Scientists Identify Key Defect in Brain Tumor Cells


“In a new study, Yale researchers identified a novel genetic defect that prevents brain tumor cells from repairing damaged DNA. They found that the defect is highly sensitive to an existing FDA-approved drug used to treat ovarian cancer—a discovery that challenges current practice for treatment of brain tumors and other cancers with the same genetic defect, said the scientists.

“The study was published on Feb. 1 by Science Translational Medicine.

“Certain and leukemias have mutations in genes known as IDH1 and IDH2. The mutations render the cancers sensitive to treatment with radiation therapy or chemotherapy, significantly increasing the survival time for patients with the mutations. To better understand this sensitivity, a cross-disciplinary team of researchers led by Yale created models of the mutation in cell cultures.”

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Agios Gets FDA Fast-Track Designation for its Experimental Leukemia Drug

Editor’s note: The U.S. Food and Drug Administration (FDA) has granted a “Fast-Track” designation to a new drug for certain patients with acute myelogenous leukemia (AML). The drug, called AG-221, is a targeted therapy that is meant to treat people with AML whose tumors have mutations in the isocitrate dehydrogenase-2 protein (IDH2), as detected by molecular testing. The Fast-Track designation means that the FDA will facilitate a faster approval process so that the drug can soon be prescribed by oncologists in the U.S.

“Agios Pharmaceuticals Inc., a Cambridge company seeking to develop new treatments for cancer, said Wednesday that the US Food and Drug Administration has granted a so-called “Fast Track” designation to its experimental treatment for a type of acute myelogenous leukemia, or AML.

“The FDA’s fast track program is designed to facilitate frequent interactions with the FDA review team to expedite clinical development and submission of a New Drug Application, or NDA. The designation is given to medicines with the potential to treat serious or life-threatening conditions and address unmet medical needs. The program provides the opportunity to submit sections of a new drug application on a rolling basis as data become available. This permits the FDA to review portions of the new drug application as they are received instead of waiting for the entire application submission.

“Agios currently calls its drug candidate AG-221, and it is designed to the treat patients with AML who harbor an isocitrate dehydrogenase-2 mutation.”

Gene Mutation May Lead to Treatment for Liver Cancer

Editor’s note: Cancer is caused by genetic mutations that lead to excess cell growth and tumor formation. Scientists have identified many specific cancer-causing mutations, and drugs have been developed to target and treat tumors with some of these specific mutations. Researchers recently discovered that two mutations—IDH1 and IDH2—can lead to the development of intrahepatic cholangiocarcinoma (iCCA). The discovery could open up new treatment options for some patients who have these mutations. Indeed, there are ongoing clinical trials testing new drugs in patients with IDH1 and IDH2 mutations.

“Two genetic mutations in liver cells may drive tumor formation in intrahepatic cholangiocarcinoma (iCCA), the second most common form of liver cancer, according to a research published in the July issue of the journal Nature.

“A team led by the Icahn School of Medicine at Mount Sinai and Harvard Medical School has discovered a link between the presence of two mutant proteins IDH1 and IDH2 and cancer. Past studies have found IDH mutations to be among the most common genetic differences seen in patients with iCCA, but how they contribute to cancer development was unknown going into the current effort.

“iCCA strikes bile ducts, tube-like structures in the liver that carry bile, which is required for the digestion of food. With so much still unknown about the disease, there is no first-line, standard of care and no successful therapies.

” ‘iCCA is resistant to standard treatments like chemotherapy and radiation,’ said Josep Maria Llovet, MD, Director of the Liver Cancer Program, Division of Medicine, Icahn School of Medicine at Mount Sinai, and contributing author. ‘Understanding the molecular mechanism of the disease is the key to finding a treatment that works.’ ”

Cancer Metabolism Drug AG-221 Shows Clinical Activity in Advanced Blood Cancers

“AG-221, a novel inhibitor of isocitrate dehydrogenase (IDH) 2-mutant metabolic enzyme, was well tolerated and showed early promise in patients with advanced and refractory blood cancers harboring IDH2 mutations, according to the initial results of a phase I study presented here at the AACR Annual Meeting 2014, April 5-9.

” ‘Mutations in the genes for the metabolic enzymes IDH1 and IDH2 are thought to be the drivers of distinct subsets of acute myeloid leukemias (AML),’ said Eytan M. Stein, M.D., assistant attending physician in the Leukemia Service at Memorial Sloan Kettering Cancer Center in New York. ‘They lead to the production of increased levels of an oncometabolite called 2-hydroxyglutarate (2-HG), which is hypothesized to prevent normal healthy bone marrow cells from maturing, leading to cancer.’ ”

Editor’s note: AG-221 is a targeted therapy drug. The goal of this phase I clinical trial was to test the safety of AG-221 for patients. The trial found that AG-221 is safe and shows real promise as a cancer-fighting treatment for patients whose blood cancers have mutations in the IDH2 gene, as detected by molecular testing.