The U.S. Department of Defense recently granted University of Colorado Cancer Center researchers Jennifer Richer, PhD, Jill Slanksy, PhD, and Virginia Borges, MD, a prestigious Breakthrough Award Level Two to deepen work investigating how triple-negative breast cancer (TNBC) tricks the immune system. Now The National Institutes of Health, specifically the National Cancer Institute, has further validated the potential of this inroad against the disease, funding two training grants for PhD candidates in the Richer lab, Lisa Greene and Thomas Rogers. Greene and Rogers, both doctoral candidates in the Anschutz Medical Campus Cancer Biology Graduate Program, are studying mechanisms that allow breast cancer to transition from a localized disease to a much more difficult to treat metastatic condition.
Thomas Rogers’s work is profiled in this recent article. Greene’s work seeks to understand how TNBC avoids detection by the immune system and how to intervene or block the ability of cancer to suppress or evade immune destruction.
“What we’re interested in doing in triple-negative breast cancer is promote the ability of T cells to recognize and kill TNBC before it spreads,” Greene says.
Her research shows that one way cancer cells evade the immune system may be by increasing the expression of TDO2, a key enzyme in the pathway that metabolizes the essential amino acid, tryptophan. Basically, more TDO2 leads to more breakdown of tryptophan, which leads to increased manufacture of a metabolite called kynurenine. Many cancer types show increased kynurenine in the bloodstream.
“This kynurenine is taken up by T cells and stops them from being able to kill the cancer cells,” Greene says.
Greene’s work hopes to target TDO2 as a way to stop TNBC cells from over-manufacturing kynurenine, allowing T cells to remain competent to attack the cancer. Importantly, Greene’s work with primary immune cells from healthy blood donors in collaboration with oncologist Virginia Borges, MD, at the CU Cancer Center shows that TNBC cells increase this immune-suppressive substance, kynurenine, even more when they are in suspension culture.
“This shows that it’s when TNBC cells are in the process of metastasizing – when they become detached from their origin in the breast and travel through a patient’s blood or lymphatic system – that they have the unique ability to upregulate expression of the TDO2 enzyme, making more kynurenine, and suppressing the immune system,” Greene says.
Greene’s grant proposal was awarded a very high ranking score, an “amazing score,” says lab-mate and fellow student in the Cancer Biology Graduate Program, Thomas Rogers.
“It makes me feel like there are people who agree that TDO2 could be an important target for these patients,” Greene says.
Now with an increased understanding of the basic science, Greene is starting preclinical studies with compounds that may target TDO2 in human patients. Another player in this tryptophan pathway, IDO, has already been the focus of drug development and clinical trials. Now, Greene points out, labs are starting to develop compounds to inhibit the less-known, but closely related, TDO2. Greene’s current work focuses on evaluating these early compounds for stability and bio-availability and testing their use in mouse models of the disease. Her recent NIH training grant ensures that Greene will be able to push forward with this strategy that could reduce the metastatic potential of TNBC.
“It’s definitely motivational to get validation from the NIH – you know you’re doing a good job,” Greene says.