New discovery may aid diagnosis
One of the worst forms of lung cancer is an adenocarcinoma that is identified by chemical changes in a normal cell communication circuit called KEAP1/NRF2. These changes also occur in another circuit, PBK. The 20 percent of tumors that display these changes are found most often in women and teenagers, reported Arlene Weintraub in Fierce Biotech.
Scientists at the Bio21 Institute at the University of Melbourne have discovered that these changes cause continuous communication between cells, which in turn causes adenocarcinomas to develop in the lungs. The researchers also discovered that drugs that interfere with “immune checkpoints” known as PD-1 and CTLA-4 act successfully against tumors.
“This is extremely important, because these tumors are chemotherapy and radiotherapy resistant, meaning there are effectively no current treatments for these patients,” said Melbourne researcher Dr. Sarah Best.
Three existing drugs, the CTLA-4 inhibitor Yervoy and the PD-1 inhibitor Opdive, made by Bristol-Myers Squibb, and the PD-1 inhibitor Keytruda made by Merck, work in some patients but not in others. Research is now being carried out to determine why.
Meanwhile, other researchers have discovered that neutrophils, white blood cells that normally act against intruders but fail against cancer, will gather around tumors without attacking them. Removing the neutrophils seems to make tumors more vulnerable to PD-1 blockers.
The new findings about chemical changes in KEAP1/NRF2 and P13K alterations may also lead to new diagnostics, i.e., a blood test, for earlier detection of these lung cancers.
“More than one in five lung adenocarcinomas have alterations in the KEAP1/NRF2 pathway, suggesting that it is a major cancer driver. These cancers are very aggressive, are resistant to standard therapies and have a poor prognosis, so new therapies are urgently needed,” said Dr. Kate Sutherland, leader of the Melbourne University study.
“Using preclinical models, we showed for the first time that these tumors have the ‘markers’ that respond to anti-PD-1 and anti-CTLA-4 immunotherapies, which are some of most exciting new cancer therapies being investigated in the clinic,” Dr. best added. “But more importantly, we showed that these immunotherapies were effective in fighting the tumors and leading to tumor regression in our preclinical models. This is the first time anyone has shown that these alterations directly cause lung adenocarcinomas. With this, we can investigate how targeting those pathogens could lead to therapies for these cancers.”
Dr. Sutherland concluded, “Working with our colleagues we were able to identify a unique trail that the cancers leave behind in the blood. Our hope is that the test could identify patients likely to respond, but also that could be a simple blood test for early detection of these lung cancers. The next steps would be to analyze human samples to prove the same is true in adenocarcinomas. But we need more funding to continue and to generate results that will lead to better detection and treatments.”