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Fox Chase Researchers Uncover Novel Mechanism of Promising Drug Treatment for Colon Cancer

CHICAGO, IL (May 29, 2013)—Monoclonal antibodies represent a promising treatment strategy for a range of cancers because they harness the immune system to specifically target and kill cancer cells while sparing normal cells, thereby reducing harmful side effects. Many monoclonal antibodies have been approved by the Food and Drug Administration (FDA), and in combination with standard chemotherapy or radiotherapy regimens, they can help to prevent tumor growth and metastasis and prolong patient survival. But these drugs are often not very effective on their own and can lead to drug resistance, highlighting the importance of developing better immunotherapy options.

Hossein Borghaei, DONow, Fox Chase Cancer Center researchers have revealed the potential molecular mechanisms of a potent immune stimulator called Ari-4175. By characterizing how this compound activates the immune system to slow the growth of tumors in a mouse model of colon cancer, the researchers have paved the way for testing the drug in clinical trials. The results of their study, spearheaded by Hossein Borghaei, DO, chief of thoracic medical oncology at Fox Chase, will be presented at the 49th Annual Meeting of the American Society of Clinical Oncology on Monday, June 3.

“This is an important preclinical study because it’s a novel mechanism of action for an oral drug that clearly, in this model, is leading to the activation of the immune system,” Borghaei says. “There are not many drugs right now on the market that can do this.”

About 40 percent of colorectal cancer patients with tumors bearing a mutation in the KRAS gene do not respond to an FDA-approved monoclonal antibody called cetuximab, which inhibits epidermal growth factor receptors that are commonly overactive in cancer cells. Borghaei and his team previously reported that Ari-4175—either alone or in combination with cetuximab—slowed the growth of colorectal tumors in mice with the KRAS mutation. This research revealed the potential value of Ari-4175 as an alternative treatment strategy to help patients overcome their resistance to cetuximab.

Based on these findings, Borghaei and his team set out to explore how Ari-4175 triggers immune system responses to inhibit the growth of tumors with KRAS mutations more effectively than cetuximab alone. In the new study, they applied Ari-4175 to a mouse model of colon cancer. They found that the drug expanded a subpopulation of myeloid cells, which make up one major lineage of blood cells that can activate the immune system. The expansion of the myeloid cell population led to an increase in the production of inflammatory cytokines and the subsequent activation of natural killer cells—white blood cells that recognize and kill tumor cells. In addition, they found that a subset of granulocytes  are increased in this model and might be responsible for killing of colon cancer cells bearing KRAS mutations.

“We’re showing evidence that the immune system is activated, and that’s how we think Ari-4175 is leading to a better tumor response. “Patients should be interested because this could potentially open up a new area of research on orally bioavailable drugs that can be used to manipulate the immune system as a single agent or in combination with other active drugs. From a clinical perspective, this is very interesting, and it’s worthy of further research.”

Beyond laying the groundwork for clinical trials, the study revealed changes caused by Ari-4175 in the peripheral blood that could be used as biomarkers to indicate whether or not a given cancer therapy is working. To follow up on this research, Borghaei and his collaborators will characterize the time course of immune system activation triggered by Ari-4175 to determine whether acute or chronic treatment would work best, pinpoint the optimal dose, search for other potential biomarkers, and investigate whether Ari-4175 is effective at slowing the growth of other types of tumors.

Co-authors on the study include Alexander Macfarlane IV, Tetyana V. Bagnyukova, and Kerry Campbell from Fox Chase; Barry Jones of Tufts University School of Medicine; and William Bachovchin of Tufts University School of Medicine and Arisaph Pharmaceuticals, Inc. This research was funded by Arisaph Pharmaceuticals, which manufactures Ari-4175.

Fox Chase Cancer Center, part of the Temple University Health System, is one of the leading cancer research and treatment centers in the United States. Founded in 1904 in Philadelphia as one of the nation’s first cancer hospitals, Fox Chase was also among the first institutions to be designated a National Cancer Institute Comprehensive Cancer Center in 1974. Fox Chase researchers have won the highest awards in their fields, including two Nobel Prizes. Fox Chase physicians are also routinely recognized in national rankings, and the Center’s nursing program has received the Magnet recognition for excellence four consecutive times. Today, Fox Chase conducts a broad array of nationally competitive basic, translational, and clinical research, with special programs in cancer prevention, detection, survivorship, and community outreach.  For more information, call 1-888-FOX CHASE or (1-888-369-2427).

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