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BIOMARKER:

SMO mutation

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Other names: SMO, Smoothened Frizzled Class Receptor, Smoothened Seven Transmembrane Spanning Receptor, Smoothened Frizzled Family Receptor, Frizzled Family Member 11, Smoothened Homolog, Protein Gx, SMOH, Seven Transmembrane Helix Receptor, Smoothened (Drosophila) Homolog, Smoothened Homolog (Drosophila), FZD11, CRJS, Gx
Entrez ID:
Related biomarkers:
25d
Correlation of Molecular Status with Preoperative Olfactory Function in Olfactory Groove Meningioma. (PubMed, Cancers (Basel))
The study highlights PSH and perifocal oedema's significant effect on olfactory function in OGM patients but finds no link between olfactory impairment and tumour mutations, possibly due to the small sample size. This suggests that age and gender affect olfactory impairment. Additional research with a larger group of participants is needed to explore the impact of OGM driver mutations on olfactory performance.
Journal
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AKT1 (V-akt murine thymoma viral oncogene homolog 1) • SMO (Smoothened Frizzled Class Receptor)
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AKT1 mutation • SMO mutation
3ms
A sterol analog inhibits hedgehog pathway by blocking cholesterylation of smoothened. (PubMed, Cell Chem Biol)
Q29 exhibits an additive inhibitory effect on medulloblastoma with vismodegib, a clinically used SMO-7TM inhibitor for treating basal cell carcinoma (BCC). Importantly, Q29 overcomes resistance caused by SMO mutants against SMO-7TM inhibitors and inhibits the activity of SMO oncogenic variants. Our work demonstrates that the SMO-CRD inhibitor can be a new way to treat Hh pathway-driven cancers.
Journal
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SMO (Smoothened Frizzled Class Receptor)
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SMO mutation
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Erivedge (vismodegib)
3ms
Plasma ctDNA Monitoring of a PTCH1-Mutant Metastatic Adult Medulloblastoma Showing a Durable Benefit With Vismodegib. (PubMed, Oncologist)
Several small studies demonstrate objective but short-lived responses to SMO inhibitors such as vismodegib or sonidegib. We present the case of a 26-year-old patient with a recurrent MB, in which next-generation sequencing (FoundationOne CDx) revealed a mutation in PTCH1, allowing the patient to be treated with vismodegib in second line, resulting in a durable benefit lasting for 1 year. Using an in-house digital PCR probe, the PTCH1 mutation could be tracked in ctDNA during treatment with first-line chemotherapy and while on treatment with vismodegib, demonstrating a precise correlation with the radiological and clinical behavior of the disease.
Journal • Circulating tumor DNA • Metastases
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TP53 (Tumor protein P53) • TERT (Telomerase Reverse Transcriptase) • PTCH1 (Patched 1) • SMO (Smoothened Frizzled Class Receptor)
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TP53 wild-type • PTCH1 mutation • SMO mutation
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FoundationOne® CDx
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Erivedge (vismodegib) • Odomzo (sonidegib)
3ms
Phase classification
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EGFR (Epidermal growth factor receptor) • HER-2 (Human epidermal growth factor receptor 2) • BRAF (B-raf proto-oncogene) • ALK (Anaplastic lymphoma kinase) • TMB (Tumor Mutational Burden) • PTCH1 (Patched 1) • SMO (Smoothened Frizzled Class Receptor)
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EGFR mutation • HER-2 overexpression • BRAF mutation • HER-2 amplification • BRAF V600 • ALK rearrangement • ALK mutation • SMO mutation
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Herceptin (trastuzumab) • Tecentriq (atezolizumab) • erlotinib • Zelboraf (vemurafenib) • Alecensa (alectinib) • Perjeta (pertuzumab) • Cotellic (cobimetinib) • Erivedge (vismodegib)
4ms
Dynamic optical coherence tomography evaluation in locally advanced basal cell carcinoma during sonidegib treatment. (PubMed, J Eur Acad Dermatol Venereol)
Sonidegib can be considered an effective treatment option in cases where surgery or radiotherapy would be unfeasible or has previously failed, although pigmented lesions did not show complete clearance, suggesting that there are factors other than the SHH pathway involved in tumour growth. Videodermoscopy and D-OCT were useful in the quick and seamless follow-up of lesions and added valuable information in assessing efficacy.
Journal • Metastases
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PTCH1 (Patched 1) • SMO (Smoothened Frizzled Class Receptor)
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PTCH1 mutation • SMO mutation
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Erivedge (vismodegib) • Odomzo (sonidegib)
5ms
Mesothelioma in situ of the peritoneum: report of three cases and review of the literature. (PubMed, Histopathology)
This work describes the histologic features and clinicopathologic characteristics of peritoneal MIS in three cases, highlights BAP1 somatic and germline mutations in peritoneal MIS, and strengthens the importance of ancillary studies (including immunohistochemical and molecular studies) in the diagnosis of MIS.
