BRD4 Inhibition Eliminates Malignant Peripheral Nerve Sheath Tumor in Mice

By: Richard Chung, PharmD Candidate c/o 2017

–

Malignant peripheral nerve sheath tumor, otherwise known commonly as MPNST, is an aggressive sarcoma that can randomly form around peripheral nerves. Approximately 1 in 100,000 of the population is diagnosed with MPNST, with only 20-50% surviving five years after initial diagnosis.¹ In addition, approximately half of the cases involve those with the autosomal genetic disorder Neurofibromatosis Type 1 (NF1), which is associated with manifestations of benign neurofibromas.² Despite numerous methods of halting the growth of the tumor, these feats are nearly impossible and even after success, they do not completely eradicate the tumor. Likewise, radiation and chemotherapy have limited effects, as the tumor is not completely erased. Surgical intervention requires surgeons to separate the tumors from the nerves and increases the risk of nerve damage. Recently however, a new study emerged which showed that blocking protein BRD4 caused the cancer cells to die, leading to potentially new treatments that can eliminate this rare form of cancer.

At the University of Texas Southwest Medical Center, scientists discovered that BRD4 played a key role in the growth of the cancer cells. BRD4 is part of the bromodomain and extraterminal (BET) family and is expressed abundantly in these cancer cells. The proteins bind to the acetylated histones on the DNA in order to regulate the expression of mitotic genes, ultimately turning them into cancer cells.^4,5 In return, this activates BCL-2, an antiapoptotic protein, which allows the cells to continue multiplying. A study was conducted using a mouse model in order to find the correlation between the BRD4 and MPNST, and to inhibit the binding of the protein. In this case, molecular inhibitors JQ1, I-BET 151, and CPI203 function as competitive inhibitors and bind to sites where BRD4 would usually bind; JQ1 inhibitor suppresses transcription elongation.^7,8 BRD4 occupies the promoter area of Cyclin D1, which can be inhibited by JQ1, causing a decrease in proliferation. Moreover, inhibition of BRD4 binding resulted in increased activity of proapoptotic BIM and a decrease in expression of BCL-2.

Overall, the use of JQ1 and other inhibitors to prevent growth and induce apoptosis has given physicians and other health practitioners an idea on how to utilize JQ1 in order to improve treatment in patients who suffer from MPNST and more importantly, patients who have NF1 disorder. The real challenge now is to prepare for the clinical studies in humans after JQ1 has shown promising outcomes in mice. Although the JQ1 inhibitor is able to undergo clinical development, I-BET 151 is still being evaluated.³ This study provides a strong basis on the relationship between inhibition of BRD4 protein and the reduction of MPNST, which can help scientists develop advanced treatments for patients diagnosed with this fatal disease.

SOURCES:

1. Ducatman BS, Scheithauer BW, Piepgras DG, Reiman HM, Ilstrup DM. Malignant peripheral nerve sheath tumors. A clinicopathologic study of 120 cases. Cancer. 1986;57:2006–2021. http://www.ncbi.nlm.nih.gov/pubmed/3082508. Accessed on January 2, 2014
2. McCaughan JA, Holloway SM, Davidson R, Lam WW. Further evidence of the increased risk for malignant peripheral nerve sheath tumour from a Scottish cohort of patients with neurofibromatosis type 1. J Med Genet. 2007;44:463–466.
3. Patel AJ, Liao C., Chen Z., Liu C., Wang Y., Le L. BET Bromodomain Inhibition Triggers Apoptosis of NF1-Associated Malignant Peripheral Nerve Sheath Tumors through BIM Induction. Cell Reports (6): 1-12. http://www.cell.com/cell-reports/abstract/S2211-1247(13)00731-6#Summary. Accessed on January 4, 2014
4. Dey A., Chitsaz F., Abbasi A., Misteli T., and Ozato, K. (2003). The double bromodomain protein Brd4 binds to acetylated chromatin during interphase and mitosis. Proc. Natl. Acad. Sci. USA 100, 8758–8763
5. Dawson, M.A., Prinjha, R.K., Dittmann, A., Giotopoulos, G., Bantscheff, M., Chan, W.-I., Robson, S.C., Chung, C.W., Hopf, C., Savitski, M.M., et al. (2011). Inhibition of BET recruitment to chromatin as an effective treatment for MLL-fusion leukaemia. Nature 478, 529–533
6. Cheng, E.H.Y.A., Wei, M.C., Weiler, S., Flavell, R.A., Mak, T.W., Lindsten, T., and Korsmeyer, S.J. (2001). BCL-2, BCL-X(L) sequester BH3 domain-only molecules preventing BAX- and BAK-mediated mitochondrial apoptosis. Mol. Cell 8, 705–711.
7. Dawson, M.A., Prinjha, R.K., Dittmann, A., Giotopoulos, G., Bantscheff, M., Chan, W.-I., Robson, S.C., Chung, C.W., Hopf, C., Savitski, M.M., et al. (2011). Inhibition of BET recruitment to chromatin as an effective treatment for MLL-fusion Leukaemia. Nature 478, 529–533
8. Love´n, J., Hoke, H.A., Lin, C.Y., Lau, A., Orlando, D.A., Vakoc, C.R., Bradner, J.E., Lee, T.I., and Young, R.A. (2013). Selective inhibition of tumor oncogenes by disruption of super-enhancers. Cell 153, 320–334.