Circulating Tumor Cell-Based Patient-Derived Xenograft Models of Metastatic Bladder Cancer as a Platform for Development of Novel Therapeutic Approaches

Project Details

Description

Chemotherapy with the drug cisplatin is the mainstay of first-line treatment for patients with bladder cancer that has spread to other parts of the body (metastatic bladder cancer). However, while this treatment is effective in causing shrinkage of cancer in a large proportion of patients, almost all patients ultimately experience progression of their cancer despite cisplatin-based chemotherapy. The reasons for the development of resistance to cisplatin are poorly understood, at least in part due to a lack of good models to use in the laboratory to study this phenomenon. This barrier not only applies to cisplatin but also to the study of a variety of novel treatments for bladder cancer. Models that are commonly used in the laboratory are based on cancer cells that have been grown in a plastic flask for long periods of time and poorly represent cancers found in patients. A newer approach to develop tumor models is to take biopsies of tumors from patients and grow these tumors in mice. While these models more closely resemble human tumors, they are very expensive to generate. Furthermore, owing for the need for biopsies or surgical removal of tumor tissue, developing multiple models from the same patient to study the evolution of cancer in the context of treatment is complicated by financial, practical, and ethical limitations. To overcome these limitations, we have developed a highly novel platform that is based on generating tumor models from tumor cells obtained from routine blood samples obtained from patients with advanced bladder cancer. We have generated several sets of these models from the same patients from blood samples obtained prior to starting cisplatin-based chemotherapy and at the time of cancer progression on this treatment. These paired models offer an unprecedented opportunity to study why tumors develop resistance and to develop novel treatments based on this information to improve upon our current therapies for advanced bladder cancer.

This project addresses the Peer Reviewed Cancer Research Program Topic Area of Bladder Cancer. The project addresses a major gap in cancer treatment that may not only impact the general population but may also have a particularly profound impact on the health and well-being of military Service members, Veterans, and their beneficiaries. 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.

This project will identify mechanisms of bladder cancer resistance to cisplatin-based chemotherapy and novel approaches to overcome such resistance. The highly novel research platform outlined herein will also contribute to identifying and validating predictive biomarkers that will enable personalize treatment options for bladder cancer patients. In addition, this research platform may be ultimately extended to a variety of other malignancies, further extending the impact of this work.

StatusActive
Effective start/end date1/01/16 → …

Funding

  • Congressionally Directed Medical Research Programs: $673,356.00

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