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Pancreatic microbiome may shed light on oncogenesis
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The microbial population in the pancreas may provide information about the development of pancreatic cancer, according to research conducted at New York University.
The study results — obtained from studies in mice — have laid the groundwork for a trial in humans that is about to get underway at the institution.
Deepak Saxena, PhD, associate professor of basic science and craniofacial biology at New York University College of Dentistry, George Miller, MD, associate professor in the departments of surgery and cell biology at New York University School of Medicine, and colleagues observed that the microbial population of the cancerous pancreas may be approximately 1,000 times larger than that of a noncancerous pancreas.
They noted ablation of the microbiome may have a protective effect against pancreatic ductal adenocarcinoma (PDA), and that transferring bacteria from hosts with PDA may promote carcinogenesis.
The results indicated an association between ablation and immunogenic reprogramming of the microenvironment of PDA tumors. Increases were observed in M1 macrophage differentiation, along with TH1 differentiation of CD4 and CD8 T cell activation. Ablation also reduced myeloid-derived suppressor cells.
The findings suggest the microbial population in the cancerous pancreas may increase immune suppression, thereby making the microbiome a potential therapeutic target.
HemOnc Today spoke with Saxena and one of the coauthors — Mautin Hundeyin, MD, postdoctoral fellow in the S. Arthur Localio Laboratory at NYU — about the experiments that served as the background for the current data set, how the trial in humans will be conducted, and the potential implications of the results from that study.
Question: How did this research come about?
Saxena: I have always been interested in the role of the microbiome in various chronic inflammatory diseases. [Miller] and I hypothesized that the gut microbiome could influence pancreatic inflammation, a known precursor for oncogenesis. We began our investigation by comparing the microbiome in patients with cancer and normal individuals. We found there was a 1,000-fold increase in the intrapancreatic microbiome of patients with cancer compared with individuals who did not have cancer. This finding was unexpected, as traditional knowledge considers the pancreas a sterile organ. The presence of bacteria in the pancreas of cancer-free individuals, which was markedly increased in the setting of cancer, was very surprising and exciting.
Hundeyin: In the scientific community, there has been increasing knowledge about the role of the gut microbiome in various gastrointestinal cancers, such as colon, gastric and liver cancers. Given the remote location of the pancreas and its connection to the rest of the GI tract via the pancreatic duct, we hypothesized that bacteria may be able to access the pancreas and, thus, have an effect on cancer progression.
Q: Can you explain how you conducted your initial study?
Hundeyin: We initially discovered that cancer-bearing mice had a distinct microbiome in their gut and pancreas compared with wild-type mice. As the next logical step, we ablated the gut bacteria in cancer-bearing mice and showed tumor protection and increased intrapancreatic immunogenicity. We also showed that repopulation of ‘bad bacteria’ from cancer-bearing mice accelerated tumor growth. In addition, we found an abundance of Bifidobacterium in the gut of cancer-bearing mice. To investigate if this bacteria could promote oncogenesis, we repopulated germ-free mice with Bifidobacterium.
Q: Did it accelerate oncogenesis?
Hundeyin: Yes, it did. Repopulation of germ-free mice with Bifidobacterium accelerated oncogenesis and promoted a local immune suppression.
Q: How is the human trial coming together, and how will it be conducted?
Hundeyin: Unfortunately, immunotherapy has failed in pancreatic cancer. Given that the gut microbiome promoted local peritumoral immune suppression, we hypothesized that it could modulate susceptibility to immunotherapy. Interestingly, ablation of the gut microbiome in mice allowed for efficacy of anti-PD1 immunotherapy. This finding was the basis for the clinical trial that we will be starting at NYU. We will give patients with locally advanced pancreatic cancer ciprofloxacin and metronidazole to eradicate gram-negative bacteria and anaerobes. Patients also will receive two doses of pembrolizumab (Keytruda, Merck), an anti PD-1 immunotherapeutic, to increase T-cell activation and promote antitumor immunity.
Q: What is the timeline for results?
Hundeyin: There are a number of logistical considerations, but we are hoping to enroll the first patient in about a year. [We hope to enroll] 20 patients.
Q: Is it too early to think of this as a potentially practice-changing approach?
Saxena: There are a few concepts that could potentially be practice changing. First, ablation of certain bacterial species could improve efficacy of chemotherapy or immunotherapy. Secondly, this raises the potential for giving patients ‘good bacteria’ or probiotics that could potentially slow tumor growth or decrease pancreatic cancer risk. Finally, we could consider the prospective of a microbial signature that could be used as a biomarker for risk stratification. – by Rob Volansky
Reference:
Pushalkar S, et al. Cancer Discov. 2018;doi:10.1158/2159-8290.CD-17-1134.
For more information:
Deepak Saxena, PhD, can be reached at 430 E. 29th St., West Tower, Alexandria Center, Suite 660, New York, NY 10016; email: ds100@nyu.edu.
Mautin Hundeyin, MD, can be reached at 430 E. 29th St., West Tower, Alexandria Center, Suite 660, New York, NY 10016; email: mautin.hundeyin@nyumc.org.
Disclosures: Saxena reports relationships with Periomics Care LLC. Hundeyin reports no relevant financial disclosures.