Precision Medicine in Platinum-Treated Lethal Bladder Cancer
Abstract
The proposed research has the potential to advance one of the Fiscal Year 2016 Peer Reviewed Cancer Research Program Topic Areas: bladder cancer. In the United States, bladder cancer is the fourth most common cancer among men and the fifth most common overall. Bladder cancer that has grown outside the bladder and spread to surrounding lymph nodes or other parts of the body is termed metastatic bladder cancer. Combinations of chemotherapy drugs are used to treat metastatic (stage IV) bladder cancer. Cisplatin, a platinum-containing drug, is the backbone of these combination chemotherapy regimens, which have significant side effects and limited benefits for most patients with metastatic bladder cancer, with a median life expectancy of 14 months. However, about 10% of patients derive significant benefit from chemotherapy and are alive at 5 years. The ability to identify these patients prior to starting treatment has been elusive, but recent scientific research has suggested a few possible approaches. The proposed research will address our limited understanding of how patients with lethal bladder cancer respond to treatment with chemotherapy by testing these approaches and exploring predictive biomarkers (biological markers or signature molecules) that may identify those patients most likely to respond to treatment. We have previously shown that mutations in a gene called ERCC2, which is involved in repair of DNA damage from cisplatin chemotherapy, leads to extreme sensitivity to cisplatin in patients who have stage II or III bladder cancer and that tumor mutations in ERCC2 and other DNA damage repair genes are associated with a longer survival in patients with stage IV bladder cancer treated with chemotherapy. We have also shown that bladder cancer can be defined by three specific RNA expression patterns. One of these subtypes of bladder cancer appears to be intrinsically resistant to cisplatin-based chemotherapy (“p53-like”), while another subtype appears to be more sensitive to chemotherapy (“basal”). The Cancer and Leukemia Group B (CALGB) 90601 trial is a large, randomized Phase III clinical trial testing whether adding bevacizumab -- a drug that stops the growth of new blood vessels (angiogenesis) in tumors -- to standard chemotherapy with gemcitabine and cisplatin leads to improved outcomes compared to chemotherapy alone in patients with advanced or metastatic bladder cancer. This trial has completed patient accrual and is ongoing, affording a unique opportunity to test prospectively whether new biomarkers for chemotherapy response from previously obtained tumor biopsies can predict which patients benefit most from chemotherapy. By testing these tumor samples, we will evaluate whether the expression of an angiogenesis signature leads to improved survival in patients treated with bevacizumab. We also hope to prove that certain RNA expression subtypes of bladder cancer have improved outcomes with chemotherapy. Finally, experiments in the laboratory will evaluate the interaction between anti-angiogenic therapy and the tumor milieu (microenvironment). If successful, implementation of these biomarker tests will enable us to offer chemotherapy to patients with lethal bladder cancer who are most likely to benefit from the treatment, while sparing the risk of side effects for those whose cancers are not likely to be controlled or killed by the treatment. Patients with resistant tumors might be best offered an alternative approach to treatment (e.g., immunotherapy, clinical trials). This project will be the largest endeavor to date to study the genetic makeup of metastatic lethal bladder cancer. Clinically, this study will represent a major step towards re-thinking the use of chemotherapy as a precision medicine in the treatment of lethal bladder cancer. Since tests such as RNA expression profiling and tumor mutation sequencing are now commonplace, we expect that these findings could be translated directl
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Oct 29, 2018
- Source ID
- W81XWH1710545
Entities
People
- Eliezer Van Allen
Organizations
- Dana–Farber Cancer Institute
- United States Army