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 | $371,569 | Project Dates | 00/00/0000 - 00/00/0000 |
Fiscal Year | 2016 | 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 Disease (25.0%) Nervous System (10.0%) Ovarian Cancer (5.0%) Prostate (15.0%) Stomach (5.0%) Urinary System (50.0%) Kidney Cancer (25.0%) 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 | |||
Aim 1: Inhibiting Met and Met-related RTK signaling in bladder cancer In 2013, 72,570 new cases of bladder cancer (BCa; urothelial (transitional) cell carcinoma of the bladder) and 15,210 bladder cancer-related deaths were estimated in the U.S. alone. Although 70% of newly diagnosed disease is non-muscle invasive (NMIBCa), recurrence and progression are frequent. The remaining 30% of new cases are more advanced, with muscle invasion, lymph node involvement or distant metastases. Half of those individuals with muscle-invasive bladder cancer (MIBCa) fail definitive therapy within 5 years and succumb to the disease. The 5- and 10-year survival rates for patients with lymph node involvement are 31 and 23%, respectively. Standard of care platinum-based chemotherapy for patients with metastatic disease provides a median survival of 15 months and a 5-year survival rate of 15%; second line therapies have worse response and survival rates. These circumstances underscore the urgent need to develop new diagnostic/prognostic methods and identify therapeutic targets for this disease. Evidence of HGF/Met pathway involvement in BCa has been found in model systems and in vivo. An analysis of 97 high-grade BCa tumors designed to identify actionable drug targets found alterations of the RTK/RAS/RAF/MAPK pathway, a well-established mediator of HGF/Met driven proliferation and invasiveness, in 35% of samples. Interrogating BCa datasets in The Cancer Genome Atlas (TCGA) project using the cBioPortal further revealed potentially oncogenic alterations in HGF or MET at an average combined frequency of 11% in 447 BCa cases. We surveyed 12 BCa-derived cell lines for evidence of Met content and functionality. Met content among these cell lines was comparable to that found in other HGF-responsive cell lines derived from other prevalent cancers. None of the cell lines produced HGF, suggesting that autocrine HGF/Met signaling is rare in BCa. Our studies showed that paracrine HGF signaling can drive invasion, proliferation, anchorage-independent growth and tumorigenesis, and that cabozantinib can block Met activation and tumor progression in a model system. Aim 2: Soluble Met (sMet) as a marker of oncogenic pathway activity and inhibitor response Studies over the last several years indicate that soluble Met ectodomain (sMet) levels in biological fluids may be related to degree of malignancy and tumor burden in cancer an/or level of Met abundance or involvement in other diseases. In that time-frame we also investigated the utility of plasma sMet as a pharmacodynamic (PD) biomarker of foretinib (XL880, GSK1363089) activity in patients enrolled in one phase I and 3 phase II clinical trials. Foretinib is a multi-kinase inhibitor whose target spectrum we recently compared to the related compound cabozantinib, developed contemporaneously. In light of potent foretinib activity on vascular endothelial growth factor receptor (VEGFR) family members, their roles in cancer progression, and prior work showing modulation of plasma VEGFA and soluble VEGFR2 (sVEGFR2) levels by VEGF pathway inhibitors, these were measured in parallel using the same electrochemiluminescent 2-site immunoassay platform. Overall patterns of fluctuation patterns for each of the four biomarkers were similar in all four clinical studies; trials using intermittent 5 days on/9 days off (5/9) dosing revealed transient, drug-associated marker changes that are well represented by the results from the trial for advanced gastric cancer. Significant increases in sMet and VEGFA, and significant decreases in VEGFR2 levels were observed for both intermittent and daily dosing schedule cohorts. Median HGF levels, though significantly higher than normal for many patients enrolled in these trials, fluctuated with sMet levels, but changes were not statistically significant. Changes in plasma VEGFA and VEGFR2 were similar to those reported for other VEGF pathway inhibitors [88-90]; the patterns for both VEGFA and s |