Vismodegib: The first drug approved for advanced and metastatic basal cell carcinoma

Dubey, Ashok Kumar; Dubey, Suparna; Handu, Shailendra; Qazi, Muhammad Akram

doi:10.4103/0022-3859.109494

Cited by 15 publications

(7 citation statements)

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“…Two SMO inhibitors, vismodegib and sonidegib, are currently FDA approved for use in patients with advanced BCC (17,52), and a number of others are in various stages of clinical trials (53). Although exhibiting dramatic initial efficacy, BCCs typically relapse after treatment due to vismodegib resistance (54,55).…”

Section: Discussionmentioning

confidence: 99%

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A CK1α Activator Penetrates the Brain and Shows Efficacy Against Drug-resistant Metastatic Medulloblastoma

Rodríguez-Blanco

Long

et al. 2019

Clinical Cancer Research

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Purpose: Although most children with medulloblastoma are cured of their disease, Sonic Hedgehog (SHH) subgroup medulloblastoma driven by TRP53 mutations is essentially lethal. Casein kinase 1a (CK1a) phosphorylates and destabilizes GLI transcription factors, thereby inhibiting the key effectors of SHH signaling. We therefore tested a secondgeneration CK1a activator against TRP53-mutant, MYCNamplified medulloblastoma.Experimental Design: The ability of this CK1a activator to block SHH signaling was determined in vitro using GLI reporter cells, granular precursor primary cultures, and PATCHED1 (PTCH1)-mutant sphere cultures. While in vivo efficacy was tested using 2 different medulloblastoma mouse models: PTCH1 and ND2:SMOA1. Finally, the clinical relevance of CK1a activators was demonstrated using a TRP53-mutant, MYCN-amplified patient-derived xenograft.Results: SSTC3 inhibited SHH activity in vitro, acting downstream of the vismodegib target SMOOTHENED (SMO), and reduced the viability of sphere cultures derived from SHH medulloblastoma. SSTC3 accumulated in the brain, inhibited growth of SHH medulloblastoma tumors, and blocked metastases in a genetically engineered vismodegib-resistant mouse model of SHH medulloblastoma. Importantly, SSTC3 attenuated growth and metastasis of orthotopic patient-derived TRP53-mutant, MYCN-amplified, SHH subgroup medulloblastoma xenografts, increasing overall survival.Conclusions: Using a newly described small-molecule, SSTC3, we show that CK1a activators could address a significant unmet clinical need for patients with SMO inhibitorresistant medulloblastoma, including those harboring mutations in TRP53. Analysis and interpretation of data (e.g., statistical analysis, biostatistics, computational analysis):

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Section: Discussionmentioning

confidence: 99%

“…One of these inhibitors, vismodegib, was FDA-approved for treatment of advanced basal cell carcinoma (BCC; ref. 17). Given its efficacy against BCC driven by SHH signaling, vismodegib was rapidly repurposed in clinical trials for patients with medulloblastoma (18).…”

Section: Introductionmentioning

confidence: 99%

A CK1α Activator Penetrates the Brain and Shows Efficacy Against Drug-resistant Metastatic Medulloblastoma

Rodríguez-Blanco

Long

et al. 2019

Clinical Cancer Research

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“…Given the importance of the HH pathway in normal embryonic and skeletal development, caution must be taken in administering these agents to children or pregnant MC patients. It could be difficult to obtain a therapeutic index, although notably, at the doses of PF-04449913 employed in our mouse MC studies 15 and those of IPI-926 for human basal cell carcinoma treatment, 52 linear growth was not affected, although there were some common adverse effects from the latter, including abdominal pain, diarrhea, hyponatremia and arthralgia 52 …”

Section: Hedgehog Pathway Antagonists For the Treatment Of MC And Othmentioning

confidence: 95%

From an orphan disease to a generalized molecular mechanism

Yang¹,

Neel²

2013

Rare Diseases

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Recently, loss-of-function mutations in PTPN11 were linked to the cartilage tumor syndrome metachondromatosis (MC), a rare inherited disorder featuring osteochondromas, endochondromas and skeletal deformation. However, the underlying molecular and cellular mechanism for MC remained incompletely understood. By studying the role of the Src homology-2 domain-containing protein tyrosine phosphatase Shp2 (encoded by mouse Ptpn11) in cathepsin K-expressing cells, we identified a novel cell population in the perichondrial groove of Ranvier. In the absence of Shp2, these cells exhibit elevated Indian hedgehog (Ihh) signaling, proliferate excessively and cause ectopic cartilage formation and tumors. Our findings establish a critical role for a protein-tyrosine phosphatase (PTP) family member, in addition to the well-known roles of receptor tyrosine kinases (RTKs), in cartilage development and homeostasis. However, whether Shp2 deficiency in other epiphyseal chondroid cells and whether signaling pathways in addition to the IHH/Parathyroid Hormone–related Peptide (PTHrP) axis attribute to the formation of enchondromas and osteochondromas remains elusive. Understanding how chondrogenic events are regulated by SHP2 could aid in the development of novel therapeutic approaches to prevent and treat cartilage diseases, such as MC and osteoarthritis (OA).

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“…Given that inactivation of PTCH‐1 or activation of SMO is a common feature of most BCCs, increasing the inhibitory action of the former and suppressing the activation of the latter, became attractive targets for the treatment of BCC and other tumours with hyperactivated Hh pathway …”

Section: Vismodegib – a First‐in‐class Oral Small Moleculementioning

confidence: 99%

Current landscape for treatment of advanced basal cell carcinoma

Foley

2015

Aust J Dermatology

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Basal cell carcinomas (BCCs) account for around 80% of non-melanoma skin cancer. Australia has the highest incidence of BCC globally and the rates continue to increase in both Australia and New Zealand. BCC causes significant morbidity, placing an enormous burden on the healthcare system. Treatment of patients with advanced BCC can be particularly challenging. A panel of UK experts recently defined advanced disease as BCC that in which current treatment modalities are considered potentially contraindicated by clinical or patient-driven factors. Research has found that mutations in the hedgehog signalling pathway underpin the pathogenesis of the vast majority of sporadic BCC, as well as Gorlin syndrome. The first-in-class oral small molecule hedgehog pathway inhibitor -vismodegib-is now approved in a number of countries for use in locally-advanced and metastatic BCC and has resulted in improved outcomes in the majority of patients treated. With a number of similar agents in the pipeline, research is now focusing on identifying mechanisms that may contribute to resistance to this agent in some lesions.

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Vismodegib: The first drug approved for advanced and metastatic basal cell carcinoma

Cited by 15 publications

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A CK1α Activator Penetrates the Brain and Shows Efficacy Against Drug-resistant Metastatic Medulloblastoma

A CK1α Activator Penetrates the Brain and Shows Efficacy Against Drug-resistant Metastatic Medulloblastoma

From an orphan disease to a generalized molecular mechanism

Current landscape for treatment of advanced basal cell carcinoma

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