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June 12, 2018 - Gene signature may help tailor chemo for colon cancer


MOBILE, Alabama (6/12/2018) -- Collaborative efforts by researchers at USA Mitchell Cancer Institute hold promise for using a patient’s own gene signature to deliver tailored chemotherapy doses, thereby reducing adverse side effects. Their work also aims at identifying natural tiny messengers with the potential to be used in targeted drug delivery and early detection screenings.

According to the American Cancer Society – when skin cancers are excluded – colorectal cancer is the third-most common cancer diagnosed in both men and women in the United States, with more than 97,000 new colon cancer and more than 43,000 new rectal cancer cases estimated for 2018.  Moreover, the ACS expects the condition to cause roughly 50,630 deaths in 2018, making it the third leading cause of cancer-related deaths in both U.S. men and women.

Medical oncologist Dr. Moh'd Khushman and cancer researcher Dr. Ajay Singh are currently exploring the role of pharmacogenomics in patients with colorectal cancer treated with a family of drugs called Fluoropyrimidines. They are also actively looking into understanding better how tumor cells communicate with other cells – both in their surroundings and at distant organ sites – enabling the growth and spread of malignancy.


Drugs and genes

Combining the science of drugs with the study of genes and their functions, pharmacogenomics is the study of how genes affect a person’s response to drugs and seeks the development of effective, safe medications and doses tailored to a person’s genetic makeup. Although this genetic signature determining both response and side effects to treatments applies to every drug, Singh and Khushman say that its implications in cancer patients treated with chemotherapy can be more significant than in patients treated with, say, antibiotics or other common drugs.

“We at MCI have recognized a genetic signature that helps us know up front if a patient is more likely to suffer side effects,” Khushman said, noting the pair published a paper recently focused on the role of the enzyme dihydropyrimidine dehydrogenase, or DPD, in a patient’s ability to tolerate Fluoropyrimidine, considered widely to be the backbone of multiple chemotherapy regimens in patients with gastrointestinal malignancies.

“DPD is one part of the genetic signature we look for to know if this drug would be toxic or not,” he said, explaining DPD typically renders roughly 80 percent of Fluoropyrimidine inactive. Consequently, patients suffering a DPD deficiency are exposed to significantly higher concentrations of the drug causing toxicity.

“Studying DPD is complex because there are multiple alterations in the genetic makeup of the enzyme, but here at MCI we have recognized a specific genetic signature that affects this specific enzyme. Further ongoing studies may enable us to determine the right doses of Fluoropyrimidine to those specific patients to limit drug toxicity, while achieving its maximum efficacy,” Khushman said.


Exosomes as biomarkers

Meanwhile, Singh explained the pair’s exosome work that holds tremendous promise for understanding better how tumor cells interact with the cells in their surroundings and at distant organ sites to facilitate their relentless growth and spread. Exosomes are the tiny membrane bubbles shed by the tumor cells that may carry tumor-specific information and can thus be “exploited as biomarkers to diagnose cancer early, know if a patient has an aggressive or indolent type of cancer, or even make assessments regarding what types of treatments would generate the optimal patient responses.”

Upon exposure to chemotherapy, he explained, tumor cells shed specific exosomes in a “counter-defense mechanism” that contains material that would render better chemo-fighting ability to other tumor cells. “We are trying to utilize this information for better therapeutic planning and to develop effective alternative approaches for treatment,” he said.

More importantly, Singh said, since exosomes are naturally-occurring messengers within the body delivering material from one cell to another, “we are trying to exploit this very property for efficient and protected drug delivery to the tumor cells.”

Khushman emphasized that screening for colon cancer is important because colon cancer is a preventable and curable disease when colon cancer or precancerous polyps are detected and treated early. “The role of exosomes to help with early diagnosis is promising, and efforts are ongoing,” he said.

USA Mitchell Cancer Institute is the only academic cancer research and treatment facility on the upper Gulf Coast corridor, with offices in Mobile, Fairhope and Monroeville.




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