Review • Journal • BRCA Biomarker
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BRCA1 (Breast cancer 1, early onset) • MTAP (Methylthioadenosine Phosphorylase) • BAP1 (BRCA1 Associated Protein 1) • TET2 (Tet Methylcytosine Dioxygenase 2) • BRCA (Breast cancer early onset) • SMO (Smoothened Frizzled Class Receptor) • U2AF1 (U2 Small Nuclear RNA Auxiliary Factor 1) • ERCC3 (ERCC Excision Repair 3, TFIIH Core Complex Helicase Subunit)
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TET2 mutation • BAP1 mutation • U2AF1 mutation • SMO mutation
6ms
Immunohistochemical and Molecular Characteristics of Anogenital Papillary Hidradenomas. (PubMed, Am J Dermatopathol)
Anogenital PHs frequently harbor PIK3CA mutations and show a PAX8-, GATA3/ER/PR/AR + immunohistochemical profile.
Journal
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HER-2 (Human epidermal growth factor receptor 2) • KRAS (KRAS proto-oncogene GTPase) • ER (Estrogen receptor) • PIK3CA (Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha) • PGR (Progesterone receptor) • AR (Androgen receptor) • MAP2K1 (Mitogen-activated protein kinase kinase 1) • MSH6 (MutS homolog 6) • PMS2 (PMS1 protein homolog 2) • SMO (Smoothened Frizzled Class Receptor) • GATA3 (GATA binding protein 3) • PAX8 (Paired box 8) • NKX3-1 (NK3 homeobox 1)
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KRAS mutation • PIK3CA mutation • HER-2 expression • AR expression • SMO mutation • ER expression
6ms
Prostate Cancer Patient Stratification by Molecular Signatures in the Veterans Precision Oncology Data Commons. (PubMed, Cold Spring Harb Mol Case Stud)
Hierarchical clustering analysis revealed two subgroups containing therapeutically targetable molecular features with novel mutational signatures distinct from those reported in the Catalogue of Somatic Mutations in Cancer database. The clustering approach presented in this study can potentially be used to clinically stratify patients based on their distinct mutational profiles and identify actionable somatic mutations for precision oncology.
Journal • Tumor mutational burden
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TMB (Tumor Mutational Burden) • ABL1 (ABL proto-oncogene 1) • PTEN (Phosphatase and tensin homolog) • NOTCH1 (Notch 1) • KMT2A (Lysine Methyltransferase 2A) • MSH6 (MutS homolog 6) • SMO (Smoothened Frizzled Class Receptor)
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PTEN mutation • NOTCH1 mutation • VHL mutation • SMO mutation
6ms
New P2 trial • Pan tumor • Metastases
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PTCH1 (Patched 1) • SMO (Smoothened Frizzled Class Receptor)
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PTCH1 mutation • SMO mutation
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Odomzo (sonidegib)
6ms
Ligand-dependent hedgehog signaling maintains an undifferentiated, malignant osteosarcoma phenotype. (PubMed, Oncogene)
Finally, we demonstrate that the SMO antagonist sonidegib (LDE225) induces growth arrest and terminal differentiation in vivo in osteosarcomas that express primary cilia and Hh ligand combined with mutations in TP53. These results provide a mechanistic framework for aberrant Hh signaling in osteosarcoma based on defining mutations in the tumor suppressor, TP53.
Journal
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TP53 (Tumor protein P53) • RB1 (RB Transcriptional Corepressor 1) • SMO (Smoothened Frizzled Class Receptor) • SHH (Sonic Hedgehog Signaling Molecule)
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TP53 mutation • SMO mutation
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Odomzo (sonidegib)
6ms
The extracellular matrix dictates regional competence for tumour initiation. (PubMed, Nature)
Decreasing the expression of collagen I in the back skin through treatment with collagenase, chronic UV exposure or natural ageing overcame the natural resistance of back-skin basal cells to undergoing EHFP reprogramming and tumour initiation after SmoM2 expression. Altogether, our study shows that the composition of the extracellular matrix regulates how susceptible different regions of the body are to tumour initiation and invasion.
Journal
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SMO (Smoothened Frizzled Class Receptor)
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SMO mutation
6ms
Whole exome sequencing of intracranial epidermoid cysts (IECs) reveals potential somatic drivers (SNO 2023)
Digital droplet PCR (ddPCR) of these samples is underway to validate the low tumor allele frequencies ( < 4%). The discovery of activating mutations in SMO is significant because it potentiates FDA-approved SMO-inhibitors like Vismodegib and Sonidegib as viable treatment options for patients with IECs.
Whole exome sequencing
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SMO (Smoothened Frizzled Class Receptor) • STIM1 (Stromal Interaction Molecule 1)
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SMO mutation
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Erivedge (vismodegib) • Odomzo (sonidegib)
7ms
Comprehensive characterisation of acinar cystic transformation of the pancreas: a systematic review. (PubMed, J Clin Pathol)
Globally considered, our findings demonstrated that ACT is a benign entity, without the need of surgical resection with the exception of symptomatic lesions. The rare occurrence of intracystic PanINs and driver mutations suggest considering follow-up if a preoperative diagnosis of ACT can be made.
Review • Journal
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KRAS (KRAS proto-oncogene GTPase) • SMO (Smoothened Frizzled Class Receptor)
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KRAS mutation • SMO mutation
8ms
Research prospect of preclinical model construction and precision therapy in ameloblastoma (PubMed, Zhonghua Kou Qiang Yi Xue Za Zhi)
Yet, it is worth mentioning that a three-dimensional organoid model presents a high potential in culturing stem-cell-like epithelial cells in AM, and it would further be used in recapitulating corresponding tumors and developing targeted medicines. In this paper, we review research progress in preclinical models and the genetic variations of AM, and raise drug screening prospect of the current organoid models, which may pave the way for the possible personalized medicine in AM.
