Researchers at City of Hope have identified a groundbreaking new approach to treating pancreatic ductal adenocarcinoma (PDAC), one of the deadliest forms of cancer worldwide. The study, published in Gastroenterology, demonstrates proof of concept for targeting transcription-replication conflicts (TRCs) as a novel therapeutic strategy against this highly resistant disease.
Led by Mustafa Raoof, M.D., M.S., assistant professor of surgery, cancer genetics and epigenetics at City of Hope, the research team has transformed what was previously considered a genetic liability into a potential therapeutic advantage.
"Transcription-replication conflicts are an important vulnerability of pancreatic cancer," said Dr. Raoof, senior author of the study. "Our study is the first to confirm proof of concept for whether exploiting this chink in cancer's armor could provide an effective therapeutic target for patients."
Understanding the Mechanism
Transcription-replication conflicts occur when cellular machinery responsible for gene expression collides with DNA replication processes. These collisions disrupt the cell's ability to accurately read and copy genes, creating replication stress—a phenomenon particularly common in pancreatic cancer cells.
In normal cells, these processes are carefully coordinated. However, in cancer cells—especially those with KRAS mutations present in approximately 95% of pancreatic cancer patients—these conflicts become more frequent and severe, causing DNA replication errors that contribute to cancer progression and treatment resistance.
Promising Preclinical and Early Clinical Results
Building on their earlier research identifying high levels of TRCs as a unique weakness in KRAS-mutated pancreatic cancers, Dr. Raoof's team employed AOH1996, an experimental drug developed at City of Hope, to target these conflicts.
Initial laboratory testing on mouse models and human-derived organoids yielded encouraging results:
- Slowed tumor growth
- Selective damage to tumor cells while sparing healthy tissue
- Extended median survival in mice from 14 days to three weeks
The team then advanced to a small clinical evaluation involving two patients with treatment-resistant pancreatic tumors (trial NCT05227326). After taking the oral medication twice daily for two months, these patients experienced up to 49% shrinkage in their liver metastases.
"The experimental approach was most effective at killing cancer cells with high replication stress, a common phenomenon that occurs when the KRAS gene goes awry in 95% of patients with pancreatic cancer," Dr. Raoof explained.
Addressing an Unmet Medical Need
Pancreatic cancer remains one of the most challenging malignancies to treat, with 90% of patients not surviving beyond five years after diagnosis. Current therapeutic options are limited, and resistance to treatment is common.
"While the KRAS mutation has suggested a strong therapeutic target, pinpointing it in human PDAC has been difficult until now," said Dr. Raoof. "With inhibitors to mutant KRAS entering clinical trials, resistance is expected. It's crucial for us to develop new approaches that target dependency on KRAS."
The selective nature of the approach represents a significant advantage. "Transcription-replication conflicts are more prevalent in cancer cells than normal cells," Dr. Raoof noted. "Therapies that interfere with how cells manage their DNA during replication could open up new ways to treat cancer, offering hope for patients who have not benefited from other approaches."
The Path Forward
While the early results are promising, Dr. Raoof emphasized caution in interpreting the findings. The small sample size of the clinical evaluation necessitates larger clinical trials and biomarker discovery studies to fully realize the potential of therapeutically targeting TRCs.
The research was supported by grants from the National Comprehensive Cancer Network, the 2020 Pancreatic Cancer Action Network Career Development Award in Memory of Skip Viragh, the National Cancer Institute, and the NCCN Foundation.
City of Hope's Linda Malkas, Ph.D., discovered and developed AOH1996, which is exclusively licensed to biotechnology company RLL, LLC. The institution recently received a historic $150 million gift from entrepreneur-philanthropists A. Emmet Stephenson Jr. and Tessa Stephenson Brand to accelerate pancreatic cancer research through collaborations with leading researchers worldwide.
City of Hope, ranked among the top 5 cancer care providers in the nation by U.S. News & World Report, has a strong history of biotech innovation, including contributions to the development of synthetic human insulin and "smart" cancer drugs like Herceptin, Rituxan, and Avastin.
