MR spectroscopy imaging reveals effects of targeted treatment of mutant IDH1 gliomas

May 18, 2018, Massachusetts General Hospital
Three-dimensional magnetic resonance spectroscopy imaging reveals a decrease in tumor levels of 2-hydroxyglurate -- a metabolite that may contribute to tumor initiation -- in a patient with IDH1-mutated glioma after a week of treatment with an investigational targeted drug. Credit: Ovidiu Andronesi, M.D., Ph.D., Martinos Center for Biomedical Imaging, Massachusetts General Hospital

Using a novel imaging method, a Massachusetts General Hospital (MGH) research team is investigating the mechanisms behind a potential targeted treatment for a subtype of the deadly brains tumors called gliomas. In their report published in Nature Communications, the researchers describe using magnetic resonance spectroscopy (MRS) imaging—which reflects metabolic rather than structural aspects of tissues—to determine whether treatment with an investigational IDH1 inhibitor reduced levels of a tumor-associated metabolite in patients with IDH1-mutated gliomas participating in a clinical trial.

"Gliomas are aggressive, primary brain tumors that lack effective treatments, and patients invariably succumb to the disease," says lead author Ovidiu Andronesi, MD, Ph.D., of the MGH-based Martinos Center for Biomedical Imaging, lead author of the paper. "There is a desperate need for progress in , and IDH mutations, which occur commonly in these tumors, offer a pathway for targeted therapy. With the new metabolic imaging method that we developed to probe treatment effects, we showed that a novel IDH1 inhibitor can quickly reduce levels of the oncometabolite 2HG in patients with this mutation. This type of methodology has the potential to accelerate clinical trials and translation of targeted therapies, such as mutant IDH inhibitors, and makes the concept of precision oncology feasible in glioma patients."

While patients with gliomas characterized by mutations in the isocitrate dehydrogenase (IDH) enzyme tend to live three to five times longer, with better response to chemo- and radiation therapy, than do patients whose tumors do not carry IDH mutations, the mutations themselves may initiate and drive the growth of the . IDH mutant tumors produce elevated levels of 2-hydroxyglurate (2HG), which is believed to contribute to tumor initiation by interfering with gene expression control. While it is unclear whether reducing 2HG level would reverse the process in patients, it could be used as a biomarker for diagnosis and monitoring of IDH mutant tumors.

The MGH and Dana-Farber Cancer Institute are one of the sites for a Phase 1 clinical trial of the IDH1 inhibitor IDH305 for IDH1-mutated glioma treatment. Of eight patients who had enrolled in the trial at time of the current study, MR imaging data collected before and a week after treatment began was available for five. Three-dimensional MRS imaging of the data found that 2HG levels dropped around 70 percent after treatment initiation. Levels of additional metabolites connected with the mutant IDH1 pathway—including glutamine and glutamate—were altered in response to IDH305 treatment, indicating a potential metabolic reprogramming of the tumor.

"MR spectroscopy is quick, noninvasive and can be performed on any clinical MR scanner, making results available before any biopsy or surgical procedure have begun," says Andronesi, and assistant professor of Radiology at Harvard Medical School. "It also can be used to track the response to treatment, since repeat biopsies are not feasible for with brain tumors, by directly probing the activity of the mutant IDH1 enzyme. Of course, our small study needs to be replicated in a larger group with longer follow-up times, as well as determining the long-term benefit of IDH1 inhibitor treatment."

Explore further: Persistence pays off in discovery that could lead to improved treatment and survivability of patient

More information: Ovidiu C. Andronesi et al, Pharmacodynamics of mutant-IDH1 inhibitors in glioma patients probed by in vivo 3D MRS imaging of 2-hydroxyglutarate, Nature Communications (2018). DOI: 10.1038/s41467-018-03905-6

Related Stories

Persistence pays off in discovery that could lead to improved treatment and survivability of patient

May 1, 2018
It's a discovery more than seven years in the making that researchers believe will vastly illuminate our understanding of deadly brain tumors.

Mutant-IDH1 inhibitor AG-120 shows early promise against solid tumors with IDH1 mutations

November 9, 2015
The investigational anticancer therapeutic AG-120, which targets mutant IDH1 protein, was well tolerated and showed signs of clinical activity in patients who had advanced solid tumors positive for mutant IDH1, according ...

Experimental drugs that change energy supply in cells could slow brain tumor growth

December 14, 2015
Experimental drugs that alter cell metabolism also halted tumor growth and extended survival in mice with cancers linked to changes in the same gene, according to a new study led by researchers at NYU Langone Medical Center, ...

TGen, Scottsdale Healthcare begin study of new drug for patients with solid tumors

June 17, 2014
The Virginia G. Piper Cancer Center at Scottsdale Healthcare and the Translational Genomics Research Institute (TGen) are studying the safety and effectiveness of a new drug, AG-120, for treatment of patients with solid tumors, ...

Study demonstrates effects of mutant IDH1 and IDH2 inhibitors in primary tumor models

April 4, 2013
Agios Pharmaceuticals announced today the publication of two articles in the journal Science by Agios scientists and their collaborators demonstrating the effects of the company's small molecule isocitrate dehydrogenase 1 ...

Genetic mutations help brain tumors evade targeting by immunotherapy treatments

March 20, 2017
Tumors of the brain and spinal cord, or gliomas, are among the most commonly occurring brain tumors. Although a majority of gliomas are classified as curable, these low-grade tumors have the potential to develop more aggressive ...

Recommended for you

A code for reprogramming immune sentinels

December 10, 2018
For the first time, a research team at Lund University in Sweden has successfully reprogrammed mouse and human skin cells into immune cells called dendritic cells. The process is quick and effective, representing a pioneering ...

Potential seen for tailoring treatment for acute myeloid leukemia

December 8, 2018
Advances in rapid screening of leukemia cells for drug susceptibility and resistance are bringing scientists closer to patient-tailored treatment for acute myeloid leukemia (AML).

Study may offer doctors a more effective way to treat neuroblastoma

December 7, 2018
A very large team of researchers, mostly from multiple institutions across Germany, has found what might be a better way to treat patients with neuroblastoma, a type of cancer. In their paper published in the journal Science, ...

Major breakthrough in quest for cancer vaccine

December 6, 2018
The idea of a cancer vaccine is something researchers have been working on for over 50 years, but until recently they were never able to prove exactly how such a vaccine would work.

'Chemo brain' caused by malfunction in three types of brain cells, study finds

December 6, 2018
More than half of cancer survivors suffer from cognitive impairment from chemotherapy that lingers for months or years after the cancer is gone. In a new study explaining the cellular mechanisms behind this condition, scientists ...

Scientists develop new technology for profiling unique genetic makeup of myeloma tumor cells

December 6, 2018
Cancer arises when cells lose control. Deciphering the "blueprint" of cancer cells—outlining how cancer cells hijack specific pathways for uncontrolled proliferation—will lead to more efficient ways to fight it. Joint ...

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.