Preclinical • Journal
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SMO (Smoothened Frizzled Class Receptor)
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BRAF mutation • SMO mutation
8ms
Meningioma (PubMed, No Shinkei Geka)
The amalgamation of molecular insights with clinical and histological parameters, alongside patient prognosis, holds significant utility in the management of patients with meningiomas. It is anticipated to pave the way for treatments founded on molecular-clinical associations.
Journal
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CDKN2A (Cyclin Dependent Kinase Inhibitor 2A) • AKT1 (V-akt murine thymoma viral oncogene homolog 1) • TERT (Telomerase Reverse Transcriptase) • CDKN2B (Cyclin Dependent Kinase Inhibitor 2B) • NF2 (Neurofibromin 2) • SMO (Smoothened Frizzled Class Receptor) • KLF4 (Kruppel-like factor 4)
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CDKN2A deletion • NF2 mutation • AKT1 mutation • TERT mutation • SMO mutation • TERT promoter mutation
8ms
Classification and Molecular Diagnosis of Benign Brain Tumors (PubMed, No Shinkei Geka)
Thus, TERT promoter mutation and homozygous deletion of CDKN2A/B should be evaluated to define grade 2 and 3 meningiomas. In mesenchymal tumors, the term "hemangiopericytoma" has been deleted from solitary fibrous tumors.
Journal
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CDKN2A (Cyclin Dependent Kinase Inhibitor 2A) • AKT1 (V-akt murine thymoma viral oncogene homolog 1) • TERT (Telomerase Reverse Transcriptase) • CDKN2B (Cyclin Dependent Kinase Inhibitor 2B) • SMO (Smoothened Frizzled Class Receptor) • KLF4 (Kruppel-like factor 4) • HTRA1 (HtrA Serine Peptidase 1) • SH3PXD2A (SH3 And PX Domains 2A)
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CDKN2A deletion • AKT1 mutation • TERT mutation • SMO mutation • TERT promoter mutation
9ms
KCTD1 is a new modulator of the KCASH family of Hedgehog suppressors. (PubMed, Neoplasia)
Consequently, KCTD1 expression reduces HDAC1 protein levels and Hh/Gli1 activity, inhibiting Hh dependent cell proliferation in Hh tumour cells. Furthermore, analysis of expression data on publicly available databases indicates that KCTD1 expression is reduced in Hh dependent MB samples, compared to normal cerebella, suggesting that KCTD1 may represent a new putative target for therapeutic approaches against Hh-dependent tumour.
Journal
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SMO (Smoothened Frizzled Class Receptor) • GLI1 (GLI Family Zinc Finger 1) • HDAC1 (Histone Deacetylase 1) • KCTD15 (Potassium Channel Tetramerization Domain Containing 15)
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SMO mutation
10ms
Genomic Landscape of Meningiomas. (PubMed, Adv Exp Med Biol)
In this chapter we will discuss the early cytogenetic and mutational changes uncovered in meningiomas, from the discovery of the loss of chromosome 22q and the neurofibromatosis-2 (NF2) gene to other non-NF2 driver mutations (KLF4, TRAF7, AKT1, SMO, etc.) discovered using next generation sequencing. We discuss each of these alterations in the context of their clinical significance and conclude the chapter by reviewing recent multiomic studies that have integrated our knowledge of these alterations together to develop novel molecular classifications for meningiomas.
Journal
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AKT1 (V-akt murine thymoma viral oncogene homolog 1) • SMO (Smoothened Frizzled Class Receptor) • KLF4 (Kruppel-like factor 4)
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AKT1 mutation • SMO mutation
11ms
Optical coherence tomography evaluation in locally advanced basal cell carcinoma during systemic treatment (WCD 2023)
With the introduction of Vismodegib and Sonidegib, two hedgehog pathway inhibitors, a response rate of 67% was observed in locally advanced disease and 38% in metastatic disease. Med. 2012;366:2171–2179
Metastases
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PTCH1 (Patched 1) • SMO (Smoothened Frizzled Class Receptor)
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PTCH1 mutation • SMO mutation
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Erivedge (vismodegib) • Odomzo (sonidegib)
12ms
Trial completion • Tumor mutational burden • Metastases
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EGFR (Epidermal growth factor receptor) • HER-2 (Human epidermal growth factor receptor 2) • BRAF (B-raf proto-oncogene) • ALK (Anaplastic lymphoma kinase) • TMB (Tumor Mutational Burden) • PTCH1 (Patched 1) • SMO (Smoothened Frizzled Class Receptor)
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EGFR mutation • HER-2 overexpression • BRAF mutation • HER-2 amplification • BRAF V600 • ALK rearrangement • ALK mutation • SMO mutation
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Herceptin (trastuzumab) • Tecentriq (atezolizumab) • erlotinib • Zelboraf (vemurafenib) • Alecensa (alectinib) • Perjeta (pertuzumab) • Cotellic (cobimetinib) • Erivedge (vismodegib)
1year
Innovative treatments for meningiomas. (PubMed, Rev Neurol (Paris))
Except in rare cases of MSH2/6 mutation or high tumor mass burden, the activity of PD-1 inhibitors remains limited; however, its combination with various radiation therapy modalities is particularly promising. On the whole, therapeutic management of high-grade meningiomas is still challenging even with multiple promising therapeutic targets and innovations.
