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Human Brain Tumor Cells Eradicated in Lab Mice

By BiotechDaily International staff writers
Posted on 02 Oct 2013
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Scientists have discovered that treatment with a repurposed US-approved pharmaceutical blocked the growth of, and ultimately left no measurable trace of, brain tumor cells taken from adult human patients.

The scientists, from Johns Hopkins University (Baltimore, MD, USA), targeted a mutation in the IDH1 (isocitrate dehydrogenase ) gene first identified in human brain tumors called gliomas by a team of Johns Hopkins cancer researchers in 2008. This mutation was found in 70%–80% of lower-grade and progressive forms of the brain cancer. The alteration transpires within a single spot along a thread of thousands of genetic coding letters, and is disruptive enough to keep the apparently innocuous protein from playing its role in converting glucose into energy. Instead, the mutation seizes the protein to make a new molecule not typically found in the cell, which is apparently essential for the process of forming and maintaining cancer cells.

The new findings, published online September 16, 2013, in the open-access journal Oncotarget, encouraged the Johns Hopkins researchers to report that they want to work rapidly to devise a clinical trial to bring what they learned in mice to humans with gliomas. In spite of the increasing understanding of IDH1 mutant gliomas, the development of effective therapies has been problematic, according to the investigators. “Usually in the lab, we’re happy to see a drug slow down tumor growth,” said Alexandra Borodovsky, a graduate student in the cellular and molecular medicine program at the Johns Hopkins University School of Medicine who performed the experiments. “We never expect tumors to regress, but that is exactly what happened here.”

“This therapy has worked amazingly well in these mice,” stated study leader Gregory J. Riggins, MD, PhD, a professor of neurosurgery and oncology at the Johns Hopkins University School of Medicine. “We have spoken with neurosurgeons here, and as soon as possible, we want to start discussing the parameters of a clinical trial to see if this will work in our patients as a follow-up to surgery.”

The researchers warned that many therapies have cured cancers in mice, and then failed in humans. The IDH1 gene produces an enzyme that controls cell metabolism. Mutations in the DNA code drive the IDH1 gene to increase production of a flawed version of the enzyme. The defective enzyme generates large amounts of a completely new molecule, called 2-hydroxyglutarate. This molecule is believed to cause groups of atoms called methyl groups to attach onto the DNA strand.

Although methylation is a normal cellular process, when too many methyl groups glom onto the DNA, reported Dr. Riggins, this can interfere with normal cell biology and eventually add to cancer formation and growth.

Drs. Borodovsky, Riggins, and their colleagues, including Timothy A. Chan, MD, PhD, from Memorial Sloan-Kettering Cancer Center (New York, NY, USA; www.mskcc.org), thought that an agent that could take out those methyl groups might be able to reverse the cancer process in those cancers with IDH1 mutations. They chose 5-azacytidine, which is approved to treat a pre-leukemia condition called myelodysplastic syndrome and is being assessed on lung and other cancers at Johns Hopkins and elsewhere.

Dr. Riggins noted that one of the difficulties in developing treatments for IDH1 mutant brain cancers is finding a model in which to study them. Cell lines containing the IDH1 mutation are difficult to grow in the laboratory, for example. Dr. Borodovsky worked with Johns Hopkins neurosurgeons to obtain tumor cells from glioma patients prone to have IDH1 mutations and injected them under the skins of mice. She did this for months, before finally getting the tumor cells to grow.

The researchers, once the tumors grew, injected the mice with 5-azacytidine for 14 weeks and saw a drastic decline in growth and what appeared to be complete regression. Then they withdrew therapy. Seven weeks later, the tumors had not regrown. The researchers, however, said they do expect the tumors to regrow at some point, and are still monitoring the mice.

The type of tumor targeted by the researchers eventually progresses to a subtype of glioblastoma multiforme. They arise as a lower-grade glioma and are first treated with surgery alone, but ultimately they advance to the more lethal form of tumor. Survival is longer than with glioblastoma, but it is found in younger patients, those under the age of 50. While both types of tumor look the same at the end, they look very different at the molecular level, Dr. Riggins noted, leading researchers to believe they may have a better opportunity at targeting the progressive tumors, which are more likely to have the IDH1 mutation.

Dr. Chan’s group at Sloan-Kettering simultaneously published an article in Oncotarget, along with Drs. Borodovsky and Riggins, which described similar findings in a different animal model using a similar drug. This is additional validation that the approach is a good one, according to Dr. Riggins.

Related Links:
Johns Hopkins University
Memorial Sloan-Kettering Cancer Center


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