibitor in the clinic. Cancer Res; 70(24); 10090–100. ©2010 AACR.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
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    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2010
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  • 4
    Online Resource
    Online Resource
    American Association for Cancer Research (AACR) ; 2011
    In:  Cancer Research Vol. 71, No. 8_Supplement ( 2011-04-15), p. 3270-3270
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 71, No. 8_Supplement ( 2011-04-15), p. 3270-3270
    Abstract: Anti-angiogenic therapy targeting the tumor vasculature has demonstrated clinical benefits in certain types of tumors. However, many patients develop resistance and eventually progress on anti-angiogenic therapy. The mechanism of resistance is largely unknown and warrants extensively investigation. We developed a human xenograft tumor model (M24met/R) in mice that has acquired resistance to VEGF receptor tyrosine kinase inhibitors (VEGFR TKI), by chronically treating the parental M24met tumors (M24met/P) with PF-0337210 (20-40 mg/kg, QD, PO) and serially passaging resistant tumor fragments in nude mice. M24met/R tumors were also resistant to axitinib, a selective VEGFR TKI in late stage clinical development. Immunohistochemical (IHC) staining revealed higher degree of hypoxia and lower microvessel density in M24met/R tumors compared to parental tumors. Compared with those in M24met/P, vessels in M24met/R tumors appeared to be larger in diameter and more mature as shown by high incidence of co-localization between endothelial cells and perivascular cells (CD31+Desmin+). Microarray analysis of tumor lysates (human UA133 2.0, mouse 430 2.0 chip) revealed distinct gene expression profiles between M24met/R tumors and size-matched M24met/P tumors. Of note, several angiogenesis-related genes, including human VEGF, bFGF, integrin α5β1, IL-8, PDGF,CSF and murine VEGF, integrin α5β1, ALK1 (activin receptor-like kinase 1), IL-8, c-Met, IL-6 were up-regulated in M24met/R tumors, whereas murine VEGFR1 and 2, PROX1, PDGFR and endogenous angiogenic inhibitor TSP-1 were down-regulated in the resistant tumors. The above observations were verified with ELISA and/or IHC. Next, targeted combination approaches were applied in an attempt to circumvent M24met/R resistance to axitinib. Concurrent administration of axitinib plus either anti-IL-8 monoclonal antibody (mAb), c-Met inhibitor, anti-integrin α5 mAb or anti-ALK1 mAb significantly improved anti-tumor efficacy compared to single agents alone. IHC analyses showed that combinatorial therapy of anti-ALK1 plus axitinib reduced the amount of CD31+Desmin+ vessels compared to axitinib alone, suggesting that targeting ALK1 destroyed VEGFR TKI-resistant vessels. Together, our results suggested that multiple alternative angiogenic factors contributed to the acquired resistance of M24met/R melanoma to VEGFR TKI. Combination treatment using inhibitor of IL-8, c-Met, integrin α5β1 or ALK1 with VEGFR TKI may represent a new strategy to mitigate resistance to VEGFR TKI in the clinic. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3270. doi:10.1158/1538-7445.AM2011-3270
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
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    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2011
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  • 5
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 79, No. 24_Supplement ( 2019-12-15), p. PR01-PR01
    Abstract: Background: KRAS mutant pancreatic ductal adenocarcinoma (PDAC) is characterized by a desmoplastic response that promotes hypovascularity, poor drug delivery, immunosuppression, and de novo resistance to chemo- and immunotherapies. Recently, we demonstrated that a combination of MEK and CDK4/6 inhibitors can potently suppress PDAC tumor cell proliferation through induction of RB-mediated senescence and trigger a senescence-associated secretory phenotype (SASP) capable of remodeling the tumor microenvironment (TME) (Ruscetti et al., Science 2018). Here, we set out to explore how senescence induction could remodel the PDAC TME and alter the treatment landscape of this disease. Methods: The Pdx1-Cre;LSL-KRASG12D;Trp53fl/wt (KPC) genetically engineered mouse model (GEMM) of PDAC, as well as immunocompetent C57BL/6 mice transplanted with PDAC organoids derived from this model, were treated for 2 weeks with the MEK inhibitor trametinib and CDK4/6 inhibitor palbociclib. Induction of senescence was determined by SA-β-gal staining, and secretion of SASP factors was determined by qPCR and cytokine array. The impact on vascularization and vascular function, as well as the immune system, was determined by immunohistochemistry and flow cytometry analysis. shRNAs targeting the p65 subunit of NF-KB were used to assess the effect of SASP knockdown on treatment responses, and high doses of a VEGFR2 blocking antibody were used to assess the effects of inhibiting neovascularization on these SASP-dependent phenotypes. Trametinib and palbociclib treatment was combined with the chemotherapeutic agent gemcitabine or PD-1 checkpoint blockade immunotherapy to study the impact on tumor responses and long-term survival of PDAC tumor-bearing animals. Results: We find that therapy-induced senescence following trametinib and palbociclib treatment produces a SASP rich in proangiogenic factors, culminating in increased vascular density and perfusion in hypovascular PDAC tumors. This SASP-dependent vascular remodeling leads to enhanced drug uptake of the chemotherapeutic agent gemcitabine, and combining our senescence-inducing therapy with gemcitabine drives tumor regressions and prolonged survival in gemcitabine-refractory PDAC GEMMs and PDXs. In addition, increased antigen presentation and SASP-mediated vascular remodeling upon treatment mediates CD8+ T cell accumulation and activation within the PDAC TME, sensitizing these tumors to PD-1 checkpoint blockade. Conclusions: These results demonstrate that therapy-induced senescence can establish emergent susceptibilities to otherwise ineffective chemo- and immunotherapies in PDAC through SASP-dependent, non-cell autonomous effects on the tumor vasculature and immune system. This abstract is also being presented as Poster A46. Citation Format: Marcus Ruscetti, John P. Morris, IV, Riccardo Mezzadra, James Russell, Josef Leibold, Paul B. Romesser, Janelle Simon, Amanda Kulick, Yu-jui Ho, Myles Fennell, Jinyang Li, Robert J. Norgard, John E. Wilkinson, Direna Alonso-Curbelo, Ramya Sridharan, Xiang Li, Daniel Heller, Elisa de Stanchina, Ben Z. Stanger, Charles J. Sherr, Scott W. Lowe. Senescence induction triggers vascular remodeling and new vulnerabilities to chemo- and immunotherapy in pancreas cancer [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Advances in Science and Clinical Care; 2019 Sept 6-9; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2019;79(24 Suppl):Abstract nr PR01.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
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    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2019
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    detail.hit.zdb_id: 410466-3
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