Review • Journal • PD(L)-1 Biomarker • IO biomarker
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MSH6 (MutS homolog 6) • MSH2 (MutS Homolog 2) • SMO (Smoothened Frizzled Class Receptor)
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MSH2 mutation • NF2 mutation • SMO mutation
1year
B13, a well-tolerated inhibitor of hedgehog pathway, exhibited potent anti-tumor effects against colorectal carcinoma in vitro and in vivo. (PubMed, Bioorg Chem)
The binding of B13 to Smo was studied by BODIPY-cyclopamine competitive binding assay and molecular docking...In vivo pharmacodynamics experiments showed that B13 was superior to Vismodegib in antitumor activity and had low toxicity in vivo. Mechanism studies have shown that B13 can bind Smo protein, inhibit the expression of downstream Gli1 and its entry into the nucleus. Notably, B13 overcomes resistance caused by Smo mutations.
Preclinical • Journal
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SMO (Smoothened Frizzled Class Receptor) • GLI1 (GLI Family Zinc Finger 1)
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SMO mutation • GLI1 expression
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Erivedge (vismodegib) • cyclopamine
1year
Molecular profiling of ctDNA from NCI-MATCH patients enrolled for treatment with mTOR1/2 inhibitor sapanisertib (arm M) and the Hedgehog pathway inhibitor vismodegib (arm T). (ASCO 2023)
Detection of the enrollment mutations in treatment arms was observed in 51.8% - 85.7% of patients tested by ctDNA with overall variant concordance between tissue and ctDNA of at least 73.6%. These findings support the use of liquid biopsy as a tool for understanding genomic profiles of cancer patients both at diagnosis and progression, less invasively than standard tissue biopsies. In addition, 7 patients were identified as MSI-H, suggesting that blood-based testing could complement tissue testing for identifying patients who may benefit from targeted therapy.
Clinical • Tumor mutational burden • MSi-H Biomarker • Circulating tumor DNA
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MSI-H/dMMR • PTCH1 mutation • TSC1 mutation • TSC2 mutation • SMO mutation
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TruSight Oncology 500 Assay
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sapanisertib (CB-228) • Erivedge (vismodegib)
1year
My Pathway: A Study Evaluating Herceptin/Perjeta, Tarceva, Zelboraf/Cotellic, Erivedge, Alecensa, and Tecentriq Treatment Targeted Against Certain Molecular Alterations in Participants With Advanced Solid Tumors (clinicaltrials.gov)
P2a, N=670, Active, not recruiting, Genentech, Inc. | Trial completion date: Sep 2023 --> May 2023 | Trial primary completion date: Sep 2023 --> May 2023
Trial completion date • Trial primary completion date • Tumor mutational burden • Metastases
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EGFR (Epidermal growth factor receptor) • HER-2 (Human epidermal growth factor receptor 2) • BRAF (B-raf proto-oncogene) • ALK (Anaplastic lymphoma kinase) • TMB (Tumor Mutational Burden) • PTCH1 (Patched 1) • SMO (Smoothened Frizzled Class Receptor)
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EGFR mutation • HER-2 overexpression • BRAF mutation • HER-2 amplification • BRAF V600 • ALK rearrangement • ALK mutation • SMO mutation
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Herceptin (trastuzumab) • Tecentriq (atezolizumab) • erlotinib • Zelboraf (vemurafenib) • Alecensa (alectinib) • Perjeta (pertuzumab) • Cotellic (cobimetinib) • Erivedge (vismodegib)
1year
Different treatment response in several head and neck squamous cell carcinoma (HNSCC) cell lines reflecting underlying genomic and molecular signatures (AACR 2023)
PI3K/mTOR dual inhibition, PI3Kalpha inhibitor, AKT inhibitor, FGFR inhibitor, ALK/IGF1R inhibitor, CDK4/6 inhibitor, BCl2 inhibitor, WEE1 inhibitor, ATR inhibitor, DNA-PK inhibitor, AT2AR inhibitor, Mcl-1 inhibitor, MEK1/2 inhibitor, EZH2 inhibitor, HDAC inhibitor, CDK9 inhibitor, DNMT3 inhibitor, BRD4/BET inhibitor, JAK2 inhibitor, CXCR4 inhibitor, FAK inhibitor, BTK inhibitor, eribulin, & VEGFR2/ PDGFR/FGFR or VEGFR2/c-MET/Axl triple blockage might be effective on TW2.6 and reverse treatment refractoriness, maybe through the inhibition of mesenchymal transformation, pRB, & PI3K/AKT /mTOR signaling and the modulation of stemness & PD1/PDL1 pathway...All cell lines will be tried to be categorized as TCGA subtypes for the reference of future drug combinations.Cell linesSCC25KBSASCAL27FaDuSCC15SCC9SCC4TW2.6Differ- entiationWellPoorPoorPoorPoorWellWellWellWell, but rapidly replicated, with high