Looking Beyond DNA Defects to Characterize Cancer

Melanoma cell

Some melanoma cells carry the ALK mutation.

Advances in gene-sequencing technologies over the past decade have revealed a treasure trove of data on the genetic mutations that can lead to cancer. But these technologies look only at changes in tumor DNA and may miss other kinds of defects — specifically, alterations in RNAs (the molecules that help turn DNA into protein) and proteins for which the DNA encodes.

Now a collaborative team from Memorial Sloan Kettering has used a different kind of technology to study pieces of RNA found in patients’ tumors and discovered that some of these abnormal RNAs and the proteins they encode may be more common than previously expected. The finding suggests that more patients may benefit from targeted therapies than previously thought.

In particular, they found a novel version of the RNA molecule that’s used to make ALK, a protein already known to play a role in lung cancer and some other tumors. The researchers learned that the ALK RNA and protein can be altered even when the gene that carries the instructions to make the protein is normal.

“We found that this special version of ALK occurs due to epigenetic mechanisms,” says MSK physician-scientist Ping Chi, who is senior author of the recent study that includes these findings, published in the journal Nature. Epigenetics refers to information that is passed down from one cell generation to the next but is not encoded in the DNA sequence. Epigenetic changes affect the way that DNA is transcribed into RNA and then translated into protein.

Epigenetics refers to information that is passed down from one cell generation to the next but is not encoded in the DNA sequence.

Although these epigenetic changes are not detectable by gene-sequencing technologies, there are other approaches to find alterations in RNAs and proteins.

“Techniques other than DNA sequencing may be useful for finding the altered ALK in tumors,” she adds. “Tests that look for this version of the ALK RNA and protein would enable us to identify more patients who might benefit from treatment with targeted therapies.”

Looking for Changes in Tumor Samples

ALK, which stands for anaplastic lymphoma kinase, is an enzyme that plays a role in the development of the brain. It is not commonly present in adult tissues except those within the nervous system. As its name implies, it is associated with anaplastic large-cell lymphoma, a rare subtype of non-Hodgkin lymphoma. The enzyme is altered at the DNA level in more than half of all cases. Changes in the ALK gene are also found in a small percentage of non-small cell lung cancers (NSCLCs), mainly adenocarcinomas; thyroid cancer; and the pediatric cancer neuroblastoma.

In the current study, Dr. Chi’s team analyzed more than 5,000 tumor samples from patients with 15 different cancer types using tests that looked for altered RNAs and proteins. They found the special ALK RNA in 11 percent of melanoma tumors and also sporadically in other cancer types.

“We could combine these other diagnostic modalities to study patients’ tumors and identify those who might benefit from treatment with ALK inhibitors,” says Dr. Chi, who is a member of MSK’s Human Oncology and Pathogenesis Program.

The special ALK RNA was found in 11 percent of melanoma tumors and also sporadically in other cancer types.

Some of these ALK-targeting medications are already being used. Crizotinib (Xalkori®) and ceritinib (ZykadiaTM) are approved by the US Food and Drug Administration for the treatment of ALK-positive NSCLCs and are being evaluated in clinical trials for other ALK-positive tumors.

Based on the current research, along with earlier studies, the investigators expect to find abnormal expression of ALK RNA and protein in melanoma, especially melanoma tumors that have metastasized (spread) to other parts of the body.

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Moving into the Clinic

“The obvious next step is to identify patients with this special form of RNA and begin clinical trials to evaluate whether ALK inhibitors are an effective treatment for them,” Dr. Chi says. “We have already shown that this novel ALK variant is sensitive to existing drugs that block ALK activity.”

“There is a lot of interest in the clinical realm to identify more patients who could benefit from these drugs,” she adds. “But much more work needs to be done to figure out how to identify the most appropriate patients and choose the most effective drug for these trials.”

Researchers hope to identify more patients who could be treated with targeted therapies.

She notes that MSK already treated one patient through compassionate use — which enables patients to access experimental treatments outside of clinical trials — and found there was some benefit. The patient, who was treated with crizotinib, had melanoma that had progressed on other standard-of-care and investigational treatments.

“It’s also conceivable that there are other cancer-causing proteins that arise through epigenetic mechanisms similar to this novel ALK variant that are not detectable by typical genomic-based studies,” Dr. Chi says. “We have plans to move forward with computational-based analysis as well as further studies in the lab to look for some of these other proteins.”

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Funding for this research was provided by the National Institutes of Health under grants NIH DP2CA174499 and K08CA151660 and by the Geoffrey Beene Cancer Research Fund.