For Weill Cornell Medical College scientist Dr. Ari Melnick, advanced technology and cutting-edge science are unlocking the mysteries of the human genome, unleashing the potential of what was once unimaginable: finding cures for human cancers.
Researchers have spent decades investigating the root causes of cancer, hoping that if they were able to pinpoint its origins, they'd not only be able to stop the disease in its tracks, but also prevent it from developing at all. Now precision medicine is bringing scientists like Dr. Melnick closer to achieving this goal.
"We are picking off cancers one by one using this modern approach in decoding the instructions for specific tumor types," said Dr. Melnick, the director of the Raymond and Beverly Sackler Center for Biomedical and Physical Sciences, the Gebroe Family Professor of Hematology/Oncology and professor of medicine at Weill Cornell Medical College, who is an expert in leukemia and lymphoma. "We're moving toward an era where we are going to treat patients with drugs that are geared to their individual tumors."
Using epigenomics, the study of chemical reactions that control the activities of genes, Dr. Melnick is trying to decode the instructions that tell a leukemia or lymphoma tumor cell how to behave. These instructions are written, controlled and interpreted by master regulatory proteins that dictate how an organism develops. If scientists learn how these instructions are written and how master regulatory proteins use them to spur cancer development, he says, they may be able to design new drugs that block the cellular actions that cause the disease.
So far, his results are compelling. In one of his lab studies, Dr. Melnick discovered that a small molecule agent his team developed, MI-2, was able to stop the growth of a markedly aggressive and chemotherapy resistant form of diffuse large B-cell lymphoma, the most common subtype of non-Hodgkin's lymphoma and the seventh most frequently diagnosed cancer, without harming healthy cells. What's more, the compound permanently inactivated MALT1, a key protein responsible for driving the growth and survival of activated B-cell - diffuse large b-cell lymphoma, the most chemotherapy-resistant form of the lymphoma.
In another study, Dr. Melnick showed that it's possible to safely shut down the action of a protein that's key to the survival of a majority of non-Hodgkin's lymphomas including the two most common types: follicular lymphomas and diffuse large B-cell lymphomas. The particular protein of interest in this case is called BCL6, and function as a master regulator of the genome by controlling expression of thousands of genes. Dr. Melnick likens BCL6 to the CPU of a computer in how its actions function as a central control mechanism for the behavior of lymphoma cells. BCL6 is normally present in a type of immune cell (called germinal center B-cells) that develops in lymph nodes, but when BCL6 becomes deregulated it forces normal immune cells to transform into malignant lymphomas. Dr. Melnick's study shows that it's possible to stop BCL6 from driving cancer development without affecting its ability to support a healthy immune system. He has developed two drugs that specifically target BCL6, and is currently working on translating this advance to treat lymphoma patients in the clinic.
"Even in cases with good chemotherapy, there is a desire to replace them with less toxic drugs so they can be just as responsive without damaging cells," Dr. Melnick said. "The way we will know what drugs to use is based on knowing what their genetic and epigenetic status is."
Dr. Melnick began his medical career as a clinician before shifting his focus to research. He developed a passion for oncology after reading a TIME magazine article about cancer as a boy in his native Argentina.
"I remember thinking, 'Wow, that's very important,'" Dr. Melnick said. "'Cancer is such a scary monster; it would be interesting to think about trying to contribute to this topic.'"
Dr. Melnick went on to medical school in Argentina, later completing a residency in internal medicine and oncology at the Mount Sinai School of Medicine, taking care of cancer patients. It was there he concluded that he could do more for patients by trying to figure out the cause of their cancer, and then devising new treatments and therapies to help them.
Dr. Melnick then turned his focus to researching how the transcription of DNA is derailed in cancerous cells, specifically leukemia, which can sometimes be cured with chemotherapy, and a type of lymphoma that remains incurable with a strategy that hasn't changed in 30 years. He was determined to change that.
"I realized that what we were doing just wasn't the answer," he said. "I would have a greater, long-term impact on these patients and their families if I was devoted to trying to figure out how cancers work and how to develop better treatments. It's a very inspiring thing because you live through the patients and their families suffering and see it in a very powerful way. Working with patients is a privilege, but I wanted to provide more comfort to them."