hyper-diploidy & complex rearrangementsHPV statusHPV 16/18HPV18--HPV 16/18--HPV 6/11-EGFR statusMediumLowHighHighMediumHighLowMedium to highUnknownDocetaxel sensitivity+++++++++++++ to +++++-+Cisplatin sensitivity+++++++++++++- to +-- to +5-FU sensitivity+++++++++++-+ to ++-- to +Afatinib sensitivity+++- to +-+++++ to +++++++++-Polo-like kinase Inhibitor sensitivity+++++++++++++ to +++- to +-- to +VEGFR2 Inhibitor sensitivity----+++++--++PI3K/ mTOR inhibitorAll cell lines sensitiveCDK4/6 Inhibitor response+++- to ++++++ to +++++++++++++ to +++Western blotsWeak p-AKT & VEGF-A, mild PDL1 and BMI-1, Gli-1(+)Weak p-AKT, mild PDL1 and strong VEGF-A & BMI-1, p16(+)Moderate p-AKT & BMI-1, high PDL1, mild VEGF-AHigh p-AKT & VEGF-A, mild PDL1 & BMI-1High VEGF-A, moderate p-AKT & PDL1, weak BMI-1, Gli-1(+)Weak p-AKT & VEGF-A, mild PDL1 & BMI-1Weak p-AKT, VEGF-A, & BMI-1, moderate PDL1Moderate p-AKT & VEGF-A, strong BMI-1, mild PDL1, Gli-1(+)High p-AKT, PDL1, & VEGF-A and moderate BMI-1NGSCCND1 gain, CDKN2A deletion, FRG1 mutation, HGF mutation, p53 mutation, ATR mutation, SMO mutation, RUNX1T1 mutationSTK11 mutation, PDGFRA mutation, IGF1 mutation, BCOR mutation, EGFR mutation, NOTCH1 mutation, MET mutation, IKZF1 mutation, NFKB1 mutation, DPYD mutation, FGFR4 mutation, BRCA1 mutation, MSH2 mutation, DNMT3A mutationKRAS mutation, MDM2 mutation, TMB-H, AXIN1 loss, RAD51D mutation, NOTCH1/2 mutation, ERBB4 mutation, PALB2 mutation, p53 mutation, POLE mutation, CASP8 mutation, BRCA2 mutation, RNF43 mutation, LRP1B mutation, MET mutationCDKN2A deletion, EGFR amplification, SMAD4 mutation, TMB-H, LRP1B mutation, APC mutation, CASP8 mutation, CREBBP mutation, PIK3CG mutation, NRAS mutation, ABL1 mutation, FGF23 mutation, HGF mutation, ATRX mutation, p53 mutation, ERBB2 mutation, ROS1 mutation, EP300 mutation, NRAS mutation, CDKN1A mutation, KDM6A mutation, FLT4 mutationCCND1 gain, CDKN2A deletion, FLCN mutation, TMB-H, LRP1B mutation, SMAD4 loss, SF3B1 mutation, FAT1 mutation, VHL mutation, NOTCH3 mutation, EPHA5 mutation, p53 mutation, ERCC2 mutationCCND1 gain, EGFR amplification, SMO mutation, ATR mutation, FAT1 loss, NTRK1 mutation, KMT2D mutation, p53 mutation, NOTCH3 mutationCDKN2A deletion, AXIN2 amplification, SMAD3 loss, HRAS mutation, ATR mutation, NF1 mutation. IGF1R mutation, FLCN mutation, KEAP1 mutation, ASXL1 mutation, PMS2 mutationCCND1 gain, NF1 loss, LRP1B mutation, NSD1 mutation, KMT2D mutation, p53 mutation, EPHA2 mutationFAT1 loss, CCND3/FGF10 amplification, PIK3CA H1047R mutation, STK11 mutation, RICTOR/FLCN amplification, VEGF-A amplification , TSC2 mutation, EPHB1 mutation, MAP2K4 mutation, KDM5A mutation, PDGFRB mutation, SETD2 mutation, RPTOR mutation, APC mutation, DDR2 mutation, ATM mutation, MDM2 mutation, p53 mutation, CDK12 mutation, HRAS mutation, MYC mutation, CDK8 mutation, ARID1B lossOutcomesBest; like TCGA CL (HPV+) subtypeLike TCGA basal subtype, but responded to particular treatments eachBasalBasalLike TCGA mesen-chymal subtype (HPV+)Like TCGA CL(HPV-) subtype, different characters between these 3 cell linesCL(HPV-) subtypeCL(HPV-) subtypeWorse; like TCGA EMT subtype (HPV-)Potential treatmentsAll sensitive maybe; Hedgehog inhibitor , HGF/c-MET inhibitor, and I/O could be tried(1) Taxane, cisplatin, PLKi (2) mTORi (3) IGF1Ri, METi, PDGFRi, FGFRi (4) Epigenetics (5) I/O(1) Taxane, cisplatin, 5-FU, PLKi (2) CDK4/6i (3) I/O (4) DDRi (5) KRASi, METi, HERi (6) p53 reactivator and MDM2/Mcl-1 inhibitor(1) Taxane, cisplatin, 5-FU, PLKi (2) CDK4/6i (3) Mild EGFRi response (4) I/O (5) NRASi, FGFRi, HGF/c-METi/ROS1i/HERi (6) p53 reactivator/DDRi/Epigenetics(1) Cisplatin, 5-FU (2) EGFRi and VEGFR2i (3) Weak to PLKi & CDK4/6i (4) I/O (5) mTORi (6) Ephi (7) DDR/Epigenetics (8) p53 reactivator (9) HIFi(1) Taxane and PLKi (2) EGFRi, VEGFR2i, CDK4/6i (3) NTRKi (4) Hedgehog inhibitor (5) DDRi, epigenetics,& p53 reactivator(1) Taxane &5-FU (2) EGFRi (3) HRASi (4) DDRi/Epigenetics (5) I/O (6) IGF1Ri (7) mTORi(1) EGFRi (2) CDK4/6i (3) I/O (4) Epigenetics (5) Ephi (6) p53 reactivator(1) CDK4/6 inhibitor (2) Multi-targeted VEGFR TKI (3) PI3K/AKT/mTOR inhibitor (4) ICIs combination (5) p53 reactivator/ DDR interventions/Epigenetics (6) Dasatinib, HRASi, EphB1/B4 interventions Further NGS analysis may translate these HNSCC cell lines to represent TCGA subtypes for the reference of future drug combinations, esp... Further NGS analysis may translate these HNSCC cell lines to represent TCGA subtypes for the reference of future drug combinations, esp. immunotherapy, basic/translational research, and animal models. LRP1B will be a potential ICIs efficacy biomarker in HNSCC.
