Understanding the “Aspirin Gene”

New $6.7 million NIH grant seeks to identify genetic pathways for preventing and treating colon cancer

 Sanford D. Markowitz, MD, PhD

The genetic pathways behind colon cancer are a seemingly endless source of inquiry for Sanford D. Markowitz, MD, PhD, Medical Oncologist, UH Seidman Cancer Center; Professor of Medicine, Case Western Reserve University School of Medicine. Over the past two decades, his research has identified two key colon cancer tumor suppressor genes, TGF-beta RII and 15-PGDH, which explain how and why colon cancer develops in certain families in whom the disease is inherited. In addition, Dr. Markowitz and his team have explained why taking aspirin can prevent colon cancer in some individuals but not others – a phenomenon linked to the 15-PGDH gene.

“Differences in colon 15-PGDH provide the molecular basis for individual sensitivity or resistance to the cancer-preventive effects of aspirin,” says Dr. Markowitz, a medical oncologist at University Hospitals Seidman Cancer Center. Dr. Markowitz also serves as head of the GI Cancer Genetics Program and as principal investigator of the National Cancer Institute-funded GI Cancers Specialized Program of Research Excellence (SPORE) at the Case Comprehensive Cancer Center.

Dr. Markowitz has received grant support for this work from the National Cancer Institute for the past 30 years. Now, he has received NIH’s largest and most prestigious individual award, an Outstanding Investigator Award of $6.7 million over seven years to further apply the lessons being learned about 15-PGDH.

“Our intent is to recognize individuals that have a high risk of colon cancer and try to design ways to lower their risk,” he says. “We will work to develop new drugs that target this pathway to prevent cancer and also try to find new ways to treat colon cancer. By design, this award will allow us to push the envelope and come up with new and different strategies and approaches.”

Already, Dr. Markowitz and his team have described a test for 15-PGDH that could be optimized by hospital laboratories. And they are working to develop new drugs that can modulate the 15-PGDH gene. In a paper reported in 2015 in the journal Science, they found that blocking 15-PGDH with a specific small molecule can help promote hematopoietic recovery after bone marrow transplantation, promote liver regeneration after liver surgery, and protect against colitis in laboratory animals.

Dr. Markowitz is aware that this seems a bit counter-intuitive, as his team had first established 15-PGDH’s role as a tumor suppressor gene.

“One explanation for this seeming paradox is that while high levels of 15-PGDH are useful in cancer prevention, in certain biological contexts, such as in bowel injury, low levels of 15-PGDH may provide a biological advantage by potentiating faster organ recovery,” he says. “More generally, these findings are an example demonstrating how regulated and short-term inhibition of a tumor suppressor gene may provide therapeutic utility without adverse effect, particularly in a disease context in which tissue repair is the immediate medical goal.”

Dr. Markowitz and his team are continuing to pursue this line of research. Plus, they’re examining what role the intestinal microbiome may play in regulating 15-PGDH and additional genetic processes underlying the development of colon cancer.

“The levels of 15-PGDH vary very dramatically from one person to another,” he says. “We believe this may, in part, be a response to the differences in the type of bugs we carry around in our intestines. Our hypothesis is that the differences in levels of 15-PGDH have to do with how much inflammation there is in the colon and that inflammation is very often caused by the different bacteria that we carry around. We predict that there will be a relationship between the bacteria, the level of inflammation in the gut, and the level of PGDH response to those bacteria, with the bacteria, in effect, turning on and off the gene.”

For more information about Dr. Markowitz’ research, please email Cancer.lnnovations@UHhospitals.org.