Hedgehog signaling pathway: a novel target for cancer therapy: vismodegib, a promising therapeutic option in treatment of basal cell carcinomas.

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Hedgehog signaling pathway: A novel target for cancer therapy: Vismodegib, a promising therapeutic option in treatment of basal cell carcinomas Afroz Abidi

ABSTRACT The Hedgehog signaling pathway is one of the major regulators of cell growth and differentiation during embryogenesis and early development. It is mostly quiescent in adults but inappropriate mutation or deregulation of the pathway is involved in the development of cancers. Therefore; recently it has been recognized as a novel therapeutic target in cancers. Basal cell carcinomas (BCC) and medulloblastomas are the two most common cancers identified with mutations in components of the hedgehog pathway. The discovery of targeted Hedgehog pathway inhibitors has shown promising results in clinical trials, several of which are still undergoing clinical evaluation. Vismodegib (GDC-0449), an oral hedgehog signaling pathway inhibitor has reached the farthest in clinical development. Initial clinical trials in basal cell carcinoma and medulloblastoma have shown good efficacy and safety and hence were approved by U.S. FDA for use in advanced basal cell carcinomas. This review highlights the molecular basis and the current knowledge of hedgehog pathway activation in different types of human cancers as well as the present and future prospects of the novel drug vismodegib.

Department of Pharmacology, Subharti Medical College, Meerut, Uttar Pradesh, India Received: 22-07-2013 Revised: 08-10-2013 Accepted: 11-11-2013 Correspondence to: Dr. Afroz Abidi, E-mail: [email protected]

KEY WORDS: Basal cell carcinoma, hedgehog signaling pathway, vismodegib

Introduction

Background

Cancer is emerging as one the major causes of death in the recent times not only in developed but also in developing countries due to lifestyle changes. The cancer related deaths worldwide are estimated to account for 7.6 million deaths (approximately 13% of all deaths).[1] Cancer biology depends on various signaling pathways for tumor growth and metastasis. One of these important signaling cascades is the hedgehog pathway which has been implicated in basal cell carcinomas, medulloblastomas and also in pancreatic, prostate, small cell lung cancers and hematological malignancies. After 20 years of exhaustive study on the hedgehog pathway, researchers discovered several hedgehog pathway inhibitors, the most advanced being vismodegib which has been approved by the U.S. FDA for use in basal cell carcinomas.

Hedgehog signaling cascade plays a major role in many processes like cell differentiation and organ formation during normal vertebrate embryonic development. [2] The name hedgehog has been derived from the polypeptide ligand called Hedgehog (Hh) found in fruit flies of the genus Drosophila. This intercellular signaling molecule was called hedgehog because mutations which led to its uncontrolled activity gave rise to fruit fly larvae that had a “spike” and “hairy” appearance of denticles instead of the normal pattern of denticles, similar to that of hedgehogs, thus inspiring the name “hedgehog”. This pathway was first discovered in 1980 by Christiane Nüsslein-Volhard and Eric Wieschaus who isolated mutations in genes which were controlling the development of the segmented anteriorposterior body axis of the fly.[3] In 1995 they shared the Nobel prize alongside Edward B. Lewis for their discoveries of a group of genes and mutations involved in the genetic control of early embryonic development and body segmentation in Drosophila which included the discovery of the hedgehog pathway.[4] The hedgehog gene was important for creating the polarized developmental distribution of the anterior and posterior parts of individual body segments of Drosophila. The hedgehog pathway becomes inactive in most adult tissues but it helps in regulating adult stem cells and is also

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Indian Journal of Pharmacology | February 2014 | Vol 46 | Issue 1

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involved in tissue maintenance and repair. The inappropriate reactivation and aberrant signaling in adult tissues is associated with the development of several human cancers, mainly basal cell carcinoma (BCC) and some medulloblastomas, prostate, small cell lung cancers, pancreatic carcinoma and leukemias.[2] Hence, this pathway may represent a potential therapeutic target for new anticancer treatments. Drugs that specifically target hedgehog signaling to fight this disease are being actively developed by a number of pharmaceutical companies. Hedgehog Signaling Pathway The hedgehog signaling pathways in vertebrates consists of Patched receptor (PTCH) which is a 12-transmembrane protein receptor [5] and Smoothened (SMO, a 7-transmembrane protein related to G protein-coupled receptors) protein. In mammals, there are three family of hedgehog genes, Sonic (Shh), Indian (Ihh) and Desert (Dhh) hedgehog out of which Sonic hedgehog (Shh) is the best studied ligand of the vertebrate pathway. There are also two PTCH genes, PTCH 1 and PTCH 2. The sequence of PTCH 2 has 54% similarity to PTCH 1.[6] All three mammalian hedgehogs bind both receptors with equal affinity; hence PTCH 1 and PTCH 2 cannot distinguish between the ligands though both have a distinct downstream signaling activity. Downstream signaling of SMO in mammals is known as Glioma associated oncogene-GLI 1, GLI 2 and GLI 3. GLI 1 and GLI 2 are transcriptional activators, whereas GLI 3 is a transcriptional repressor. In the absence of hedgehog ligand, PTCH located on the cell membrane at the base of primary cilia, a cellular structure found in most mammalian cells, suppresses the SMO from entering the cilium, thereby preventing the initiation of downstream signaling events.[7] PTCH acts like a sterol pump and removes oxysterols that have been created by 7-dehydrocholesterol reductase, thereby restraining the SMO initiated pathway.[8] GLI 1 activators along with SUFU (Suppressor of fused) which is a negative suppressor prevents the transcription of GLI 1 target genes thereby keeping the pathway off [Figure 1a]. Hedgehog signaling pathway is commenced by binding of the Hedgehog ligand to the PTCH 1 receptor. This causes PTCH 1 translocation and internalization causing the sterol pumps to be Figure 1a: Hedgehog signaling pathways in vertebrates-without hedgehog ligand

