Molecular Targets & Therapeutic Resistance Program

Overview | Leaders | Research | Publications

 

Scientific Accomplishments

A large number of scientific accomplishments from the Program have been published over recent years. These include the following, representative of all Specific Aims of the Program:

  • Identification of Caveolin-1 (CAV1) as an EWS/FLI1 target and a determinant of Ewing's sarcoma cells response to chemo- and radio-therapeutic treatments (Tirado et al., Cancer Res, 2006).
  • Demonstration that through functional interactions with different Protein kinase C isoforms, PCPH plays key roles in the regulation of the invasiveness of prostate cancer cells and their resistance to chemotherapeutic agents (Villar et al., Cancer Res 2007; Villar et al., Cancer Res 2009).
  • Identification of novel mechanisms by which scatter factor (SF) [hepatocyte growth factor, HGF] functions to mediate of chemo/radioresistance (Fan et al., J Biol Chem 2008; Fan et al., Oncogene 2007; Xu et al., Oncogene 2007; Fan et al., Oncogene 2005).
  • Identification of BRCA1 as a major regulator of telomerase activity and telomere length (Xiong et al., Mol Cell Biol 2003).
  • Development and integration of global gene expression and radiation metabolomics analyses (Lu et al., Cancer Res, 2008; Radiat Res, 2008).
  • Identification of NF-kB (p65) as a target for radiosensitization that enhances the susceptibility of tumor cells to HDAC inhibition (Kim et al., Mol Cancer Ther, 2004; Kim et al., Carcinogenesis, 2005).
  • Demonstration of transcriptional regulation as a novel function of PARP (Lonskaya et al., J Biol Chem, 2005; Amiri et al., Oncogene, 2006).
  • Identification of novel mechanisms of growth suppression in human cells and their alterations in glioblastoma multiforme (Kim et al., Mol Cell Biol 2007; Solomon et al., Cancer Res 2008).
  • Demonstration that the PCPH oncoprotein antagonizes the pro-apoptotic role of mTOR in the response of normal cells to ionizing radiation (Tirado et al., Cancer Res, 2003).
  • Completion of Phase I studies of liposomal c-Raf-1 antisense oligonucleotides against solid tumors, alone or in combination with radiation, in collaboration with Dr. John Marshall and members of the 3DT Program (Rudin et al., Clin Cancer Res, 2004; Dritschilo et al., Clin Cancer Res, 2006).
  • Completion of preclinical studies demonstrate effectiveness of AS-ODNs specific for the EWS/FLI1 gene to inhibit growth, induce apoptosis, and sensitize Ewing's sarcoma to chemo- and radio-therapeutic treatments (Mateo-Lozano et al., Clin Cancer Res, 2006).
  • Development of interlaced microbeam radiation therapy (MRT), a novel radiosurgical approach with clinical potential (Dilmanian et al., PNAS USA 2006).
  • Identification of novel mechanism in the functional regulation of Base Excision Repair (BER) and Nucleotide Excision Repair (NER) pathways in mammalian cells (Adhikari et al., J Biol Chem, 2008).
  • Discovery of novel functions of BRCA1 in inducing antioxidant gene expression, protecting cells against oxidative stress, and regulating the responses to xenobiotic stress (Bae et al., Cancer Res 2004; Kang et al., J Biol Chem 2006).
  • The discoveries that low (physiological) concentrations of diindolylmethane, a metabolite of indole-3-carbinol, protects against oxidative stress by stimulating BRCA1 signaling and inhibiting autophagy (Fan et al. Cancer Res, Accepted pending minor revisions).