MUSC Hollings Cancer Center researchers discovered a novel mechanism showing how a certain gene mutation can allow tumors to evade detection by the immune system in colorectal cancer patients. The study, which was published July 22 in Oncogene, is the most recent example of team science at Hollings.

“The work is the first time we are aware of that someone has shown how a checkpoint inhibitor is regulated due to loss of the adenomatous polyposis coli (APC) gene function,” said 

, director of Hollings Cancer Center and a senior author of the study.

Colorectal cancer is the third most common malignancy and the second leading cause of cancer-related death in the United States. Although colonoscopy screening is an effective way to detect and prevent colorectal cancer by polyp removal, colorectal cancer continues to be responsible for significant mortality. DuBois said existing therapies have limited efficacy for long-term survival in patients with stage 4 disease.

“The five-year survival rate for these patients is unacceptable, between 5% and 15%, which underscores the importance of this research,” DuBois said.

The DuBois lab team has been working to understand the molecular mechanisms that cause colorectal cancer initiation, growth and progression to discover new strategies for prevention and interception.

Immune response to cancer is regulated by a balance between co-stimulatory and inhibitory (checkpoint) pathways. Immune checkpoints put brakes on the immune system, preventing inflammatory tissue damage and autoimmune diseases. For example, one immune checkpoint pathway is activated by PD-L1, an immune system regulatory molecule that suppresses immune responses when it interacts with its receptor, PD-1.

“PD-L1 levels are elevated in a variety of human cancers, including colorectal cancer, and this sometimes leads to a poor prognosis,” DuBois said. “We know that high levels of PD-L1 on the surface of cancer cells are related to the tumor’s ability to evade the immune system. However, the exact role PD-L1 plays in colorectal cancer is unclear. Some reports in the literature present conflicting results as to whether the presence of PD-L1 is indicative of a better or worse cancer prognosis.”

T-cells, which are crucial white blood cells that help to mediate the immune system, can kill cancerous or virally infected cells. Tumor cells, therefore, must evade them if they are to survive by directly impairing the cytotoxic activity of T-cells. Tumor cells also inhibit the spread of T-cells by employing immune checkpoint receptors such as PD-1. PD-1 and PD-L1 interact to inhibit T-cell function while increasing immunosuppression by regulatory T-cells (Tregs). While this complex dance of T-cells, checkpoint receptors and Tregs occurs, tumor cells slip past and evade the immune system.

Normally, people possess two copies of the APC gene, having inherited them from their parents. The APC gene provides instructions for creating the APC protein, which helps to control how often a cell divides and how it attaches to other cells within a tissue. Thus, the APC protein acts as a tumor suppressor, preventing uncontrolled growth and division of cells. If one copy of the APC gene has a mutation, there is an increased chance of developing certain types of cancer, such as colorectal cancer and other cancers of the stomach, thyroid, pancreas, liver and central nervous system.

Previous animal studies provided direct evidence demonstrating that the loss of APC causes the formation of adenomas, which are noncancerous tumors that can become cancerous in time. The APC protein can form a complex with β-catenin, which plays an essential role in stem cell renewal and organ regeneration. DuBois’ team carried out several experiments that showed β-catenin is required for APC mutation and increased levels of PD-L1.

DuBois’ team found that in mouse models, APC gene mutations are always accompanied by very high levels of PD-L1. With that knowledge, they developed several mouse models where they removed the gene and examined the effect on the colon.

“When we corrected the mutation in the mouse model, the checkpoint inhibitor went away, and when we reintroduced the mutation, it returned,” DuBois explained.

“This discovery represents the first evidence that we know of demonstrating that the loss of APC results in stimulation of PD-L1 in colon cancer cells via the b-catenin complex binding to the PD-L1 promoter,” DuBois said.

Their findings also revealed a novel mechanism by which APC mutations allow colonic tumors to evade immune system detection via an immune checkpoint pathway and increased resistance to T-cells. “These results expand our understanding of the role of APC in colorectal cancer and pave the way for developing new target drugs as possible b-catenin inhibitors for use as alternative immune checkpoint inhibitors in colorectal cancer therapies,” DuBois said. These new therapies could be especially useful in intercepting colorectal cancer disease progression at a very early stage.

DuBois’ lab plans to investigate the effectiveness of the combined use of checkpoint inhibitors with existing therapies, such as small molecule drugs. He hopes that this discovery will encourage related research by other institutions and eventually explain why colorectal cancer patients typically do not respond well to immunotherapy.