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turned off allowing oxysterols to accumulate around SMO thus removing its inhibitory effect over SMO. Activated SMO then moves to the cell membrane of the cilium where it triggers the activation of GLI family of transcription factors by cleaving it from the SUFU protein thus removing its inhibitory effect. These activated GLI proteins enter the nucleus and bind to GLI-promoters stimulating the transcription of mammalian target genes [Figure 1b]. These target genes are mainly involved in cell proliferation, organ development and tissue repair. The result of hedgehog signaling depends on the receiving cell type and can express a variety of transcription factors mediating different developmental responses. The major reactions demonstrated were stimulation of Cyclin proteins (cyclin D1 and B1) leading to cell proliferation, upregulation of anti-apoptotic protein BCL 2 and a decrease in apoptotic genes (Fas) controlling the cell survival, production of VEGF (Vascular endothelial growth factor) and angiogenic factors angiopoietin-1 and angiopoietin-2, regulating angiogenesis, an increase in SNAIL (Zinc finger protein SNAI1) protein transcription initiating the epithelial mesenchymal process in metastasis and a decrease in E-cadherin and tight junctions which holds the epithelial cells together, so that the cells now can invade and metastasize. Thus, the disturbed and aberrant signaling of the hedgehog pathway may lead to a number of cancers. Role in Human Diseases The hedgehog gene family plays a key role in the embryonic developmental processes. Saunders and Gasseling in 1968 studied the development of the chick limb bud and Harfe et al., proposed a model which states that both the concentration and the time of exposure to Shh determines which digit the tissue will develop into in the mouse embryo.[9] Mammalian development also follows the same pattern. Mutations in the hedgehog signaling or consumption of teratogenic drugs by the pregnant mother during embryonic development disrupted the hedgehog signaling pathway and led to severe developmental abnormalities in the fetus. The common abnormality linked to mutations in genes of the hedgehog pathway including Shh and PTCH are holoprosencephaly i.e the failure of the embryonic prosencephalon to divide to form cerebral hemispheres Figure 1b: Hedgehog signaling pathway in vertebrates — with hedgehog ligand


which occurs with a frequency of about 1 in 16,000 live births and about 1 in 200 spontaneous abortions in humans. If the hedgehog pathway inhibitor cyclopamine was consumed by gestating mammals it resulted in cyclopia, one of the most severe defects of holoprosencephaly.[10] The pathway is also relevant in the adult as Sonic hedgehog promotes the proliferation of adult stem cells in various tissues, including primitive hematopoietic cells, mammary and neural stem cells. Some studies have also reported that activation of the hedgehog pathway is required for transition of the hair follicle from the resting to the growth phase.[11] Efforts were on to develop a hedgehog agonist which could be used for treatment of hair growth disorders, but these efforts failed due to toxicities found in animal models. Activation of the hedgehog signaling pathway plays an important role in the pathogenesis of various types of cancers including skin, mammary gland, brain, lung and prostate. Aberrant activation of the pathway which is normally quiescent in the adults leads to development of cancers by transforming the adult stem cells into cancer cells that give rise to tumors. Basal cell carcinoma, a form of skin cancer, was found to be associated with disruptions in the hedgehog signaling. Mutations in PTCH and SMO were found in patients with this disease.[12] Thus development of specific hedgehog signaling inhibitors may provide an efficient therapeutic option for a wide range of malignancies. It has been found in pre-clinical animal models that the hedgehog pathway was up regulated after a stroke or an anginal event and provided a protective barrier against cell death and ischemia. Thus the researchers were attempting to turn this pathway on after a patient had a stroke or heart attack in order to prevent necrosis and apoptosis which are common after such events. But since the pathway has been associated with a number of lethal cancers a stable hedgehog agonist needs to be developed which can provide specific therapeutic benefits with minimum adverse effects. Hedgehog Signaling Pathway and Cancers Abnormal activation of the hedgehog signaling pathway has been implicated in the development of certain types of cancers. Three different mechanisms have been proposed in various types of cancers.[13] 1. Type I- Ligand-independent signaling driven by mutations (e.g. in basal cell carcinoma and medulloblastoma) 2. Type II- Ligand-dependent signaling in autocrine or juxtacrine manner determined by over expression of hedgehog ligand by the same or neighboring tumor cells (e.g. in ovarian cancer, colorectal cancer, pancreatic cancer) 3. Type III- Ligand-dependent signaling in paracrine manner motivated by over expression of hedgehog ligand by the tumor cells which are received by the distant cells in the stroma and provides the signals like VEGF, IGF (Insulinlike growth factor) etc. back to the tumor to promote its growth and survival (e.g. pancreatic, prostate and colon cancer). A variant of this type of cancer may be a reverse paracrine signaling in which the hedgehog ligand is directly secreted by the stromal cells and are received by the tumor cells.

