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ASCO 2021

ASCO 2021 Science of Oncology Award and Lecture

(UroToday.com) Dr. Arul Chinnaiyan, Director, Michigan Center for Translational Pathology, S.P. Hicks Endowed Professor of Pathology was awarded the Science of Oncology Award for facilitating the delivery of precision medicine and advancing the field of cancer genomics and functional biology. In this lecture, Dr. Arul Chinnaiyan highlighted some of the accomplishments of his group over the past several years. He first described the discovery of the TMPRSS2-ERG fusion,1 which was fundamental work leading to a broader understanding of the incidence of gene fusions in solid tumors. This was discovered initially using microarray expression data from cancer samples looking for transcripts expressed at outlier levels. This approach identified outlier expression of ERG, and subsequent analysis uncovered fusion of a 3’ portion of this gene with the upstream enhancer and 5’ end of the androgen regulated TMPRSS2 gene. Mechanistically, the fusion facilitates androgen regulation of ERG protein expression in the prostate, is found a large proportion of prostate cancer, has been shown to promote prostate carcinogenesis in pre-clinical models, and has clear utility as a diagnostic biomarker for pathologists. Many gene fusions in solid tumors have been identified subsequently, including in prostate cancer, a summary of which is shown below. Ongoing work focused on ERG over-expression in prostate cancer includes the development of urine-based prostate cancer screening tests, and peptidomimetics for blocking ERG function.

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Building upon the utility of high-throughput sequencing to elucidate novel biology in cancer, the University of Michigan created one of the first integrated clinical sequencing platforms, though this is now much more widespread and can be done commercially or through many academic centers. As part of this clinical sequencing platform, the group at Michigan created a precision medicine tumor board to annotate detected variants and use them to make clinical treatment recommendations. A substantial subset of patients who received sequencing-directed therapy had notable response to targeted therapy. Genomic tumor boards have been presented in detailed discussion at other conference educational sessions.

Another sequencing study through the SU2C effort for advanced prostate cancer identified numerous genetic alterations in this disease, most notably alterations in the DNA repair pathway in genes such as BRCA2. Alterations in these genes are now targetable with specific therapy: (1) the PARP inhibitors olaparib and rucaparib in advanced prostate cancer harboring certain alterations in homologous recombination repair and (2) potentially with immune checkpoint blockade for patients with biallelic CDK12 loss.

Finally, Dr. Chinnaiyan shared a developing story from his group focusing on how targeting the chromatin-modifying SWI/SNF complex may have therapeutic efficacy. By specifically targeting components of this large complex, his group has demonstrated modification to key enhancer involved in regulating the androgen receptor/FOXA1 expression program, which inhibits growth in pre-clinical models of advanced prostate cancer.

Presented by: Arul Chinnaiyan, MD, PhD, S. P. Hicks Endowed Professor of Pathology and Professor of Urology at the University of Michigan

Written by: Alok Tewari, MD, PhD, Medical Oncologist at the Dana-Farber Cancer Institute, at the 2021 American Society of Clinical Oncology (ASCO) Annual Meeting, Virtual Annual Meeting #ASCO21, June, 4-8, 2021

Reference: 
1. Tomlins  S., Rhodes D., Perner S., et al., Recurrent fusion of TMPRSS2 and ETS transcription factor genes in prostate cancer. Science. (2005);310(5748):644-8