Lung cancer is by far the most common cause of cancer deaths both in the United States and worldwide, and even though scientists have made great strides with targeted therapies and immunotherapy, almost all patients with advanced lung cancer eventually become resistant to treatment.
Thoracic surgeon Dan J. Raz, M.D., M.A.S., Co-Director of City of Hope’s Lung Cancer and Thoracic Oncology Program, and Ravid Straussman, M.D., Ph.D., an expert in molecular cell biology at the Weizmann Institute of Science in Rehovot, Israel, are working hard to improve that prognosis. The pair is striving to identify the biological mechanisms by which lung cancer sufferers become resistant to therapies, in particular by discovering and cataloguing the specific bacteria that appear within different types of tumor tissue and interfere with the effectiveness of drugs and chemotherapy treatment.
Normally, a healthy immune system fights off any bacteria that try to invade internal organs, but because cancers evade the immune system, different types of bacteria can flourish in tumor tissue and help the cancer grow. More than that, the bacteria work to weaken the effects of treatment.
It turns out that each type of cancer — pancreatic, breast, lung — has its own unique set of bacteria, which when identified can potentially lead to even more targeted, effective therapies. In one example, the types of bacteria that are found in people who have lung cancer but never smoked are different from the bacteria in those who have lung cancer and are smokers.
Raz and Straussman are hoping that their efforts to catalog these bacteria, and the treatments to which they are most resistant, will lead to new drugs that can counteract the bacteria’s interference. Raz and Straussman’s collaboration is the result of a grant from the Jacki and Bruce Barron Cancer Research Scholars’ Program, which was established in 2016 by a gift from The Harvey L. Miller Family Foundation to support the exchange of ideas, strategies and therapies between City of Hope and Israeli investigators backed by the Israel Cancer Research Fund. Their newest efforts are a continuation of studies they began with support from a Barron grant they received in 2016-17.
“This is a project that draws on the strengths of two people who ordinarily probably wouldn’t have connected,” said Raz. “Israel has this incredible culture of innovation and technology. To be able to collaborate with that type of culture is really exciting. If it wasn’t for this funding mechanism, I don’t think we would have ever gotten together. It’s been amazing.”
The novel approach that Raz and Straussman are taking has its origins in the latter’s earlier work with pancreatic cancer. Straussman and his team did a study where they were able to identify exactly how specific bacteria within patients’ cancers led to resistance to one of the most commonly used types of chemotherapy for pancreatic cancer. They discovered that the bacteria make an enzyme that breaks down the chemotherapy. But in subsequent trials using mice, they were able to modify the bacteria so that it no longer produced the enzyme, and the tumors suddenly became sensitive to the chemotherapy again. “That was a big success story,” Raz said.
Straussman then approached Raz, who joined City of Hope in 2012, about doing similar studies to explore bacteria in nonsmall cell lung cancers. First, they used tissue samples from hundreds of lung cancer patients who had been operated on at City of Hope to identify the many different types of bacteria in those tumors. Now, they are trying to determine which bacteria cause resistance to which commonly employed treatments — and precisely how they block the therapies.
“Ravid has a way to do this high-throughput screening where they can determine if the bacteria causes resistance to different types of drugs,” said Raz. “We grow the bacteria, and then we take the cultures — the ‘broth’ or ‘soup’ that it’s sitting in — and we add it to different cancer cells and different medications to see if that causes resistance.”
Specifically, Raz and Straussman are focusing on the two most common targeted therapies for lung cancer — one is used to treat the EGFR mutation, and the other is used to treat EML4-ALK. Both mutations produce a protein in the tumor that advances the cancer, and the two scientists have thus far been able to identify bacteria for each of them that seem to cause resistance to their therapies.
If they can discover the precise mechanism by which those bacteria lead to resistance, they can potentially develop new treatments that block it and clear a path for the chemotherapy. Ultimately, as with Straussman’s pancreatic cancer study, they plan to do further studies using mice to test these new therapies.
“My research is all about trying to overcome resistance to treatment, but I don’t think I ever would have gone down this route if it weren’t for Ravid,” said Raz. “He has all these incredible tools that he’s developed.”
Straussman has devised hundreds of probes that use the genetic sequence of the bacteria to identify them in the tissue, and the high-throughput method he’s designed allows him to do hundreds of experiments at a time in which he applies a variety of drugs to different cells that contain the bacterial broth.
“He’s brilliant, and he’s a super nice guy,” Raz said of Straussman. “He’s got an incredible team that works for him, and they just get things done. He elevates my research game.”
For the time being, Raz and Straussman are employing a division of labor: Straussman is focusing on the ELM4-ALK resistance, and Raz is investigating the EGFR resistance. “Basically, we’re trying to determine the mechanism by which the specific bacteria we’ve identified lead to resistance of these targeted therapies,” said Raz. “That takes some time, but once we’ve done that then the next step is to use a clinical model to show that when we modify whatever it is that we find, it leads to sensitivity to the drug. The eventual application would be to either create a new drug or use some kind of antibiotic to improve sensitivity to treatments.”
The prospect of breaking new ground on advanced lung cancer treatment and what that could mean for patients fuels Raz’s enthusiasm for the work that the Barron program has made possible. “This is a very novel approach that really no one other than Ravid’s group has looked at,” Raz said. “It’s very exciting that this has the potential to improve or extend survival in people with advanced lung cancer. That’s why we do this: to try to find something that helps people live longer.”