CANCER BIOLOGY & THERAPY 2016, VOL. 17, NO. 3, 231–232 http://dx.doi.org/10.1080/15384047.2016.1139270

JOURNAL CLUB

Building a hit list for the fight against metastatic castration resistant prostate cancer Jonathan D. Strope, Douglas K. Price, and William D. Figg Genitourinary Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA

ABSTRACT

ARTICLE HISTORY

Identification of genetic alterations in Metastatic Castration Resistant Prostate Cancer (mCRPC) may provide scientists and clinicians with a list of new targets for drug research and development. Recently published in Cell, Robinson et al. present the first look at genetic data from mCRPC lesions gathered over multiple years and from many institutions.

Received 4 December 2015 Accepted 1 January 2016

While the identification of genetic alterations in metastatic castration resistant prostate cancer (mCRPC) has not been extensively studied, it has great potential to direct targeted therapies. Recently published in Cell, Robinson et al., discuss their findings gathered from prospective multi-institutional genetic testing of mCRPC lesion sites compared to normal tissues.1 Their findings emphasize the importance of targeted genetic therapies for patients and reinforce the long held belief that no 2 cancers are identical, particularly in the metastatic setting. The authors estimate that within their cohort, nearly 90% of mCRPC patients harbored clinically actionable aberrations. Genetic alterations present in primary prostate cancer have been well-studied and characterized but haven’t lead to many “actionable tumors.“2 Robinson et al. has defined this as, “predicting response or resistance to a therapy, having diagnostic or prognostic utility across tumor types.” Androgen deprivation by chemical or surgical means and/or radiation provides an initial response and decreases tumor burden, however, many patients progress to castration resistant prostate cancer. The authors note that studies of the genetic makeup of tumors in mCRPC are difficult to accomplish so they designed a study in which tumor biopsies were obtained from multiple lesion sites from living patients, allowing for a more comprehensive study pool. The study utilized a multi-facility consortium wherein patients being treated with the standard of care also had tumor biopsies taken at baseline or before treatment. Of the 150 total tumor samples taken and meeting criteria, 42% were from lymph nodes, 28.7% were from bone, 12.7% were from liver, and 16.7% from other soft tissue. Integrated clinical sequencing showed that the average mutation rate in mCRPC was 4.4 mutations/Mb with some reaching as high as 50 mutations/Mb. In most cases, a driver aberration, one in an oncogene or tumor suppressor, was found among the tumor samples. Types of alterations found include

KEYWORDS

Actionable tumors; androgen deprivation; androgen receptor; genetic alterations; mCRPC; PTEN; translational medication

99% single nucleotide variants, 60% gene fusions, 50% gene deletions, and 54% gene amplifications. A surprisingly large amount of mCRPC samples contained aberrations in the Androgen Receptor (AR). Excluding the AR, 65% of samples contained clinically actionable aberrations including: 49% in the PI3K pathway, 19% in DNA repair pathway, 3% in RAF kinases, 7% in CDK inhibitors, and 5% in the WNT signaling pathway. Amplification and deletion aberrations in the AR pathway were present in 71.3% of samples where AR alterations were present. One patient, with 2 different mutations each encoding a functional AR, demonstrates that heterogeneity exists between tumors in mCRPC. AR splice variants, a recent focus of investigation, were distributed throughout the samples. ARv7 was present in patients not treated with abiraterone, a CYP17A1 inhibitor, or enzalutamide, an AR inhibitor both approved by the FDA for treatment of mCRPC. Studies have shown resistance to enzalutamide and abiraterone is observed with the ARv7 mutant present,3 however, levels of ARv7 were much lower than full length AR in these patients. Previously undiscovered, mutations in the androgen-regulated ZBTB16 gene were present in 5% of samples. New discoveries were also made in non-androgen associated pathways. Alterations in PIK3CB of the PI3K pathway were seen in samples that were also PTEN deficient. The PI3K pathway is heavily involved in cell motility, survival, and metabolism. Previous studies have implicated the PI3K pathway and PTEN in mCRPC progression.4,5 In the WNT pathway, the authors note that aberrations not previously reported were consistently seen in APC, a tumor suppressor interacting with Bcatenin. Biallelic deletion of BRCA2 was observed in 12.7% of patients and the deletions have been linked in an ongoing study by the authors to PARP inhibition treatments. According to the

CONTACT William D. Figg fi[email protected] Disclaimer: The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does the mention of trade names, commercial products, or organization imply endorsement by the US Government. This article not subject to US copyright law.

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authors, PARP inhibition sensitivity has also been associated with ATM and BRCA1. The androgen pathway has been heavily implicated in progression of mCRPC leading to targeted drugs like enzalutamide and abiraterone. Based on the findings of Robinson et al., it is clear why there are meaningful benefits from these treatments. This study has demonstrated that current approaches utilizing small molecule inhibitors directly targeting specific pathways are logical. Genetic hits on pathways that have yet to be tested show promise for future development. The ability to predict a patient’s outcome prior to starting treatment delivers many positives including financial, physical, and emotional savings. Unfortunately, translation of lab results into clinical results has so far proven difficult. In reality, only a small percentage of the “90% actionable” aberrations will lead to changes in therapeutic outcomes. However, the benefits far outweigh the difficulties and any meaningful treatment associated with a specific genetic alteration will translate to patients with an overall better outcome. The authors point to future studies where they will begin to correlate patient outcomes with genetic makeup, and hope to prove how well genetically tailored treatments work in the clinical setting.

Reference 1. Robinson D, Van Allen EM, Wu YM, Schultz N, Lonigro RJ, Mosquera JM, Montgomery B, Taplin ME, Pritchard CC, Attard G, et al. Integrative clinical genomics of advanced prostate cancer. Cell 2015; 161:1215-28; PMID:26000489; http://dx.doi.org/10.1016/ j.cell.2015.05.001 2. Taylor BS, Schultz N, Hieronymus H, Gopalan A, Xiao Y, Carver BS, Arora VK, Kaushik P, Cerami E, Reva B, et al. Integrative genomic profiling of human prostate cancer. Cancer Cell 2010; 18:11-22; PMID:20579941; http://dx.doi.org/10.1016/j.ccr.2010.05.026 3. Antonarakis ES, Lu C, Wang H, Luber B, Nakazawa M, Roeser JC, Chen Y, Mohammad TA, Chen Y, Fedor H, et al. AR-V7 and resistance to enzalutamide and abiraterone in prostate cancer. New Eng J Med 2014; 371:1028-38; PMID:25184630; http://dx. doi.org/10.1056/NEJMoa1315815 4. Wang X, Trotman LC, Koppie T, Alimonti A, Chen Z, Gao Z, Wang J, Erdjument-Bromage H, Tempst P, Cordon-Cardo C, et al. NEDD4-1 is a proto-oncogenic ubiquitin ligase for PTEN. Cell 2007; 128:129-39; PMID:17218260; http://dx.doi.org/10.1016/j. cell.2006.11.039 5. Li J, Yen C, Liaw D, Podsypanina K, Bose S, Wang SI, Puc J, Miliaresis C, Rodgers L, McCombie R, et al. PTEN, a putative protein tyrosine phosphatase gene mutated in human brain, breast, and prostate cancer. Science 1997; 275:1943-7; PMID:9072974; http://dx.doi.org/10.1126/ science.275.5308.1943