Camptothecin Analog FL118 Can Overcome Treatment Resistance, Outperform Approved Therapies

BUFFALO, N.Y. — The latest research from the team that discovered the novel anticancer agent FL118 highlights distinctive characteristics of this small-molecule compound and provides insights into its ability to overcome the persistent problem of treatment resistance. In findings reported in Molecular Cancer, Fengzhi Li, PhD, of Roswell Park Comprehensive Cancer Center, and colleagues provide new evidence that FL118 may be more effective than two structurally similar injectable drugs and, additionally, may be effective as an oral agent.

Like the FDA-approved cancer therapies irinotecan and topotecan, FL118 is an analog of camptothecin, a natural compound used in traditional Chinese medicine. But unlike those drugs, Dr. Li and co-authors report, FL118 activates the tumor-suppressor protein p53 independent of ATM, or the ataxia-telangiectasia mutated protein kinase. That distinct mechanism of action means that FL118 can effectively bypass treatment resistance resulting from overexpression of the drug-efflux pump protein ABCG2, a limitation associated with both irinotecan and topotecan.

“This new study provides additional evidence distinguishing FL118 from irinotecan and topotecan, and our finding that FL118 can bypass ABCG2-mediated resistance opens up the highly attractive prospect of developing FL118 as an orally administered treatment for cancer,” notes Dr. Li, Associate Professor of Oncology in the Department of Pharmacology and Therapeutics at Roswell Park.

In this latest study, FL118 extended time to progression in both human colorectal and lung xenograft tumor models by more than 50%, in comparison with irinotecan. The nonpolar nature of FL118, the authors note, plays a role in overcoming resistance, since the tested FL118 analogs feature polar substitutions in the B-ring and show affinity for ABCG2. The scientists, who include the paper’s first author, David Westover, a graduate student in Dr. Li’s lab, employed multiple approaches to verify their findings, including pharmacological inhibition of ABCG2 activity and genetic silencing of ABCG2.

Dr. Li and his colleagues believe FL118 may prove to be effective against a number of solid and liquid tumors, and have previously pursued studies to assess its performance in controlling colorectal, pancreatic and ovarian cancers, as well as melanoma and chronic lymphocytic leukemia.

The study, entitled “FL118, a novel camptothecin derivative, is insensitive to ABCG2 expression and shows improved efficacy in comparison with irinotecan in colon and lung cancer models with ABCG2-induced resistance,” is available at molecular-cancer.com.

This work was funded in part by grants from the U.S. Department of Defense (W81XWH-12-1-0305), the National Cancer Institute, or NCI (R21CA180764), and the Roswell Park Alliance Foundation. The study also used shared resources supported by Roswell Park’s Cancer Center Support Grant from the NCI (P30CA016056).

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