New methods for treating lung cancer cells that have become resistant to new anti-cancer agents

Apr 24 2007

Researchers at the Ireland Cancer Center of University Hospitals Case Medical Center have developed methods for treating lung cancer cells that have become resistant to new anti-cancer agents.

Led by Balazs Halmos, MD, hematologist/oncologist with the Ireland Cancer Center, the research team followed up on their previous study, published in the New England Journal of Medicine, which found that lung cancer cells can become resistant to novel targeted agents, such as Tarceva (erlotinib), a medication in widespread use for non-small-cell lung cancer (NSCLC). Tarceva is among a new generation of cancer therapies that disrupt the molecular target responsible for stimulating tumor growth. The drug targets the receptor for the epidermal growth factor protein (EGFR) to halt the spread of cancer cells. Clinical applications of the new drug initially yielded good results with approximately 10 percent of patients experiencing complete remission of their disease.

However, in spite of the therapy's initial success, patients inevitably suffered a relapse of their disease. Dr. Halmos' studies confirmed the existence of a mutation, and insertion of this mutation into test cells rendered them resistant to Tarceva. These cells became resistant by undergoing a miniscule molecular change in the EGFR protein that the medication targets. Further analysis revealed that the newly identified mutation was altering the protein's drug-binding pocket and thereby changing the "keyhole" so that the "key" , Tarceva , no longer fit. The researchers found that new second-generation Tarceva-like medications can overcome this change and such drugs are now in development, including in clinical trials at the Ireland Cancer Center.

In this latest study, that received an award at the annual American Association for Cancer Research (AACR) meeting where it was presented earlier this month, Dr. Halmos and his team were able to predict molecular changes the tumors might take next to become resistant to this new class of agents. "We tried to outsmart tumors by anticipating their next moves," says Dr. Halmos, a lung cancer specialist and Assistant Professor of Medicine at Case Western Reserve University School of Medicine. "This research revealed a number of new changes that EGFR can undergo that leads to resistance and also found ways to conquer this next generation of mutants."

The research team developed compounds to overcome the resistance with innovative combinations of medications. "Using these combinations early on can prevent resistance," explains Dr. Halmos. "Through this research, we are redefining our tools and anticipating ways to fight lung cancer."

Other significant presentations at AACR by Ireland Cancer Center physicians include:

• Dr. Sanford Markowitz and Dr. Halmos identified a gene, PGDH, known to be important in controlling colon cancer cell growth as a protein that participates in the growth pathways regulated by an important lung cancer "brake" gene, HNF3beta. PGDH is an enzyme that regulates the amount of certain hormone-like substances called prostaglandins in the tissues and bloodstream. This activity can be modified by medications that may prove effective in cancer treatment.
• Dr. Patrick Ma and his research team have identified a unique genetic mutation in the receptor protein EGFR that desensitizes the response to Tarceva (erlotinib) but yet differentially sensitized the response to another medication, Iressa (gefitinib), further. The mutation was initially identified in one of Dr. Ma's patients who responded dramatically to Iressa prescribed for her terminal complication from her lung cancer metastatic to the spinal cord (leptomeningeal metastasis), a case that was recently published in the Nature Clinical Practice Oncology. Dr. Ma's team conducted further study on the mutation and identified the mutation to occupy a location that constitutes a highly conserved salt bridge structure across the whole human kinome (more than 300 protein kinases with many of which as "druggable" therapeutic targets). His findings suggest that genetic mutations altering the salt bridge structure in the kinome proteins may affect cancer cell signaling, drug inhibitor binding and drug sensitivity. Theses insights would have wide implications in the principle of novel targeted cancer therapeutics. Dr. Ma's team also continues to make promising progress in their work on the development of alternative targeted therapeutics against a novel receptor target c-MET with the goal of optimizing lung cancer treatment, especially in those with resistance to EGFR inhibitors.