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The dawn of hedgehog inhibitors: Vismodegib.

Sandhiya S, Melvin G, Kumar SS, Dkhar SA - J Pharmacol Pharmacother (2013)

Bottom Line: Recently there has been lots of interest regarding the hedgehog (Hh) pathway, which plays a significant role in the development of organs and tissues during embryonic and postnatal periods.One of the newer drugs namely vismodegib involves the inhibition of Hh pathway and has shown promising results in the treatment of advanced basal-cell carcinoma as well as medulloblastoma.It has been granted approval by US Food and Drug Administration's (US FDA) priority review program on January 30, 2012 for the treatment of advanced basal-cell carcinoma.

View Article: PubMed Central - PubMed

Affiliation: Division of Clinical Pharmacology, Jawaharlal Institute of Postgradute Medical Education and Research, Puducherry, India.

ABSTRACT
Cancer, one of the leading causes of death worldwide is estimated to increase to approximately 13.1 million by 2030. This has amplified the research in oncology towards the exploration of novel targets. Recently there has been lots of interest regarding the hedgehog (Hh) pathway, which plays a significant role in the development of organs and tissues during embryonic and postnatal periods. In a normal person, the Hh signaling pathway is under inhibition and gets activated upon the binding of Hh ligand to a transmembrane receptor called Patched (PTCH1) thus allowing the transmembrane protein, smoothened (SMO) to transfer signals through various proteins. One of the newer drugs namely vismodegib involves the inhibition of Hh pathway and has shown promising results in the treatment of advanced basal-cell carcinoma as well as medulloblastoma. It has been granted approval by US Food and Drug Administration's (US FDA) priority review program on January 30, 2012 for the treatment of advanced basal-cell carcinoma. The drug is also being evaluated in malignancies like medulloblastoma, pancreatic cancer, multiple myeloma, chondrosarcoma and prostate cancer. Moreover various Hh inhibitors namely LDE 225, saridegib, BMS 833923, LEQ 506, PF- 04449913 and TAK-441 are also undergoing phase I and II trials for different neoplasms. Hence this review will describe briefly the Hh pathway and the novel drug vismodegib.

No MeSH data available.


Related in: MedlinePlus

Schematic diagram explaining the mechanism of action of Hedgehog (Hh) pathway. PTCH1 - Patched 1, transmembrane receptor; SMO - smoothened, transmembrane protein; Hh - Hedgehog. (a) shows that during normal conditions, PTCH1 keeps SMO under repression. (b) shows that Hh ligand binds to PTCH1 receptor and inhibits its inhibitory effect on SMO, thus promoting the signal transduction via Hh pathway
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Figure 1: Schematic diagram explaining the mechanism of action of Hedgehog (Hh) pathway. PTCH1 - Patched 1, transmembrane receptor; SMO - smoothened, transmembrane protein; Hh - Hedgehog. (a) shows that during normal conditions, PTCH1 keeps SMO under repression. (b) shows that Hh ligand binds to PTCH1 receptor and inhibits its inhibitory effect on SMO, thus promoting the signal transduction via Hh pathway

Mentions: The hedgehog pathway was first recognized in mutant fruit flies by Christiane Nusslein and Eric Wieschaus in 1980. It was named after the larvae of mutant fruit fly, which resembled hedgehogs and the discovery was awarded Nobel Prize for physiology or medicine in 1995.[10] The Hh pathway plays a significant role in the development of organs and tissues during embryonic and postnatal periods. It is involved in determining the site of growth of fingers in the limb buds and the formation of motor neurons in the developing spinal cord.[11] Under physiological conditions, the Hh signaling pathway is under inhibition and gets activated upon the binding of Hh ligand to a transmembrane receptor called Patched (PTCH1) as shown in Figure 1. The activation of Hh pathway allows the transmembrane protein, smoothened (SMO) to transfer signals through various proteins.[4] The abnormal Hh signaling resulting in new tumors or acceleration of existing tumors could be due to mutation in the Hh pathway, paracrine or autocrine activation by Hh ligands, involvement of stroma or activation of cancer stem cells (CSCs).[612] It has been hypothesized that the activation of cancer stem cells (CSCs) through abnormal Hh signaling could be a reason for uncontrolled self-renewal of tumor cells and the occurrence of metastasis. Among the various cancers, studies have shown the significance of mutations in PTCH leading to the pathogenesis of sporadic BCCs and medulloblastoma.[1314]


The dawn of hedgehog inhibitors: Vismodegib.

