The Therapeutic Potential of Targeting MYC Activity in Renal Tumorigenesis

Research project


Renal cancer (RCC) contributes to over 10,000 mortalities in the United States each year. Although surgery is potentially curative, recurring and inoperable late stage cancers are usually fatal. In recent years, a number of drugs approved by the FDA have shown promise in the clinic. These drugs, however, all primarily target two biological pathways- the VEGF receptor and the mTOR signaling pathway. An investigation into additional biological pathways that can be therapeutically targeted in renal cancer will thus greatly expand options for treatment in the clinic.
We and others have observed amplified MYC signaling in a subset of clear cell renal cell carcinomas (ccRCCs). MYC is a transcription factor that heterodimerizes with its partner, MAX, to bind E-box motifs in DNA. Together, MYC/MAX regulate transcription of genes involved in cell homeostasis. Aberrant activation of MYC in cancer can occur through diverse mechanisms including translocations, amplifications, enhanced protein translation or protein stability. In most cases, however, MYC signaling is thought to occur through indirect activation by alterations in other signaling pathways. Abnormal MYC signaling is thought to contribute to tumorigenesis through a number of context dependent cell processes including unrestrained cell growth and proliferation, alterations in cell metabolism, angiogenesis and genomic instability. The current tally for MYC activation in all human cancers is thought to be ~70% thus further supporting the already accepted notion that MYC plays an important role in tumorigenesis.
Although MYC is clearly recognized as an important factor in the pathogenesis of a wide spectrum of cancers, MYC itself is currently an “undruggable” target. The discovery of alternative strategies to target MYC activity would thus be of immense significance to cancer therapeutics. In recent years, increasing evidence has pointed to the importance of epigenetic protein families in regulating the activities of transcription factors such as MYC and as “druggable” targets in cancer therapy. As such, the discovery of a small molecule inhibitor of the BET family GSK 1210151A (I-BET151), a bromodomain inhibitor that has shown promise in treating MLL and myelomas, is one such evidence of the potential of targeting the MYC transcription factor via epigenetic mechanisms.
The research proposed here is innovative and uses novel reagents. We have generated a genetically engineered mouse model of MYC-induced renal tumorigenesis and observed that the viability of the MYC-induced mouse tumors cells in culture is dependent on transgenic MYC expression. Withdrawal of transgenic MYC expression resulted in a significant decrease in cell viability. In Aim 1, we plan to take advantage of this model system to screen a RNAi library targeting known chromatin regulators. We propose to identify siRNAs to epigenetic factors that impede the viability of MYC-induced mouse renal tumors cells in culture. We wish to identify epigenetic regulators that are essential for MYC activity. In Aim 2, we will explore the therapeutic efficacy of targeting MYC activity in RCC patient-derived xenografts (PDXs) enriched for a MYC signature using I-BET151. We and others have observed that RCC PDXs can be revived, grown and serially passaged, with the grafted tumors sharing similar histological characteristics as the original tumor. The advantage of using PDXs is the opportunity to look more directly at patient tumor response to I-BET151 in vivo. To this end we propose the following aims:
Effective start/end date4/1/153/31/17


  • NIH National Cancer Institute (NCI)


Kidney Neoplasms
Transcription Factors
Cell Culture Techniques
Pharmaceutical Preparations
E-Box Elements
Vascular Endothelial Growth Factor Receptor
Protein Stability
Genomic Instability
Protein Biosynthesis
RNA Interference
Renal Cell Carcinoma
Cell Survival