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More on How Dr. Frattini is Changing Chemotherapy

Research and Clinical Trials

Return to How Dr. Frattini is Changing Chemotherapy Overview

More on How Dr. Frattini is Changing Chemotherapy

How Dr. Frattini is Changing Chemotherapy

NEW YORK (Sep 1, 2013)

A NewYork-Presbyterian doctor is developing ways to personalize chemotherapy and help patients beat cancer. Traditional chemotherapy is great at killing cancer cells but it destroys healthy cells too, leaving patients with a plethora of side effects including a suppressed immune system, hair loss, and a weakened digestive tract. The issue troubled Mark G. Frattini, M.D., Ph.D., Director of Research for the Hematologic Malignancies Section in the Hematology/Oncology Division at NewYork-Presbyterian/Columbia University Medical Center.

Mark G. Frattini, M.D., Ph.D.
Mark G. Frattini, M.D., Ph.D.

Dr. Frattini and his colleagues worked to discover a small molecule that could inhibit a protein known as cell division cycle 7 (Cdc7) kinase. Kinase is an enzyme that sparks a chemical reaction and provides a positive growth signal and nutrients to cells, allowing them to multiply. Normally, this protein acts as a regulator of the processes that control the repair of DNA damage and DNA replication in healthy cells. In patients with cancer, the Cdc7 kinase is found at much higher levels making the cancer cells more sensitive to the inhibition of this regulator, resulting in the preferential death of cancer cells. Shutting down this process in cancer cells essentially destroys them by starvation.

"When we began our research eight years ago, I thought the Cdc7 kinase was a good therapeutic target because it was a pathway that was directly linked to cancer cell growth and one that had not been previously examined," said Dr. Frattini, who began his career at Memorial Sloan Kettering Cancer Center. He noticed that cancer cells seemed to be very dependent on this kinase pathway for survival. "The cancer cells are addicted to this kinase pathway and if we are able to target it, then we can more precisely kill cancer instead of normal cells," he explained.

After discovering the small molecule, Dr. Frattini's laboratory then made human kinase and used it to screen more than 300,000 different compounds. From this, they pursued several compounds more extensively, and ultimately picked one to develop as a possible anti-cancer therapeutic, a compound they called MSK-777. Results in several animal studies show that MSK-777 is very effective at destroying cancer cells but leaving healthy cells intact. "It is highly efficacious against cell lines and animal models of many different types of cancer, but has minimal effects on normal, healthy cells. We are very excited to more precisely target and kill cancer cells," he said. Currently, Dr. Frattini's team has completed additional animal testing and required FDA regulatory studies with plans to begin Phase I clinical trials of MSK-777 for patients with relapsed and/or chemotherapy-refractory leukemias in early 2014.

In another project, Dr. Frattini's laboratory also developed a simple test to help doctors determine how their patients would react to various types of chemotherapy. "The test entails placing patient cancer cells in a tissue culture dish and exposing them to various single and combination chemotherapeutic agents. We evaluate the percentage of cells that go into apoptosis, or commit to cell death, as a result of that particular chemotherapeutic agent or combination," he said.

The test allows doctors to assess the efficacy of various chemotherapeutic agents for individual patients. In this way, doctors are able to uniquely tailor chemotherapy regimens based on how each patient responds to a particular agent or combination and minimize harm to healthy cells. "In the era of genomics and next generation sequencing, this test is a very powerful companion diagnostic tool and perhaps the best test to determine whether or not a patient will ultimately respond to a particular chemotherapeutic regimen," said Dr. Frattini.

Currently, Dr. Frattini's focus is on testing patients with acute leukemias who have failed several lines of therapy, as this group of patients could achieve an immediate benefit from a regimen that controls their cancer and allows for the potential of a life-saving bone marrow transplant. In the future, Dr. Frattini hopes to translate this personalized approach to therapy to other types of cancer as well.

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