Prostate cancer is the second leading cause of cancer-related death in American men, resulting in 29,480 fatalities last year. Death from prostate cancer most frequently occurs following the development of resistance to first- or second-line androgen deprivation therapy (ADT). As such, there is a critical need to discover early drivers of ADT resistance to help guide selection of patients for earlier intensification of therapy.
The majority of cancer biomarker research has focused, to date, on protein-coding genes, which are pieces of DNA that are converted to RNA and then converted to protein. Our team instead focuses on investigating long noncoding RNAs (lncRNAs), which are pieces of DNA that are converted to RNA but are not further converted to protein. These lncRNAs, which function as RNAs instead of proteins, represent an underexplored, but crucial, area of cancer biology. Our team recently identified over 45,000 novel lncRNAs, and determined that several lncRNAs, including one named SChLAP1, were better indicators of disease progression than conventional protein-coding genes.
Based on our initial findings, we hypothesize that lncRNAs serve as important mediators of treatment resistance in prostate cancer. The goals of this application are: 1) to investigate the mechanism by which our top candidate lncRNA, SChLAP1, promotes ADT resistance and 2) to determine if SChLAP1 and other lncRNAs can serve as predictive biomarkers to guide therapy selection in patients with aggressive prostate cancer, using tumor samples from a phase III clinical trial.
Adenocarcinoma is the most common type of lung cancer, and the majority of people diagnosed with this disease will die from metastases. Chemotherapy is the standard way to treat this cancer, and this provides clear benefits including increasing the lifespan of patients. However this benefit is limited and all patients eventually become resistant to standard therapy. Therefore new types of treatment need to be developed. Immunotherapy is a type of treatment designed to get a patient’s own immune system to kill their cancer. Very recently it was demonstrated that an immunotherapy called anti-PD1 has surprisingly good activity in lung cancer. Rapid and prolonged regressions of tumors occur in about one quarter of patients. Now it is important to develop combination therapies with this agent that may help the three quarters of patients who do not respond to anti-PD1. One such approach would be to combine anti-PD1 with a therapeutic cancer vaccine. Vaccines are designed to increase the number of lymphocytes in patients that can recognize and kill cancer cells. Many of these sorts of vaccines have been developed that are very effective in accomplishing this lymphocyte expansion, but none have been very good at killing tumors. One reason for this is that tumor cells can produce a protein called PD-L1 that binds to PD1, another protein on the surface of the lymphocytes activated by the vaccines, which shuts down their ability to kill cancer cells. Anti-PD1 prevents this from happening. We propose to combine anti-PD1 with a cancer vaccine for the first time to treat patients with advanced stage lung adenocarcinoma. We will use a vaccine that activates lymphocytes that recognize a protein called mesothelin which is produced by many lung adenocarcinomas and has been shown previously to expand the number of mesothelin-specific lymphocytes in cancer patients. We expect that combining this vaccine with anti-PD1 will be synergistic, producing improved clinical outcomes. We will also comprehensively analyze the immune systems of the patients and characteristics of their tumors which may be responsible for producing resistance to anti-PD1 and/ or the vaccine. This information can then be used to suggest additional agents that can be added to the anti-PD1/ vaccine combination in the future to further improve the effectiveness of this therapy.
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