Small Molecule Pak 1 Inhibitors May be an Effective Therapy for Colorectal Cancer

PHILADELPHIA (August 27, 2018) – A new study suggests that targeting Group I p21-activated kinases (Paks) with small-molecule inhibitors could be a promising therapeutic approach in colorectal cancer. Researchers led by Jonathan Chernoff, MD, PhD, chief scientific officer at Fox Chase Cancer Center, designed a transgenic mouse model that conditionally expresses an inhibitory peptide to block the catalytic function of Group I Paks, and noted its efficacy in reducing adenomas and impeding progression to carcinomas. The paper appears in the journal Nature Communications.

Group I Paks are associated with invasive and metastatic colorectal lesions, and previous studies have shown that they may be plausible drug targets. In this study the researchers designed a mouse that naturally expressed a small-molecule inhibitor to bind to the kinases and inhibit their enzyme activity. Importantly, Chernoff and his colleagues opted to breed the inhibitor into the mice rather than edit the gene to eliminate the Pak protein altogether. This approach provided a more realistic approximation of the way a drug could work in a cancer patient.

“We designed a model that closely mimics the effects of a small-molecule inhibitor that targets a known regulator of colorectal cancer formation and progression,” said Chernoff.

The mice that were bred with the small-molecule inhibitor developed dramatically fewer benign adenomas in the small and large intestine, and no malignant tumors. The group has already begun similar experiments to test the inhibition of Group II Paks as potential therapeutic targets for pancreatic cancer.

Fox Chase Cancer Center (Fox Chase), which includes the Institute for Cancer Research and the American Oncologic Hospital and is a part of Temple Health, is one of the leading comprehensive cancer 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 is also one of just 10 members of the Alliance of Dedicated Cancer Centers. 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 six 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. It is the policy of Fox Chase Cancer Center that there shall be no exclusion from, or participation in, and no one denied the benefits of, the delivery of quality medical care on the basis of race, ethnicity, religion, sexual orientation, gender, gender identity/expression, disability, age, ancestry, color, national origin, physical ability, level of education, or source of payment.

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