Type I- Ligand-Independent Signaling The first evidence of this type of cancer was found in patients of basal cell nevus syndrome (Gorlin syndrome). These patients inherited mutations in PTCH 1 which lead to constitutive activation of hedgehog signaling pathway in absence of the ligand. Thus, they had a risk for development of Basal cell carcinomas (BCC), medulloblastomas and rhabdomyosarcomas. Basal cell carcinoma patients showed inactivating mutations of PTCH 1 or activating mutations of SMO so that it can no longer be inhibited by PTCH 1 [Figure 2a].[14] Medulloblastomas (pediatric cancer of cerebellum) and rhabdomyosarcomas (muscle cancer in children) were also linked to mutations in PTCH 1 or SUFU. Thus these patients with Gorlin syndrome manifesting thousands of BCC all over the body or with recurring or metastatic BCC and patients with medulloblastomas and rhabdomyosarcomas would be excellent candidates for hedgehog pathway inhibitors.[15] These antagonistic drugs act at the level of SMO or downstream signals and not at the level of PTCH 1 as these cancers are associated with ligand independent pathways. Type II- Ligand-Dependent Signaling in Autocrine or Juxtacrine Manner Ligand dependent cancers implicated with over expression of hedgehog pathway are associated with ovarian, colorectal, upper GIT, pancreatic, lung, breast, prostate cancer and melanomas. The hedgehog ligand secreted from the tumor cells act on itself or on the nearby tumor cells in an autocrine or juxtacrine manner and activates the downstream signals of the hedgehog pathway thereby stimulating the growth and proliferation of the cancerous tissues [Figure 2b]. These patients, apart from SMO or downstream signals inhibitors may show effectiveness to direct hedgehog ligand and PTCH 1 antagonistic drugs.[2] Type III- Ligand-Dependent Signaling The activation of hedgehog pathway in a paracrine manner has been linked to prostate, pancreatic and colon cancers. The hedgehog ligand secreted by the tumor cells are received by the remote cells in the stroma which provides the signals like Figure 2a: Hedgehog signaling pathway in cancers-Type I-Ligand-independent cancers


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VEGF, IGF etc back to the tumor in order to support its growth and survival [Figure 2c].[16] These tumors may be inhibited by SMO or downstream signals inhibitors, hedgehog ligand and PTCH 1 inhibitors and also drugs targeting the stromal response. The reverse paracrine signaling model was seen in B-cell lymphomas, multiple myelomas and leukemia. In this model the hedgehog ligand is directly secreted by the stromal cells rather than from tumor cells. These ligands in hematological malignancies is produced by the bone marrow stroma and are received by the tumor cells which help in the proliferation and growth of the cancerous tissue by upregulating the anti-apoptotic gene Bcl 2. The stromal hedgehog provides satisfactory environment for tumor growth [Figure 2d].[17] Therefore in addition to SMO and hedgehog inhibitors, antiapoptotic drugs or stromal inhibitors will be required for complete response.

and more soluble cyclopamine derivative, IPI-269609 has been developed. This compound has better physiochemical properties and inhibited the metastasis of pancreatic Figure 2b: Hedgehog signaling pathway in cancers -Type II- Autocrine Ligand-dependent cancers

Hedgehog Signaling in Cancer Stem Cells Another model suggests that hedgehog signaling is also important for the maintenance of cancer stem cells. These stem cells have the capacity to divide disproportionately and differentiate to produce all cell types in the tumor.[18] Since, these stem cells are potentially resistant to chemotherapy and radiotherapy they are thought to be the main cause of relapse after treatments. Hence, they may be the prospective targets in future for complete eradication of the cancerous tissue. The hedgehog inhibitors can thus be a promising group of drugs for eliminating these populations of cancer cells in combination with the routine chemotherapy and radiotherapy.

Figure 2c: Hedgehog signaling pathway in cancers -Type III- Paracrine Ligand-dependent cancers

Targeting the Hedgehog Pathway The drugs developed for targeting the hedgehog signaling pathway will depend upon the tumor model. Type I, ligandindependent cancers will respond to drugs which modulate SMO or downstream signals. Some antagonist and agonist of SMO which effect the pathway regulation downstream have already been developed and some are in the developing phase. The type II, ligand-dependent cancers signaling in an autocrine manner which express all the components of hedgehog pathway will require direct hedgehog ligand and PTCH 1 antagonistic drugs other than SMO or downstream signals inhibitors. The drugs targeting the type III, liganddependent cancers signaling in a paracrine manner necessitates the use of drugs which controls the stromal hedgehog signals though they may not have a complete beneficial therapeutic response as the tumors have variable needs depending on the activation of stromal components induced by hedgehog pathway. Hence combination therapy is required in these types of cancers. The most clinically advanced SMO targeting agent is cyclopamine. This compound was isolated as a teratogen from corn lilies. It inhibits the hedgehog pathway by antagonizing the Smoothened receptors and was the first SMO inhibitor to be tested in humans.[19] Its cream formulation application topically in patients of basal cell carcinomas every 3-4 h showed regression of the tumor. But because cyclopamine has poor oral bioavailability, low affinity to the receptors and inadequate pharmacokinetics, a more potent, acid stable 6


