Dissecting response and resistance to next-generation AR inhibitors
Recent years have seen the approval of two novel agents (abiraterone acetate and enzalutamide) targeting persistent AR signaling in metastatic castration-resistant prostate cancer (CRPC). However, many patients do not initially respond and all patients eventually progress. There are also unanswered questions as to optimal treatment selection, if abiraterone and enzalutamide can be used sequentially and in what sequence. The major challenge in addressing these issues is the absence of treatment-predictive biomarkers for CRPC patients. Contributing to this problem is the lack of tissues available that reflect the disease. CRPC typically arises years from the initial diagnosis after the selective and adaptive pressures of castration therapy. Thus the initial biopsies are not reflective of the CRPC state. Biopsy of CRPC metastases are difficult and of low yield as the disease is bone-predominant (90% of patients), lymph node metastases are usually small and retroperitoneal, and visceral metastases are uncommon. Conversely, the analysis of circulating cell-free DNA (cfDNA) in plasma has been described as a minimally invasive approach to genetically profile tumours. Our preliminary work suggests that AR gene alterations detectable in cfDNA of CRPC patients may predict response to AR-targeted therapies. In this study we are correlating clinical outcomes with deep targeted cfDNA sequencing from patients with metastatic CRPC enrolled onto a randomized phase 2 cross-over clinical trial of abiraterone vs enzalutamide (lead by medical oncologist Dr. Kim Chi). This research is generously funded by: CCSRI through a 2014 Innovation Award; Prostate Cancer Canada through a 2014 Movember Discovery Award; as well as 2015 grants from the Pacific Northwest Prostate Cancer SPORE and the Candian Urological Oncology Group (CUOG).
Predicting response to cabazitaxel
Cabazitaxel is a novel taxane-based chemotherapy recently approved for use in metastatic castration-resistant prostate cancer (CRPC). As with all CRPC therapies, including androgen receptor (AR)-targeted agents enzalutiamide and abiraterone, many patients exhibit primary resistance, and all eventually acquire resistance. Unfortunately, resistance mechanisms are unclear and clinically unvalidated; and there are no treatment-predictive biomarkers to guide optimal therapy sequencing. We are carrying out a correlative biomarker study (using ctDNA and CTCs) in the context of an ongoing, prospective, randomized, cross-over, clinical trial with cabazitaxel versus enzalutamide/abiraterone in poor-prognosis mCRPC (lead by medical oncologist Dr. Kim Chi). We expect to identify genomic aberrations associated with response or resistance to cabazitaxel and/or AR-targeted agents. This research is generously funded by Prostate Cancer Canada through a 2015 Movember Discovery Grant.
Detecting druggable DNA repair defects in advanced prostate cancer
Global sequencing efforts have revealed that germline or somatic defects to DNA damage repair genes (e.g. BRCA2) are present in 20-30% of mCRPC patients, and that these patients may be susceptible to genotoxic chemotherapies or DNA repair inhibitors. There is an urgent need for practical biomarkers to identify patients with actionable DNA repair defects in their tumors, and for clinical development of effective therapeutic agents to exploit this cancer-specific weakness. In this project we are performing deep targeted sequencing on germline and cfDNA from a large retrospective cohort of mCRPC patients to determine the precise frequency of therapeutically-targetable DNA damage repair defects. We will then use bi-allelic DNA repair defects present in ctDNA as a biomarker to prospectively identify mCRPC patients for treatment with a WEE1 inhibitor, and will determine whether WEE1 inhibition is effective in this enriched population. This research is generously funded by Prostate Cancer Canada through a 2016 Rising Star Award.
Genomic predictors of docetaxel resistance in men with advanced prostate cancer
Although docetaxel is the front-line chemotherapy for men with CRPC, the response rate is only 50%, and resistance is ultimately inevitable. Given the significant morbidity associated with chemotherapy, it is important to develop predictive markers of treatment response, and therefore allow patients to avoid unnecessary toxicity and facilitate earlier access to different and potentially effective therapeutic agents. We are collecting tissue and liquid biopsies from a variety of clinical settings where docetaxel is administered, including both early and late stage patients. We aim to identify genomic aberrations associated with docetaxel response, in order to better predict the subset of men that will benefit from chemotherapy.
Precision oncology ‘umbrella’ clinical trial
The Wyatt laboratory is leading the genomics aspect of a unique phase II umbrella trial for patients with mCRPC, launching in early 2016. The trial, lead by Dr. Kim Chi, aims to create a multi-centre precision medicine program whereby targeted therapies are matched to patients on the basis of alterations found in pre-treatment circulating cell-free DNA. This project will implement many of the predictive molecular biomarkers established in the studies described above.