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Leif Ellisen, MD, PhD discusses the promise of molecular fingerprinting and targeted therapies.
“I’ve been in cancer research 25 years and everything has changed since I started,” says Leif Ellisen, MD, PhD, an oncologist at the Massachusetts General Hospital Cancer Center specializing in breast cancer. Discoveries are being made that can match patients to better, “smart drug” treatments.
Leading the way in this new era of cancer care — which uses knowledge gained at the molecular genetic level — is Massachusetts General Hospital’s new Molecular Pathology Translational Research Lab, which Ellisen co-directs with A. John Iafrate, MD, PhD, director of the Diagnostic Molecular Pathology Laboratory at Mass General. As many as 100 new cancer diagnoses are made at the Cancer Center weekly. Researchers at the Translational Research Lab have developed methods to “genotype” some tumors to find genetic abnormalities that have been activated. If there’s a drug than can de-activate those abnormalities, there is hope of a cure, says Ellisen.
We now know there are molecular pathways in normal cells that are activated or dysregulated to turn it into a tumor cell. There are more than a dozen of these major cancer pathways. Tumor genotyping is the detection of abnormalities in the genes within the tumor that have made a normal cell into a tumor cell. It’s not something that is inherited. It’s something that has happened in the tumor cell itself and is specific to that tumor.
Currently cancers are classified by the organs where they arise. If you look under a microscope you can easily distinguish a breast cancer from a lung cancer. However it’s possible that that breast cancer and that lung cancer have the same genetic abnormality. Many of the same genetic mutations are shared between different types of tumors. Potentially they could be treated with the same therapeutic agent if you have one that targets that abnormality. That’s the concept behind targeted therapy and the so-called smart drugs that are being developed.
Dr. Leif Ellisen
Right. Chemotherapy is directed at the very general property of cancer cells that they grow a little bit faster than normal cells. But chemotherapy can also damage normal cells since they have to grow and proliferate too. Our new molecular understanding of cancer has revealed that tumor cells are very dependent on the pathways they activate for their survival. That’s their Achilles’ heel. If you have a targeted drug that can shut off the activation of that pathway, it can be very effective against the tumor cell without a lot of side effects on the normal cell. Targeted therapy only works if the drug hits the target. Genotyping the tumor finds the target.
I think we’ve already seen some of the fruits of this approach. One example is breast cancer. About 30 percent of breast cancers have a genetic abnormality called Her2 amplification. This used to mean a bad prognosis. But a drug called Herceptin, developed to target the Her2 gene, has increased the cure rate by about 50 percent. That’s a dramatic increase in permanent cures for patients with that particular cancer. But you have to know that the person’s cancer is Her2 positive because Herceptin doesn’t work very well in patients who are not Her2 positive.
There are basic science efforts to identify more of these genetic abnormalities and pharmaceutical efforts to develop new drugs that will target them. The real focus of our Translational Research Lab is to bring those two things together and identify the molecular genetic abnormality of an individual’s tumor and see if we can give them the right targeted therapy. We are starting to test specific tumors for many, many genetic abnormalities, which takes a large-scale effort, cutting-edge robotic technology, and an infrastructure that can perform these tests as routinely as all the usual pathology tests.
Currently there are a number of drugs in clinical use that are associated with specific pathway abnormalities. Two of the prime examples are Herceptin for Her2-positive tumors, and an inhibitor of a growth factor receptor called EGFR for lung cancers and other cancers that have amplification or genetic mutation of the EGFR gene, which was first identified at the Cancer Center. There are also many inhibitor drugs in the pipeline in various stages of clinical trial. One of the goals of our Translational Research Lab is to try to accelerate the process of matching the drug to the patient who is most likely to benefit from it. Clinical trials typically take an inhibitor drug and try it on all patients with, for example, lung cancer. That takes years. Instead, why not just test the new drug on those patients whose tumors have the genetically abnormal pathways that the drug is supposed to inhibit? We believe this is the most efficient and quickest way to find the most effective inhibitors and get them to the patients who can most benefit from them.
It used to take 10 years for cancer research results to be translated from bench to bedside. Now it takes just months to bring new therapies to patients. It’s a whole new era.
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