“We know there are other pro-inflammatory pathways that inhibit the ability of the immune system to attack tumor cells that are different from the immune checkpoint pathway. We are using animal models to test compounds that can block those inflammatory pathways. Now we are using those in addition to checkpoint inhibitors, and the combination of both approaches could turn out to be a game-changing and effective new therapy.”

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MUSC Hollings Cancer Center researchers discovered a novel mechanism showing how a certain gene mutation can allow tumors to evade detection by the immune system in colorectal cancer patients.

New Discovery Enhances Understanding of Colorectal Cancer

Protecting cancer patients from COVID-19 and its new variants continues to be a priority at 

. Hollings researcher and radiation oncologist 

a new study in the Journal of Thoracic Oncology detailing new findings and early markers of COVID-19 in lung cancer patients.

In the study, Warren pooled CT scans from several institutions around the world selected from patients who had undergone image-guided radiotherapy and developed COVID-19 during treatment. In the majority of cases studied, the scans revealed the presence of infiltrates, which refers to the hazy gray areas that can show up on scans of the lungs and serves as a marker of COVID-19 before the patient showed any symptoms.

“We want to try to identify a cancer patient’s risk of having COVID-19 very quickly because these patients have a higher risk of complications and mortality,” Warren said. “By using scans to discover potential positive COVID-19 cases early on, we can help to decrease the risk of exposure to other patients as well as facilitate earlier diagnosis and treatment for patients who have COVID.”

In the study, researchers reviewed the scans of nine lung cancer patients from Turkey, Spain, Belgium, Egypt and the United States who had tested positive for COVID-19. Warren said, surprisingly, that eight out of the nine patient scans revealed the presence of infiltrates in the lungs.

“These findings are extremely important,” he said. “If a doctor notices something on the patient’s scan, they can have them tested for COVID-19 or ask them how they are doing. This gives us the opportunity to identify patients who may have a higher risk of having COVID-19, whether they are symptomatic or not.”

Identifying COVID-19 is especially important in cancer settings because patients receiving cancer treatment are at higher risk for severe complications and death from COVID. Warren said that although chemotherapy and pneumonia can also cause infiltrates to form in the lungs, the finding in this international study is significant.

“Lung cancer patients receiving radiation are unique because they are already getting routine lung scans,” Warren said. “We can use the radiation setup already in place to identify risk of COVID-19, and we can accomplish this without significant changes to our standard radiotherapy procedures.”

With the number of new cases surging in some areas due to highly contagious variants, Warren said that further studies are needed to understand more fully the early markings of the virus and ways to protect those most at risk. At Hollings, positive COVID-19 cases among cancer patients are handled on an individual case basis.

“We have to deal with the patient and his or her diagnosis and also keep in mind exposure to other people,” he said. “If a patient develops COVID-19 during cancer treatment, then we try and treat that person at the end of the day, having staff wear appropriate protective clothing to reduce the risk of exposure to others. If patients show symptoms, we can modify treatment or stop treatment if needed.”

According to Warren, two recommendations resulted from the study. First, radiation oncologists and radiation departments should strongly consider reviewing image guidance for new pulmonary infiltrates and consider immediate COVID-19 testing in patients who show new infiltrates even with no obvious COVID-19 symptoms. Second, substantially more data is needed to determine the sensitivity and specificity of these findings and refine this approach in standard clinical care.

It is likely that COVID-19 will remain an important consideration for society and medical care. It’s also likely that variants will continue to evolve, and cases may present with different symptoms and imaging findings, he said. It will be important to continue monitoring patients during cancer treatment for years to come.

“With current COVID-19 variants and symptoms, these imaging findings could be extremely useful to help to minimize risk and infection,” said Warren. “These findings directly align with strategies to identify optimal cancer treatment strategies coupled with harm reduction strategies for COVID-19. These simple findings can reduce risk and exposure and can immediately improve the lives of cancer patients during cancer treatment.”

MUSC Hollings Cancer Center researcher and radiation oncologist Graham Warren, MD, PhD, published a new study in the Journal of Thoracic Oncology detailing new findings and early markers of COVID-19 in lung cancer patients.

Hollings Researcher Finds Surprising Results in COVID-19-Positive Lung Cancer Patients

Carolyn D. Britten, MD, a noted expert in phase I cancer clinical trials, has been named Director of the Hematology/Oncology Division in the Department of Medicine at the Medical University of South Carolina (MUSC). She continues in her role as Associate Director for Clinical Investigations at the MUSC Hollings Cancer Center, one of 68 National Cancer Institute (NCI)-designated cancer centers in the U.S.

