Novel Anti-androgen strategies in Prostate Cancer

Division Of Basic Sciences - Nci

Investigators

Abstract

Serial Assessments of Circulating Tumor Cells (CTCs) in Patients Treated with Enzalutamide To better understand the mechanistic development of resistance to enzalutamide, we collaborated with Epic Sciences (San Diego, CA) to evaluate androgen receptor splice variant 7 (ARV-7) emergence in patients treated with enzalutamide (regardless of randomization) on A Randomized Phase II Trial Combining Vaccine Therapy with Prostvac and Enzalutamide vs. Enzalutamide Alone in Men with Metastatic Castration Resistant Prostate Cancer. This is the only serial assessment using their platform of patients with mCRPC treated with enzalutamide. CTCs were generally evaluated every 3 months and paired with re-staging scans (CT and Tc99 bone scans). For all patients initial confirmed PSA rise occurred at 6.4 months, while radiographic progression occurred at a median of 23.3 months. 31 patients had paired CTC draws serially and have experienced radiographic progression. Of these patients, 8 developed ARV-7 positive CTCs. Interestingly, CTCs frequently developed within 3 months of radiographic progression and only in 2 of 13 patients with radiographic progression beyond 20 months were ARV-7 positive. Six of 18 patients with radiographic progression within 20 months were CTC positive. These hypothesis generating data suggest that ARV-7 positive CTCs may be a trigger for imaging in patients with rising PSA on enzalutamide. Biologically speaking, it appears as though ARV-7 may not be the main driver of resistance in long term responders to enzalutamide (i.e. more than 2 years). We are continuing our collaboration with epic sciences to better understand how CTCs correlate with radiographic progression in this and other studies. A Phase 2 Open-Label Study to Evaluate the Efficacy and Safety of VT-464 (seviteronel)in Patients with Metastatic Castration Resistant Prostate Cancer Who Have Previously Been Treated with Enzalutamide We have conducted a clinical trial with seviteronel, a next-generation CYP17 lyase inhibitor with androgen receptor binding properties, in patients with mCRPC with disease progression of mCRPC. After phase 1 studies were completed, Dr. Figg and his team worked to analyze the pharmacokinetics of this novel agent. Unfortunately, the agent triggered an abundant amount of central nervous system toxicities that manifested in the form of fatigue, confusion/diminished cognition and dizziness. After demonstrating minimal efficacy and substantial toxicity in the 17 patients enrolled, the study was closed. A Single-Arm Pilot Study Combining CRLX101(NLG207), a Nanoparticle Camptothecin, with Enzalutamide in Patients with Progressive Metastatic Castration-Resistant Prostate Cancer Following Prior Enzalutamide Treatment Intratumoral hypoxia has been associated with aggressive disease in prostate cancer. ADT has been shown to increase hypoxia leading to increased transcriptional activity of the androgen receptor. Hypoxia Inducible Factor (HIF)-1a has been implicated in cancer cell survival and treatment resistance. Furthermore, data suggests substantial cross-talk between the androgen receptor and HIF-1a pathways. Based on these findings, Dr. Figg and his Molecular Pharmacology Section further investigations have demonstrated that dual targeting of the androgen receptor and HIF-1a can have anti-tumor effects on castration resistant cell lines. NLG207 (formerly CRLX101) is a nanoparticle-drug conjugate comprised of a linear cyclodextrin-polyethylene glycol-base polymer conjugated to multiple 20(S)-camptothecin molecules (Poly-CD-PEG-Camptothecin). Campothecin have anti-HIF-1a properties and has demonstrated activity in multiple prostate cancer cell lines in vitro. Building on the preclinical data with NLG207 from the Molecular Pharmacology Section including potential combination efficacy with enzalutamide, we launched a phase 1/2 study evaluating of NLG207 and enzalutamide in mCRPC patients who have previously had disease progression on enzalutamide.. Unfortunately, the phase 1 portion of the study had an early DLT and this study was discontinued for toxicity.