Figure 2d: Hedgehog signaling pathway in cancers -Type IIIb-Reverse Paracrine Ligand-dependent cancers


xenografts after oral administration.[20] Another compound IPI-926, a structural congener of IPI-269609 is more selective, metabolically stable, more potent and has already entered into phase I trials.[21] A more potent cyclopamine derivative KAAD-cyclopamine was also developed but could not be studied further. Curis developed another synthetic topical SMO inhibitor Cur-61414 which was successful in eradicating the basal cell carcinomas in mouse ex-vivo model but failed in phase I trials in humans as it could not penetrate the human skin. A different formulation which can easily penetrate the human skin or a different route needs to be developed for its success. SANT1SANT4 are other small molecule synthetic SMO inhibitors which have not yet been tested in humans. These hedgehog antagonists were developed as more potent oral SMO inhibitors which helped in suppressing the growth of type- III paracrine tumors, but was successful in completely eradicating the medulloblastomas in mice. A novel, potent, synthetic and selective oral SMO inhibitor GDC-0449 was developed by Genentech and Curis. It was found to inhibit the growth of pancreatic xenograft without inhibiting pancreatic cell proliferation. In phase I trials GDC-0449 was administered in doses of 150,270 and 540 mg in patients of locally advanced or metastatic solid tumors.[22] In another phase I study,[23] GDC-0449 was used in patients of basal cell carcinomas which showed significant tumor regression. After successful completion of phase I trials it has now entered phase II trials in patients of advanced basal cell carcinomas, for maintenance therapy in remissions of ovarian cancer and in metastatic colorectal cancer. Alternative targets can be hedgehog ligands or PTCH. The hedgehog blocking antibody 5E1 which is a monoclonal antibody has in vivo activity but has still not been tested in humans. A recently discovered small molecule inhibitor Robotnikinin has been found to inhibit hedgehog pathway in vitro only, thus necessitating further studies and research.[24] PTCH 1 antibody i.e Anti-PTCH 1 also blocks the hedgehog pathway though its potency and efficacy needs to be tested. Another large molecular protein HHIP extracellular domain may either block the binding site of hedgehog protein on PTCH 1 or may remove hedgehog away from PTCH 1.

Sometimes cancers may occur due to mutations in the downstream signal pathways such as GLI amplifications or SUFU inactivation which occur independent of hedgehog pathway. Thus these can also be potential targets for future drug discovery research. Such small molecule inhibitors GANT-61, identified by Toftgard et al., and GANT-58[25] are direct antagonist of GLI 1 protein transcriptional activity. They were found to have significant in vivo activity in mice and in GLI 1-positive human prostate cancer xenografts but further human studies and toxicity profile has to be cleared before it can be used in patients. Arsenic trioxide has also been shown to inhibit hedgehog signaling by interfering with GLI function and transcription. It obstructs the accumulation of GLI-2 to primary cilia thus reducing the steady-state GLI-2 protein levels, resulting in inhibition of medulloblastoma growth in mouse models. Since it is already approved by FDA for clinical use in acute promyelocytic leukemia, it may be a beneficial therapy for resistant BCCs in the near future.[26] Recognition of modulators of GLI activity may show a promising future for prevention or treatment of resistant tumors. Novel signal pathways S6K1 are regulating GLI-1 activity downstream of mTOR, therefore combination therapy with mTOR inhibitors and hedgehog inhibitors may prevent the development of resistance in the tumor cells. In vitro preclinical studies of esophageal adenocarcinoma xenografts advocated that combination therapy of mTOR inhibitors with vismodegib works synergistically and delays the growth of Smo antagonist– resistant tumors.[27] Table 1 shows other candidates for future trials including IPI-926 (Saridegib) of Infinity Pharmaceuticals/Mundipharma, Novartis’ LDE-225 and LEQ506, Pfizer’s PF-04449913, Bristol-Myers Squibb’s BMS-833923 (XL139) and Millennium Pharmaceuticals’ TAK-441. Vismodegib (GDC-0449) Vismodegib, earlier named GDC-0449 is the first of the Hedgehog (Hh) signaling pathway inhibitors to reach the clinics. Chemical structure It belongs to 2-arylpyridine class of drug. Its chemical name is - 2-Chloro- N -(4-chloro-3-pyridin-2-ylphenyl)-4methylsulfonylbenzamide.