Britten was recruited to MUSC in 2012 from the Jonsson Comprehensive Cancer Center at the University of California, Los Angeles (UCLA), where she held several leadership positions from 2001 to 2012, including Associate Director of the Signal Transduction and Therapeutics Research Program. At MUSC, she holds the Charles Westfield Coker Endowed Chair in GI Oncology, which is part of the prestigious South Carolina SmartState Centers of Excellence. Since arriving at MUSC, Dr. Britten has spearheaded the development of a Phase I Clinical Trials Program that now includes a portfolio of more than 20 actively accruing trials for patients with advanced cancer.

Patrick Cawley, M.D., vice president for clinical operations at MUSC and chief executive officer for the MUSC Medical Center, commented, “I am excited to have Dr. Britten join the oncology senior leadership team in MUSC Health. She has a collaborative, approachable, and persistent style that makes her a successful leader. In addition, she is a noted scientist and clinician, and she will continue the Hollings Cancer Center tradition of bridging the research lab and clinical care which is vital in the care of cancer patients today.”

Originally from Canada, Dr. Britten received her medical degree from the University of Toronto, and completed internship, residency and chief residency at the University of Western Ontario. She subsequently trained in medical oncology at the University of British Columbia in Vancouver, and completed a research fellowship in cancer drug development at the Institute for Drug Development at the University of Texas at San Antonio. She then joined the faculty at UCLA, where she developed their solid tumor Phase I clinical trials program.

“After joining MUSC in 2012, Dr. Britten quickly became a sought after collaborator among the scientists at Hollings,” according to Dr. Anthony J. Alberg, interim director of the Hollings Cancer Center. “With a keen insight into the latest scientific underpinnings of cancer, she has been able to work with our scientists to translate their laboratory findings directly into the clinic via clinical trials.

Not many places in the country can claim to have this capability, but the scientists at the Hollings Cancer Center, with Dr. Britten’s insight and leadership, have been able to do this.”

Dr. Britten has extensive experience in the medical oncology field at a national level. In addition to her Phase I clinical trials expertise, she specializes in the treatment of gastrointestinal cancers. Dr. Britten has served on multiple committees for the American Society of Clinical Oncology and is highly active in national oncology networks. She recently co-led Hollings Cancer Center’s effort to become one of 12 sites funded as a minority-based institutional site for the NCI Community Oncology Research Program which conducts multi-site, NCI-sponsored cancer clinical trials and cancer care delivery research studies.

In her new role as Director of the Hematology/Oncology Division, Dr. Britten has a vision to greatly expand the clinical services and research within the division through doubling the numbers of clinicians committed to clinical and translational research, leading the development of partnerships with regional community-based cancer programs to extend the specialized oncology services of the division, and refining the training within the division’s fellowship program to yield a new generation of medical oncologists equipped to practice in an era of targeted therapies.

According to Don Rockey, M.D., chair of the MUSC Department of Medicine, “We launched a national search for this critical leadership position within the Department and the Hollings Cancer Center, and it became clear to the search committee early on that we had one of the best and brightest talents in the field of medical oncology already in our own ranks. Dr. Britten brings great energy, passion and leadership to this position, and we all anticipate great things for both her and the division. I look forward to working with her, and I am certain that she is going to have a great impact within a short time frame not only within the institution, but also for the community we serve, in delivering the very best in patient-oriented cancer care.”

The Hollings Cancer Center at the Medical University of South Carolina is a National Cancer Institute-designated cancer center and the largest academic-based cancer research program in South Carolina. The cancer center is comprised of more than 120 faculty cancer scientists with a research funding portfolio of $43 million and a dedication to reducing the cancer burden in South Carolina.

Hollings offers state-of-the-art diagnostic capabilities, therapies and surgical techniques within multidisciplinary clinics that include surgeons, medical oncologists, radiation therapists, radiologists, pathologists, psychologists and other specialists equipped for the full range of cancer care, including more than 200 clinical trials. For more information, please visit www.hcc.musc.edu.

Britten continues as Associate Director for Clinical Investigations for the MUSC Hollings Cancer Center. 


Hollings Cancer Center

Articles

New Discovery Enhances Understanding of Colorectal Cancer

Hollings Researcher Finds Surprising Results in COVID-19-Positive Lung Cancer Patients

Cancer Phase I Trials Expert Carolyn D. Britten, MD, Named Director of Hematology/Oncology Division for Medical University of South Carolina