Targeting MYC driven malignancies
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).
Targeting JAK2 in myeoloproliferative neoplasms (MPN)
Myeloproliferative Neoplasms (MPNs) are blood cancers that occur when the body makes too many white or red blood cells, or platelets. This overproduction of blood cells in the bone marrow can create problems for blood flow and lead to various symptoms. MPNs were called Myeloproliferative Diseases until 2008 when the World Health Organization re-classified them as cancers and named them Myeloproliferative Neoplasms.
There are three main types of MPNs:
- Primary Myelofibrosis (PMF)
- Polycythemia vera (PV)
- Essential thrombocythemia (ET)
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, downregulation 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).