Engineered molecule expected to enter human clinical trial testing in near future
COLUMBUS, Ohio – Scientists have identified a viable drug therapy target for the treatment of BRCA-mutated, triple-negative breast cancer (TNBC), according to new data published by researchers at The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute (OSUCCC – James).
In a study, Zhiwei Hu, MD, PhD, of the OSUCCC – James, and colleagues report the first evidence that a specific molecule (called tissue factor or TF) is highly expressed in TNBC—both on the surface of TNBC cancer cells and throughout the majority of the tumor mass. It is also expressed within the inner layer of tumor blood vessels, which supply oxygen and nutrients to cancer cells and serve as a conduit for them to spread to distant organs.
Additionally, the team has shown that an injectable, second-generation TF-targeting therapeutic molecule is highly effective at targeting TNBC cells in laboratory and preclinical animal models. The drug works by triggering the immune system to destroy cancer cells and to stop the tumor growth.
The team reports its findings in the medical journal Cancer Immunology Research.
The normal function of TF is to initiate blood clotting. The engineered second-generation molecule, known as L-ICON, works by targeting TF expressed specifically on the interior surface of TNBC cells, cutting off blood supply to the tumor vessels.
“Understanding how we can harness the immune system to selectively target TF to stop growth of cancer presents many opportunities,” says Hu, senior author of the study. “What is exciting about this particular study is that our data shows this second-generation drug is effective for treating TNBC, either with or without BRCA1 and BRCA2 mutations, and is more effective at penetrating and targeting the tumor microenvironment than the first-generation drug.”
Hu was involved in development of the first generation drug, ICON, while at Yale University. Both drugs have two components: a targeting domain recognizing TF on the surface of the malignant cells paired with a natural antibody domain that activates an attack by the immune system against cancer cells that bind the engineered molecule.
The immune system then attacks tumor blood vessels specifically, and the cancerous tissue dies due to lack of blood supply. The first-generation agent is being tested in clinical trials for patients with ocular melanoma and macular generation. The team is planning to translate the second-generation L-ICON molecule into an early-phase clinical trial for patients with TNBC.
This study was supported by the Dr. Ralph and Marian Falk Medical Research Trust Awards Program and partly by National Center for Advancing Translational Sciences (grant UL1TR001070) through The Ohio State University Center for Clinical and Translational Science and the Translational Therapeutics Program of the OSUCCC – James.
Collaborators in this study include Rulong Shen, MD, Lianbo Yu, PhD, Bhuvaneswari Ramaswamy, MD, Cheryl London, DVM, PhD, and William Carson III, MD, of the OSUCCC – James, and Tian Xu, PhD, of Yale University.
About the OSUCCC – James
The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute strives to create a cancer-free world by integrating scientific research with excellence in education and patient-centered care, a strategy that leads to better methods of prevention, detection and treatment. Ohio State is one of 49 National Cancer Institute-designated Comprehensive Cancer Centers and one of only a few centers funded by the NCI to conduct both phase I and phase II clinical trials on novel anticancer drugs. As the cancer program’s 308-bed adult patient-care component, The James is one of the top cancer hospitals in the nation as ranked by U.S. News & World Report and has achieved Magnet® designation, the highest honor an organization can receive for quality patient care and professional nursing practice. With 21 floors and more than 1.1 million square feet, The James is a transformational facility that fosters collaboration and integration of cancer research and clinical cancer care. For more information, visit cancer.osu.edu.
Amanda J. Harper
OSUCCC – James Media Relations