Drug Development Targeting Transcription Drivers in Cancer

Dysregulation of gene expression is a hallmark of all cancers. It is critical for self-renewal and chemo-resistance of cancer cells, which contribute to the inability to completely eradicate cancer cells, thereby leading to relapse. The specific gene expression program that confers these properties derives from the aberrant activity of specific transcription factors that are drivers of disease. Clearly, the most direct and effective approach to alter this gene expression program is to directly target the activity of the transcription factors driving the disease. There are numerous examples of such transcription factor drivers in cancer such as fusion proteins of RUNX1 and CBFβ in leukemia, fusion proteins of ERG in prostate cancer and Ewing’s sarcoma, ETV-1 in melanoma, other members of the Ets family of transcription factors in a variety of different cancers, etc. Transcription factors were traditionally viewed as “undruggable” due to the need to target more challenging protein-protein or protein nucleic acid interactions through which these proteins act. There are still relatively few examples of such agents for cancer treatment, with the MDM2-p53 inhibitors being one example of such an agent that has progressed to the clinic. We are exploring several unique approaches to target this important class of proteins for drug development.

We have developed an inhibitor targeting the CBFβ-SMMHC fusion protein that occurs in inv(16) acute myeloid leukemia (AML). This inhibitor is a protein-protein interaction inhibitor that restores RUNX1 function in these cells. We have shown it is effective in a mouse model of inv(16) AML as well as against human inv(16) AML patient cells. Furthermore, we have shown that much of the effect of the compound is mediated by a dramatic reduction in expression of MYC, a key transcription factor driver in many cancers. This drug has been licensed to Systems Oncology and is progressing toward clinical testing.

Example publications:

  • Illendula A, Pulikkan JA, Zong H, Grembecka J, Xue L, Sen S, Zhou Y, Boulton A, Kuntimaddi A, Gao Y, Rajewski RA, Guzman ML, Castilla LH, Bushweller JH. Chemical biology. A small-molecule inhibitor of the aberrant transcription factor CBFβ-SMMHC delays leukemia in mice. Science. 2015 Feb 13;347(6223):779-84. PubMed PMID: 25678665; PubMed Central PMCID: PMC4423805.
  • Illendula A, Gilmour J, Grembecka J, Tirumala VSS, Boulton A, Kuntimaddi A, Schmidt C, , Wang L, John A. Pulikkan, Hongliang Zong, Mahmut Parlak, Cem Kuscu, Anna Pickin, Yunpeng Zhou, Yan Gao Y, Mishra L, Adli M, Castilla LH, Rajewski RA, Janes KA, Guzman ML, Bonifer C, and Bushweller JH. Small Molecule Inhibitor of CBFb-RUNX Binding for RUNX Transcription Factor Driven Cancers. EBioMedicine. 2016 8: 117-131. Pubmed PMID: 27428424; PubMed Central PMCID: PMC4919611.
  • Pulikkan JA, Hegde M, Belaghzal H, Illendula A, Yu J, Ahmed H, O’Hagan K, Ou J, Muller-Tidow C, Wolfe SA, Zhu LJ, Dekker J, Bushweller JH, Castilla LH. CBFβ-SMMHC inhibition leads to alteration of chromatin dynamics at MYC distal enhancers and abrogation of inv(16) leukemia. Cell. June 28, 2018 174(1):172-186. PubMed PMID: 29958106.