Regulation of gene expression in skeletal metastasis of breast and prostate cancer, autocrine motility factor/phosphoglucose isomerase as a causal factor in cancer cachexia, and potential role of prostate PSA in skeletal metastasis

The Chirgwin laboratory, in close collaboration with that of Theresa Guise , studies the molecular bases of cancer metastases to bone, with a particular focus on identification, development and preclinical testing of therapeutic interventions that target the molecular interactions between tumor cells and bone cells.  The group has established that such molecular interactions within the bone microenvironment drive a vicious cycle that perpetuates bone metastases and makes them resistant to treatment. The laboratory focuses on breast and prostate cancers, the two major solid tumors that metastasize to the skeleton. The bone microenvironment stimulates tumor production of secreted factors, several of which have been identified by gene microarray experiments supported by the Biomolecular Research Facility (DNA Core). Molecular mechanisms are tested by stable gain- and loss-of-function experiments in tumor cells that are then analyzed in animal models with extensive support of Animal and Biostatistics Cores that are parts of prostate and breast cancer program projects (D. Theodorescu and S Parsons, PIs) and the Cancer Center BioS Core.

Hypoxia in the microenvironment and TGFbeta from bone stimulate tumor cells to secrete bone-stimulatory factors, such as parathryroid-hormone related protein, PTHrP.  PTHrP-neutralizing antibody tested by the group is now in clinical trials in patients with cancer bone metastases, as is an endothelin receptor antagonist   Drugs targeted the hypoxic-response pathway (such as 2-methoxyestradiol) and TGFbeta receptor kinase are being tested in animal models of bone metastases.  Tumor-secreted factors that have been identified include endothelin-1, adrenomedullin, connective tissue growth factor (CTGF), and Cyr61.  Endothelin-1 receptor antagonists are being tested against additional metastasis models (collaboration with D. Theodorescu, Urology). Adrenomedullin small molecule antagonists are being developed in collaboration with H. Geysen and T. MacDonald (Chemistry). CTGF- neutralizing antibody is being tested against breast cancer bone metastases.  Control of CTGF and Cyr61 expression by BRCA1 in breast cancer is being studied in collaboration with R. Li (Biochemistry and Molecular Genetics.  The mechanism of action of CTGF and Cyr61 via integrin activation is being studied in collaboration with S. Parsons, J.T. Parsons and A. Bouton, Microbiology). An additional project in the laboratory has developed an animal model of cancer-induced cachexia, due to tumor expressed autocrine motility factor, for which recombinant protein expression methods have been developed.  High resolution X-ray structures for mouse and human protein have been solved.