Susan Bullman, PhD, assistant member in the Human Biology Division at Fred Hutchinson Cancer Research Center (Fred Hutch), discussed the role of tumor microbiota in gastrointestinal (GI) cancer progression and response to treatment during her keynote lecture on January 25. In an interview with ASCO Daily News, she reflected on her accomplishments to date, trending research in the field of GI malignancies, and ways in which new research could impact the treatment of GI cancers.
Q: Which research accomplishments do you consider the most relevant in your career to date?
Dr. Bullman: Two major research findings have catalyzed the development of my research program at Fred Hutch. The first is the finding that dominant colorectal tumor microbiota persist in distal metastases to the liver, and the second is the observation that antimicrobial treatment of patient-derived xenografts harboring their native microbiota significantly reduces tumor growth. Specifically, when we treated the mice harboring patient-derived tumors with metronidazole, we saw a significant reduction in tumor growth and a decrease in the bacterial (specifically Fusobacterium) load of tumors. Both findings suggest that the microbiota are intrinsic and important components of the tumor microenvironment for colorectal tumors, and that microbiota modulation could change the course of this disease. I was fortunate to receive the NIH Pathway to Independence Award (K99/R00) to expand upon these findings published in late 2017.
Q: Who has helped shape your career and research interests?
Dr. Bullman: I have had the opportunity to interact with numerous inspiring scientists at different stages of my career. These include Cynthia Sears, MD, at Johns Hopkins Medicine, who is a leader in the field of colorectal cancer microbiome research and a major role model for me, my laboratory, and my science. Another person who has been incredibly helpful is Denise Galloway, PhD, Scientific Director of the Pathogen-Associated Malignancies Integrated Research Center here at Fred Hutch. Her research has been fundamental to the development of the HPV vaccine. Dr. Galloway led the search committee that recruited me to Fred Hutch, and she continues to support my research program as a mentor.
Q: What is your current research focus?
Dr. Bullman: My laboratory focuses on understanding the role of tumor microbiota in GI cancer progression and response to treatment, including both chemotherapies and immunotherapies. One of the goals is to understand how/whether members of the tumor microbiota, which are metabolically active, metabolize chemotherapeutics and affect drug efficacy during patient treatment. We are also interested in understanding why GI cancers have not been responsive to immunotherapies.
Specifically, we are looking at the lack of response of colorectal tumors to immunotherapies and trying to understand whether the microbial composition of tumors is contributing to the patient’s immune response. We are also interested in assessing the microbial communities in responders versus nonresponders and understanding whether microbiome modulation could impact patient treatment response.
“We are looking at the lack of response of colorectal tumors to immunotherapies and trying to understand whether the microbial composition of tumors is contributing to the patient’s immune response.”—Dr. Susan Bullman
So far, we have identified microbial communities that are enriched in colorectal tumors compared to adjacent normal tissues. These microbial communities tend to be dominated by anaerobic bacterial that typically reside in the oral cavity, such as Fusobacterium nucleatum (F. nucleatum), Selenomonas, and Prevotella species. I have begun collaborating with Dr. Stacey Cohen, MD, with the Seattle Cancer Care Alliance, and we are now investigating novel inhibitors of specific microbes that dominate the tumor microbiota of patients with colorectal cancer.
Q: Which questions remain unanswered about the role of tumor microbiota in GI cancers?
Dr. Bullman: This field is very much in its infancy. We are still wondering if we should be focusing on a single microbe, like F. nucleatum, or if we should be thinking about the collective microbial communities and the potential for concerted contributions to tumor growth and development. It is important to keep an open mind in this area.
A related question we need to ask is can we specifically target a key microbe, like F. nucleatum, with narrow-spectrum inhibitors and whether this will be sufficient to reduce tumor growth. It is not ideal to give patients a broad-spectrum antibiotic that will also knock out beneficial microbiota and leave them susceptible to other types of opportunistic infections. The question is, can we develop a targeted approach where we will selectively target specific members of the tumor microbiota to achieve a reduction in tumor growth?
Q: Is there any practice-changing research going on at the moment?
Dr. Bullman: A recent study in pancreatic cancer has demonstrated that the patient tumor microbiome composition may be a predictor of survival.2 I think that such findings, if reproducible across multiple cohorts, have the potential to impact patient stratification and treatment decisions in GI oncology.
There have also been some mechanistic studies assessing the role of specific bacterial species in cancer. For organisms, such as F. nucleatum, a major challenge is the heterogeneity between bacterial strains which cause conflicting results. Nevertheless, there have been several compelling mechanistic studies from Dr. Sears, a leader in the research on enterotoxigenic Bacteroides fragilis, and Christian Jobin, PhD, of the University of Florida, relating to pks-positive E. coli, which delve into the mechanisms of specific virulence factors and how they may contribute to colorectal cancer. For an organism like F. nucleatum, which exhibits enormous strain heterogeneity, it has been very difficult to pinpoint the mechanism. We have yet to identify specific virulence factors that are consistently associated with carcinogenesis or progression of tumors.
Another question that my laboratory is aiming to answer is whether we should take a patient’s tumor microbiome into consideration when deciding on the optimal treatment. The hypothesis driving my research is that if a bacterial agent can contribute to cancer initiation or progression, then these organisms are viable targets for the prevention and treatment of these cancers. — Jasenka Piljac Žegarac, PhD
