PMC: The Role of Hedgehog Pathway in Uterine Leiomyosarcoma (Houghton Lab)

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Natalia Garcia,1 Mara Ulin,2 Ayman Al-Hendy,3 and Qiwei Yang3

DESCRIPTION

The uterine Leiomyosarcoma (LMS) represents 3%-7% of all uterine cancers. This rare tumor has an annual incidence of 0.8 per 100,00 women. Unfortunately, LMS is well known for its poor prognosis due to its high recurrence rate and resistance to the currently available treatment options. These features open the field for new therapeutic options.

The Hedgehog (HH) pathway is a mechanism and a signaling cascade that directs the development of embryonic cells in animals. Since its first discovery in the 1980’s, the HH pathway has been identified to play a crucial role in many biological processes, including embryonic development, tissue differentiation, and tissue maintenance. The activation of the HH pathway promotes GLI translocation into the nucleus leading to the overactivation of several target genes, which regulate cell differentiation, proliferation and apoptosis, cell cycle, DNA damage, angiogenesis, and adhesion, contributing to the pathogenesis of diseases including cancer.

The activation of the HH signaling pathway has been characterized in several types of female cancer, including breast, ovarian, endometrium, cervical, and uterine leiomyosarcoma [1]. Several compounds have been identified to inhibit the HH signaling pathway and can be categorized as HH ligand inhibitors (HH neutralizing antibodies and small molecule Robotnikinin), SMO antagonists {(cyclopamine and its derivatives (IPI-926 and Cyc-T)} and synthetic compounds such as Vismodegib and Sonidegib), and GLI transcriptional inhibitors (Gant58 and Gant61). Clinical applications of HH pathway inhibitors have shown to significantly benefit preclinical and clinical studies to treat several types of female cancer.

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