Targeted therapies, or treatments directed towards specific biomarkers in tumor cells, have been effective in treating many patients with advanced-stage non-small cell lung cancer (NSCLC).
Tumors that have the ALK protein fused with another cancer-driving protein, such as the EML4 protein, are often referred to as ALK-positive tumors. Approximately 5% of advanced-stage adenocarcinoma, a type of NSCLC, will test positive for an ALK-fusion biomarker. Treating patients with ALK-positive lung cancer with a class of drugs called tyrosine kinase inhibitors (TKIs) has been an effective approach. However, as seen in other types of lung cancers treated with TKIs, eventually the tumors develop resistance to treatment and the tumor begins to grow again.
“As a pathologist, I don’t see lung cancer patients directly. I study their biopsies and test results, and I thereby help develop their treatment plans,” explains John Iafrate, MD, PhD, of Massachusetts General Hospital, who has a long-standing interest in lung cancer patients whose tumors test positive for ALK fusions. Dr. Iafrate was part of the team that helped develop crizotinib, the first FDA-approved TKI for ALK-positive lung cancer.
Dr. Iafrate was frustrated seeing drug resistance develop in cancers treated with TKIs.
I wanted to identify a new way to target and kill cancer cells that didn’t involve TKI drugs. I wanted to develop a treatment with a new mechanism, so it could be used with the TKI treatment and help reduce the chance of drug resistance.Dr. John Iafrate
“This type of high-risk high-reward project would have been very hard to get funded by the NIH (National Institutes of Health). NIH is really good at providing funding for research that is mature, where there is a lot of preliminary data and the project needs to be expanded and taken to completion,” says Dr. Iafrate.
In 2020, Dr. Iafrate was awarded a grant from LUNGevity Foundation, in partnership with ALK Positive, a patient-led advocacy group focused on improving outcomes for ALK-positive cancer patients. The goal of this research was to identify potential new treatment approaches by using computational biology techniques to screen a library of approximately 4,000 compounds (small molecules) that are known to bind irreversibly to their targets.
“Organizations like ALK-Positive and LUNGevity fill a critical niche. They are so valuable to the lung cancer field. Especially for these types of early-stage projects that probably wouldn’t have gotten off the ground without their help.”
Through the research grant, Dr. Iafrate and his team found a potential new targeted therapy for lung cancer patients with ALK-EML4 fusions — a small molecule that binds to the EML4 section of the fusion protein. “This is exciting because the traditional TKIs used to treat ALK-positive lung cancer are designed to target the ALK side of the fusion protein,” explains Dr. Iafrate. “With this new molecule, we are hoping to develop a combination approach to target both sides of the ALK-EML4 fusion protein at the same time.”
This work also brings hope for lung cancer patients with other biomarkers. For example, there are patients whose tumors have the rarer fusion of EML4-RET who could potentially benefit from this new drug.
“There are many types of innovative work going on. And a lot of hope in the field. Personally, I’m excited for where our research is heading,” notes Dr. Iafrate. His team continues to do work to understand how the potential new drug works within tumor cells with the ultimate goal of treating patients with tumors that have ALK-EML4 fusions. “We’re working as fast as we can to bring this treatment to patients in a safe way,” adds Dr. Iafrate. “I know patients are waiting for these results.”
”It’s been very meaningful for me, on a personal level, to interact with ALK-Positive“ says Dr. Iafrate. “I’ve really been able to get to know the patient community through this group. I care a lot about these patients and I keep a close eye on their progress in terms of developing resistance to treatments and also on their quality of life.”
Developing a new class of drugs to treat lung cancer is critical for patients. It’s also important for the researchers themselves. “If it works out the way we think it will, certainly it’ll be great for my career. But more importantly, this will have a big impact on the careers of the junior people working on the project,” explains Dr. Iafrate. “For example, Dr. Liron Bar-Peled, my co-PI — he’s smarter than I am, but he’s junior to me. Success here means a lot for him in terms of continued research funding. And then, we should consider Dr. Diane Yang, the post-doc who’s done a lot of this amazing work. This is how we can help build her career. This award and others like it are how we build a strong future full of talented lung cancer researchers doing life-saving work.”
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