Posted February 23, 2018

Howard Scher, M.D., Memorial Sloan Kettering Cancer Center
Daniel Danila, M.D., Memorial Sloan Kettering Cancer Center

In recent years, drug development for metastatic castrate resistance prostate cancer (mCRPC) has shifted towards a precision medicine approach, where the choice of treatment is based on the biologic profile of an individual patient's tumor. However, this requires the ability to assess the molecular basis of a patient's cancer using an analytically valid biomarker assay at the time of treatment, which is not currently available. To support the advancement of precision medicine, the PCRP awarded Dr. Howard Scher and his research team at Memorial Sloan Kettering Cancer Center a FY12 Transformative Impact Award to implement a systematic approach to biomarker development that begins with an analytically valid assay, followed by a clinical validation program.

Dr. Scher's team began by focusing their efforts on developing an analytically valid assay to reliably measure the level of a variant androgen receptor protein, AR-V7, which has been associated with poor clinical prognosis and resistance to next generation androgen receptor signaling inhibitors (ARSi), such as enzalutamide and abiraterone. With support from the Transformative Impact Award as well as a FY08 Physician Research Training Award to Dr. Daniel Danila, Dr. Scher's team investigated the correlation between the level of detectable AR-V7 protein in cancer cells circulating in a patient's bloodstream, called circulating tumor cells (CTCs), with clinical progression by measuring changes in prostate antigen (PSA) and time to radiographic progression free and overall survival. The research team analyzed CTCs in patients treated with either taxane-based chemotherapy or ARSi inhibitors and at the point in their disease management where a change in therapy was needed to a different standard-of-care drug. These studies demonstrated that patients treated with taxane-based chemotherapy responded well to the therapy only if AR-V7 protein was present in the nuclei of their CTCs. On the contrary, they discovered that the presence of both nuclear and non-nuclear localization of AR-V7 protein corresponded to patients that responded well to ARSi inhibitors. These results suggest that presence of only the nuclear AR-V7 protein could be a predictor of positive response to taxane-based treatment and the nuclear localization of AR-V7 may provide guidance for treatment decisions for men with mCRPC.

Dr. Scher's group also utilized the PCRP-funded Prostate Cancer Clinical Trials Consortium to evaluate the correlation between CTC phenotypic heterogeneity, or the amount of variation in both gene expression and morphology, and patient response to either taxane or ARSi inhibitor therapy. They found that for mCRPC patients whose CTCs lacked AR-V7 expression, low CTC phenotypic heterogeneity was associated with better overall survival in patients treated with ARSi inhibitors, whereas high CTC heterogeneity was associated with better overall survival in patients treated with taxane chemotherapy. This work therefore provided evidence that another measurable variable, phenotypic heterogeneity, may be informative for the selection of treatment in patients without the AR-V7 splice variant.

These findings are now being translated into assays that could be validated across multiple Clinical Laboratory Improvement Amendment (CLIA) laboratories to show low variability regardless of where the assay is performed. Collaborations between Dr. Scher and industry partners Epic Sciences and Genomic Health has resulted in an AR-V7 liquid biopsy test (Oncotype DX AR-V7 Nucleus Detect Test), which Dr. Scher's team is completing the analysis of in an independent data set of patients, including some who were treated outside of Memorial Sloan Kettering; it is expected this test will be available to physicians in mid-2018. Efforts to demonstrate the clinical utility of using CTC phenotypic heterogeneity at the single cell level as a predictive biomarker for treatment decisions are still ongoing; a larger cohort study is planned, and assessment of longitudinal and kinetic changes over time in response to therapy are ongoing, both within the context of mCRPC clinical decisions and outside of prostate cancer. Separately, a PCCTC-led prospective clinical trial testing the ability of CTC AR-V7 mRNA and nuclear-specific AR-V7 protein in matched samples to predict treatment response (NCT02269982) is ongoing.

The processes established by Dr. Scher's Transformative Impact Award have allowed his team to continue working on validating biomarker assays for additional prostate cancer biomarkers. Development of standardized, validated biomarker assays have the potential to advance personalized medicine by reducing exposing of patients to ineffective, potentially toxic, and costly treatments, and may also impact the development of new therapies by enabling the timely conduct of clinical trials enriched for patients most likely to respond.

Publications:

Scher HI, Lu D, Schreiber NA, et al. 2016. Association of AR-V7 on circulating tumor cells as a treatment-specific biomarker with outcomes and survival in castration-resistant prostate cancer. JAMA Oncol, vol. 2, pp. 1441-1449.

Scher HI, Graf RP, Schreiber NA, et al. 2017. Nuclear-specific AR-V7 protein localization is necessary to guide treatment selection in metastatic castration-resistant prostate cancer. Eur Urol, vol. 71, pp. 874-882.

Scher HI, Graf RP, Schreiber NA, et al. 2017. Phenotypic heterogeneity of circulating tumor cells informs clinical decisions between AR signaling inhibitors and taxanes in metastatic prostate cancer. 2017. Cancer Res., vol. 77, pp. 5687-5698.

Links:

Toward the Practice of Precision Medicine: A Biomarker Validation Coordinating Center

Circulating Tumor Cells as Biomarkers for Patients with Metastatic Prostate Cancer: Developing Assays for Androgen Receptor Signaling Pathway

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