Metastases are late and incurable complications of tumors. The majority of patients with advanced breast or prostate cancers have bone metastases characterized by unusual molecular interactions between tumor and the bone microenvironment, which offer unique targets for therapeutic intervention. We previously found that the 21 amino acid peptide endothelin-1 is a causal factor in the osteoblastic bone metastases characteristic of prostate cancer. Antagonists of the endothelin A receptor are now in Phase III clinical trials. We are using a similar strategy toward another vasoactive pain peptide, adrenomedullin, which is produced by prostate cancer cells and potently stimulates osteoblastic metastases. We identified two small molecule adrenomedullin receptor antagonists and are developing them in preclinical animal models to treat metastatic disease. Parathyroid hormone-related protein (PTHrP) made by cancers stimulates osteolytic bone destruction characteristic of breast cancers. Prostate-specific antigen, PSA, is a protease that cleaves PTHrP into a 23 amino acid fragment that we found stimulates osteoblastic new bone formation, characteristic of prostate bone metastases. The fragment may act by a novel molecular mimetic action on the endothelin A receptor.

Tumor hypoxia is a general characteristic of bone metastases. We found that hypoxia potentiates TGFbeta signaling - a major driver of bone metastases - by additive actions on VEGF and CXCR4 promoters involving proximal Smad and HIF-1alpha transcriptional complexes bridged by p300. The anti-hypoxic drug 2-methoxyestradiol effectively blocks bone metastases in our animal models. At the same time it increases bone quality and quality, whereas most cancer treatments have destructive effects on the skeleton. The drug is being tested in a number of metastatic tumor models.

Another complication of advanced cancers is muscle wasting due to tumor secretion into the circulation of poorly characterized cachectic factors. Secreted phosphoglucose isomerase (PGI, which is also a glycolytic enzyme) is increased in patients and an animal model of cachexia. The recombinant protein reproduced the response in mice. We are determining the structural basis of the response, guided by the crystal structure of the protein, including identification of the PGI receptor.

Selected References

Kingsley LA, Fournier PG, Chirgwin JM, Guise TA. (2007) "Molecular biology of bone metastasis." Mol Cancer Ther. 6(10):2609-17. [PubMed]

Chirgwin JM, Guise TA. (2007) "Skeletal metastases: Decreasing tumor burden by targeting the bone microenvironment." J Cell Biochem. Dec 102:1333-42. [PubMed]

Siclari VA, Guise TA, Chirgwin JM. (2006) "Molecular interactions between breast cancer cells and the bone microenvironment drive skeletal metastases." Cancer Metastasis Rev. 25:621-33. [PubMed]

Clines GA, Mohammad KS, Bao Y, Stephens OW, Suva LJ, Shaughnessy JD Jr, Fox JW,Chirgwin JM, Guise TA. (2007) "Dickkopf homolog 1 mediates endothelin-1-stimulated new bone formation." Mol Endocrinol. 21:486-98. Epub 2006 Oct 26. [PubMed]

Bartholin L, Wessner LL, Chirgwin JM, Guise TA. (2007) "The human Cyr61 gene is a transcriptional target of transforming growth factor beta in cancer cells." Cancer Lett. Feb 246(1-2):230-6. Epub 2006 Apr 17. [PubMed]

Zudaire E, Martinez A, Garayoa M, Pio R, Kaur G, Woolhiser MR, Metcalfe DD, HookWA, Siraganian RP, Guise TA, Chirgwin JM, Cuttitta F. (2006) "Adrenomedullin is a cross-talk molecule that regulates tumor and mast cell function during human carcinogenesis." Am J Pathol. 168:280-91. [PubMed]