Pre-IND Development of Polymeric Micelles with Dual Drug Payloads for HCC Therapy - PROJECT SUMMARY Hepatocellular carcinoma (HCC) is increasing in prevalence, yet chemotherapy options remain very limited. Resistance to systemic therapy and recurrence at local and distant sites following systemic therapy are major problems in HCC. Innovative combination therapy is an appealing strategy for treating HCC. Cancer stem cells (CSC) are a small subset of self-renewing, pluripotent, slowly proliferating malignant cells that play key roles in tumor initiation, metastasis, recurrence, and multidrug resistance in various cancer types, including HCC. Targeting CSCs may offer a promising avenue for effective anti-HCC therapy. However, targeting CSC alone would be insufficient because new CSCs could be constantly derived from non-CSC tumor cells through activation of epithelial-to-mesenchymal transition (EMT). It is therefore critical to simultaneously eliminate CSCs and proliferating non-CSC tumor cells. To date, pharmacologic approaches toward this goal remain largely unsatisfactory. This proposal seeks to develop a polymeric micelle-based solution to drug resistance in HCC. The polymeric micellar delivery system is co-formulated with cyclopamine (CPA), a naturally occurring hedgehog (Hh) signaling inhibitor capable of eliminating CSCs, and paclitaxel (PTX), a cytotoxic chemotherapeutic agent that blocks the progression of mitosis and triggers apoptosis. In preliminary studies, we have demonstrated that polymeric micelles containing both CPA and PTX, termed M-CPA/PTX, significantly prolonged median survival of transgenic mice with spontaneous c-Myc-driven HCC in both preventive and therapeutic settings. Moreover, M-CPA/PTX was significantly more efficacious than PTX alone, CPA alone, or a physical mixture of CPA + PTX. M-CPA/PTX downregulated c-Myc, suppressed tumor spheroid formation, inhibited EMT, and decreased components of extracellular matrix in favor of vastly improved tumor disposition of both drugs. Taken together, our preliminary warrant further pre-IND development of the M-CPA/PTX technology. There are two primary goals for this project: to de-risk clinical translation of M-CPA/PTX and to obtain a robust IND package. To achieve our goals, we will pursue 3 specific aims: 1) to scale up synthesis of high-quality M-CPA/PTX and fully characterize the resulting products; 2) to determine the antitumor efficacy, biodistribution, pharmacokinetics (PK), toxicity, pharmacodynamics (PD), and PK/PD correlation of M-CPA/PTX in preclinical models of HCC; 3) to evaluate the mechanism by which M-CPA/PTX exerts its anti-HCC activity. Our ultimate goal is to translate M-CPA/PTX into the clinic as a safe and effective therapy that improves survival of patients with HCC. This project will have exceptional impact because it will pave the path for clinical translation of a potentially effective systemic therapy for HCC patients and provide insight into the role of CSCs and tumor stroma in resistance to anti-HCC therapy.
