Shh Signaling as a Therapeutic Target in Prostate Cancer

University Of Wisconsin Madison, Madison WI

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Abstract

DESCRIPTION (provided by applicant): The epithelial-mesenchymal interactions of prostate cancer are a promising target for new therapies to arrest tumor growth. We have shown that hedgehog signaling plays a critical role in initiating fetal prostate development. This pathway is downregulated in the normal adult prostate but is re-activated in human prostate cancer. During mouse fetal prostate development, the urogenital sinus epithelium expresses Sonic hedgehog (Shh). Secreted Shh peptide activates a transcription factor, Gli, in the surrounding mesenchymal cells and thereby turns on the target genes activated in response to hedgehog signaling. Blockade of hedgehog signaling prevents mesenchymal Gli activation and abrogates prostate development. Shh and Gli are downregulated shortly after birth and are expressed at only low levels in the adult prostate. Shh and Gli are similarly expressed in the developing human prostate and down-regulated in the adult. However, Shh and Gli are routinely and coordinately re-expressed in prostate cancer. We postulated that cancer cells commandeer hedgehog signaling to recruit stromal cells to support tumor growth and used the LNCaP xenograft tumor model to demonstrate: (1) that Shh expressed by LNCaP tumor cells activates Gli expression in the tumor stroma, (2) that LNCaP Shh overexpression increases stromal Gli expression, and (3) that Shh overexpresision dramatically accelerates tumor growth. We propose to test the hypothesis that blockade of hedgehog signaling will inhibit prostate tumor growth. We will use two complementary approaches. We will engineer LNCaP cells to overexpress hedgehog interacting protein (Hip), a secreted inhibitor of hedgehog signaling to determine whether constitutive Hip expression prevents xenograft tumor formation and whether induced Hip overexpression inhibits growth of an established tumor. We will also engineer prostate-specific Hip overexpression in the LADY transgenic mouse prostate cancer model to determine whether blockade of hedgehog signaling prevents tumor development. The goal of these experiments is to show that interruption of hedgelhog signaling can be used as a novel strategy to slow or arrest prostate cancer growth.