Table 1: Selected hedgehog inhibitors in clinical development Drug candidate

Company

Target

Indications

Phase

IPI-926 (Saridegib)

Cyclopaminederived SMO inhibitor SMO inhibitor

Chondrosarcoma, Myelofibrosis, Advanced/metastatic solid tumors, Hematological malignancies

Phase II

LDE225

Infinity Pharmaceuticals/ Mundipharma Novartis

Phase I, II, and III

PF-04449913 LEQ506

Pfizer Novartis

SMO inhibitor SMO inhibitor

BMS-833923 (XL139) TAK-441

Bristol-Myers Squibb/ Exelixis Millennium Pharmaceuticals

SMO inhibitor

Myelofibrosis, Basal cell carcinoma [Phase III or Pivotal], Medulloblastoma [Phase I/II (Confirmatory)], Solid tumors [Phase I/II (Confirmatory) — Exploratory] Acute Myeloid Leukemia Advanced Solid Tumors, Medulloblastoma, Locally Advanced or Metastatic Basal Cell Carcinoma Solid Tumors, Small cell lung cancer, myeloma, Gastroesophageal cancer, metastatic cancer Advanced Nonhematologic Malignancies

Gli1 mRNA

Phase Phase I Phase I Phase I


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The molecular formula is C19H14Cl2N2O3S. The molecular weight is 421.30 g/mol and the structural formula is:

and gender do not have a clinically significant pharmacokinetic influence on the systemic exposure of vismodegib. Adverse Drug Reactions

Vismodegib is a crystalline free base with a pKa (pyridinium cation) of 3.8, appearing as a white to tan powder. The solubility of vismodegib is pH dependent with 0.1 μg/mL at pH 7 and 0.99 mg/mL at pH 1.[28] Mechanism of Action Vismodegib is a small molecule, orally administered hedgehog inhibitor discovered by Genentech in collaboration with Curis. The hedgehog pathway is critical in embryonic development as it is activated in the fetus, but is usually dormant in adults. It is assumed to play a role in regulating adult stem cell function, especially maintenance and regeneration of adult tissue. Reactivation of hedgehog pathway in adults is concerned with the development of various cancers, including BCC and medulloblastoma. [2,23] Vismodegib suppresses hedgehog signaling by binding to the SMO, smoothened transmembrane protein that provides activating downstream signals to the pathway, providing a strong validation for its use in the treatment of cancers. Preclinical studies demonstrated the antitumor activity of vismodegib in mouse models of medulloblastoma (MB) and in xenograft models of colorectal and pancreatic cancer. Phase I and II clinical trials in patients with various carcinomas have shown a positive objective response to vismodegib. Pharmacokinetics[28] Vismodegib is a highly permeable compound with low aqueous solubility (BCS Class 2). The absolute bioavailability of vismodegib is 31.8% after single dose. Absorption is saturable after a single dose of 270 mg or 540 mg vismodegib as there is lack of dose proportional increase in exposure. Vismodegib capsules may be taken without consideration to meals because the systemic exposure of vismodegib at steady state is not affected by food. The volume of distribution of vismodegib ranges from 16.4 to 26.6 L and its plasma protein binding is more than 99%. Vismodegib binds to both human serum albumin and alpha-1-acid glycoprotein (AAG) but the binding to AAG is saturable. The parent drug accounts for > 98% of the total circulating drug-related components. Metabolic pathways of vismodegib in humans include oxidation, glucuronidation and pyridine ring cleavage. It is mainly metabolized by CYP2C9, CYP3A4/5 and P glycoproteins. Vismodegib and its metabolites are eliminated mostly by the hepatic route as 82% of the administered dose was recovered in the feces and 4.4% was recovered in urine. The probable elimination half-life (t1/2) of vismodegib is 4 days after continuous once-daily dosing and 12 days after a single dose. The effect of hepatic and renal impairment on the systemic exposure of vismodegib has not been studied. Population analyses showed that weight (range: 41-140 kg), age (range: 26-89 years), creatinine clearance (range: 30 to 80 mL/min), 8


Several clinical trials of vismodegib administered orally as monotherapy at doses of 150 mg once daily in patients of advanced basal cell carcinoma (BCC) for 6 months or longer demonstrated varied side effects. The most common adverse reactions were muscle spasms, alopecia, dysgeusia/ageusia, weight loss, fatigue, nausea, vomiting, diarrhea, decreased appetite and arthralgias. [28] These adverse events were observed in 20-40% of the patients. Amenorrhea was reported in 3 pre-menopausal women and serious grade 3 laboratory abnormalities like hyponatremia, hypokalemia, and azotemia were detected in a few patients. Hyponatremia and fatigue were reversible and subsided on discontinuation of the drug. Resistance to vismodegib developed in a medulloblastoma patient after it initially regressed the tumor. This individual showed a resistance mutation in Smoothened (SMO), but amplifications were also seen in transcription factor Gli2 and the Hh target gene cyclin D1, indicating that resistance may also occur downstream of SMO.[29] Safety in Special Situations Vismodegib is a pregnancy Category D drug and can cause fetal harm and severe birth defects when administered to pregnant females. It was found to be teratogenic and embryolethal in rats at doses corresponding to an exposure of 20% of the exposure at the recommended human dose. In rats, malformations included craniofacial anomalies, open perineum, and absent or fused digits. If vismodegib is used during pregnancy, or if the patient becomes pregnant while taking this drug she should immediately contact her health care provider and should be explained of the potential hazard to the embryo or fetus. Both female and male patients of reproductive age group should be counseled regarding pregnancy prevention and contraception.[28] It is not known whether vismodegib is excreted in human milk. Depending on the disease status of the lactating mother the physician should make a decision whether to discontinue nursing or to withdraw the drug. The safety and efficacy of vismodegib has not been established in pediatric patients but in repeat-dose toxicology studies in rats, oral vismodegib resulted in toxicities in bone and teeth. Similarly its safety and efficacy have not been established in geriatric patients and in patients with hepatic and renal impairment. Moreover patients are advised not to donate blood or blood products while receiving the drug and for at least 7 months after the last dose of vismodegib. There is no information regarding overdosage in humans.[28] Precautions and Warning The labeling for vismodegib includes a boxed warning regarding the potential for severe birth defects or fetal death. Both male and female patients must be cautioned of this risk. In addition, 7 days before starting treatment with vismodegib, physicians must confirm a female patient’s pregnancy status and must counsel both the partners for the need of a highly effective contraception during therapy and for 7 months after the last dose


