Thursday, July 15, 2021
7/15/2021
PROJECT SUMMARYTO APPLICATION This application is in direct response to the RFA-CA-19-049 “Revision Applications for Mechanisms of Cancer Drug Resistance”, to investigate a non-classical mechanism driving the chemoresistance of locally advanced bladder carcinomas. Advanced bladder cancer claims approximately 18,000 deaths annually in the United States; yet, funding and research devoted to this cancer-type are significantly under-proportioned. A major clinical setback for bladder cancer treatment lies in the poor patient response towards chemotherapy with treatments providing only a dismal 5% improvement in overall survival. Thus, the goal of this application aims to understand the less-studied biology, i.e., cancer cell-extrinsic mechanisms, causing chemotherapy drug resistance. The success of chemotherapy is long thought to depend on its direct cytotoxic effects upon tumor cells and this has attracted much research interest in the past decades. However, there is growing evidence, as shown by our own research and others, that successful chemotherapy is also dependent on: 1) feedforward signals between dying cancer cells and the stromal fibroblast microenvironment, and 2) the active role(s) of collagens secreted from cancer associated fibroblasts to serve as a protective niche for chemoresistant cancer cells. Our proposal will leverage existing patient-derived cancer associated fibroblasts and patient-derived primary tumor cultures/xenografts developed from the parent grant NCI CA175397, which allow us to venture into a new research direction: i.e., how cell death associated release of extracellular factors impacts the fibrotic environment, consequently serves as a protective niche to fuel chemoresistant cancer cells? This proposal is innovative to elucidate the intricate feedforward loops between dying cancer cells, cancer-associated fibroblasts, and residual cancer stem cells during the emergence of chemoresistance. The success of this study will be innovative and impactful to challenge the current paradigm that chemotherapy drug resistance is primarily driven by cancer cell-intrinsic properties. Indeed, success of our proposal will establish an original concept: Dying cancer cells provide feedforward signals to cultivate a collagen-rich fibrotic environment, consequently initiating a “vicious cycle” of epithelial-stromal feedforward signaling loop to fuel chemoresistance. Also, our proposal will provide new insights into the rational design of future intervention strategies to “break” this vicious cycle, and thus, improve chemotherapy response. Such a concept likely extends beyond bladder carcinomas into other cancer types.
HHS’ Tracking Accountability in Government Grants System (TAGGS) website provides access to detailed descriptions of grants, loans, aggregated direct payments and other types of financial assistance awarded by the HHS Operating Divisions (OPDIVs) and the Office of the Secretary Staff Divisions (STAFFDIVs).
