Combined treatment approach for locally advanced pancreatic cancer aims to identify biomarkers

Investigators are developing a novel, multistep investigational treatment for locally advanced pancreatic cancer, which is complex and difficult to treat.

Locally advanced pancreatic cancer has the lowest survival rate of any solid tumor, with a cumulative 5-year survival rate of only 4% for all stages of disease. Surgery is rarely an option for patients because tumors often involve vital blood vessels. Chemotherapy and radiotherapy given concurrently remain the mainstay treatment, yet to-date, no treatment has had a significant impact on improving outcomes.

"To move the needle forward toward prolonged survival and better treatment outcomes, our research team created a combined investigational regimen for patients with locally advanced pancreatic cancer," said Richard Tuli, MD, PhD, a radiation oncologist in the Department of Radiation Oncology and a member of the Cedars-Sinai Samuel Oschin Comprehensive Cancer Institute in Los Angeles, California. "Coupled with this research treatment, we are also looking to identify patient biomarkers, or molecular signatures, that may provide clues to how and why some patients respond better than others."

Tuli was the first author of a preclinical study recently published in Translational Oncology (2014; doi:10.1016/j.tranon.2014.04.003). Using animal models, the study evaluated a novel treatment for pancreatic cancer that combines radiation, chemotherapy, and treatment with a specific drug that can inhibit the repair of cancer cells damaged by chemotherapy and radiation. Successful research findings led to a clinical trial now enrolling eligible patients.

Many standard cancer treatments for pancreatic cancer, including chemotherapy and radiation therapy, kill tumors by damaging their DNA. When such DNA damage occurs, proteins known as PARPs move to the site of damage and begin to mend these broken strands of DNA, allowing cancerous cells and tumors to recover, grow, and proliferate, thereby escaping the effects of treatment.

With this knowledge, researchers combined radiation with a drug to prevent PARP from repairing cancerous cells. When the treatment was given to laboratory mice, the combination resulted in prolonged survival.

"Based on this research, we are now conducting a first-in-human study combining the PARP inhibitor with radiation and chemotherapy in patients with locally advanced pancreatic cancer, with an ultimate goal of improving survival rates and treatment outcomes," said Tuli.

The investigational treatment regimen could prove beneficial to patients with other forms of cancer, too. Recent research findings suggest PARP could be beneficial for patients who carry either or both the BRCA1 or BRCA2 mutations. Normal BRCA genes help suppress tumor formation and repair damaged DNA; the mutated genes' protective mechanisms are compromised, leading to genetic defects that result in cancer. But the defective repair capability is a process that may be exploited by treatments, such as PARP inhibition, which further impairs the ability of tumors to repair their own DNA after insult with radiation.

In addition to adding a novel PARP inhibitor to the regimen, investigators are seeking to identify other markers related to DNA damage that could provide a molecular signature, or biomarker, to forecast how a patients' tumor would respond to treatment and help guide personalized treatment options in the near future.

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