of vismodegib. Male patients must be informed of the hazard of exposing their partners to vismodegib through semen.[28] Drug Interactions Effects of Other Drugs on Vismodegib Vismodegib is metabolized mainly by CYP2C9 and CYP3A4 but CYP inhibitors (i.e. erythromycin, fluconazole) and inducers (i.e. carbamazepine, modafinil, phenobarbital) do not alter the systemic vismodegib concentration since similar steady-state plasma vismodegib levels were observed in patients in clinical trials. In vitro studies indicate that vismodegib is also a substrate of the efflux transporter P-glycoprotein (P-gp), hence coadministration with drugs that inhibit P-gp (e.g. clarithromycin, erythromycin, azithromycin), increases the systemic exposure and incidence of adverse events. Co-administration of vismodegib with drugs that alter the pH of the upper GI tract (e.g. proton pump inhibitors, H2receptor antagonists and antacids) may affect the solubility of vismodegib and reduce its bioavailability.[28] Effects of Vismodegib on Other Drugs Drug-drug interaction study conducted in cancer patients demonstrated that the systemic exposure of rosiglitazone (a CYP2C8 substrate) or oral contraceptives (ethinyl estradiol and norethindrone) is not altered when either drug was coadministered with vismodegib.[30] In vitro studies indicate that vismodegib is an inhibitor of CYP2C8, CYP2C9, CYP2C19 and the transporter BCRP but it does not induce CYP1A2, CYP2B6, or CYP3A4/5 in human hepatocytes.[28] Clinical Trials of Vismodegib Phase 1 On the basis of preclinical studies, jointly validated by Genentech and Curis, Inc, Genentech filed an Investigational New Drug (IND) application with the FDA in September 2006 to conduct clinical trials. A phase 1 clinical trial was conducted by Von Hoff et al., in 2009 to assess the safety and pharmacokinetics of GDC0449 (vismodegib) in metastatic or locally advanced basalcell carcinoma. Of the 33 patients with metastatic or locally advanced basal-cell carcinoma, 17 patients received oral vismodegib 150 mg per day, 15 patients received 270 mg per day, and 1 patient received 540 mg per day for 9.8 months. Eighteen patients (54.5%) demonstrated an objective response to vismodegib, 7 according to imaging assessments and 11 on physical examination and 1 patient on both. Two patients (6.0%) had a complete response and 16 (48.5%) had a partial response. The other 15 patients had either stable disease (11 patients) or progressive disease (4 patients). Eight grade 3 adverse events were reported in 6 patients, including 4 with fatigue, 2 with hyponatremia, one with muscle spasm, and one with atrial fibrillation.[23] A phase I, open label, single-center study by Graham et al., in 2011 enrolled 6 healthy female volunteers of non childbearing potential. The objectives of the mass balance analysis was to determine the absorption, extent of vismodegib metabolism after a single oral dose administration and routes of elimination including identification of metabolites in plasma, urine, and

