TARGETING MYC driven malignancies:
OMT-001 & OMT-002
The MYC oncogene is a dominant driver in many human cancers, and its amplification is concomitant with poor prognosis in hematological, breast, prostate, colon cancers, and neuroblastoma. In addition, c-MYC overexpression together with gene amplification has been reported in over 50% of ovarian cancers, in ∼30% of hepatocellular carcinoma and in a high percentage of small-cell and non–small-cell lung cancers. This high frequency of c-MYC family deregulation in human cancers suggests that a strategy to target c-MYC driven cancers may be relevant for a broad population of patients.
Ohm Oncology has currently two programs running in the c-MYC domain namely BET inhibitor (OMT-002) and dual BET-JAK2 inhibitor (OMT-001). BET epigenetic regulators, especially BRD4, is a key modulator of c-MYC transcription acting at super-enhancers. The turnover of c-MYC transcription has been directly linked to BRD4 activity. Inhibition of BRD4 has been proven to be a key strategy to inhibit c-MYC transcription in a spectrum of malignancies.
Ohm has identified a BET inhibitor eliciting BRD4 inhibition with favorable DMPK properties (OMT-002).
To counter the resistance, downregulation of c-MYC transcription may not be enough to subvert c-MYC protein activity since it can be manipulated by three concerted mechanisms that can increasec-MYC cellular levels:
- Increase of c-MYC protein stability via deactivation of GSK 3B through PI3K-Akt axis
- Increase of c-MYC transcription by STAT5 by a largely unclear mechanism
- Increase of c-MYC transcription via BRD4 activity
Hence, the ultimate c-MYC down-regulation as well as inactivation, calls for synergistic inhibition of the three processes.
JAK2/JAK2 (V617F), as an upstream player, regulating c-MYC protein turnover in many malignancies. This, appears to be a synergistic target along with BET and has the potential to preclude resistance to BET targeted therapy in cancer.
Funakoshi-Tago M, Sumi K, Kasahara T, Tago K (2013) Critical Roles of MYC-ODC Axis in the Cellular Transformation Induced by Myeloproliferative Neoplasm-Associated JAK2 V617F Mutant. PLoS ONE 8(1): e52844.
Using Dual Prong Rational Technology (DPRT™) we have identified key dual inhibitor molecules (OMT-001; inhibiting BRD4 and JAK2) with excellent DMPK properties which exert near tumor elimination in leukemia xenograft models.