Stanford University School of Medicine Stanford, California
Suzy Yuan-Huey Hung Endowed Professor of Medical Oncology Medical Director, Clinical/Translational Research Unit Associate Dean for Clinical Research Quality
Developing and testing novel therapies to improve outcomes for patients with triple-negative breast cancer.
Receptors are cell proteins that act like antennas to receive and transmit signals to instruct cells when to grow and divide and, most importantly, when to stop. Ligands are circulating proteins that bind to receptors and turn them on. Some tumors can hijack receptors and/or ligands so that receptors become stuck in the “on” position—this leads to uncontrolled cell growth, a hallmark of cancer. Two ligands, oncostatin M (OSM) and leukemia inhibitory factor (LIF), have been implicated in poor breast cancer outcomes when present in high levels, presumably by activating specific receptors. Dr. Pegram is conducting laboratory studies to determine whether either of these are viable targets for breast cancer treatment. Triple-negative breast cancer (TNBC) is a highly aggressive subtype of breast cancer with few treatment options and high mortality rates. Therefore, Dr. Pegram is focusing his investigations on TNBC and hopes his studies will lead to the development of a first-in-class therapy to expand the treatment options for patients with TNBC that currently have limited targeted therapies.
The Pegram team and others showed that the LIF protein and its receptor (LIF-receptor) can activate multiple growth signaling pathways in TNBC. Moreover, LIF levels are elevated in TNBC, and this overexpression is associated with worsened risk of relapse for this subtype of breast cancer. These observations suggest that LIF functions as a growth factor in, particularly in TNBC. Dr. Pegram and his colleagues created a potent variant of the LIF-receptor protein—a decoy receptor—that can bind to and trap LIF to prevent it from activating native LIF-receptors. Next, they combined the decoy receptor with an antibody fragment to create a novel drug called eLIFR-Fc—importantly, this drug binds LIF with 50-fold higher affinity compared to native LIFR. The investigators found that another protein ligand, oncostatin M (OSM), can also bind the LIF-receptor although not at the same receptor site.
In the next year, Dr. Pegram and his team will perform similar studies with OSM, ultimately engineering another novel drug to prevent OSM from activating the native receptor. Dr. Pegram hypothesizes that these receptor decoys could inhibit both ligands and provide a novel and attractive treatment approach that is potentially more effective than targeting either ligand alone. His team will test the receptor decoys in preclinical experiments using TNBC models. They hope to advance this synergistic therapeutic approach into phase I clinical trials with the goal of giving patients with TNBC more treatment options.
Mark Pegram, MD is the Suzy Yuan-Huey Hung Endowed Professor of Medical Oncology at the Stanford Comprehensive Cancer Institute, Associate Dean for Clinical Research Quality, and Medical Director of the Clinical Translational Research Unit at Stanford University School of Medicine. He is a renowned clinician and scholar in breast cancer research and a leader in translational medicine and played a major role in developing the drug Herceptin® as a treatment for HER2-positive breast cancer. His laboratory experiments demonstrated that combining Herceptin® with chemotherapy effectively killed cancer cells that overproduced the growth factor HER2. Dr. Pegram and others then conducted clinical trials showing that Herceptin® improved survival rates and even cured some breast cancer patients. This remains one of the premier examples of bench-to-bedside translational research.
Dr. Pegram’s research efforts have been focused on the cancer-associated gene that encodes HER2 and developing new ways to target cancer cells expressing this protein. He is also pursuing strategies to target estrogen receptors, implicated in some 70 percent of all breast cancer cases. Dr. Pegram is an expert in pre-clinical and early clinical development of oncologic therapeutics, with a focus on breast cancer. Recently, Dr. Pegram has turned this extensive experience in translational research and drug development towards addressing hard to treat TNBCs.
2013
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