feces. Vismodegib was slowly eliminated by a combination of metabolism (oxidation, glucuronidation, and pyridine ring cleavage) and excretion of parent drug, most of which was recovered in feces. The excretion of the administered dose was 86.6% with 82.2 and 4.43% recovered in feces and urine, respectively. It was predominant in plasma, with concentrations representing >98% of the total circulating drugrelated components. No adverse events were reported which were greater than Common Terminology Criteria for Adverse Events grade 1 or those which were considered to be related to vismodegib.[31] Another phase I trial by LoRusso et al., in 2011 assessed GDC-0449 (vismodegib) treatment in patients with solid tumors refractory to current therapies or for which no standard therapy existed, recruited 68 patients receiving vismodegib at escalating doses. Thirty-three of 68 patients had advanced basal cell carcinoma (BCC), 8 had pancreatic cancer, 1 had medulloblastoma and 17 other types of cancer were also included. Forty one patients received vismodegib at 150mg/d, 23 received 270 mg/d and 4 patients received 540mg/d. Tumor response were observed in 20 patients (19 with BCC and 1 unconfirmed response in medulloblastoma), 14 patients had stable disease and 28 had progressive disease. Evidence of GLI 1 down-modulation was observed in non-involved skin signifying the inhibition of hedgehog pathway. Six patients (8.8%) experienced 7 grade 4 events (hyponatremia, fatigue, pyelonephritis, presyncope, resectable pancreatic adenocarcinoma, and paranoia with hyperglycemia) and 27.9% of patients experienced a grade 3 event, commonly hyponatremia (10.3%), abdominal pain (7.4%) and fatigue (5.9%). The recommended phase II dose was 150 mg/d, based on attainment of maximal plasma concentration, pharmacodynamic response and no dose- limiting toxicity at this dose.[32] A phase Ib, open labelled, randomized, multicenter trial was conducted by LoRusso et al., (2011) in 67 patients of locally advanced or metastatic solid malignancy that had progressed after 1st-line and 2nd-line therapy or for which there was no standard therapy. Vismodegib was administered in 3 regimens:150 mg QD (once daily) in 23 patients, TIW (3 times/week) in 22 patient and QW (once weekly) in 22 patient for up to 42 days after an 11-day loading phase (150 mg QD). Vismodegib 150 mg TIW or QW failed to attain unbound plasma concentrations previously associated with efficacy in patients with advanced basal cell carcinoma and medulloblastoma, even after a loading dose period thus concluding that 150 mg QD regimen is appropriate for vismodegib based on its clinical efficacy and safety. Adverse events incidence and severity were similar to the previous trials regardless of dosing schedule.[33] Another phase I, open-label, multicenter trial conducted by Graham et al., in 2011 on 68 patients of locally advanced or metastatic solid tumors, refractory to standard therapy, or for whom no standard therapy was available. The objective was to describe GDC-0449 PK profile: high-affinity binding to alpha-1-acid glycoprotein (AAG) with tight correlation to plasma AAG levels over time and consistently low, unbound drug levels. A linear relationship between total GDC-0449 and AAG plasma concentrations was observed across dose groups (R2 = 0.73). In several patients, GDC-0449 levels varied with Indian Journal of Pharmacology | February 2014 | Vol 46 | Issue 1

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fluctuations in AAG levels over time. Steady-state, unbound GDC-0449 levels were less than 1% of total, independent of dose or total plasma concentration. The side effect profile was not commented upon.[34] Phase 2 A phase II study by Tang et al., in 2012 was a, randomized, double-blind, placebo-controlled clinical trial in patients of basal-cell nevus syndrome. Forty one patients at 3 clinical centers were recruited. The rate of new surgically eligible basal-cell carcinomas was lower with vismodegib than with placebo (2 vs. 29 cases P < 0.001), as was the size of existing clinically significant basal-cell carcinomas (P = 0.003). In some patients, all basal-cell carcinomas clinically regressed and none progressed during treatment with vismodegib. Vismodegib patients had grade 1 or 2 adverse events- loss of taste, muscle cramps, hair and weight loss. Overall, 54% of patients (14 of 26) receiving vismodegib discontinued drug treatment owing to adverse events.[35] Sekulic et al., in 2012 conducted a phase II, open labelled, multicenter, two-cohort, non-randomized trial in patients of metastatic or locally advanced basal cell carcinoma which was inoperable (ERIVANCE BCC study). They recruited 33 patients of metastatic and 63 patients of locally advanced basal cell carcinoma at 31 centers and assessed the objective response rate. In patients with metastatic BCC the independently assessed response rate was 30% (P = 0.001). In patients with locally advanced BCC, the response rate was 43% (P 30% of patients were muscle spasms, alopecia, dysgeusia, weight loss, and fatigue. Serious adverse events were reported in 25% of patients with 7 deaths due to adverse events.[36] Kaye et al., in 2012 conducted a phase II, randomized, placebo-controlled clinical trial in 104 patients with ovarian cancer in 2nd or 3rd complete remission. The objective was to determine the efficacy and investigator-assessed progression-free survival (PFS). The vismodegib and placebo median PFS was 7.5 months and 5.8 months respectively. Adverse events in the vismodegib arm were dysgeusia/ ageusia, muscle spasms and alopecia. Grade 3/4 adverse events occurred in 12 patients (23.1%) with vismodegib and six (11.5%) with placebo.[37] Another phase II, randomized, placebo controlled trial was conducted by Berlin et al., in 2013 on 199 patients with metastatic colorectal cancer (mCRC). The purpose was to

