Candidate Anticancer Drug Effectively Treats Drug-resistant Pancreatic Cancer

The compound, code-named FL118, being studied by investigators at the Roswell Park Comprehensive Cancer Center (Buffalo, NY, USA) was a synthetic derivative of camptothecin, a compound used in traditional Chinese medicine that was obtained from the bark of the Camptotheca acuminate tree.

In a pre-clinical trial carried out in mouse and dog models of pancreatic cancer, the investigators tested FL118’s efficacy in treatment of resistant pancreatic cancer. Over the course of the study, they employed multiple analytical techniques including: cell culture; immunoblotting analysis to test protein expression; DNA sub-G1 flow cytometry analyses to test cell death; MTT assay to test cell viability; pancreatic cancer stem cell assays (fluorescence microscopy tracing; matrigel assay; CD44-positive cell colony formation assay); human luciferase-labeled pancreatic tumor orthotopic animal model in vivo imaging; pancreatic cancer patient-derived xenograft (PDX) animal models; and toxicology studies with immune-competent BALB/cj mice and beagle dogs.

Results published in the October 3, 2018, online edition of the Journal of Experimental & Clinical Cancer Research revealed that FL118 alone preferentially killed cisplatin-resistant cancer cells, while a combination of FL118 with cisplatin synergistically killed resistant pancreatic cancer cells and reduced spheroid formation of treatment-resistant pancreatic cancer stem-like cells. Furthermore, in vivo-imaging showed that FL118 in combination with cisplatin strongly inhibited both drug-resistant pancreatic xenograft tumor growth and metastasis. FL118 alone effectively eliminated PDX tumors, while FL118 in combination with gemcitabine eliminated PDX tumors that showed relative resistance (less sensitivity) to treatment with FL118.

FL118 did not produce the signs of toxicity common to other camptothecin-based agents and was generally well tolerated at therapeutic dose levels.

Overall the results obtained during this study suggested that FL118 was a promising anticancer drug for further clinical development to effectively treat drug-resistant pancreatic cancer alone or in combination with other pancreatic cancer chemotherapeutic drugs.

“Drugs that can more effectively reach and eliminate pancreatic tumors are urgently needed to treat this devastating disease,” said senior author Dr. Fengzhi Li, associate professor of oncology at Roswell Park Comprehensive Cancer Center. “FL118’s high anticancer efficacy, along with its favorable toxicology profile, is consistent with the fact that this drug targets several key proteins involved in pancreatic cancer progression and treatment resistance.”

Related Links:
Roswell Park Comprehensive Cancer Center