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Project

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.
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System

Categories
  • FOR (ANZSRC)

    0601 Biochemistry and Cell Biology

  • FOR (ANZSRC)

    1112 Oncology and Carcinogenesis

  • RCDC

    Cancer

  • HRCS HC

    Cancer

  • HRCS RAC

    2.1 Biological and endogenous factors

  • HRCS RAC

    5.1 Pharmaceuticals

  • Health Research Areas

    Biomedical

  • Broad Research Areas

    Basic Science