Preclinical • Tumor mutational burden • BRCA Biomarker • PD(L)-1 Biomarker • IO biomarker
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HER-2 (Human epidermal growth factor receptor 2) • KRAS (KRAS proto-oncogene GTPase) • PIK3CA (Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha) • TMB (Tumor Mutational Burden) • ABL1 (ABL proto-oncogene 1) • NRAS (Neuroblastoma RAS viral oncogene homolog) • BRCA1 (Breast cancer 1, early onset) • BRCA2 (Breast cancer 2, early onset) • MYC (V-myc avian myelocytomatosis viral oncogene homolog) • ROS1 (Proto-Oncogene Tyrosine-Protein Kinase ROS) • NTRK1 (Neurotrophic tyrosine kinase, receptor, type 1) • ATM (ATM serine/threonine kinase) • STK11 (Serine/threonine kinase 11) • HRAS (Harvey rat sarcoma viral oncogene homolog) • CDKN2A (Cyclin Dependent Kinase Inhibitor 2A) • DNMT3A (DNA methyltransferase 1) • PDGFRA (Platelet Derived Growth Factor Receptor Alpha) • NOTCH1 (Notch 1) • NF1 (Neurofibromin 1) • KEAP1 (Kelch Like ECH Associated Protein 1) • POLE (DNA Polymerase Epsilon) • AXL (AXL Receptor Tyrosine Kinase) • SF3B1 (Splicing Factor 3b Subunit 1) • ASXL1 (ASXL Transcriptional Regulator 1) • CCND1 (Cyclin D1) • MDM2 (E3 ubiquitin protein ligase) • PALB2 (Partner and localizer of BRCA2) • CXCR4 (Chemokine (C-X-C motif) receptor 4) • PDGFRB (Platelet Derived Growth Factor Receptor Beta) • KMT2D (Lysine Methyltransferase 2D) • LRP1B (LDL Receptor Related Protein 1B) • FGFR4 (Fibroblast growth factor receptor 4) • MSH2 (MutS Homolog 2) • RNF43 (Ring Finger Protein 43) • CDK12 (Cyclin dependent kinase 12) • SMAD4 (SMAD family member 4) • IKZF1 (IKAROS Family Zinc Finger 1) • ERCC2 (Excision repair cross-complementation group 2) • PMS2 (PMS1 protein homolog 2) • VHL (von Hippel-Lindau tumor suppressor) • APC (APC Regulator Of WNT Signaling Pathway) • ATRX (ATRX Chromatin Remodeler) • TSC2 (TSC complex subunit 2) • IGF1R (Insulin-like growth factor 1 receptor) • NOTCH2 (Notch 2) • CREBBP (CREB binding protein) • RUNX1T1 (RUNX1 Partner Transcriptional Co-Repressor 1) • SMO (Smoothened Frizzled Class Receptor) • BCOR (BCL6 Corepressor) • ERBB4 (erb-b2 receptor tyrosine kinase 4) • FAT1 (FAT atypical cadherin 1) • KDM6A (Lysine Demethylase 6A) • SETD2 (SET Domain Containing 2, Histone Lysine Methyltransferase) • PIK3CG (Phosphatidylinositol-4,5-Bisphosphate 3-Kinase Catalytic Subunit Gamma) • NOTCH3 (Notch Receptor 3) • ARID1B (AT-Rich Interaction Domain 1B) • EP300 (E1A binding protein p300) • FLT4 (Fms-related tyrosine kinase 4) • IGF1 (Insulin-like growth factor 1) • NSD1 (Nuclear Receptor Binding SET Domain Protein 1) • RAD51D (RAD51 paralog D) • RICTOR (RPTOR Independent Companion Of MTOR Complex 2) • EPHA2 (EPH receptor A2) • BMI1 (BMI1 proto-oncogene, polycomb ring finger) • CASP8 (Caspase 8) • CCND3 (Cyclin D3) • BRD4 (Bromodomain Containing 4) • DDR2 (Discoidin domain receptor 2) • FLCN (Folliculin) • KDM5A (Lysine Demethylase 5A) • CDKN1A (Cyclin-dependent kinase inhibitor 1A) • DPYD (Dihydropyrimidine Dehydrogenase) • EPHA5 (EPH Receptor A5) • EPHB1 (EPH Receptor B1) • FGF10 (Fibroblast Growth Factor 10) • FGF23 (Fibroblast Growth Factor 23) • MAP2K4 (Mitogen-Activated Protein Kinase Kinase 4) • SMAD3 (SMAD Family Member 3)
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TP53 mutation • KRAS mutation • BRCA2 mutation • BRCA1 mutation • EGFR mutation • TMB-H • NRAS mutation • PIK3CA mutation • EGFR amplification • ATM mutation • PIK3CA H1047R • STK11 mutation • DNMT3A mutation • PALB2 mutation • POLE mutation • NF1 mutation • NOTCH1 mutation • ASXL1 mutation • CDKN2A deletion • BCL2 overexpression • KEAP1 mutation • SF3B1 mutation • CDKN2A mutation • KMT2D mutation • CDK12 mutation • LRP1B mutation • VHL mutation • PIK3CA amplification • HRAS mutation • APC mutation • ATR mutation • ATRX mutation • CCND1 amplification • PDGFRA mutation • CREBBP mutation • MSH2 mutation • RNF43 mutation • ROS1 mutation • SMAD4 mutation • BCOR mutation • FGFR4 mutation • KDM6A mutation • RAD51D mutation • TSC2 mutation • FAT1 mutation • MYC mutation • ARID1B mutation • NOTCH3 mutation • PMS2 mutation • SMO mutation • IKZF1 mutation • MDM2 mutation • NTRK1 mutation • EP300 mutation • ERBB4 mutation • NSD1 mutation • PIK3CA H1047R + PIK3C2B amplification • PIK3CG mutation • SETD2 mutation • EPHA5 mutation • EPHB1 mutation • ERCC2 mutation • FGF10 amplification • FGF23 mutation • FLCN mutation • HGF mutation • PDGFRB mutation • RAD51 mutation
