Drug Development for Prostate Cancer and other Metastatic Processes

Division Of Basic Sciences - Nci

Investigators

Linked publications, trials & patents

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. The use of non-invasive imaging techniques to increase our understanding of prostate cancer development, progression and to aid physicians in risk stratification is a rapidly expanding field. Gadoxetate disodium is an FDA-approved gadolinium-based hepatoselective MRI contrast agent that has a proven role in improving the diagnosis and classification of liver lesions. Gadoxetate disodium is a substrate of OATP1B3, and its uptake has been shown to correlate with OATP1B3 expression in other cancers. OATP1B3 is expressed de novo in primary prostate cancer tissue and to a greater degree in prostate cancer metastases. We aimed to evaluate use of gadoxetate disodium to image prostate cancer and to track its utility as a biomarker. In collaboration with Drs. Peter Choyke and Baris Turkbey (Molecular Imaging Branch, CCR, NCI), we conducted a single center open-label non-randomized pilot study of men with (1) localized, and (2) metastatic castration resistant prostate cancer (mCRPC). Gadoxetate disodium-enhanced MRI was performed at four timepoints post-injection. The Wilcoxon signed rank test was used to compare MRI contrast enhancement ratio (CER) pre-injection and post-injection. OATP1B3 expression was evaluated via immunohistochemistry (IHC) and a pharmacogenomic analysis of OATP1B3, NCTP and OATP1B1 was conducted. The mCRPC subgroup (n = 9) demonstrated significant enhancement compared to pre-contrast images at 20-, 40- and 60-min timepoints (p0.0078). The localized cancer subgroup (n = 11) demonstrated earlier enhancement compared to the mCRPC group, but no retention over time. OATP1B3 expression on IHC trended higher contrast enhancement between 20-40 min (p0.064) and was associated with contrast enhancement at 60 min (p = 0.0422). OATP1B1 haplotype, with N130D and V174A substitutions, impacted enhancement at 40-60 min (p0.038). mCRPC lesions demonstrate enhancement after injection of gadoxetate disodium on MRI and retention over 60 min. As inter-individual variability in OATP1B3 expression and function has both predictive and prognostic significance, gadoxetate disodium has potential as a biomarker in prostate cancer. 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 evaluated in preclinical prostate cancer models of enzalutamide resistance. The effect of NLG207 and enzalutamide on average tumor volume and tumor re-growth after 3 weeks of treatment was evaluated in vivo using the subcutaneous 22Rv1 xenograft and castrated subcutaneous VCaP xenograft models. Correlative assessments of antitumor activity were evaluated in vitro using cell proliferation and qPCR assays. NLG207 8 mg/kg alone and in combination with enzalutamide reduced average tumor volume by 93% after 3 weeks of treatment (P 0.05) in comparison with vehicle control in the subcutaneous 22Rv1 xenograft model. Notably, the addition of NLG207 also enhanced the efficacy of enzalutamide alone in the castrated subcutaneous VCaP xenograft model, decreasing the median rate of tumor growth by 51% (P = 0.0001) in comparison with enzalutamide alone. In vitro assessments of cell proliferation and gene expression further demonstrated antitumor activity via AR-HIF-1a crosstalk inhibition. Combination treatment with NLG207 and enzalutamide was shown to be effective in preclinical prostate cancer models of enzalutamide resistance. Clinical investigation of this treatment combination is ongoing (NCT03531827). Furthermore, we conducted a population pharmacokinetic analysis of nanoparticle-bound and free camptothecin after administration of NLG207 in adults with advanced solid tumors. The present study sought to characterize the complex PK of NLG207 and better describe CPT release from nanoparticles using a semi-mechanistic population PK (popPK) model. The semi-mechanistic popPK model confirmed nanoparticle behavior of bound CPT and mechanistically characterized CPT release from NLG207. The current analysis provides a strong foundation for future study as a potential predictive tool in ongoing NLG207 clinical trials.