Timothy Graubert, MD, an expert on the genetics of leukemia, plans to accelerate the translation of research to new therapies to treat blood cancers.

People with leukemia, lymphoma, multiple myeloma and other blood cancers are in desperate need of new treatment options that can keep their cancers in remission. About every three minutes, someone in the United States is diagnosed with one of these blood cancers. As the treatment for cancer increasingly becomes driven by the genetic make-up of each individual cancer, the Massachusetts General Hospital Cancer Center is aggressively pursuing gene-targeted treatments for blood cancers.

“We are now in a period of exponential growth in cancer gene discovery that will provide many new therapeutic targets for hematologic cancers.”

“We are now in a period of exponential growth in cancer gene discovery that will provide many new therapeutic targets for hematologic cancers,” says Timothy A. Graubert, MD, the MGH Hagler Family Chair of Hematologic Malignancies. Dr. Graubert, a leading authority on the genetic basis of blood cancers and a pioneer in the use of genome sequencing technology, is the new head of the Mass General Cancer Center’s Hematologic Malignancies Program.

Hematological cancers are those that affect the blood, bone marrow and lymph nodes. They include leukemia, lymphoma and multiple myeloma. Most of these cancers start in the bone marrow where blood cells are produced. The Hematologic Malignancies Program also encompasses bone marrow transplantation, a procedure used to restore healthy bone marrow cells.

A Treasure Trove of Genes

Dr. Graubert’s research focuses on identifying new genes and gene mutations involved in causing acute myeloid leukemia (AML), a rare but deadly form of leukemia, and myelodysplastic syndromes (MDS), disorders of blood-forming cells in bone marrow that can progress to AML.

His research team at Washington University in St. Louis—from which he was recruited by Mass General in 2013—was the first to sequence the genome of a patient with cancer. They used a method called whole-genome sequencing to search the DNA of AML cancer cells to find genetic changes that don’t exist in healthy cells. Since then, he and colleagues have identified a treasure trove of genes with mutations, including genes named DNMT3A, IDH2 and U2AF1. They have also learned how these genes contribute to cancer progression.

“Establishing the relevance of individual mutations is a major challenge,” Dr. Graubert says.  “However, as the genetic rules of cancer are becoming known, new approaches for diagnosis, assessing risk and individualized treatment are now possible for cancer patients.”

They have added about 50 additional gene mutations related to blood cancers for which a patient’s tumor cells can be screened.

Mutations Related to Blood Cancers

Dr. Graubert believes it is a natural extension of his blood cancer work in the lab to translate these advances into new therapies for patients as quickly as possible. The Mass General Cancer Center is a world leader in personalized cancer medicine, the concept of targeting treatments to specific gene abnormalities that enable cancers to grow and thrive.

The Mass General Cancer Center is at the forefront of developing ways to identify cancer-causing gene mutations from a sample of a patient’s cancer cells. If a patient’s cancer cells harbor a known mutation, doctors can then see if there is a drug or combination of drugs—either approved or experimental—that target and potentially deactivate the genetic abnormality.

Dr. Graubert is collaborating with A. John Iafrate, MD, PhD, co-director of the MGH Translational Research Laboratory. The lab has recently developed a next-generation gene sequencing technique, which allows them to search the entire length of genes for mutations with greater sensitivity and precision. They have added about 50 additional gene mutations related to blood cancers for which a patient’s tumor cells can be screened.

Dr. Graubert confers with Amy Bertino, PhD, a research scientist in his lab.
Dr. Graubert confers with Amy Bertino, PhD, a research scientist in his lab.

“This allows us to both look more broadly for mutations and to find those that might be present in only a minority of cancer cells,” Dr. Graubert says.

Exciting New Drug Possibilities

A majority of adult patients successfully treated for AML, for example, eventually relapse, so new drugs and drug combinations are desperately needed. Two oral drugs that target the isocitrate dehydrogenase (IDH) gene mutations that Dr. Graubert and his colleagues discovered in AML are generating much optimism. IDH mutations are present in about 25 percent of patients with AML and 5-10 percent of those with MDS. Mass General is one of the lead participants in early clinical trials among a select group of institutions in the United States and Europe that are testing these promising drugs in patients with MDS and AML.

“This is one of the most exciting advances in treating AML that has happened in my career,” says Dr. Graubert, who graduated from Harvard Medical School in 1988 and chose to specialize in hematology because there was so much unknown at the time.

Though the ability to help people with blood cancers has grown immensely since then, there is much more to do. Dr. Graubert is seeking philanthropic support to recruit top-notch researchers and clinicians to expand the hunt for new molecular targets and new treatment approaches.

To learn more about Mass General Cancer Center’s Hematologic Malignancies Program, please contact us.