UPMC Hillman Cancer Center

November 2018

When DNA Isn't Properly Repaired

I would guess that many of you are familiar with the expression "gene mutation" and are aware that mutations that are inherited from a parent (such as those in the infamous BRCA1 "breast cancer" gene) or occur spontaneously (such as those from exposure to the sun's UV rays, cigarette smoking, or carcinogenic chemicals) make individuals more susceptible to developing cancer. Understanding the underlying causes of gene mutations and how they can lead to cancer are important areas of basic research in which Hillman investigators excel. Oftentimes, the fault lies in the inability to properly repair DNA "lesions" (chemical modifications of the DNA).

It has been estimated that every cell in the human body suffers at least one type of DNA lesion every five seconds. Furthermore, once cells become cancerous, they often lose the ability to properly maintain and repair their DNA, which leads to additional mutations, as well as rearrangements and other changes in the chromosomes of the cell nucleus. If the level of non-repaired DNA damage is extremely high, the cell will die. This is exploited in the treatment of cancer.

The Hillman researchers who study the molecules and mechanical processes required for proper DNA repair and chromosome maintenance belong to our new Genome Stability Program being led by Drs. Patricia Opresko and Ben Van Houten. The members of this program have a prior history of collaborating with each other—and with scientists from other Hillman programs and cancer centers—on studies published in some of the highest-ranked professional journals.

Dr. Opresko focuses on DNA damage and repair at telomeres—the tips of repeating DNA sequences found at the ends of each chromosome, which shorten with aging, yet are abnormally lengthened in tumor cells. Dr. Van Houten, in collaboration with Dr. Simon Watkins, a Genome Stability Program member who directs Hillman's state-of-the-art Cell and Tissue Imaging Facility and the University's Center for Biologic Imaging, has generated stunning fluorescent microscopy images and videos showing how individual DNA repair protein molecules recognize and respond to a specific site of DNA damage.

Altogether, Hillman's Genome Stability Program comprises over 35 investigators, many of whom study DNA repair and chromosome maintenance. Included in this group are: Dr. Kara Bernstein who first tests her novel hypotheses of how DNA repair proteins interact in rapidly dividing yeast cells before moving into the slower growing and more complicated cells of humans and other mammals; Dr. Roderick O'Sullivan, who studies how chromosomal telomeres become elongated in highly aggressive adult and pediatric cancers, and Dr. Christopher Bakkenist who has conducted comprehensive studies on two molecules known as ATM kinase and ATR kinase that regulate DNA replication and repair.

Dr. Bakkenist's work is particularly exciting, because his basic laboratory findings have stimulated collaborative development of a new class of targeted anti-cancer drugs. In the absence of significant additional toxicity, ATR inhibitor drugs increase the effectiveness of "cytotoxic" therapies (radiotherapy and traditional chemotherapy drugs) that purposely introduce DNA lesions in order to cause a cascade of effects that lead to the death of tumor cells.

VX-970 (also known as M6620) is an ATR kinase inhibitor that has been advanced into a Phase I clinical trial in the National Cancer Institute (NCI) Experimental Therapeutics Clinical Trials Network (ETCTN), with Dr. Liza Villaruz of Hillman's Cancer Therapeutics Program as Principal Investigator and Chair of the ETCTN VX-970 Working Group. Patients with different types of cancer are now being enrolled onto the trial entitled VX-970 and Irinotecan Hydrochloride in Treating Patients With Solid Tumors That Are Metastatic or Cannot Be Removed by Surgery (UPCI 15-164/NCT02595931) at Hillman and 16 other cancer centers. (Hillman is one of only 11 cancer centers in the U.S. to be selected as an ETCTN Lead Academic Site, with Hillman Deputy Director and Cancer Therapeutics Program Co-Leader Dr. Edward Chu serving as our Principal Investigator.)

I am especially pleased to announce the arrival of several new faculty to the Genome Stability Group. Dr. Heath Skinner, who left MD Anderson Cancer Center to join Hillman in September, is a physician-scientist who is treating patients as a practicing radiation oncologist, and running a laboratory to study why some tumors are resistant to radiotherapy. (He has already identified several contributing mutations.) Dr. Skinner is also designing and conducting clinical trials to test new strategies for overcoming radioresistance, including a national-level trial in the NCI National Clinical Trials Network on which he is the Co-Principal Investigator (UPCI 15-121/NCT02186847, now closed to enrollment).

In mid-November we welcome two new investigators who are just launching their independent academic careers as first-time Assistant Professors and members of the Genome Stability Program. Dr. Jacob Stewart-Ornstein will be arriving from Harvard Medical School with highly coveted Pathway to Independence Award funding from the National Cancer Institute to study the role of DNA repair in resistance to cytotoxic therapy. Dr. Yael Nechemia-Arbely will be arriving from the Ludwig Institute for Cancer Research at the University of California, San Diego to study the mechanisms for ensuring that our chromosomes are properly replicated and maintained.

Lastly, those of you who have a strong family history of certain malignancies (e.g., breast, ovarian, leukemia, and/or lymphoma), especially when they occur at a young age, may want to discuss genetic testing for inherited mutations that prevent proper DNA repair with your gynecologist or primary care physician.


Robert L. Ferris, MD, PhD