One of the most deadly illnesses current and past smokers can face is squamous cell lung cancer. Until now, though, no drugs have targeted the gene mutations that cause this disease
In an extensive new study of tumor cells taken from squamous cell lung cancer patients, researchers have identified enzymes that affect that cancer’s growth and possibly can be slowed or stopped by a new batch of cancer drug treatments.
Matthew Meyerson, MD, PhD, professor of pathology at Dana-Farber Cancer Institute and Harvard Medical School in Boston, co-led the research.
The study is part of the Cancer Genome Atlas, a project by the National Institutes of Health (NIH) dedicated to the study of genetic abnormalities in cancer. More than 300 authors contributed to this paper.
Scientists have already made advances in developing drug therapies that zero in on adenocarcinomas, which are the most common type of lung cancer.
But these treatments have failed, for the most part, in treating squamous cell cancer, which is the second most common type of lung cancer.
Squamous cell tumors frequently grow in the large airways in the center of the lungs, while adenocarcinomas appear on the edges of the lungs. Non-smokers occasionally get adenocarcinomas, but smokers almost exclusively get lung squamous cell carcinomas (or cancers).
Genes Are Key to Controlling Cancer
For this study, lung tissue samples from 178 patients with untreated lung squamous cell carcinomas were examined. About 96 percent of these patients had a history of tobacco use.
Researchers compared the genes in the cancerous tissue to normal tissue. They noted a large number of gene changes in the tumors that appeared to negatively affect pathways related to the start and spread of cancer.
Genes that help detoxify cells and repair cell damage were often changed compared to the normal tissue.
The altered genes were connected to enzymes that act like on-and-off switches when it comes to cell growth. In cancer, the enzymes are often stuck in the on position.
In many of the tumors analyzed, investigators discovered mutations of three families of enzymes called tyrosine kinases. These are enzymes that are frequently altered in cancer.
In pre-clinical studies, these enzymes have been identified as potential targets for drug therapies. In clinical studies, researchers have examined these enzymes in other cancers and confirmed them as targets for drug therapy.
Dr. Meyerson said in an interview with the Nation Cancer Institute, “I think a lot of the drugs that could be useful are currently in clinical trials. These include fibroblast growth factor receptors, or FGFR inhibitors, and PI3-kinase inhibitors.
That means, of course, we don’t know yet how they’re going to perform. I think there are going to be other drugs that will include many of the classes of enzymes that we’ve found to be mutated in adenocarcinomas.”
While genes and mutations varied from patient to patient, some alterations were common. The TP53 gene was changed in 90 percent of tumors and the CDKN2A gene was inactivated in 72 percent of tumors. These genes normally block cancer, but when turned off, tumors can grow freely.
Potential for a Cancer Vaccine
Investigators also identified a previously unreported mutation in the HLA-A gene in tumors. That gene controls how the immune system distinguishes the body’s own cells from foreign invaders.
Dr. Meyerson said that this new HLA-A discovery provides information on how cancers evade the immune system.
“People have long suspected that the immune system controls the development of cancer,” said Dr. Meyerson.
“In recent years, therapies that increase the strength of the immune response have shown to be effective for cancer. Some of the genes on the surface of cells that make them recognized by the immune system are lost with these cancer cells making them potentially less recognizable by the immune system. This suggests that immune-directed therapy could be effective.”
Dr. Meyerson added that the fact that gene mutation appears to affect the immune response “supports the concept of a lung tumor vaccination.” The National Cancer Institute is actively pursuing a program to develop a cancer vaccine, especially for prostate cancer.
Drugs That May Help
An enzyme inhibitor called a kinase inhibitor is a drug that may prove effective in treating these genes. Drugs that are in development or could soon be in development may be able to target these genes and fight against the abnormalities.
Bruce Evan Johnson, MD, a lung cancer doctor at Dana-Farber and an author of the research, said that next steps will be to verify that the mutations identified in the squamous cells actually promote tumor growth. Not all mutations are related to cancer.
Investigators expect to conduct studies adding mutated genes to normal cells in mice to see if they become cancerous cells. Also, they expect to develop research examining the effects of kinase inhibitors on the cancerous cells—confirming that these drugs can “turn off” the enzyme that promotes these cancer cells.
Future studies may find that established tyrosine kinase inhibitors, such as leukemia drugs Gleevec from Novartis and Bosulif from Pfizer, can be effective at fighting squamous cell cancers as well.
The authors believe the research is promising for those who have lung cancer because it can lead to individual targeted therapies that will address squamous cell lung cancer in addition to adenocarcinomas.
"These findings should stimulate a wide variety of new clinical trials for patients with squamous cell lung cancer," said Dr. Meyerson. "These will include clinical trials of kinase inhibitors as well as ways to select patients for trials of lung cancer treatments that dial down the immune response."
Getting a drug from the test stage to FDA approval, can take three years or more. Crizotinib, a therapy developed by Pfizer that targets a mutated gene in some adenocarcinomas, was tested on lung cancer subjects in 2008 and approved for patient use by 2011.
This study is part of the Cancer Genome Atlas, an extensive, ongoing project by the National Institutes of Health cataloging genetic abnormalities responsible for cancer. So far, the Cancer Genome Atlas Research Network has published work on colorectal cancer, ovarian cancer, and brain tumors.
Research gathered for the atlas has revealed that each patient’s cancer can be very different, and because of this, very personalized treatment and drug therapy is required.
Dr. Meyerson said that he expects to see Atlas research on kidney cancer, endometrial cancer, lung adenocarcinoma, head and neck cancer, and possibly melanoma and bladder cancer in the next year.
The study was published in the September issue of Nature.