Project 1: Targeting BRD4-HOXB13 Transcriptional Network in Metastatic Prostate Cancers

  • Highlights:
  • HOXB13, a homeodomain containing transcription factor, is linked to aggressive Prostate Cancer (PCs). However, to date its critical epigenetic regulators and effectors in PC metastasis remain largely unknown. This study identifies for the first time the BET bromodomain protein family, including BRD4, as epigenetic regulators of HOXB13. BRD4-HOXB13 combination in turn regulates a unique transcriptional network (HOTBIN10) that is Androgen receptor independent and upregulated during metastasis. To target the pro-proliferative HOXB13 driven transcriptional network, we utilized dual activity Bromodomain kinase inhibitors to block transcription of the HOXB13 gene, suppress the network and mitigate the growth of metastatic PCs.
  • Reference: Nerlakanti N, Yao J, Nguyen DT, Patel AK, Eroshkin AE, Lawrence HR, Ayaz M, Kuenzi BM, Agarwal N, Chen Y, Gunawan S, Karim RM, Brendt N, Puskas J, Magliocco A, Coppola D, Dhillon J, Zhang J, Shymalagovindarajan S, Rix U, Kim Y, Perera R, Lawrence NJ, Schonbrunn E and Mahajan K*. Targeting the BRD4-HOXB13 Co-regulated Transcriptional Networks with Bromodomain-Kinase Inhibitors to Suppress Metastatic Castration-Resistant Prostate Cancer. Molecular Cancer Therapeutics, 2018; In press.

Project 2: Characterization of novel small molecule inhibitors of histone demethylases for the treatment of prostate and breast cancers

  • Highlights:
  • Deregulated histone methylation/demethylation is linked to many cancers including prostate, ovarian, and breast cancers. KDM3A is associated with the removal of transcriptionally repressive histone H3K9 mono and dimethyl residues. KDM3A interacts with the Androgen receptor and  promotes expression of AR target genes in prostate cancer. KDM3A promotes cell growth and proliferation. No known selective small molecule inhibitors for KDM3A. To characterize a set of potential inhibitors as the first step to bring us closer to developing drugs to inhibit KDM3A in prostate cancer.
  • Reference: Mahajan K*, Lawrence H, Lawrence NJ and Mahajan NP*. ACK1 Tyrosine Kinase Interacts with KDM3A to Regulate the Mammary Tumor Oncogene HOXA1. J Biol Chem, 289:28179-91, 2014.

Project 3: Role of lineage-specific long non-coding RNAs in prostate cancer development, progression to metastasis and resistance to anti-androgens

  • Highlights:
  • Recently, the contribution of long noncoding RNAs (lncRNAs) in the pathogenesis of prostate cancers has acquired prominence as they are known to epigenetically regulate the function of critical tumor promoting transcription factors. Bishop et al have reported upregulation of PD-L1 in dendritic cells in Enzalutamide resistant patients and in pre-clinical models of ENZ resistance. It is unclear whether specific factors aberrantly expressed in CRPCs simultaneously modulate castration resistance as well as immune regulation to promote lethal disease. Recently, reports indicate that that BET-bromodomain epigenetically regulate PD-L1 expression in ovarian cancers.  BET inhibition  with  the prototype inhibitor JQ1 promotes anti-tumor immunity by downregulating PD-L1 expression in both immune cells and ovarian tumor  cells, and in addition increases CD8+cytotoxic T cell activity to limit ovarian tumor progression in syngeneic mouse models. We are characterizing several new long non-coding RNAs for their roles in immune regulation.
  • Reference: Mahajan K* and Mahajan NP. Cross talk of Tyrosine Kinases with the DNA Damage Signaling Pathways. Nucleic Acids Research, 43(22):10588-601, 2015.