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 | $396,445 | Project Dates | null - null |
Fiscal Year | 2018 | Project Type | Intramural |
Research Topics w/ Percent Relevance | Cancer Types w/ Percent Relevance | ||
Cancer (100.0%) Digestive Diseases (10.0%) |
Bladder (25.0%) Brain (10.0%) Breast (5.0%) Cervical Cancer (5.0%) Kidney Disease (25.0%) Liver Cancer (5.0%) Nervous System (10.0%) Ovarian Cancer (5.0%) Prostate (15.0%) Stomach (5.0%) Urinary System (50.0%) Wilm's Tumor (2.0%) Kidney Cancer (25.0%) |
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Research Type | |||
Cancer Initiation: Oncogenes & Tumor Suppressor Genes Systemic Therapies - Discovery and Development |
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Abstract | |||
Aim 1 and 2: In 2018, 81,190 new cases of bladder cancer (BCa; urothelial (transitional) cell carcinoma of the bladder) and 17,240 bladder cancer-related deaths were estimated in the U.S. alone. Although 70% of newly diagnosed disease is confined to the mucosa, recurrence and progression are frequent and long-term surveillance by cystoscopy is required. 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 fail definitive therapy (surgery or chemoradiation) 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 combination platinum-based chemotherapy for patients with metastatic disease provides a median survival of only 15 months and a 5-year survival rate of 15%. These circumstances underscore the urgent need to identify oncogenic pathways and therapeutic targets for this disease. Interrogating BCa datasets in The Cancer Genome Atlas (TCGA) project using the cBioPortal revealed potentially oncogenic alterations in MET or the gene encoding its cognate ligand, HGF in 15% of cases in the TCGA Provisional dataset. In addition to genetic alterations, overproduction of wild type RTKs and/or their cognate ligands, by tumor cells or by the tumor microenvironment (TME), can contribute profoundly to tumor cell survival, proliferation, immunosuppression and metastasis. In particular, overproduction of HGF in the TME has been found in many cases where genetic alterations in MET are absent: HGF overproduction was found in 50% head and neck cancers and high levels were correlated with metastasis, and with concerning frequency in cases of drug resistance in melanoma, colorectal, pancreatic, breast and lung cancers. Evidence of HGF/Met pathway involvement in BCa has been found in model systems and in vivo. Positive interim results from a phase II NCI clinical trial of the multikinase inhibitor cabozantinib for patients with advanced BCa (see NCT01688999/NCI-12-C-0205-N: ""A Phase 2 Study of Cabozantinib (XL184) in Patients With Advanced /Metastatic Urothelial Carcinoma, Principal Investigator: AB Apolo, GMB, NCI) also implicate RTKs in disease progression. Known cabozantinib targets include the RTKs encoded by MET, KDR, RET, VEGFR1, VEGFR3, KIT, FLT3, ROS1, and AXL. Our unpublished results (below) identify those encoded by MERTK, TYRO3, CSF1R, DDR1, and DDR2 as additional high affinity targets. Potentially oncogenic gene alterations of these 18 RTKs occur in a combined 68% of cases in the BCa TCGA Provisional database as determined using tools available in the cBioPortal. Moreover, 6 of these BCa-associated RTKs (BCaRTKs) show significant co-occurrence of >2-fold expression for their cognate ligands in 34% of TCGA BCa cases combined, suggestive of oncogenic autocrine activation. Identifying the BCaRTKs that are likely to mediate clinical responses to existing TKIs will provide a basis for improving RTK inhibitor-based therapies by informing drug combination strategies, driving the development of inhibitors with relevant target selectivity, and guiding the development of needed biomarkers for patient selection. This information will also further define BCa molecular pathogenesis and diversity. Quantitative mRNA analysis of RTKs and their cognate ligands in BCa-derived cell lines revealed robust co-expression of MST1R/MST1, AXL/GAS6 and CSF1R/CSF1 in 13/13, 10/13 and 8/13 BCa cell lines, respectively. In the same cell lines we found mRNA overexpression of 11 common downstream transcriptional activators (TAs) known to promote cell cycle progression and/or contribute to epithelial to mesenchymal transition (EMT): ZEB1, ZEB2, RUNX2, SOX2, SOX9, POU5F1, NANOG, MYC, SNAI1, SNAI2 and TWIST1. These genes were also queried for overexpression (mRNA z-score >2) in the BCa Provisional TCGA dataset using the cBioPortal. Ove |