Background: Cisplatin-based chemotherapy represents the mainstay of first-line treatment for advanced bladder cancer, with most patients experiencing tumor regression. However, the vast majority of patients experience disease progression despite cisplatin-based chemotherapy, and only one new therapy has approved by the US Food and Drug Administration in this setting in the past several decades. This lack of progress is largely a result of a poor understanding of the pathogenesis of the advanced bladder cancer stemming, at least in part, from a lack of model systems that recapitulate the evolution of the disease in the context of treatment. In order to address this limitation, we have recently developed a cohort of patient-derived xenograft (PDX) models derived from circulating tumor cells (CTC) obtained from the peripheral blood of patients with metastatic bladder cancer. Importantly, we have developed paired models from patients derived from CTC samples obtained prior to initiating, and at the time of disease progression on, cisplatin-based chemotherapy. These models offer an unparalleled opportunity to study mechanisms of acquired resistance. Transcriptomic profiling of these paired cisplatin-sensitive and -resistant CTC-PDX models has unveiled novel, potentially targetable pathways driving disease progression. Central to this proposal, DNA damage response mechanisms are significantly enriched during this process.Hypothesis/Objectives: We hypothesize that CTC-PDX models of advanced bladder cancer can be used to identify targetable mechanisms of cisplatin resistance. The objectives of this proposal are to expand and molecularly profile this innovative model system platform, characterize the DNA damage response mechanisms that contribute to cisplatin resistance, and identify novel therapeutic approaches.Specific Aims: In Aim 1, we will (a) expand the cohort of bladder CTC-PDX models and (b) define their genomic alterations. In Aim 2, we will define the DNA damage pathways altered in cisplatin-resistant CTC-PDX models. Finally, in Aim 3 we will determine the preclinical anti-cancer effects of targeting DNA damage response pathways in paired cisplatin-sensitive and -resistant PDX models.Study Design: We will expand our cohort of cisplatin-sensitive and -resistant CTC-PDX models, perform whole transcriptome and exome sequencing, functionally characterize the key DNA repair signaling genes that contribute to cisplatin resistance in CTC-based organoid models and test the anticancer effects of small molecule inhibitors of DNA repair in CTC-based organoid and CTC-PDX models.Innovation: This proposal pairs a highly innovative concept with a highly unique resource (CTC-PDX models) to identify mechanisms of resistance to cisplatin. This platform has clear implications beyond this specific, though highly important, research question and may be used to explore sensitivity and resistance to a variety of novel therapeutic approaches in molecularly defined bladder cancer models.Military Relevance: Bladder cancer represents the fourth most common type of cancer diagnosed in the Department of Veterans Affairs (VA) Health System, and tobacco use is the major risk factor for bladder cancer. Recent studies demonstrate that approximately 32% of active-duty military personnel and 22% of all Veterans smoke, compared with just over 20% of the US adult population (Combating Tobacco Use in Military and Veteran Populations, Institute of Medicine). Furthermore, the prevalence of smoking is over 50% higher in military personnel who have been deployed than in those who have not. Addressing sources of tobacco-related morbidity and mortality has clear and important implications for military Service members, Veterans, and their beneficiaries.
|Effective start/end date||1/08/17 → 31/07/19|
- Congressionally Directed Medical Research Programs: $673,356.00