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Targeting TAM (Tyro3-Axl-Mer) family of transmembrane receptor tyrosine kinases in bladder cancer.

Funder: Bladder Cancer Advocacy Network

Funding period
USD 2 K
Funding amount
Abstract
Bladder cancer (BCa) patients refractory to platinum chemotherapy and immunotherapy with checkpoint inhibitors, are in need of effective systemic therapies. Studies establish that TAM (Tyro3-Axl-Mer) family of transmembrane RTKs mediate activation of oncogenic signaling pathways and also play important roles in acquired resistance to targeted therapies and conventional cytotoxic drugs. Binding of ligand, Gas6, stimulates autophosphorylation, thus initiating a downstream signaling cascade, activating PI3K and ERK kinase pathways, that can regulate tumor cell survival, proliferation, migration, invasion and angiogenesis, thereby promoting tumor progression, metastasis and chemoresistance. TAM RTK overexpression is also associated with poor prognosis in human malignancies from epithelial and hematological origins. Whether TAM RTKs play an oncogenic role in BCa has not been interrogated.The study hypothesizes that inhibition/knockdown of expression of Axl or Mer would reduce tumorigenic potential of BCa cells. Furthermore, given the properties of good oral bioavailability, solubility, and other DMPK properties from in vivo studies in other cancers, we hypothesize that TP0903 and UNC2025, small molecule Mer and Axl inhibitors, could be promising candidates for BCa treatment.Specific aims are:1) Determine if knockdown/inhibition of Axl and/or Mer TK expression leads to reduced cell migration, invasion and anchorage independent growth in BCa cells; 2) Determine if levels of Axl/Mer and Gas6 could serve as potential biomarkers.Results will provide new insights into the signaling mechanisms regulated by TAM receptors and Gas6 in BCa. Deciphering the oncogenic role of Axl and Mer TK and Gas6 co-expression, will define their importance as potential therapeutic targets in BCa treatment. Data would also help understand if use of small molecule inhibitors of Axl and Mer TK, TP0903 and UNC2025, would be instrumental in reducing the tumorigenic potential of BCa cells.

 
18
Projects
USD 17.3 M
Aggregated funding amount
USD 1.0 M
Average funding amount
Project list item
Novel Biomarkers for the Clinical Management of Bladder Cancer

National Cancer Institute to VINATA B LOKESHWAR

USD 466,211
2018 - 2023
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Subtyping Bladder Cancer: A Multi-omic, Exposure-informed, Genealogical Approach (MErGE)

National Cancer Institute to HEIDI ANNE HANSON

USD 149,405
2018 - 2023
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Identify the DNA Adduct and Associated Metabolic Alterations in Bladder Cancer of Smokers

National Cancer Institute to NAGIREDDY PUTLURI, RANDA A EL-ZEIN

USD 810,976
2018 - 2023
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Potentiation of Immunotherapy with targeted nanoporphyrin in bladder cancer

United States Department of Veterans Affairs to CHONG-XIAN PAN

 
2018 - 2022
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New Drug and Technology Assessment in Bladder Cancer: Creation of a Novel Canadian Policy Model for Bladder Cancer

Canadian Institutes of Health Research to Murray Dale Krahn, Girish Satish Kulkarni, William Wai Lun Wong, George Andrew Tomlinson, Nathan Perlis, Wassim Kassouf, Peter Colin Black, Shabbir Muhammad Husayn Alibhai

USD 77,161
2018 - 2019
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Delivery of Targeting Nano-Photo-Imiquimod to Enhance Response Rate of Advanced Bladder Cancer to Check Point Blockade Antibody Therapy

Congressionally Directed Medical Research Programs to Kit S Lam

USD 4,634,675
2017 - 2018
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Racial Disparity in Bladder Cancer and Identification of Altered Metabolism in African American Compare to European Bladder Cancer

National Cancer Institute to NAGIREDDY PUTLURI

USD 1,086,461
2017 - 2022
Project list item
Development of Novel Noninvasive Tests for Prognostic Predictions for Bladder Cancer

Congressionally Directed Medical Research Programs to Vinata B Lokeshwar

USD 608,000
2016 - 2017
Project list item
Sh3gl2 and chemosensitivity of bladder cancer

National Cancer Institute to ROSALYN M ADAM

USD 492,035
2016 - 2019
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Regulation of Urinary Bladder Carcinogenesis and Progression by SPARC

National Cancer Institute to NEVEEN SAID

USD 1,407,614
2016 - 2020
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Development of a sensitive epigenomic biomarker for urothelial cancer

Japan Society for the Promotion of Science to Hiromu SUZUKI, Naoya MASUMORI

USD 32,060
2015 - 2017
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Novel anti-cancer therapeutic strategy with mTORC1/2 inhibitor against bladder cancer

Japan Society for the Promotion of Science to Eiji KIKUCHI, TAKEO KOSAKA, Akira MIYAJIMA

USD 45,237
2014 - 2017
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Investigation of anti-tumor effect of Axl kinase inhibitor in urothelial carcinoma.

Japan Society for the Promotion of Science to Seiya Hattori

USD 33,260
2014 - 2016
Project list item
Targeting the MET pathway in urothelial carcinoma

National Cancer Institute to ANDREA APOLO

USD 3,393,436
2014 - 2018
Project list item
Metabolomics in the prediction of recurrence and progression of non-muscle invasive bladder cancer

Swiss National Science Foundation to Malte Rieken

 
2013 - 2013
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Investigation of Mechanism of Action of Steroid Sulfatase in Bladder Cancer

Japan Society for the Promotion of Science to Satoshi TAMADA, Minoru KATO, Min WEI

USD 55,375
2012 - 2015
Project list item
Non-AR mediated DHT-promoted Bladder Cancer initiation and progression

National Cancer Institute to CHAWNSHANG CHANG

USD 1,574,087
2011 - 2017
Project list item
Mechanisms of Bladder Cancer Progression

National Cancer Institute to VINATA B LOKESHWAR

USD 2,399,189
1997 - 2017