Drugs show potential for combating aggressive form of lung cancer

"The main challenge of small cell lung cancer is that patients initially respond well to chemotherapy, but the tumor inevitably relapses within a short while, and after relapse it no longer responds to chemotherapy or radiation," said Piyali Dasgupta, Ph.D., associate professor of pharmacology, physiology and toxicology at Marshall University's Joan C. Edwards School of Medicine and the study's senior author. "Our hope is that the therapies we're investigating could combine with chemotherapy to delay that relapse and improve patient outcomes."

Dasgupta and her colleagues used an approach designed to starve the cells of blood supply, thus inhibiting their growth. The team will present the new research at the American Society for Investigative Pathology Annual Meeting during Experimental Biology 2016.

About 98 percent of people diagnosed with stage IV small cell lung cancer die in less than five years. Catching the disease early offers a slightly better outlook, yet only about 30 percent of those diagnosed with stage I small cell lung cancer survive for at least five years.

A unique feature of small cell lung cancer is that it occurs almost exclusively in smokers. Nicotine, the addictive chemical in cigarette smoke, is known to accelerate the progression of lung cancer by helping the tumor to recruit blood vessels.

"Nicotine is not a carcinogen -- it doesn't cause cancer -- but once the cancerous process is initiated, nicotine helps the cancer cells to grow and survive," said Zachary Robateau, a Marshall University graduate student who worked with Dasgupta on the research. "If you can block that process, you could potentially suppress the growth of these small cell lung cancer cells."

Nicotine helps small cell lung cancer cells increase their blood supply by binding to a protein called the alpha7-nicotinic receptor on the surface of these cancer cells. The researchers sought to test compounds that would block nicotine from binding to this target.

Because nicotine's effects on the ability for small cell lung cancer cells to recruit blood supply are somewhat permanent, the researchers hypothesize that drugs blocking this receptor would be effective even in lung cancer patients who have already quit smoking.

In an initial proof-of-concept study, they tested MG624, a well-known blocker of nicotine-alpha7-nAChR interaction, and found that MG624 successfully blocked the recruitment of blood vessels to small cell lung cancer tumors and suppressed tumor growth in mice.

Following up on those promising results, the researchers are now in the process of testing whether a compound called Memanitine could have a similar effect. Memantine is an existing drug approved by the Food and Drug Administration for the treatment of mild to moderate Alzheimer's disease and dementia that is known to bind to the alpha7-nicotinic receptor.

"A lot of the appeal of Memantine, in particular, is that it's already used in the clinic and is well tolerated by patients" said Dasgupta. "If Memantine blocks the blood supply to small cell lung cancers, then it may be beneficial in conjunction with chemotherapy in patients. Plus, the bench-to-bedside process may be quicker since the drug is already in clinical use."

Although it's unlikely that either of these compounds alone would kill cancer cells, Dasgupta said that Memantine- or MG624-based treatments, in combination with chemotherapy, could help to delay a tumor's relapse. The team's next step is to test Memantine in human small cell lung cancer cells grown within mouse models.