Upender Manne, Ph.D.,
Photography: Ian LogueResearchers from the University of Alabama at Birmingham have identified a promising new combination therapy for metastatic colorectal cancer that enhances the effectiveness of existing treatment while reducing harmful side effects. The study, published in the Journal of Experimental & Cancer Research, focused on regorafenib, a drug that modestly improves survival in mCRC patients but often leads to severe toxicities. By pairing regorafenib with a dual JAK/HDAC inhibitor at low doses, the researchers were able to significantly boost the drug’s anticancer activity.
Colorectal cancer is a leading cause of cancer-related deaths worldwide. For patients with metastatic disease, treatment options are limited and the prognosis is often poor. Regorafenib, a multiple-kinase inhibitor, is one of the few drugs available for these patients; but its use is hampered by significant toxicity, limiting its clinical benefit.
The research team, led by UAB Department of Pathology Professor Upender Manne, Ph.D., conducted a series of experiments using colorectal cancer cell lines, patient-derived xenografts and mouse models to test the efficacy of the combination therapy. They examined the effects of the combination on cell viability, cell cycle progression, apoptosis (programmed cell death) and molecular signaling pathways. Researchers explored how the treatment influenced the immune response to the tumors.
“Findings of our study has opened a new hope for translating this breakthrough into a widely accessible treatment for metastatic colorectal cancer,” Manne said. “For our team, this is a continuation of our quest to outsmart cancer, one discovery at a time.”
The combination therapy outperformed regorafenib alone across several metrics. It significantly reduced tumor cell viability, induced cell cycle arrest at the G0-G1 phase and promoted apoptosis. The combination also inhibited key molecular pathways involved in cancer growth, including those regulated by JAKs, STAT3 and EGFR. Importantly, the treatment enhanced the immune system’s ability to target the tumor, as evidenced by increased infiltration of immune cells in the tumor microenvironment.
Prachi Bajpai, Ph.D.
Photography: Ian LogueIn animal models, the combination therapy led to a significant reduction in tumor growth and metastasis. Pharmacokinetic studies further revealed that the combination increased the bioavailability of regorafenib, meaning more of the drug was available to exert its effects, potentially allowing for lower doses and reducing toxicity.
The study’s findings suggest that combining regorafenib with a dual JAK/HDAC inhibitor could be a more effective and safer approach to treating metastatic colorectal cancer. The promising preclinical results pave the way for clinical trials to evaluate the potential of this combination therapy in patients. If successful, this approach could provide a new lifeline for those battling advanced colorectal cancer, offering hope for improved outcomes with fewer side effects.
Prachi Bajpai served as primary author of this manuscript and additional authors include, Sumit Agarwal, Farrukh Afaq, Sameer Al Diffalha, Darshan S. Chandrashekar, Kyung-Gyoon Kim, Abigail Shelton, Ryan Miller, and Sooryanarayana Varambally of UAB Department of Pathology and the UAB O’Neal Comprehensive Cancer Center; Santosh Singh and Rajesh Singh of Department of Microbiology, Biochemistry and Immunology, Morehouse School of Medicine; Ganji Purnachandra Nagaraju of UAB Department of Medicine; Ashish Manne of Department of Internal Medicine, the Ohio State University Comprehensive Cancer Center; Ravi Paluri of Department of Hematology and Oncology, Wake Forest School of Medicine; and Moh’d Khushman of Department of Medicine, Washington University in St. Louis/Siteman Cancer Center.
This study is supported, in part, by grant 5U54CA118948 of the National Institute of Health, National Cancer Institute, and by institutional funds (Department of Pathology and Heersink School of Medicine of UAB) awarded to Upender Manne.