Aldo-keto reductase 1 C3 (AKR1C3) is overexpressed in a range of leukemias, prostate and other cancers, where it functions to regulate myeloid and lymphoblast cell differentiation, proliferation and apoptosis, synthesize potent androgens that drive cancer progression and contributes to drug resistance across several classes of chemotherapeutic. Our preliminary results have identified the most selective AKR1C3 isoform inhibitors ever reported. These inhibitors provide significant potentiation effect (up to 208-fold) across four classes of chemotherapeutics in six different acute myeloid leukemia (AML) and castration-resistant prostate cancer (CRPC) cell lines, and in primary relapsed patient-derived T-cell acute lymphoblastic leukemia (T-ALL) cells. We hypothesize that isoform selective inhibition of AKR1C3 by rationally designed small molecules will have significant effect to potentiate the cytotoxicity of clinical chemotherapeutics across a range of malignancies. The goal of this proposal is to optimize this new scaffold for greater potency, stability and potentiation effect, to characterize the role of AKR1C3 in cancer, and to validate the AKR1C3 isoform as a target for the treatment of AML, T-ALL and CRPC. The overall impact of this proposal is the in vivo proof-of-concept that isoform selective AKR1C3 inhibitors enhance the therapeutic window of clinical chemotherapeutics; enhancing efficacy, countering resistance and reducing side effects. Thus enabling the use of clinically approved anticancer agents in vulnerable pediatric and geriatric patients.
Acute myeloid leukemia (AML), T-cell acute lymphoblastic leukemia (T-ALL) and castration-resistant prostate cancer (CRPC) primarily occur in two vulnerable age groups ? young children and the elderly; the high systemic toxicity associated with standard chemotherapeutics and rapid development of drug resistance results in poor prognosis in these cancers. In this project, we will develop isoform selective inhibitors of AKR1C3, an enzyme integral to the differentiation, survival and proliferation of myeloid and lymphoblast cells, responsible for the in situ production of androgens that drive CRPC progression, and a primary resistance mechanism for several cancers. If successful, the addition of an isoform selective AKR1C3 inhibitor to AML, T- ALL and CRPC treatment regimens will enhance the therapeutic index of antineoplastic drugs and act to counter resistance.