determine the progression-free survival (PFS), efficacy, safety, and pharmacokinetic drug interactions of adding vismodegib to first-line treatment for metastatic CRC and evaluation of predictive biomarkers. Median PFS hazard ratio (HR) for vismodegib treatment compared with placebo was 1.25 (P = 0.28). The overall response rates for placebo-treated and vismodegib-treated patients were 51% and 46% respectively. No vismodegib-associated benefit and no pharmacokinetic drug interactions was observed in combination with either Folfox, Folfiri or bevacizumab. Vismodegib does not add to the efficacy of standard therapy for mCRC. Grade 3 to 5 adverse events reported for more than 5% of patients that occurred more frequently with vismodegib-were fatigue, nausea, asthenia, mucositis, peripheral sensory neuropathy, weight loss, decreased appetite, and dehydration.[38] The objective of a phase II single-arm, open-label study by Lorusso et al., in 2013 on patient of locally advanced or metastatic solid malignancies was to determine the clinical drug-drug interaction (DDI) assessment of vismodegib’s with rosiglitazone and oral contraceptives (OCs). DDI study demonstrated that systemic exposure of rosiglitazone (a CYP2C8 substrate) or OC (ethinyl estradiol/norethindrone) is not altered with concomitant vismodegib.[30] Approval In September 2011, after successful phase II trials, Genentech submitted the New Drug Application (NDA) for vismodegib for use in adults with advanced BCC. Based on the results of the above mentioned trials and mainly the pivotal phase 2 ERIVANCE BCC study,[36] FDA approved oral Vismodegib (Erivedge ® Genentech) on January 30, 2012 in a priority review program for the treatment of metastatic basal-cell carcinoma (BCC) or locally advanced BCC that has recurred following surgery or patients who are not candidates for surgery or radiation.[39] The approval of vismodegib represents the first Hedgehog signaling pathway targeting agent to gain U.S. Food and Drug Administration (FDA) approval. The drug is also undergoing clinical trials for metastatic colorectal cancer, small-cell lung cancer, advanced stomach cancer, pancreatic cancer, medulloblastoma and chondrosarcoma. The drug was developed by the biotechnology/pharmaceutical company Genentech, arm of the Roche Group which is headquartered at South San Francisco, California, USA. Various pharmaceutical companies are continuing to investigate vismodegib in several ongoing studies. Genentech/Roche and National Cancer Institute (NCI) are conducting a number of ongoing studies which are currently recruiting patients [Table 2].

Table 2: Ongoing clinical trials of Vismodegib Company

Tumors Targeted/Mechanism

Status

Genentech

Advanced Solid Malignancies Including Hepatocellular Carcinoma

NCT01546519

Roche Pharma AG Genentech National Cancer Institute (NCI)

Pancreatic Ductal Adenocarcinoma (PDAC) Metastatic Breast Cancer that cannot be removed by Surgery Advanced Pancreatic Cancer

Phase Ib, open-label, multiple-center, multiple-dose study. Phase 2 Phase 1 Phase 2

NCT01195415

National Cancer Institute (NCI) 10


ClinicalTrials.gov Identifier

NCT01096732 NCT01071564


Indications and Drug Administration ERIVEDGE® (Vismodegib of Genentech) capsule is a hedgehog pathway inhibitor indicated for the treatment of adults with metastatic basal cell carcinoma, or with locally advanced basal cell carcinoma that has recurred following surgery or who are not candidates for surgery or radiation. Basal-cell carcinoma is a very common skin cancer. More than two million cases of this skin cancer are diagnosed in the United States each year as it is much more common in fairskinned individuals more so with a family history of basal-cell cancer. It is a slow-growing form of skin cancer caused by long-term exposure to ultraviolet (UV) radiation from sunlight. Basal cell skin cancer is most common in people over the age of 45 years but can occur in younger people too. It starts in the basal layer of the epidermis. Most basal cell cancers occur on that part of the skin which is regularly exposed to sunlight or other ultraviolet radiation such as on the head, scalp, neck, face commonly on the nose and back of the hands, though one-third of it can also occur on other parts of the body not exposed to sunlight including the trunk, legs, and arms. It can be highly disfiguring as it may involve cartilages, bones and soft tissues but is rarely fatal. The recommended dose of vismodegib is 150 mg orally once daily for at least 10 months, or until disease progresses or unacceptable toxicity occurs. Vismodegib capsules should be swallowed whole and may be taken with or without food. Development of Resistance to Vismodegib Though vismodegib is a new medication for use in patients with locally advanced or metastatic basal cell carcinoma, nevertheless it is not free from the development of resistance. This resistance was seen in a patient of medulloblastoma with a previously recognized PTCH mutation. Initially the patient responded to vismodegib treatment, but later there was progression of the disease. Samples were obtained and analyzed which demonstrated a new mutation in SMO i.e D473, along with the preexisting PTCH mutation. This newer mutation affected binding of vismodegib to SMO, hence new SMO inhibitors needs to be developed which would inhibit this mutation. There may be other types of resistance emerging which may be highlighted in the novel ongoing trials and can guide the future researches.[40] Future Prospects The hedgehog inhibitors are a promising group of drugs to be used in cancer chemotherapy. Though vismodegib showed encouraging results in early clinical trials which lead to its hastened approval by the U.S. FDA for advanced Basal cell carcinoma, but still its long term efficacy and safety needs to be determined in well designed phase III clinical trials. Moreover no trials have been conducted in India for demonstrating the efficacy and safety in Indian population. These areas need further evaluation before it can be approved in wider population and for other tumors. Apart from vismodegib other hedgehog inhibitors are also in early phases of clinical trials for advanced solid tumors and other malignancies, but the approving authorities should be careful and vigilant before approving such drugs as they are potentially toxic and may require watchful and intense monitoring. Still, these drugs may become a boon in the future for the treatment of chemoresistant tumors with poor prognosis.

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Cite this article as: Abidi A. Hedgehog signaling pathway: A novel target for cancer therapy: Vismodegib, a promising therapeutic option in treatment of basal cell carcinomas. Indian J Pharmacol 2014;46:3-12. Source of Support: This study was not supported financially or otherwise, Conflict of Interest: None declared.

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