Therapeutic Targeting of p300/CBP in Clear Cell Renal Cell Carcinoma
Abstract
The majority of clear cell renal cell carcinoma (ccRCC) lacks von Hippel-Lindau (VHL) protein. Loss of VHL results in the aberrant accumulation of HIF proteins, and thereby enhanced expression of pro-angiogenic factors, the leading cause of tumor angiogenesis. In the case of VHL-defective ccRCC, HIF-2 acts as an oncogene whereas HIF-1 acts as a tumor suppressor. HIF-2 signaling is regulated via its acetylation by CBP. CBP also target a significant number of non-histone proteins for acetylation, including proteins involved in metabolic processes. Furthermore, lack of VHL function causes a metabolic switch to aerobic glycolysis or Warburg effect. This is associated with a high glucose influx, a decreased gluconeogenesis and an increased lactate concentration in the tumor microenvironment, which is associated with an impaired immune recognition. Moreover, lactate promotes histone acetylation and gene expression through histone deacetylase (HDAC) inhibition contributing to tumor metastasis and resistance to therapy. P300/CBP serve as transcriptional coactivators of LDH-A. Notably, p300 knockout reduces lactate production. The proposed experiments will evaluate the therapeutic efficacy of novel clinically relevant p300/CBP inhibitor CCS1477 as monotherapy or in combination with TKIs. The experiments will provide rationale for transitioning CCS1477 to a clinical trial addressing the treatment of patients with ccRCC.
Document Details
- Document Type
- Technical Report
- Publication Date
- Jul 01, 2023
- Accession Number
- AD1216912
Entities
People
- Petr Makhov