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cisplatin • Gilotrif (afatinib) • dasatinib • 5-fluorouracil • Halaven (eribulin mesylate)
over1year
Risk prediction in early childhood SHH medulloblastoma treated with radiation-avoiding chemotherapy: Evidence for more than two subgroups. (PubMed, Neuro Oncol)
These data suggest further heterogeneity within early childhood SHH-DMB/MBEN: SHH-2 splits into a very low-risk group SHH-2a enriched for MBEN histology and SMO mutations, and SHH-2b comprising older DMB patients with higher risk of relapse.
Journal
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SMO (Smoothened Frizzled Class Receptor) • SHH (Sonic Hedgehog Signaling Molecule)
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SMO mutation • SHH mutation
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methotrexate
over1year
Utility of GLI1 RNA in Situ Hybridization in Distinguishing Between Cutaneous Basal Cell Carcinoma and Other Epithelial Neoplasms (USCAP 2023)
With careful evaluation, GLI1 RNA CISH is highly sensitive (100%) and specific (97%) in distinguishing between BCC and non-follicular epithelial tumors. The specificity is lower (38%) among basaloid follicular tumors, likely reflecting the importance of Hh pathway signaling in the normal development of hair follicles. Overall, detection of GLI1 RNA by CISH may be a useful tool for more precise classification of difficult basaloid neoplasms, particularly in the setting of small biopsy specimens, metaplastic differentiation, or metastatic disease.
SMO (Smoothened Frizzled Class Receptor) • GLI1 (GLI Family Zinc Finger 1)
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SMO mutation • GLI1 expression
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RNAscope™ ISH Probe High Risk HPV
over1year
My Pathway: A Study Evaluating Herceptin/Perjeta, Tarceva, Zelboraf/Cotellic, Erivedge, Alecensa, and Tecentriq Treatment Targeted Against Certain Molecular Alterations in Participants With Advanced Solid Tumors (clinicaltrials.gov)
P2a, N=670, Active, not recruiting, Genentech, Inc. | Trial completion date: Jan 2023 --> Sep 2023 | Trial primary completion date: Jan 2023 --> Sep 2023
Trial completion date • Trial primary completion date • Tumor mutational burden • Metastases
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EGFR (Epidermal growth factor receptor) • HER-2 (Human epidermal growth factor receptor 2) • BRAF (B-raf proto-oncogene) • ALK (Anaplastic lymphoma kinase) • TMB (Tumor Mutational Burden) • PTCH1 (Patched 1) • SMO (Smoothened Frizzled Class Receptor)
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EGFR mutation • HER-2 overexpression • BRAF mutation • HER-2 amplification • BRAF V600 • ALK rearrangement • ALK mutation • SMO mutation
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Herceptin (trastuzumab) • Tecentriq (atezolizumab) • erlotinib • Zelboraf (vemurafenib) • Alecensa (alectinib) • Perjeta (pertuzumab) • Cotellic (cobimetinib) • Erivedge (vismodegib)
over1year
Analysis of residual disease in periocular basal cell carcinoma following hedgehog pathway inhibition: Follow up to the VISORB trial. (PubMed, PLoS One)
Our recent clinical trial highlighted the utility of vismodegib for preserving visual organs in opBCC patients: 67% of patients displayed a complete response histologically...In the age of targeted therapies, linking molecular genetic analysis to prospective clinical trials may be necessary to provide mechanistic understanding of clinical outcomes. Trial Registration: ClinicalTrials.gov Identifier: NCT02436408.
