Due to the role of aberrant Hedgehog signaling in tumor progression[1][2][3][4][5][6] and cancer stem cell maintenance[7][8][9] across cancer types, inhibition of the Hedgehog signaling pathway can be a useful strategy for restricting tumor growth and for preventing the recurrence of the disease post-surgery, post-radiotherapy, or post-chemotherapy.
[10][11][12] At least three Hedgehog pathway inhibitors have been approved by the Food and Drug Administration (FDA) for cancer treatment.
[12] The classical Hedgehog signaling pathway involves glycoproteins that are secreted by cells into the intercellular space.
Upon the inactivation of PTCH1 by Shh, glioma-associated (GLI) transcription factors enter the nucleus and activate the expression of multiple genes including Myc, Bcl-2, NANOG, and SOX2.
The first major breakthrough in understanding the role of Shh signaling in cancer progression was the discovery that mutations in the PTCH1 gene, which codes for the PTCH1 protein, were responsible for Gorlin syndrome.
[22][23] Gorlin syndrome is an autosomal dominant disorder characterized by developmental abnormalities and increased risk of developing basal cell carcinoma or medulloblastoma.
Overexpression of Shh ligand has been reported in multiple cancer types including pancreatic, colorectal,[26] prostate,[27] and gliomas.
Further, Shh ligands can stimulate the production of growth factors by stromal cells present in the tumor microenvironment.
In chronic myeloid leukemia and breast cancer, inhibition of Shh signaling has been shown to reduce stem cell propagation and renewal.
[30][31] CSCs exhibit increased potential for self-renewal, differentiation, and for starting secondary tumors at distant organ sites.
Inhibition of the transmembrane protein Smoothened (SMO) prevents the induction of GLI transcriptional activity upon exposure of cancer cells to Shh ligands.
Two such inhibitors, Sonidegib and Vismodegib have been approved by the Food and Drug Administration (FDA) for treating basal cell carcinoma.
[40] It received FDA approval in July 2015 and is being used for the treatment of BCC that has recurred post-surgery or post-radiation therapy.
Effectiveness of this drug in other cancer types including hematological malignancies is currently being tested in multiple clinical trials.
Thus, inhibition of GLIs abrogates the ability of Hedgehog signaling to trigger processes that contribute towards tumor progression and recurrence.