Translational development studies of a novel combination therapy for castration-resistant prostate cancer

ABSTRACT This proposal was designed in accord with NCI Clinical and Translational Exploratory/Development Studies FOA (R21; PAR-16-176) to undertake pre-IND (investigational new drug) translational development work to support the combination of hexokinase 2 (HK2) inhibitor 2-deoxyglucose (2-DG) and autophagy inhibitor hydroxychloroquine (HCQ, Plaquenil) as a novel and efficacious oral therapy for HK2-Warburg effect-addicted castration resistant prostate cancer (CRPC), the major cause of prostate cancer (PCa) mortality. Our published and compelling preliminary data have demonstrated, as proof of principle, that parenteral delivery of 2-DG/CQ [chloroquine] may target as many as 60% of CRPC (i.e., those with HK2 overexpression due to PTEN-/TP53-defects or PTEN-defects/AR amplification) through cancer-selective apoptosis. Since HCQ is a safer oral drug than CQ with reduced retinal toxicity for patients, we hypothesize that combining 2-DG to inhibit HK2-mediated Warburg effect with HCQ to abolish 2-DG-induced anti-apoptotic autophagy effectively eradicate CRPC through un-opposed apoptosis with minimal risk of toxicity to hosts. For pre-IND translation development of 2-DG/HCQ as a practical and patient self-administered combination modality, our objectives are two folds: (1) Efficacy validation of 2-DG/HCQ combination through the much preferred oral route of drug administration in CRPC models. (2) Preliminary toxicology (Tox) assessment of this combination in mature male rats and dogs to inform optimal design and execution of the costly IND-enabling GMP/GLP toxicology (Tox) and pharmacokinetics (PK) packages in the near future. Our 2 specific aims are: 1. Test and validate the therapeutic efficacy of oral administration of 2-DG/HCQ combination against two clinically relevant xenograft models of HK2-driven CRPC. We will generate CRPC xenografts in SCID mice with LNCaP-AR cells (PTEN- defective, AR overexpression) and JAX PDX TM002928 line and treat with 2-DG/HCQ by daily gavage. We will determine the level of each drug in peripheral circulation and tumors to correlate with efficacy indices. 2. Assess the preliminary Tox of 2-DG/HCQ combination in mature male rats and dogs. Although 2-DG has been tested for safety in Phase I/II clinical trials and HCQ is FDA-approved drug for malaria and autoimmune diseases such as lupus and rheumatoid arthritis, the safety profile of 2-DG/HCQ combination needs to be rigorously tested for any unexpected adverse interactions to support IND. Given known MTD of 2-DG, we will use dose-escalation design with HCQ to interrogate whether the two drugs are additive, antagonistic or synergistic for causing adverse effects. Their Tox metrics will be correlated with PK parameters of each drug in the dogs. The results from the proposed studies will propel further translational developments toward IND- enabling PK/Tox packages and subsequent IND submission in the near future, and ultimately early stage clinical trials with 2-DG and HCQ combination for the precision therapy of major subsets of CRPC.