BERKELEY, CA (UroToday.com) - As per American Urological Association (AUA) guidelines, the only treatment option to-date for non-metastatic castration-resistant prostate cancer (CRPC) is continued androgen deprivation therapy (ADT) and follow-up by the patientâs oncologist; there are currently no FDA-approved therapies to prevent CRPC metastasis. Once a patient progresses to metastatic CRPC, several treatment modalities such as chemotherapy, immunotherapy, and radiotherapy are available depending on symptoms and pre- or post-docetaxel status, including abiraterone and prednisone, sipuleucel-T, docetaxel, cabazitaxel, enzalutamide, radionucleotide therapy, etc. Docetaxel remains the most frequently utilized chemotherapeutic agent for metastatic CRPC. However, many patients cannot tolerate docetaxel chemotherapy due to advanced age, medical comorbidities, and limited bone marrow reserves. Additionally, docetaxel is only initially effective in approximately 50% of metastatic CRPC patients, and all of those individuals eventually develop docetaxel-resistant disease. Many of these therapies provide a modest extension of progression-free and overall survival, but often with significant side effects, a toll on quality-of-life, and considerable monetary expense. Alternative therapeutic options are needed for CRPC.
By taking advantage of âWarburg effectâ-related metabolic aberrations noted in metastatic CRPC cells, such as high constitutive activity of Akt, decrease AMP-activated protein kinase activity, and over expression and hyperactivity of cholesterol and fatty acid anabolic rate-limiting enzymes, we demonstrated the preclinical development of combination simvastatin and metformin chemotherapy for prevention and treatment of metastatic CRPC. Dose ratio of 1:500 combination of simvastatin and metformin, within plasma pharmacological range, synergistically inhibited viability of C4-2B osseous metastatic CRPC cells, with minimal effect on normal prostate epithelial cell viability, significantly inhibited C4-2B metastatic properties, ameliorated metabolic aberrations of C4-2B cells, and inhibited primary prostate tumor growth and prevented osseous metastasis in a castrated orthotopic mouse model of metastatic CRPC.
Our group is currently performing analyses of castration-resistant and metastatic prostate cancer clinical specimens to determine if combination simvastatin and metformin chemotherapy may be clinically translatable. Based on these results, a clinical trial utilizing combination simvastatin and metformin for prevention and treatment of CRPC metastasis will be pursued. We are optimistic that combination simvastatin and metformin may prove to be a clinically relevant and effective chemotherapy for the prevention of CRPC progression to metastasis (for which no preventive therapy currently exists) and for the treatment of metastatic CRPC. Compared to current chemotherapeutic options for metastatic CRPC, simvastatin and metformin treatment is more convenient (taken per oral, and would not require frequent doctor appointments for administration of chemo-, immuno-, or radiotherapies); inexpensive (direct cost for a year supply of simvastatin and metformin is < $2,000, or significantly cheaper when generic is used, compared to approximately $3,000 per treatment cycle of docetaxel or $93,000 per treatment of sipuleucel-T); and less toxic (grade 3 and 4 toxicities not associated with simvastatin and metformin use, even in normo-cholesterolemic and normo-glycemic patients), all of which may also improve patient compliance with treatment.
Combination simvastatin and metformin also synergistically and significantly reduced viability of docetaxel-resistant, bone metastasis-derived androgen-independent PC-3 D12 prostate cancer cells, demonstrating a potentially broader applicability of combination simvastatin and metformin as second-line chemotherapy in metastatic prostate cancer following docetaxel failure.
Melissa A. Babcook, PhD and Sanjay Gupta, PhD as part of Beyond the Abstract on UroToday.com. This initiative offers a method of publishing for the professional urology community. Authors are given an opportunity to expand on the circumstances, limitations etc... of their research by referencing the published abstract.
Case Western Reserve University, Department of Urology, Cleveland, OH USA