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A New and Targetable Epigenetic Biomarker for the Most Common Cancer

Basal cell carcinoma (BCC) is the most common cancer in people of Caucasian descent. BCC affects 2-3.5 million Americans yearly, and in some countries such as Denmark, BCCs outnumber all other cancers combined. Most BCCs can be successfully treated with surgery, particularly using Mohs micrographic surgical techniques, but some BCC tumors are more aggressive and can recur and invade deeply, making successful treatment quite challenging. Aggressive tumors in sensitive locations such as the face, and particularly around the eyes, ears and mouth, are also quite challenging to treat. Currently, diagnosis of BCC is based on strict histologic criteria, using standard staining and microscopy. However, histology is not particularly predictive of a BCC tumor’s clinical aggressiveness. Ideally, molecular genetic markers would complement histologic criteria to provide a better predictive test. In addition, such molecular genetic markers may serve as therapeutic targets, so that medical therapies could be used to improve the success of treatment. A new key marker, EZH2, is an enzyme involved in epigenetic regulation of cell identity that appears to be critical in cancer biology.Basal Cell Carcinoma - cancerBasal Cell Carcinoma - Cancer

For locally advanced and metastatic BCCs, only two US FDA-approved medications exist. These medications, vismodegib and sonidegib, work by blocking a crucial BCC growth pathway known as hedgehog signaling. However, their role in preserving organ function and improving long-term outcomes is still unclear.

A newly-initiated clinical trial (VISORB – https://clinicaltrials.gov/ct2/show/NCT02436408), led by Dr. Alon Kahana at the University of Michigan (U-M), Associate Professor of Ophthalmology & Visual Sciences, and the William Davidson Emerging Scholar at the A. Alfred Taubman Medical Research Institute (AATMRI), aims to study the role of the hedgehog inhibitor vismodegib in treating BCC around the eye. The study, partially funded by an investigator-initiated research grant from Genentech, Inc., maker of vismodegib, is directly testing whether medical treatment can improve visual outcomes in patients with advanced BCC around the eye. As part of this research project, Dr. Kahana, an ophthalmic plastic surgeon, has collaborated with U-M faculty including the Leslie and Abigail Wexner Emerging Scholar at the AATMRI, Dr. Rajesh C. Rao, a retina surgeon and Assistant Professor of Ophthalmology & Visual Sciences, and Pathology; Assistant Professor of Pathology and dermatopathologist Dr. May P. Chan; and Dr. Christopher Andrews at the Center for Statistical Consultation & Research to identify and characterize molecular markers for aggressive BCC tumors. Their report, just published in the prestigious journal JAMA Oncology (Rao et al., 2016: http://oncology.jamanetwork.com/article.aspx?articleid=2511036), identifies a new key marker: EZH2 – an enzyme involved in epigenetic regulation of cell identity that appears to be critical in cancer biology. Evaluating the expression pattern of EZH2 in BCC tumor samples from 60 patients, along with assessment of cell proliferation and histologic grade, revealed that expression of EZH2 protein is increased in more aggressive forms of BCCs vs. less aggressive tumors. Furthermore, EZH2 expression correlated with Ki67 expression, a marker of cell proliferation. Together, EZH2 and Ki67 expression was highly correlative with histologic grade.

This report has implications beyond biomarker discovery. Over the last 10-15 years, U-M researchers Drs. Arul Chinnaiyan and Celina Kleer have found that EZH2 is over-expressed in aggressive forms of prostate and breast cancers, respectively. Other scientists have found that blocking EZH2 can reduce the growth of cancers in the laboratory. The data has become so promising that there are now several clinical trials testing anti-EZH2 drugs in a variety of aggressive cancers. This report suggests that anti-EZH2 therapy may be effective for aggressive forms of BCC as well, possibly in combination with hedgehog pathway inhibitors such as vismodegib, or as an adjuvant to surgery. Future studies, as well as the VISORB clinical trial, are underway.

Original Article:
Rao RC, Chan MP, Andrews CA, & Kahana A (2016). EZH2, Proliferation Rate, and Aggressive Tumor Subtypes in Cutaneous Basal Cell Carcinoma. JAMA oncology PMID: 27054919

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Rajesh Rao

Rajesh Rao