ZIA BC 011124 (ZIA) | |||
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Title | Oncogenic Met Signaling in Urologic Malignancies | ||
Institution | NCI, Bethesda, MD | ||
Principal Investigator | Bottaro, Donald | NCI Program Director | N/A |
Cancer Activity | N/A | Division | CCR |
Funded Amount | $340,579 | Project Dates | 01/01/2007 - 00/00/0000 |
Fiscal Year | 2015 | Project Type | Intramural |
Research Topics w/ Percent Relevance | Cancer Types w/ Percent Relevance | ||
Cancer (100.0%) Digestive Diseases (5.0%) |
Bladder (25.0%) Brain (10.0%) Breast (10.0%) Cervical Cancer (5.0%) Kidney Cancer (25.0%) Kidney Disease (25.0%) Nervous System (10.0%) Ovarian Cancer (5.0%) Prostate (15.0%) Stomach (5.0%) Urinary System (50.0%) Wilm's Tumor (2.0%) |
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Research Type | |||
Cancer Initiation: Oncogenes & Tumor Suppressor Genes Systemic Therapies - Discovery and Development |
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Abstract | |||
1. Defining Met-driven Oncogenic Signaling Pathways in Urologic Malignancies. Loss of von Hippel-Lindau (VHL) tumor suppressor gene function occurs in familial and most sporadic clear cell renal cell carcinoma (ccRCC), resulting in the aberrant expression of genes that control cell proliferation, invasion and angiogenesis. The molecular mechanisms by which VHL loss leads to tumorigenesis are not yet fully defined. We previously found that VHL loss allows robust ccRCC cell motility, invasiveness and morphogenesis in response to hepatocyte growth factor (HGF) stimulation, processes that are known to contribute to tumor invasiveness and metastatic potential, and showed that beta-catenin, a junctional protein and gene transactivator, was a critical intracellular mediator of these activities. HGF signaling also contributes to disease progression, tumor invasiveness and metastasis in kidney cancers other than the clear cell type; in particular, MET kinase domain mutations in a hereditary form of papillary renal carcinoma (PRC) are primary drivers of that disease, and Met overabundance is common in both hereditary and sporadic forms. VHL loss of function is rare in PRC, but tumor hypoxia is not; hypoxia strongly enhances HGF-mediated invasiveness and metastasis in a variety of model systems, through largely undefined molecular mechanisms. HGF-driven beta-catenin transcriptional activity is suppressed when VHL is functional, suggesting that the integration of hypoxia and HGF driven cell invasiveness in PRC involves other primary intracellular signaling routes downstream of Met. Over the course of our continued investigation we found that the integration of these signaling pathways involves three parallel routes: (1) hypoxia-induced reactive oxygen species (ROS) production and decreased expression of the mitogen-activated protein kinase (MAPK) negative regulator DUSP2, leading to enhanced cascade activation; (2) ROS-induced diacylglycerol production by phospholipase C leading to protein kinase C activation and increased protein phosphatase-2A activity, thereby suppressing HGF-induced Akt activation; and (3) a profound shift from HGF-enhanced, proliferation-oriented metabolism to autophagy-dependent invasion and suppression of proliferation. These results define the molecular basis of growth factor and hypoxia invasive synergy in VHL-competent papillary RCC cells, illustrate the plasticity of invasive and proliferative tumor cell states and provide signaling profiles by which they may be predicted. 2. Evaluation of pathway antagonists, through structural analysis of HGF/Met interaction and analysis of commercially-developed Met-targeting agents. In collaboration with Amgen scientists that developed HGF- and Met-targeted agents, we developed a model of acquired drug resistance to rilotumumab, a fully human HGF-neutralizing monoclonal antibody now in phase II and III clinical trials. Acquired drug resistance is a long-standing problem of cancer therapeutics, and this issue has become even more vexing with the development of highly selective targeted agents. Anticipating acquired resistance and understanding its basis should help develop clinical strategies to prevent or circumvent its occurrence. We developed our model of rilotumumab resistance using glioblastoma multiformae (GBM)-derived cells, because HGF/Met signaling is a likely contributor to oncogenesis and tumor progression in that disease. In anticipation of acquired resistance to rilotumumab, models of acquired resistance were generated by growing GBM-derived U87 MG cells in maximally effective drug concentrations and by low dose treatment of mice implanted with U87 MG cells. Remarkably, in both approaches rilotumumab resistant cell lines and tumors remained sensitive to a selective Met tyrosine kinase inhibitor, and therefore dependent on HGF/Met signaling. Resistant cell lines developed in vitro and cell lines derived from rilotumumab resistant mouse xenografts uniformly displa |