Prostate cancer is one of the leading causes of cancer-related mortality in American men, second only to lung cancer. Primary and advanced prostate cancers respond to androgen ablation therapy initially, which is followed by progression to castration resistance within a short frame of time for many patients. Recently a second-generation anti-androgen, enzalutamide has been approved by the FDA for the treatment of chemotherapy-nave as well as post-chemotherapy prostate cancers. But innate and acquired resistance to enzalutamide treatment has been observed in the clinic and the mechanisms are still being studied. Use of PSA as a biomarker does not predict the possible outcome of patients with respect to development of resistance. Identification of biomarkers which facilitate risk assessment and predict which patients will respond to treatment would better inform treatment choices and improve patient care. MicroRNAs may serve as ideal non-invasive biomarkers due to their specificity and proportionality to disease development. MicroRNAs can be analyzed in biofluids such as blood, sera, urine, plasma etc., and in exosomes isolated from these biofluids. Our preliminary data show that miR-Let-7c is downregulated in enzalutamide-resistant prostate cancer, while its master regulator, Lin28 is upregulated. We also show that both Let-7c and Lin28 can be reliably measured in exosomes derived from human prostate cancer cells. Hence, we hypothesize that the alteration of the Let- 7c:Lin28 ratio in tumor-derived exosomes may serve as a potential predictor of therapy-resistance in prostate cancer.
In aim 1, we will validate preliminary data in a systematic study involving the measurement of expression levels of Let-7c and Lin28 in prostate cancer samples and tumor-derived exosomes from the UC Davis Cancer Center Biorepository and the Prostate Cancer Biorepository Network (PCBN) using quantitative real-time PCR.
In aim 2, we will develop bioassays to assess the Let-7c:Lin28 status in tumor-derived exosomes from xenografts of human prostate cancer cells. These bioassays will be validated in a limited cohort human study using blood samples from patients with enzalutamide-treated prostate cancer. Blood samples will be collected at 4 time points during the treatment of patients with enzalutamide and prostate- derived exosomes will be isolated. The ability of the ratio of Let-7c:Lin28 to predict the development of resistance to enzalutamide will be evaluated following the measurement of Let-7c and Lin28 levels in exosomes using quantitative real-time PCR. These studies will provide a rationale for the assessment of the ability of the ratio of Let-7c:Lin28 to predict whether they will respond to enzalutamide in a larger cohort of patients.
Prostate cancer is the second leading cancer in incidence and mortality in American men. Responsive to androgen ablation therapy initially, almost all patients progress to a castration resistant stage, for which no effective treatment is available. Next generation anti-androgens such as enzalutamide, though they provide overall survival benefit to patients, have already begun to show clinical signs of acquired or primary resistance. The biomarker universally used in prostate cancer screening, PSA, does not predict these outcomes effectively. In this research proposal, we hypothesize that the loss of a microRNA (Let-7c) accompanied by gain of its master regulator (Lin28) may be a potential predictor of therapy resistant progression of prostate cancer. If successful, this project will have a major impact on PCa research and lead to the potential development of a reliable biomarker. Hence, this is an innovative proposal with strong translational implications and relevance to public health.
