University of Cincinnati Cancer Center researchers have identified a novel therapeutic target for pancreatic ductal adenocarcinoma (PDAC) and developed a corresponding drug that showed promising results in preclinical studies. The research, published in two manuscripts in the journal Cancers in January and April 2025, focuses on overcoming the unique challenges posed by PDAC's immunosuppressive tumor microenvironment.
Targeting the Immunosuppressive Tumor Microenvironment
The research team, led by postdoctoral fellow Ahmet Kaynak, PhD, examined the distinctive characteristics of PDAC's tumor microenvironment—the ecosystem that includes the tumor and surrounding immune cells, blood vessels, and other tissue. According to Kaynak, PDAC's microenvironment presents unique challenges that "suppress the immune system's ability to attack the cancer cells (causing immunosuppression), hinder drug delivery, and promote resistance to chemotherapy, radiotherapy and immunotherapy."
"There is an unmet need for the development of novel treatment approaches," said Kaynak, a trainee associate member of the Cancer Center and postdoctoral fellow in the Hematology & Oncology Division of the Department of Internal Medicine in UC's College of Medicine. "In this project, we asked the question of what the factors are that lead to immunosuppression in the tumor microenvironment."
Hsp70 Protein Identified as Key Target
The research team identified that a protein called Hsp70 contributes significantly to tumor immunosuppression. While Hsp70's crucial role in cellular homeostasis was already well established, its role and mechanism of action supporting immunosuppression in the tumor microenvironment was not widely acknowledged before this research.
This discovery led to the development of a targeted therapeutic approach that could potentially overcome the treatment resistance commonly seen in pancreatic cancer patients.
Novel Drug Development Shows Promise
Building on their target identification, the team developed a drug called SapC-DOPG that specifically targets cancer cells by binding to phosphatidylserine, a lipid on the cells' surface. The drug was designed to target Hsp70 within PDAC cells, offering a precision approach to treating this challenging cancer.
This work builds upon research by Kaynak's mentor, Xiaoyang Qi, PhD, who developed a similar drug called SapC-DOPS that is currently in Phase 2 clinical trials as a lung cancer treatment. The success of SapC-DOPS in clinical development provides a foundation for the potential translation of SapC-DOPG.
Promising Preclinical Results
In animal models of PDAC, SapC-DOPG demonstrated encouraging therapeutic potential. The drug was well tolerated and resulted in smaller tumor size and increased survival compared to controls. These results suggest that targeting Hsp70 through this mechanism could offer a new therapeutic avenue for pancreatic cancer patients.
Clinical Translation Plans
"We hope to transition to clinical settings and investigate whether SapC-DOPG can be used as a therapeutic agent in pancreatic cancer patients," Kaynak said. "The safety of the analog SapC-DOPS has been proven in clinical trials with patients. We hope our novel drug can also be safely used in patients in the future."
The research team's confidence in moving toward clinical development is bolstered by the established safety profile of the related compound SapC-DOPS, which has already demonstrated tolerability in human clinical trials.
Kaynak will present his research findings at the American Association for Cancer Research's Special Conference in Pancreatic Cancer on September 28 in Boston, providing an opportunity to share these developments with the broader pancreatic cancer research community. One of Kaynak's publications on the research was selected as the Cancer Center's Trainee Associate Membership Paper of the Year in the spring, highlighting the significance of this work in advancing pancreatic cancer research.
