TARGETING gliomas through dual mutant IDH1/2 – BET inhibition
Brain tumors are the most common cancer among those age 0-19 (leukemia is the second). It is the second leading cause of cancer-related deaths in children (males and females) under age 20 (leukemia is the first) (Source: http://www.abta.org/).
The dual connection
It has been reported that IDH1 R132H mutation directly correlates with MYC expression [J. Neurooncology. 2013 Nov; 115(2)]. Furthermore, down regulation of c-MYC reduces patient derived glioma neurospheres (Nature Communications, 5:4632). Essentially, this opens the space for BET inhibition and indeed tumor regression has been observed in glioma xenograft studies using BET inhibitor (Epigenetics 9:4, 611–620; April 2014).
Hence, based on these findings, we believe that targeting onco-metabolism regulator mutant IDH 1/2 and BET would have a synergistic effect in glioma therapy.
Ohm oncology has undertaken dual mutant IDH – BET inhibitor designing and screening program using the DPRT™ after its successful application in BET-JAK2 program.
The rationale (IDH mutant targeting)
- Low-level of 2-HG under normal homeostasis is rapidly cleared via conversion to αKG by chirality-specific dehydrogenases (D-2HGDH or L-2HGDH).
- Mutant IDH1/2 leads to enhanced production of 2HG that cannot be converted back to α-KG.
- 2HG is the oncometabolite that inhibits hypoxia induced factor (HIF) as well as αKG dependent dioxygenase leading to genome wide epigenetic changes.