Repurposing Thymoquinone as Therapy for Metastatic Castration-Resistant Prostate Cancer
Abstract
Prostate cancer (PCa) is the second leading cause of cancer death in men, and it is estimated that more than 26,730 American men will die of this disease in 2017. The treatment of metastatic castration-resistant PCa (mCRPC) remains challenging. Two large, randomized clinical trials have demonstrated a survival benefit for docetaxel-based chemotherapy. Today, docetaxel is the standard care of chemotherapy agent for patients with mCRPC. Although docetaxel confers an improvement in survival, the measurable tumor response and the response rates of patients with mCRPC to docetaxel are relatively low. Thus, one strategy to further improve the survival of patients with mCRPC is to improve the level of response and the response rates of mCRPC to docetaxel. Most PCa is less sensitive to chemotherapy at the time of relapse than it was at the time of initial presentation. This decreased responsiveness to chemotherapy, and docetaxel chemotherapy in particular, leaves patients with limited treatment options, and the vast majority of affected patients will, unfortunately, die of their disease. Our application describes an innovative strategy to improve docetaxel chemotherapy. We propose to increase the therapeutic ratio of docetaxel using a novel agent, thymoquinone (TQ), which can sensitize PCa cells to the effects of docetaxel. TQ is a natural compound found in the plant Nigella sativa. It has been shown to sensitize tumor cells to the effects of chemotherapy. However, its clinical translation was prevented by its poor solubility in blood, low drug stability, and high toxicity. To renew its clinical translation potential, we have developed a novel PBM nanoparticle (our patented technology) formulation of TQ. We demonstrated that nanoparticle delivery has improved solubility and stability, as well as lowered the toxicity of TQ. More importantly, we found that the PBM nanoparticle TQ is more effective than TQ alone. Since nearly all advanced PCa cells express prostate-specific membrane antigen (PSMA), we will utilize the A10 aptamer attached on the NP surface, which targets PSMA, as a targeting ligand to target PCa epithelial cell (PCEC) and anti-CD133 antibody conjugation to target PCa stem cells (PCSC). We are aware that targeted delivery of drugs to CSCs without damaging normal stem cells is challenging because of shared cell surface markers. The hypoxia-inducible factor (HIF) pathway may be one such pathway in PCa. HIF signaling is elevated in the PCSC population and promotes stemness and self-renewal of PCSCs. Considering that hypoxia often presents in the tumor microenvironment instead of the normal state, targeting HIF signaling may inhibit PCSCs without damaging normal stem cells. In this application, we are targeting not only the PCEC, but also PCSC, without affecting the normal cells. We aim to engineer nanoparticle formulations of TQ and evaluate their efficacy using tumor cell lines and mouse models (CDX and PDX) of PCa. To enable rapid clinical translation, we will utilize a highly innovative nanoparticle, the planetary ball-milling (PBM) nanoparticle. We believe that the success of our proposal will result in new therapeutic agents, as well as a new treatment strategy for mCRPC. Our approach has the potential to further improve the survival of mCRPC patients by several months with minimal additional toxicity. Our proposed work also has broad implications. It can promote more nanomedicine approaches for the treatment of mCRPC. It can also facilitate the clinical translation of other nanoparticle-based therapeutics. Lastly, this strategy can be adopted for other cancers that rely on systemic chemotherapy.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Oct 29, 2018
- Source ID
- W81XWH1810429
Entities
People
- Rajesh Singh
Organizations
- Morehouse School of Medicine
- United States Army