Hedgehog Pathway Antagonism for the Prevention and Treatment of Metastatic Prostate Cancer

Prostate cancer is the most commonly diagnosed malignancy in men in the United States. Although most prostate cancers are localized and grow too slowly to cause harm, an important minority develop the ability to grow rapidly and metastasize. Researchers have demonstrated that Hedgehog (Hh) pathway activity is required for tumor growth in several gut-derived organs in which the pathway is important during embryonic patterning. Such a role has been proposed for Hh signaling during the initial growth and patterning of prostate ducts from the urogenital sinus, a structure that develops at the caudal end of the primitive gut. .In a systematic analysis of the expression of Hh pathway components in prostate tumors, we found that both localized and metastatic tumors express transcripts encoding the Sonic and Indian hedgehog ligands. Among localized tumors, however, only a small fraction (3 of 20 = 15%) expressed the Hh pathway transcriptional target genes PATCHED (PTCH) and GLI at low levels, whereas these transcripts were present at high levels in all metastatic tumors and cell lines derived from metastases (21 of 21 = 100%)indicating high level Hh pathway activity. JHU researchers further demonstrated that Hh pathway activity and growth in these androgen-independent tumor cells is ligand-dependent, being subject to inhibition either by a neutralizing antibody directed against Hh ligands or by cyclopamine, an antagonist of Hh pathway response. Furthermore, pathway blockade resulted in complete and durable regression of subcutaneous PC3 and CWR22RV1 human prostate cancer xenografts, prevented death to metastatic spread of highly aggressive rat prostate cancer xenografts. These results suggest that metastatic potential in prostate cancer depends upon an ability to autonomously produce and respond to Hh signal. These results further indicate that metastatic potential can be identified in prostate tumors by expression of the Hedgehog target genes PTCH and GL1 and that metastatic tumors can be treated with small molecule Hh antagonists such as cyclopamine or with antibodies that neutralize Hh ligands. Description (Set) Proposed Use (Set) This innovation may be used as a target for the treatment of androgen-independent metastatic prostate cancers. The expression of PTCH and GL1I may be used for the identification of prostate cancers with metastatic potential prior to metastasis.

Inventor(s): Beachy, Philip A.

Type of Offer: Licensing

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