Outlet Full Name: Science Life
Author Name: Matt Wood
Oncologists used to divide lung cancer into two types: small-cell and non-small cell. But as genetic research uncovered more mutations that cause lung cancer, non-small cell lung cancer has been subdivided further into an alphabet soup of acronyms: EML4-ALK translocations, ROS1 translocations or KRAS mutations, among others.
Ravi Salgia, MD, PhD, director of the Thoracic Oncology Program at the University of Chicago Medicine, said these discoveries change the definition of the disease.
“Lung cancer is no longer just lung cancer,” he said.
Each of these lung cancer subgroups provides a new pathway for potential treatment, and Salgia has a history of exploiting these targets. He and his colleagues participated in a Phase I trial of the drug crizotinib, which inhibits, or switches off, the mutated, cancer-causing EML4-ALK gene formed when part of one gene breaks off its chromosome and reattaches itself to a neighboring gene. This ultimately led to the drug’s approval for patients with altered ALK in lung cancer.
Other forms of non-small cell lung cancer have been more elusive though. Cancers caused by mutations in the KRAS gene, which plays a role in regulating cell division, don’t have effective, targeted therapies like crizotinib. But new research by Salgia leading to another clinical trial at UChicago may add a new acronym to the list of genetic mutations that can be targeted to treat lung cancer.
In a study published in PLOS One, Salgia and his colleagues showed that a protein receptor called EphB4 in lung cancer tumors can be treated with an inhibitor that blocks the receptor and kills the cancer cells. And when combined with the chemotherapy drug paclitaxel, the tumors actually disappear.
EphB4 is a receptor tyrosine kinase, which is a protein that helps cells recognize signals from their environment and interact with other cells. It’s involved in cell proliferation as well as angiogenesis, or the growth of blood vessels, and is implicated in a number of cancers in the upper body, including mesothelioma, lung cancer, esophageal cancer, head and neck cancers, and other tumors.
“We’re so excited that we have such great collaborators, we have such great people here and that we have been able to work together to make a difference for our patients.”
Salgia and his colleagues found that EphB4 is overexpressed in non-small cell lung cancer tumors, and the section of DNA that expresses it is often copied a greater number of times than normal. Salgia said previous research on breast cancer suggested EphB4 could be a tumor suppressor, but this study showed that the receptor facilitates growth of the lung cancer cells, making it an attractive target for treatment.
“It turns out that it actually acts as an oncogene, so that was also going against the grain of the literature,” he said. “Having it brought to clinical fruition, I think that makes perfect sense.”
Parkash Gill, one of the study’s co-authors from the University of Southern California, created a drug called soluble EphB4 that mimics the receptor as an antibody and prevents it from receiving signals. In their experiments, this drug killed cancer cells with the KRAS mutation and other mutations in lung cancer. When combined with paclitaxel, the tumors shrank and disappeared.
The treatment worked against not only non-small cell lung cancer but also small cell cancers as well, which Salgia said makes it such an encouraging strategy.
“In terms of therapeutic decision making, we were quite excited,” Salgia said.
Gill is already conducting a Phase I clinical trial at USC using soluble EphB4 to treat non-small cell lung cancer, and Salgia is working with him to activate a trial at the University of Chicago as well.
With some treatments taking months or even years to move from the research lab to clinical trials, Salgia said he’s encouraged to begin as soon as possible.
“How often do you hear that they went from preclinical research to clinical trials in a very short period of time?” he said. “We’re so excited that we have such great collaborators, we have such great people here and that we have been able to work together to make a difference for our patients.”