A collaborative research effort has led to significant advancements in developing next-generation therapies for pancreatic and gastrointestinal (GI) cancers. Researchers at the University of California, Riverside (UCR), have developed a novel strategy to degrade the oncogenic enzyme Pin1, a protein overexpressed in many tumors, including pancreatic cancer. This approach involves designing compounds that bind to Pin1 and destabilize its structure, leading to its cellular degradation.
The UCR team, led by distinguished Professor Maurizio Pellecchia, has collaborated with a team of scientists led by Dr. Mustafa Raoof at the City of Hope in Duarte, California. Together, they have improved the plasma stability of their earlier Pin1 inhibitors and studied their mode of action on cancer cells and cancer-associated fibroblasts derived from patient biopsies. This research has shown that Pin1 regulates the activity of both oncogenes and tumor suppressors in cancer cells and the surrounding stroma.
The efficacy of their novel Pin1 degrading compounds was tested in a mouse model of pancreatic cancer peritoneal metastases, a common and devastating complication of pancreatic, GI, and other abdominal cancers with limited effective treatments. The study found that these degraders suppress pancreatic cancer peritoneal metastases, suggesting their potential as effective therapeutics against peritoneal metastases in pancreatic and other GI and abdominal cancers.
The findings were published in the journal Molecular Therapy Oncology. Dr. Pellecchia highlights the dire outcomes associated with peritoneal metastases in advanced colorectal and gastric cancers, where resistance to systemic chemotherapy leads to poor survival rates. In pancreatic cancer, patients with peritoneal metastases have a mean survival of less than three months.
Dr. Raoof emphasizes the significance of targeting Pin1, as earlier studies have shown promise in making pancreatic cancer more susceptible to chemotherapy and immunotherapy. However, more potent drugs were needed for clinical translation. The collaboration between UCR and City of Hope has demonstrated proof-of-concept activity and reinforced their commitment to advancing novel therapies toward clinical trials.
The U54 grant from the National Cancer Institute, part of the National Institutes of Health, funded this collaborative work, enabling the development of long-term partnerships between the institutions. This partnership combines UCR’s expertise in chemical biology and modern drug discovery with City of Hope’s expertise in cancer biology and clinical oncology, leading to the conception and advancement of innovative therapeutic strategies.