Abstract 3196: Analysis of taxane drug target engagement of microtubules in circulating tumor cells from metastatic castration resistant prostate cancer patients treated with CRLX301, a nanoparticle of docetaxel

Abstract

Abstract We reviewed the radiographic response of three patients with metastatic castration-resistant prostate cancer (mCRPC) treated with CRLX301, a docetaxel nanoparticle. For these three patients, we isolated and analyzed circulating tumor cells (CTC) to explore microtubule (MT) drug-target engagement (MT-DTE) as a biomarker of response to treatment. We quantitatively assessed the MT cytoskeleton in CTCs from pre- and post-treatment patient samples as a potential read-out of CRLX301 activity. We isolated CTCs using negative CD45+ depletion and subjected them to multiplex confocal microscopy using our established protocol. CTCs were identified as CD45-/CK+/DAPI+ cells and MT-DTE was determined using our developed, semi-high-throughput, high-content imaging algorithm to quantify MT bundling in CTCs across multiple time points, from baseline to on-treatment to disease progression. We collected CTCs at seven time points from three mCRPC patients. Clinical response was evaluated by RECIST v.1.1 criteria in those patients with measurable disease. Of the three patients who received CRLX301, one experienced partial response and two patients were unevaluable per RECIST given bone only disease, however showed stable disease clinically per bone scans. MT-DTE across all time points revealed that, early time points within four and 24 hours of drug administration exhibited the highest levels of drug engagement as compared to baseline but did not discriminate the responding patient from the patients with stable disease. However, the limited sample size makes this an observation that warrants validation in a larger cohort of patients. We observed that the CTCs collected one week after the first or second dose of CRLX301 treatment in the responding patient had numerically higher levels of MT-DTE as compared to the other two patients. MT-DTE can be detected and analyzed quantitatively in CTCs by tubulin immunofluorescence. The clinical utility of the 1-week CTC DTE should be tested and validated in future clinical trials involving nanoparticle formulations of taxanes or taxanes in general. Citation Format: Eiman Mukhtar, Daniel Worroll, Giuseppe Galletti, Shelly Schuster, Sarina A. Piha-Paul, Paraskevi Giannakakou. Analysis of taxane drug target engagement of microtubules in circulating tumor cells from metastatic castration resistant prostate cancer patients treated with CRLX301, a nanoparticle of docetaxel [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3196.