Pitt moves closer to developing specialized cancer treatment

After discovering an alternative way that certain cells divide, Pitt researchers could be on the way to developing treatments for specific types of cancer.

The lab of Dr. Roderick O’Sullivan, a University of Pittsburgh Cancer Institute member, at the Hillman Cancer Center published findings about cancer cell division in Cell Reports, a journal of peer-reviewed studies, on Nov. 8.

Whether at the Hillman Cancer Center or another facility, Pitt’s campus has played a large role in cancer research.

The U.S. Congressionally Directed Medical Research Program of the Department of Defense awarded Pitt and Carnegie Mellon University researchers a grant in June to use 3-D printing to create models that could help doctors identify cancer. Patrick Moore, a researcher at Pitt’s Cancer Institute Cancer Virology Program, won a multi-million dollar grant in March for his research on the link between cancer and viruses. The University of Pittsburgh Cancer Institute partnered with Magee-Womens Hospital of UPMC in Oct. 2015 to test for the most successful breast cancer treatments.

In O’Sullivan’s lab, researchers are examining how cancer cells override the body’s natural defense system to prevent cells from multiplying too much.

According to O’Sullivan, an assistant professor of pharmacology and chemical biology at Pitt’s School of Medicine, cells have checkpoints that prevent them from growing in an uncontrolled manner. Each time cells divide, their telomeres — caps on the end of each DNA strand — shorten, triggering a checkpoint. Very short telomeres trigger cell death.

Cancer cells bypass these checkpoints, overriding the signal that stops cell growth and therefore acquiring mutations and becoming immortal.

Originally, scientists thought cancer cells only tricked the telomeres by using telomerase, a telomere-lengthening enzyme. The discovery found another method in which cancer cells operate to the same end, called alternative lengthening of telomeres, or the ALT pathway.

Kara Bernstein, a professor in the department of microbiology and molecular genetics, studies the rate at which double-strand DNA repairs protein. Double-strand DNA breaks are often seen in cancers.  

“We understand that the prognosis for patients who have cancers that use the ALT pathway have a poorer prognosis. Understanding the mechanisms has important ramifications for cancer, treatments and understanding of agent,” Bernstein, a colleague of O’Sullivan’s, said.

According to a UPCI press release, during ALT, cancer cells manipulate the telomere and lengthen it every time it shortens, tricking the cell into thinking it can divide and therefore spreading the tumor.

ALT is used by 15 percent of cancers, such as neuroblastoma — the most common pediatric cancer in the world — pancreatic, endocrine and soft tissue cancers.

According to O’Sullivan, cancers using ALT pathways are more resistant to chemotherapy compared to cancers that use telomerase, but why that’s the case is unknown. It is possible that the resistance to chemotherapy occurs because the changes cancerous cells make to other cells’ DNA is hidden. As cancer cells divide, they can change, acquiring distinct mutations later on in their cell life.

The researchers used innovative technology –– called proximity dependent biotinylation, or BioID –– that allowed them to identify cancer cells that use the ALT pathway, O’Sullivan said. BioID works by identifying which proteins are close to one another, and therefore, which proteins could be involved in how telomeres lengthen in cancer cells.

These small differences can have big consequences, though.

“This is basic research, but the word ‘basic’ is not meant in the literal sense. Knowing how ALT telomeres are regulated and what they are composed of provides a foundation for subsequent studies that might provide a better understanding of cancer cell growth,” O’Sullivan said.

Targeting ALT telomeres will allow researchers to develop more adequate treatments for patients.

“Pitt can use this discovery to create treatments tailored to the patient’s specific prognosis. We have all the facilities available,” O’Sullivan said, referring to the departments of Pharmacology and Chemical Biology, the Drug Discovery Labs and Hillman Cancer Center, which is one of the NCI cancer centers.  “Pitt is fully capable. ”