July 1, 2013 (Vol. 33, No. 13)

Scientists Are Investigating How Genes Controlling Metabolism Are Connected with Cancers

The metabolic switch-hitting of cancer cells that enables them to reorganize their energies to support maximum growth and metastases and escape normal control mechanisms are now well recognized. And as Jiyeon Kim, M.D., and Ralph J. DeBerardinis, M.D., Ph.D., of the Children’s Medical Research Center, University of Texas Southwestern Medical Center, pointed out in their May 3 Science article, metabolic reprogramming in cancer may provide a source of potential therapeutic targets. But since these rearrangements also reflect enhancement of normal metabolic activities, developing therapeutic strategies targeting tumor cells without affecting normal tissues has been problematic.

Until recently, few solid links between mutations in genes controlling metabolism and cancers had been found, connections that could be exploited for therapeutic gain.

But in the last few years, scientists have identified mutant forms of enzymes peculiar to cancer cells that can exert control over their metabolism. Recently characterized isocitrate dehydrogenase enzyme (IDH) mutations (IDH1 and IDH2) in leukemia and glioblastoma have introduced a cancer-specific role for metabolic genes essential to cellular respiration.

These findings also link aberrant IDH1 and IDH2 activity to an altered metabolite profile, as the enzymes function “at a crossroads of cellular metabolism” in lipid synthesis, cellular defense against oxidative stress, oxidative respiration, and oxygen-sensing signal transduction.

Normally, IDH catalyzes the conversion of isocitrate to α-ketoglutarate (α-KG), both metabolites ultimately derived from glucose in the course of cellular respiration. Alpha-KG is also required for the activity of about 60 other enzymes.

But somatic mutations in these enzymes endow them with so-called “gain of function” activities that causes them to produce an altered form of their normal product. Among its other effects, the mutated enzyme’s activity results in overproduction of the right enantiomer of its normal α-KG product. This isomer, R-2-hydroxyglutarate, inhibits the activity of DNA-modifying enzymes, including TET2, part of the TET family of 5-methylsytosine hydroxylases, thereby altering gene transcription.

Tumors with IDH1/IDH2 mutations display a distinctive profile of DNA and histone hypermethylation, and express genes associated with undifferentiated progenitor cells.

To date, recurrent mutations in IDH1 and IDH2 have been identified in gliomas, acute myeloid leukemia (AML), and chondrosarcomas, and all these abnormal enzyme isoforms share the novel enzymatic property of producing 2-hydroxyglutarate (2HG) from α-ketoglutarate.

Studies of alterations in these metabolic enzymes have provided insights into the metabolism of cancer cells and suggested novel avenues for development of anticancer therapeutics which are being pursued, in particular, by Agios Pharmaceuticals.

Results of mechanistic studies reported in 2012 by Chao Lu and colleagues indicated that 2HG-producing IDH mutants can prevent the histone demethylation that is required for lineage-specific progenitor cells to undergo differentiation. In tumor samples from glioma patients, IDH mutations were associated with a distinct gene expression profile enriched for genes expressed in neural progenitor cells. The authors further found that either IDH mutant enzymes or cell-permeable 2HG was associated with repression of both the inducible expression of lineage-specific differentiation genes and a block to differentiation.

Fast forward to 2013: Drs. Kim and DeBerardini commented in their Science article on two papers appearing in the May 3 issue of the same journal. Those reported that small molecules targeting mutant IDH1 or mutant IDH2 release the differentiation block and/or impede tumor growth, providing a proof-of-concept that mutant IDHs are therapeutically targetable and that their effects are reversible.

In the papers, scientists from Agios Pharmaceuticals and their collaborators elsewhere described the effects of small molecule IDH 1 and 2 mutant-specific inhibitors in primary tumor models. According to Agios, the data adds to the body of work demonstrating the potential value of targeting the mutant enzymes to treat cancer. Agios is focused on discovering and developing novel drugs in the fields of cancer metabolism and rare metabolic genetic diseases.

In one study, led by Dan Rohie of the human oncology and pathogenesis program at Memorial Sloan Kettering Cancer Center, the investigators determined the role of mutant IDH1 in fully transformed cells with endogenous IDH1 mutations. A selective R132H-IDH1 inhibitor (AGI-5198) identified through a high-throughput screening blocked, in a dose-dependent manner, the ability of the mutant enzyme (mIDH1) to produce R-2HG. Under conditions of near-complete R-2HG inhibition, the mIDH1 inhibitor induced demethylation of histone H3K9me3 and expression of genes associated with gliogenic differentiation.

Blockade of the mutant enzyme also impaired the growth of IDH1-mutant—but not IDH1–wild-type—glioma cells without changes in genome-wide DNA methylation. This data, the authors concluded, suggests that mIDH1 may promote glioma growth through mechanisms beyond its well-characterized epigenetic effects.

In the same issue of Science, Agios’ Fang Wang, Ph.D., and collaborators describe the ability of another small molecule inhibitor, AGI-6780, to induce differentiation of a GMCSF-dependent TF-1 erythroleukemia cell line and primary human acute myelogenous leukemia cells in vitro. Expression of a block in erythroid differentiation was reversed by treatment with the inhibitor. This and other data supports, the investigators said, the clinical evaluation of IDH2 mutant-targeted agents in AML and other malignancies.

Diagnostic Partnership

In April, Agios and Foundation Medicine announced a multiyear diagnostic partnership for Agios’ lead programs in cancer metabolism focused on developing new cancer metabolism inhibitors targeting tumors carrying mutations in either the IDH1 or IDH2 metabolic enzymes. Foundation Medicine and Agios are collaborating to identify tumor genomic alterations that can be used to identify which patients are most likely to respond to Agios’ IDH1 and IDH2 drug candidates, and to develop and potentially commercialize diagnostic products for these programs.

David Schenkein, M.D., Agios CEO, said: “Our lead IDH1 and IDH2 programs demonstrate Agios’ ability to leverage deep understanding of cancer metabolism to design first-in-class cancer medicines for genetically defined patient populations.”

And Agios has proven popular with investors—the firm, launched in 2008, has raised $261 million to date. More than half of those funds came from Celgene, which has been granted licensing rights to compounds arising from Agios’ new collaboration with Foundation, where Agios’ Schenkein has served on the board of directors since 2010. Agios and Foundation, which did not disclose financial details of their agreement, share a common investor in Third Rock Ventures, which helped found Agios.

Kevin Starr, a partner at Third Rock Ventures, which provided part of the company’s $33 million Series A funding, told Xconomy that Agios “locked up as much intellectual property as it could in cancer metabolism.” At the same time, he said, it built a discovery platform that merged oncology and metabolism.

“To discover what those metabolic pathways are doing in cancer, we needed to build joint insight,” Starr said. “A big pharma company might have expertise in both cancer and metabolism, but it’s difficult for them to merge the two. When you’re a new company, it’s more straightforward.”

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