Novel agent targets key protein responsible for pancreatic, colorectal cancers
NEW YORK 01/06- A novel agent, FL118, eliminated pancreatic and colorectal cancer cells in preclinical studies by targeting the oncoprotein DDX5 (p68), researchers have found.
"Our work in these latest studies to identify FL118's target is a major step that will not only guide our work to develop targeted therapies, but will help us identify patients who will benefit most from treatment with this agent," Dr. Fengzhi Li of Roswell Park Cancer Center in Buffalo, New York, told Reuters Health by email.
"We are eager to advance this work to the clinic," said Dr. Li, who with colleagues developed FL118 10 years ago. The agent is derived from camptothecin, a component of the bark and stem of a tree native to China.
The US Food and Drug Administration has approved two synthetic camptothecin analogs - irinotecan and topotecan - to treat various cancers, but both are highly toxic. The current study suggests that FL118 may have greater potency and lower toxicity than the approved drugs.
"We are currently conducting bridge studies, repeating FL118 toxicology studies using a new formulation of FL118," Dr. Li said. "We hope to move to clinical-stage research in pancreatic cancer and colorectal cancer within the next year, if we can raise enough funds."
As reported in Clinical and Translational Medicine, Dr. Li and colleagues used various technologies in human colorectal cancer/pancreatic ductal adenocarcinoma (PDAC) cell and tumor models to identify FL118's direct target. They found that FL118 strongly binds to, dephosphorylates and degrades the DDX5 oncoprotein via the proteasome degradation pathway, without decreasing DDX5 mRNA.
They then used CRISPR technology to remove DDX5 from PDACs and created various preclinical models of human cancer. Most PDAC tumor cells died after DDX5 was removed, but Dr. Li and his colleagues were able to obtain several cell clones that appeared to be less reliant on DDX5 for survival. These surviving clones showed resistance to FL118, confirming that DDX5 was in fact a direct target of the synthetic camptothecin analog.
Similarly, the team's human tumor animal model studies showed that FL118 effectively eliminated human PDAC and CRC tumors that highly express DDX5, while FL118 showed less effectiveness in PDAC and CRC tumors with low DDX5 expression.
Further, two types of PDACs were resistant to FL118 treatment (likely due to low DDX5 expression) in these models, yet both were sensitive to combination therapy with gemcitabine. However, one type required only a very low dose of FL118 in the combination, but the other type required a high dose. The authors suggest that these findings show the heterogeneity of individual PDAC tumors.
"DDX5 is a bona fide FL118 direct target and can act as a biomarker for predicting PDAC and CRC tumor sensitivity to FL118," the authors write. "This would greatly impact FL118 precision medicine for patients with advanced PDAC or advanced CRC in the clinic."
Dr. Lynn Matrisian, Chief Science Officer at the Pancreatic Cancer Action Network, which funded the study, commented in an email to Reuters Health, "We are very encouraged by (the) results that identify binding and degradation of DDX5 as the mechanism of action of FL118 and confirm a strong anti-tumor effect in mouse tumors derived from human pancreatic cancer tissue."
"We are aware that single-agent strategies rarely work well for pancreatic cancer and note the addition of the frequently used chemotherapeutic gemcitabine enhanced the effect of FL118 in some patient-derived mouse tumors," she said. "This is a promising observation that will likely guide future clinical work with this agent."
"FL118 is a small molecule inhibitor similar to camptothecin and its analogues, which should facilitate production and patient testing as this agent moves from preclinical to clinical development," she added.
Canget BioTekpharma LLC, a Roswell Park Comprehensive Cancer Center spinoff company, will further develop FL118 and FL118 platform-based analogues. Dr. Li and another coauthor are among the initial investors.