Development of a Combination Therapy for Prostate Cancer by Targeting Stat3 and HIF-1alpha
Abstract
There are two signaling pathways: HIF-1alpha and Stat3 are important targets for prostate cancer (PC) therapy. HIF-1alpha is the key gene that controls the amount of the transcription of hypoxia-inducible genes. Overexpression of HIF-1alpha not only strongly enhances the rate of tumor growth and metastatic potential, but also contributes to resistance to radiotherapy and chemotherapy, leading to treatment failure and increased patient mortality. Stat3 participates in oncogenesis through the upregulation of genes encoding apoptosis inhibitors, cell-cycle regulators, and inducers of angiogenesis in many human cancers, including prostate cancer. Also, Stat3 suppresses anti-tumor immune responses and mediates the cancer-promoting properties. Previously, we demonstrated that treatment of PC in preclinical models with a combination of a Stat3 inhibitor and a HIF-1alpha inhibitor greatly enhanced drug efficacy and dramatically increased apoptosis in human tumors compared with the use of either agent alone, showing that targeting both Stat3 and HIF-1alpha together can improve tumor response. In this research period, we have developed TEL03, a dual inhibitor from nature products, for cancer therapy. TEL03 targets both HIF-1alpha and Stat3, blocks the expression of their down-regulated oncogenes and significantly suppresses tumor growth in vivo. TEL03 also demonstrated a greater-than-expected in vivo potency, perhaps because of synergy arising from the ability of this agent to simultaneously target two critical oncogenic pathways.
Document Details
- Document Type
- Technical Report
- Publication Date
- Jul 01, 2012
- Accession Number
- ADA564134
Entities
People
- Naijie Jing
Organizations
- Baylor College of Medicine