Nanoparticle-based delivery and combinatorial therapies for cancer
Prostate cancer is the most common malignancy and the second cause of cancer-related deaths in men. Despite the progress in the treatment of localized prostate cancer, management of locally advanced and metastatic disease is still a critical unmet need. Resistance to hormonal therapy and chemotherapy is common in advanced stages of the disease. Due to the limited efficacy of the current treatment, it is imperative to expand the horizon of the therapeutic options for advanced prostate cancer. Intratumoral heterogeneity with the complex interplay between genetic and epigenetic variability in tumor cell subpopulations and the inevitable emergence of treatment-resistant tumor cells limit the efficacy of current treatment modalities. Despite their limited efficacy as single agents, epigenetic drugs, such as the inhibitors of BET proteins, are very attractive for combinatorial treatment giving the possibility of counteracting epigenetic processes associated with stemness, treatment-resistance, metastasis and disease progression. Our preclinical data indicate that combining BET inhibitors with other anticancer drugs may represent an effective strategy for improving the current treatment outcome in patients with advanced prostate cancer. We have tested recently the efficacy of combinations of a BET inhibitor (INCB057643) with docetaxel, carboplatin or olaparib in prostate cancer models. Notably, the latter three drugs are currently in clinical use and BET inhibitors are in multiple clinical trials. Thus, translation of our findings into clinical studies is highly feasible. Our preclinical studies indicate that concomitant treatment with these drugs is highly synergistic in vitro in cell cultures and highly effective in tumor xenografts. Combined treatment with multiple anticancer drugs is an effective and common practice in oncology. However, individual drug toxicity and cumulative effects of the combinations often limit the clinical applicability. In this project, we plan to build a biodegradable micellar system for delivery of synergistic drug combinations for treatment of advanced prostate cancer.