Drug Development for Prostate Cancer and other Metastatic Processes

Division Of Basic Sciences - Nci

Investigators

Linked publications & trials

Abstract

Our understanding of the biology of CRPC progression has led to the discovery of more effective targeted approaches that involve modulation of the androgen-AR system. We are interested in the preclinical and clinical development of novel therapeutics with efforts on characterizing their molecular and clinical pharmacology as well as evaluating for potential biomarkers of treatment response and resistance. We are also interested in understanding the mechanisms of resistance of prostate cancer regimens. Intratumoral hypoxia is also associated with CRPC progression and treatment resistance. Upregulation of hypoxia inducible factor-1alpha (HIF-1a) in hypoxic tumor cells provides a mechanism of acquired resistance to current hormonal therapies and chemotherapies by increasing angiogenesis and metastasis. Effective treatments for patients with mCRPC following disease progression on enzalutamide are currently an unmet clinical need. We previously demonstrated that simultaneous inhibition of the HIF-1and androgen receptor (AR) pathways can overcome enzalutamide resistance in vitro. Combination treatment with NLG207, a nanoparticle-drug conjugate of camptothecin and inhibitor of HIF-1a, and enzalutamide was shown to be effective in preclinical prostate cancer models of enzalutamide resistance. Despite the clinical efficacy of enzalutamide monotherapy in patients with advanced prostate cancer, therapeutic resistance and disease progression are inevitable. We next investigated NLG207 in combination with enzalutamide in patients with mCRPC following progression on enzalutamide. This was a single-arm, optimal two-stage, phase II study to evaluate the efficacy of NLG207 in combination with enzalutamide in patients with mCRPC who received prior enzalutamide (NCT03531827). A lead-in dose escalation evaluated the recommended phase 2 dose of NLG207 in combination with enzalutamide. Patients received NLG207 via IV infusion every 2 weeks and enzalutamide 160 mg orally once daily. Between March 2019 and June 2021, four patients were accrued to the lead-in dose escalation. Two of the four patients were evaluable and both experienced DLTs at the NLG207 12 mg/m2 dose level; one DLT was related to a dose delay for noninfective cystitis and myelosuppression, the other a grade 3 noninfective cystitis. Further evaluation of NLG207 in combination with enzalutamide was halted and the study was ultimately terminated. PSA declines from baseline were observed in two patients. NLG207 12 mg/m2 in combination with enzalutamide was not well tolerated in patients with mCRPC following several lines of the standard of care therapy. We are currently developing novel targeted therapies against metastatic CRPC. We have embarked upon a new drug screening project to identify novel drug targets and develop rationale combination therapies using next-generation sequencing and a matrix combination screening platform that is designed to identify novel drug targets/pathways for CRPC. We are currently testing promising combinations in various preclinical prostate cancer models with the goal of selecting the best treatment combination to move towards clinical development.