Sandhiya S, Melvin G, Kumar SS, Dkhar SA - J Pharmacol Pharmacother (2013)

Schematic diagram explaining the mechanism of action of Hedgehog (Hh) pathway. PTCH1 - Patched 1, transmembrane receptor; SMO - smoothened, transmembrane protein; Hh - Hedgehog. (a) shows that during normal conditions, PTCH1 keeps SMO under repression. (b) shows that Hh ligand binds to PTCH1 receptor and inhibits its inhibitory effect on SMO, thus promoting the signal transduction via Hh pathway
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3643342&req=5

Figure 1: Schematic diagram explaining the mechanism of action of Hedgehog (Hh) pathway. PTCH1 - Patched 1, transmembrane receptor; SMO - smoothened, transmembrane protein; Hh - Hedgehog. (a) shows that during normal conditions, PTCH1 keeps SMO under repression. (b) shows that Hh ligand binds to PTCH1 receptor and inhibits its inhibitory effect on SMO, thus promoting the signal transduction via Hh pathway
Mentions: The hedgehog pathway was first recognized in mutant fruit flies by Christiane Nusslein and Eric Wieschaus in 1980. It was named after the larvae of mutant fruit fly, which resembled hedgehogs and the discovery was awarded Nobel Prize for physiology or medicine in 1995.[10] The Hh pathway plays a significant role in the development of organs and tissues during embryonic and postnatal periods. It is involved in determining the site of growth of fingers in the limb buds and the formation of motor neurons in the developing spinal cord.[11] Under physiological conditions, the Hh signaling pathway is under inhibition and gets activated upon the binding of Hh ligand to a transmembrane receptor called Patched (PTCH1) as shown in Figure 1. The activation of Hh pathway allows the transmembrane protein, smoothened (SMO) to transfer signals through various proteins.[4] The abnormal Hh signaling resulting in new tumors or acceleration of existing tumors could be due to mutation in the Hh pathway, paracrine or autocrine activation by Hh ligands, involvement of stroma or activation of cancer stem cells (CSCs).[612] It has been hypothesized that the activation of cancer stem cells (CSCs) through abnormal Hh signaling could be a reason for uncontrolled self-renewal of tumor cells and the occurrence of metastasis. Among the various cancers, studies have shown the significance of mutations in PTCH leading to the pathogenesis of sporadic BCCs and medulloblastoma.[1314]

Bottom Line: Recently there has been lots of interest regarding the hedgehog (Hh) pathway, which plays a significant role in the development of organs and tissues during embryonic and postnatal periods.One of the newer drugs namely vismodegib involves the inhibition of Hh pathway and has shown promising results in the treatment of advanced basal-cell carcinoma as well as medulloblastoma.It has been granted approval by US Food and Drug Administration's (US FDA) priority review program on January 30, 2012 for the treatment of advanced basal-cell carcinoma.

View Article: PubMed Central - PubMed

Affiliation: Division of Clinical Pharmacology, Jawaharlal Institute of Postgradute Medical Education and Research, Puducherry, India.

ABSTRACT
Cancer, one of the leading causes of death worldwide is estimated to increase to approximately 13.1 million by 2030. This has amplified the research in oncology towards the exploration of novel targets. Recently there has been lots of interest regarding the hedgehog (Hh) pathway, which plays a significant role in the development of organs and tissues during embryonic and postnatal periods. In a normal person, the Hh signaling pathway is under inhibition and gets activated upon the binding of Hh ligand to a transmembrane receptor called Patched (PTCH1) thus allowing the transmembrane protein, smoothened (SMO) to transfer signals through various proteins. One of the newer drugs namely vismodegib involves the inhibition of Hh pathway and has shown promising results in the treatment of advanced basal-cell carcinoma as well as medulloblastoma. It has been granted approval by US Food and Drug Administration's (US FDA) priority review program on January 30, 2012 for the treatment of advanced basal-cell carcinoma. The drug is also being evaluated in malignancies like medulloblastoma, pancreatic cancer, multiple myeloma, chondrosarcoma and prostate cancer. Moreover various Hh inhibitors namely LDE 225, saridegib, BMS 833923, LEQ 506, PF- 04449913 and TAK-441 are also undergoing phase I and II trials for different neoplasms. Hence this review will describe briefly the Hh pathway and the novel drug vismodegib.

No MeSH data available.


Related in: MedlinePlus