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Project

Precision Cotargeting Tumor and Its Microenvironment in Bladder Cancer

Funder: Congressionally Directed Medical Research Programs

Funding period
USD 706 K
Funding amount
Abstract
PUBLIC ABSTRACT

Bladder cancer (BCa) metastasis is lethal with a median survival of only 15 months. Chemotherapy has been the mainstay treatment for metastatic BCa, however only ~30% patients respond, and those who respond inevitably develop treatment resistance. Novel therapies targeting metastatic, chemo-resistant BCa is urgently needed. Historically, tumor cell-directed therapy is notorious for limited response (i.e., high de novo resistance rate) and transient response. With increasing understanding of the tumor microenvironment interaction with the tumor supporting its growth, we hypothesize a paradigm shifting combination treatment regime by co-targeting the tumor and its microenvironment, using a precision targeting approach. We have identified key genetics alterations that are druggable in metastatic BCa patients who succumbed to the disease. Here, we will perform (i) the first-in-field study to precision target the metastatic BCa cells that exhibit amplification of cell survival pathway cyclin D1 (CCND1) in combination with stromal-targeting TGFß1 in our newly developed metastatic BCa patient-derived xenografts (PDX) models. In addition, we will (ii) systemically map the interaction between tumor and its microenvironment in clinical BCa metastases from our rapid autopsy program. We will perform the first-in-field paired global gene expression profiling to unravel novel tumor-stromal interaction that fuels tumor BCa growth at metastatic sites. We focus on metastatic BCa that are resistant to chemotherapy – the most advanced and lethal form of BCa for which essentially no durable treatment option is currently available. The proposed use of Food and Drug Administration-approved CDK4/6 inhibitor Palbociclib (to inhibit cyclin D1) and TGFß inhibitor Galunisertib that is already in clinical trial will ensure fast translation to clinic within 3 years.



The BCa metastases specimens acquired in the rapid autopsy program provided a valuable resource for us to dissect the tumor and its microenvironment interaction in fueling tumor growth. This project will use cutting edge paired laser-captured microdissection and integrated analysis to dissect survival contribution from the tumor cells and the stromal cells, providing rationale for a paradigm-shifting strategy from targeting tumor cells to co-targeting seed and soil (i.e., tumor and its microenvironment). This immense co-targeting stress is likely to reduce de novo resistance and delay therapy resistance when compared to monotherapy. Importantly, we will conduct preclinical co-targeting using our newly developed, first-in-field metastatic BCa PDX.



This project will address the FY18 PRCRP Topic area on BCa and in short-term, generate important data on potential innovative tumor-stromal co-targeting therapy and key oncogenic events in the tumor microenvironment ecosystem for mechanistic studies and precision targeting. Our long-term goal is to increase survival improve the quality of life by decreasing the impact of BCa on active duty Service members, their families, and the public.



Relevance to military focus area: The military population is at a disproportionally higher risk for BCa and the diagnosis of aggressive BCa refrains mission readiness. By revealing key interactions between tumor and its microenvironment, the project provides a basis for paradigm-shifting treatment from tumor-directed therapy to co-targeting tumor and its microenvironment. This work will not only be impactful in understanding BCa metastasis, but also fill the critically unmet gap in effectively targeting BCa metastasis and increase survivorship.
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System

Categories
  • FOR (ANZSRC)

    1112 Oncology and Carcinogenesis

  • RCDC

    Biotechnology

  • RCDC

    Cancer

  • RCDC

    Urologic Diseases

  • HRCS HC

    Cancer

  • HRCS RAC

    5.1 Pharmaceuticals

  • Health Research Areas

    Biomedical

  • Broad Research Areas

    Clinical Medicine and Science