A team of Texas A&M University researchers has received a $2.3-millon grant from the National Institutes of Health to further explore a unique immunotherapy that could be the first of its kind to treat colon cancer and could hold the key to treating other forms of cancer as well.
The collaborative, four-year project will determine how to best utilize a new class of drugs developed in the laboratory of Dr. Stephen Safe, a Distinguished Professor in the Texas A&M School of Veterinary Medicine & Biomedical Sciences’ (VMBS) Department of Veterinary Physiology & Pharmacology. The project will also explore the effects of the new compounds on human and murine (mice/related rodent) cancer cells.
Led by Safe, the team also includes VMBS researchers Gus Wright and James Cai, as well as College of Agriculture and Life Sciences researcher Robert Chapkin and Houston Methodist Hospital oncologist Maen Abdelrahim.
Safe’s compounds target two receptors — NR4A1 and NR4A2 — that are normally responsible for helping humans and animals lower stress levels but are overexpressed in colon cancer and other solid tumors.
“In the case of solid tumors, these two receptors are bad; they regulate the growth of a cell, how it metastasizes, how it invades, and how it survives,” Safe said. “When we screened these receptors, we found out that our compounds that we've been working on over the years bind with high affinity (binding strongly). Binding can sometimes be bad, making the tumor worse, or binding can be good, by being an antagonist. In this case, the compounds are antagonists — they just wipe out the tumor.”
Not only does their preliminary data indicate that their compounds act as an immunotherapy and kill the tumor, but the compounds also rejuvenate the immune system, which becomes exhausted as it responds to cancer.
“Immune cells play a very important role in cancer treatment,” Safe said. “But what happens with tumor development is that eventually, the immune cells just get exhausted and become unable to mount a ‘tumor-killing’ response.
“Dr. Jim Allison and Dr. Tasuku Honjo’s Nobel Prize-winning work found that at least one of the reasons the immune cells don't work is that they're not only exhausted, but they don't function because tumors can suppress immune cells, especially T-cells (which target specific foreign particles, such as cancer cells) and thereby avoid immune cell-dependent tumor surveillance (the tumors are misidentified as immune cells by the immune system),” Safe said.
Immunotherapies work by separating the T-cells from the tumor, allowing the immune system to destroy the tumor the way it would any other infection in your body.
“One of the signals (the communication mechanism between T-cells and tumors), or checkpoints, is a gene called PD-L1, which is a checkpoint inhibitor; checkpoints bring the immune cell and the tumor cell together,” Safe said. “We found that in breast and colon cancer, NR4A1 regulates PD-L1 in the tumor, and treatment with our antagonist decreases PD-L1 expression and sensitizes the tumor to immune surveillance, killing it.”
By isolating the immune cells, Wright, an associate research scientist in the VMBS Department of Veterinary Pathobiology, was able to analyze the T-cells for markers of exhaustion and determined that with Safe’s compounds, those markers were “wiped out.”
“Previous studies showed that NR4A1 played a role in T-cell exhaustion, and our unique NR4A1 antagonists not only target NR4A1 in the tumor but also in T-cells; this dual targeting (the killing of the tumor and rejuvenating the immune system) is consistent with their high anticancer activity in mouse models.”
In the next phase of their research, the team will use the NIH grant to explore other areas of how the compounds work to, hopefully, prepare it for clinical trials.
While Safe works to “maximize” the compounds — that is, to select the most effective molecules for achieving their end goal — and to assess compound dosages, Abdelrahim, who is co-principal investigator on the project, will be examining the effects of the compound on human tissue; Wright will be working to further explore implications on the immune system; Cai, an associate professor in the VMBS Department of Integrative Biosciences, will be investigating how other individual cell types are affected by the compounds; and Chapkin, the Allen Endowed Chair in Nutrition & Chronic Disease Prevention and a University Distinguished Professor, will be further analyzing effects of NR4A1-targeting compounds on colonic epithelial stem cells in tumors.
Chapkin, Wright and Cai will also perform a single cell multi-omic analysis of the colon tumor microenvironment to probe the mechanistic underpinnings of NR4A1-dependent modulation of T-cell exhaustion.
Ultimately, Safe believes their NR4A1-targeting drugs will also attenuate other types of cancer, including breast cancer, glioblastoma and rhabdomyosarcoma, the most common soft tissue sarcoma in children.
“A lot of drugs that oncologists use now just target the specific genes/pathways in tumor cell — the drug kills it and the tumor usually regresses,” he said. “Those drugs are effective and inhibit some tumor growth, but they're only targeting the tumor; they're not targeting immune cells. I'm not sure how many drugs currently being used target both the tumor and the immune cells, but ours do, and this accounts for their potency in preclinical animal models.”
By Jennifer Gauntt, Texas A&M University School of Veterinary Medicine & Biomedical Sciences