Abstract IA02: Molecular pathogenesis of IDH mutant cancers and evolving treatment strategies

IDH1 and IDH2 mutations have now been described in a variety of cancers including gliomas, acute myelogenous leukemias, chondrosarcomas, cholangiocarcinomas, and angioimmunoblastic T-cell lymphoma. Tumor-associated IDH1 and IDH2 mutants produce large amounts of the R enantiomer of 2-hydroxyglutarate (R-2HG), which accumulates to mM levels in IDH mutant tumor cells. R-2HG modulates (usually inhibits) various 2-oxoglutarate-dependent enzymes, including various 2-oxoglutarate-dependent dioxygenases. Examples of such dioxygenases include the JmjC family of histone demethylases and the TET methylcytosine hydroxylases. The challenge for the field has been to determine which enzymes, when modulated by R-2HG, drive transformation and which are simply bystanders. We developed a cell-based assay for hematopoietic transformation by mutant IDH and showed that transformation in this setting is indeed mediated by R-2HG and that its effects are reversible. Moreover, we and others provided evidence that inhibition of TET2 by R-2HG contributes to leukemic transformation in cells carrying IDH mutations. Small molecules that block R-2HG production appear promising based on early Phase 1 data in IDH1 and IDH2 mutant leukemias. We also developed a model of astrocytic transformation by IDH. We found that activation of the EglN prolyl hydroxylases, which target the HIF transcription factor for destruction, by R-2HG promotes soft agar growth by immortalized astrocytes but is not sufficient to promot...
Source: Cancer Research - Category: Cancer & Oncology Authors: Tags: Metabolism/IDH/Epigenetics Source Type: research