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2020, 2022 & 2024 Grantee: Fengzhi Li, PhD
Roswell Park Comprehensive Cancer Center
Research Project: Validation of Targets as Biomarkers for Targeted Pancreatic Cancer Therapy
Award: 2020 Pancreatic Cancer Action Network Translational Research Grant
Award Period: July 1, 2020 – June 30, 2022
Amount: $500,000
Award Extension: 2022 Pancreatic Cancer Action Network Translational Research Grant Extension funded by Kenneth D. Custance and Gladys C. Custance, honoring the memory of Martha ‘Molly’ Reed Woodroofe
Award Period: July 1, 2022 – June 30, 2023
Amount: $250,000
Research Project: Elucidation of the small molecule FL118 as an effective PDAC desmoplasia disrupter impacting the DDX5-Agrin pathway
Award: 2024 Pancreatic Cancer Action Network Catalyst Grant honoring the memory of Christine Shaffer
Award Period: September 1, 2023 – August 31, 2024
Amount: $125,000
Biographical Highlights
Dr. Li became a faculty member of Roswell Park Comprehensive Cancer Center in 2001 after finishing his postdoctoral training in Dr. Dario C. Altieri’s laboratory at the Boyer Center for Molecular Medicine, Yale Medical School. During his postdoctoral training, he focused his research on characterizing the function, regulation and expression of the protein survivin, which is involved in blocking a form of programmed cell death called apoptosis.
In 2006, Dr. Li was promoted to an associate professor of oncology at Roswell Park. Using the survivin gene as a target and biomarker for targeted anticancer drug discovery, he has over the past decade transitioned his Roswell Park cancer research lab from basic to translational cancer research. His current research interests focus on targeted anticancer drug discovery, development and mechanism of action studies. His goal is to move his lab-discovered targeted anticancer drug into clinical trials in order for it to become clinically available to patients with pancreatic cancer, colorectal cancer and other cancer types.
Project Overview: 2020 Translational Research Grant
Dr. Li and his team have identified a novel anticancer drug (named FL118) that can eliminate pancreatic cancer patient-derived xenografts in animal models. Patient-derived xenografts are created by implanting a small sample of a patient’s pancreatic cancer tissue under the skin or into the pancreas of a mouse and allowing the tissue to form a tumor in the mouse.
The researchers found that FL118 directly binds to and induces the degradation (breakdown) of a protein called DDX5. DDX5 is involved in blocking a type of programmed cell death – like cell suicide – called apoptosis. When FL118 blocks DDX5’s activity, apoptosis is allowed to occur in the pancreatic cancer cells.
About 83% of pancreatic ductal adenocarcinoma (the most common type of pancreatic cancer) tumors are thought to express DDX5. And, the higher the expression (amount) of DDX5, the more likely the cancer cells are to respond to FL118 treatment. Therefore, Dr. Li and colleagues propose to use DDX5 expression as a biomarker, or biological clue, to determine which patients may benefit from FL118 treatment.
Experiments in patient-derived xenografts have also revealed that, in addition to DDX5 expression, pancreatic tumors that express mutant KRAS and mutant p53 are especially susceptible to cell death caused by FL118. KRAS and p53 are among the most commonly mutated proteins in pancreatic tumors.
In this grant, the investigators will validate the target and biomarker roles of DDX5, mutant KRAS and mutant p53 for evaluating pancreatic tumor sensitivity to FL118. In preparation for future targeted clinical trials testing FL118 in patients, Dr. Li and his team will study how FL118 causes the breakdown of DDX5 and continue to determine whether and how DDX5, mutant KRAS and mutant p53 expression can predict response to FL118.
Project Overview: 2022 Extension
Dr. Fengzhi Li was the recipient of a 2020 PanCAN Translational Research Grant, focused on a novel anticancer drug named FL118 that was identified by his research team. Dr. Li and his colleagues found that FL118 directly binds to and induces the degradation (breakdown) of a protein called DDX5. Dr. Li and colleagues’ findings from the first two years of PanCAN funding was published in the high-impact biomedical journal, Clinical and Translational Medicine, in May 2022. The paper described results showing that DDX5 is a direct target of FL118 in pancreatic and colorectal cancer, and that the presence of DDX5 in a patient’s tumor may serve as a biomarker (clue) to indicate that use of FL118 treatment could work well for the patient.
Based on the promising results to date, Dr. Li has been awarded a one-year extension of his Translational Research Grant to deepen his understanding of FL118 and DDX5. With this additional funding, Dr. Li and team will investigate which cellular proteins’ expression are regulated by DDX5. The Li lab can conduct these experiments through genome-wide analyses of pancreatic cancer cells with natural DDX5 expression, cells without DDX5 expression (knocked out/disrupted) and cells in which DDX5 expression was disrupted and then re-expressed. Each cell type will be exposed to FL118, and then the response will be measured relative to DDX5 status.
Next, the team seeks to explore which proteins bind (attach) directly to the DDX5 protein before and after the FL118 drug binding to DDX5. Their evidence suggests that FL118 breaks down DDX5 through a process known as ubiquitination, by which small ubiquitin molecules get attached to a protein to signal cellular proteasome machinery to degrade it. However, the exact proteins responsible for DDX5’s ubiquitination and degradation following FL118 exposure are unknown. These studies will strengthen FL118’s candidacy as an investigational drug for clinical testing in patients with pancreatic cancer.
Project Overview: 2024 Catalyst Grant
Dr. Fengzhi Li has identified a promising small molecule drug, FL118, that demonstrates potent efficacy against pancreatic cancer in human-relevant mouse models. He has dedicated significant efforts to unraveling the mechanism(s) underlying FL118’s anti-cancer function. He and his team pinpointed the drug’s direct molecular target as DDX5, a multi-functional enzyme overexpressed in pancreatic cancer that regulates numerous key oncogenic proteins and processes, such as immune suppression, metabolism, and DNA repair. Dr. Li and his team demonstrated that FL118 binds to and impairs DDX5 function by promoting DDX5 protein degradation, ultimately hindering tumor growth.
One challenging hallmark of pancreatic cancer is the tumor’s dense extracellular matrix (ECM), a network of proteins and other non-cellular components that stiffen the connective tissue that surrounds and supports cancer cells. It acts like a “scaffolding” or “framework” that helps the tumor grow, while simultaneously serving as a physical barrier that obstructs drug delivery, preventing the treatment from reaching the cancer cells. Dr. Li and his team’s recent preliminary discovery suggests that FL118 may also function as an ECM disruptor. In this 2024 PanCAN Catalyst Grant, Dr. Li aims to investigate the potential dual mechanism of FL118, which not only targets pancreatic cancer cells but may also weaken the ECM to improve drug delivery. He will confirm the downstream molecular mechanism and targets of the DDX5 pathway that play a role in FL118-mediated disruption of ECM. Dr. Li and his team will quantify the cancer-promoting behaviors regulated by the FL118-DDX5 axis, and they will characterize the consequences of FL118 treatment on ECM integrity. This work will further position FL118 as a promising candidate for combination therapy (for example, with immunotherapy) or even as monotherapy for patients with pancreatic cancer.