Journal
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SMO (Smoothened Frizzled Class Receptor) • GLI1 (GLI Family Zinc Finger 1)
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SMO mutation • SMO W535L
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Erivedge (vismodegib)
over1year
The PROTAC selectively degrading Bcl-x represents a novel Hedgehog pathway inhibitor with capacity of combating resistance to Smoothened inhibitors while sparing bone growth. (PubMed, Theranostics)
Moreover, treatment with SIAIS361034 results in no impairment on the bone growth of young mice, accompanying no alteration of the expression of Bcl-x and Gli1 proteins. Our findings demonstrate that selectively targeting Bcl-x by PROTAC is a promising strategy for combating resistance to Smo inhibitors without causing on-target drug toxicities of bone growth.
Journal • IO biomarker
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BCL2 (B-cell CLL/lymphoma 2) • BCL2L1 (BCL2-like 1) • CRBN (Cereblon) • SMO (Smoothened Frizzled Class Receptor) • GLI1 (GLI Family Zinc Finger 1) • GLI2 (GLI Family Zinc Finger 2)
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SMO mutation • CRBN expression
over1year
SMO mutation predicts the effect of immune checkpoint inhibitor: From NSCLC to multiple cancers. (PubMed, Front Immunol)
Upon further exploration, the SMO mutation status was found to be related to a higher TMB, more neoantigen load, more DNA damage repair (DDR) mutations, higher microsatellite instability (MSI) score, and higher CD8 T-cell infiltration. The SMO mutation status is an independent prognostic factor that can be used to predict better clinical outcomes of ICI treatment across multiple cancer types.
Journal • Checkpoint inhibition • Tumor Mutational Burden • IO biomarker
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TMB (Tumor Mutational Burden) • MSI (Microsatellite instability) • CD8 (cluster of differentiation 8) • SMO (Smoothened Frizzled Class Receptor)
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TMB-H • SMO mutation
over1year
Towards Precision Oncology: The Role of Smoothened and Its Variants in Cancer. (PubMed, J Pers Med)
Drug resistance is a common challenge in cancer therapies targeting Smo, and data analysis shows that healthy individuals also harbour resistance mutations. Based on the importance of Smo in cancer progression and the high incidence of resistance towards Smo inhibitors, this review suggests that detection of Smo variants through tumour profiling could lead to increased precision and improved outcomes of anti-cancer treatments.
Review • Journal
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SMO (Smoothened Frizzled Class Receptor)
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SMO mutation
over1year
Protein arginine methyltransferase 5 regulates SHH-subgroup medulloblastoma progression. (PubMed, Neurooncol Adv)
PRMT5 is a requisite driver of SHH-MB that regulates tumor progression. A clinically relevant PRMT5 inhibitor represents a promising candidate drug for SHH-MB therapy.
Journal
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SMO (Smoothened Frizzled Class Receptor) • GLI1 (GLI Family Zinc Finger 1) • PRMT5 (Protein Arginine Methyltransferase 5) • SHH (Sonic Hedgehog Signaling Molecule)
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SMO mutation
over1year
Metastatic basal cell carcinoma to the bone: A case of bone metastasis in uncommon sites. (PubMed, Dermatol Reports)
We report the rare case of a man with multiple bony metastasis, with a resistance to vismodegib, and we evaluated all manuscripts in literature reporting bone metastasis. Moreover, we review all the manuscripts in literature reporting bone metastasis, and we summarize the main therapeutic strategies, and the further perspectives.
Journal • IO biomarker
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SMO (Smoothened Frizzled Class Receptor)
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SMO mutation
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Erivedge (vismodegib)
over1year
ABT-737 suppresses aberrant Hedgehog pathway and overcomes resistance to smoothened antagonists by blocking Gli. (PubMed, Med Oncol)
More importantly, ABT-737 also delayed the growth of drug-refractory Hh-dependent MB xenografts derived from genetically engineered mouse model in vivo. These findings identify ABT-737 as a therapeutical substance for cancers with excessive Hh signaling activity, especially for those with primary or acquired resistance to Smo inhibitors in clinic.
Journal
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SMO (Smoothened Frizzled Class Receptor)
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SMO mutation
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ABT-737
almost2years
A druggable UHRF1/DNMT1/GLI complex regulates Sonic hedgehog dependent tumor growth. (PubMed, Mol Cancer Res)
Importantly, we show that UHRF1/DNMT1/GLI complex stability is targeted by a repurposed FDA-approved therapy, with a subsequent reduction in the growth of SHH-dependent MB ex vivo and in vivo. Implications: This work describes a novel, druggable UHRF1/DNMT1/GLI complex that regulates SHH-dependent tumor growth, and highlights an FDA-approved drug capable of disrupting this complex to attenuate tumor growth.
Journal
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SMO (Smoothened Frizzled Class Receptor) • DNMT1 (DNA methyltransferase 1) • UHRF1 (Ubiquitin Like With PHD And Ring Finger Domains 1)
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SMO mutation
almost2years
A phase II study evaluating the safety and efficacy of ENV-101 (taladegib) in patients with advanced solid tumors harboring PTCH1 loss of function mutations (ESMO 2022)
Stage 1 (phase IIa) of this protocol will enroll a total of 44 patients randomized between two dose levels. In the presence of acceptable efficacy, stage 2 (phase IIb) of this protocol will expand enrollment using a single dose level.
Clinical • P2 data
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PTCH1 (Patched 1) • SMO (Smoothened Frizzled Class Receptor)
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PTCH1 mutation • SMO mutation
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taladegib (ENV 101)
almost2years
Periocular Pigmented Basal Cell Carcinomas: Clinicopathologic Features and Mutational Profile. (PubMed, Ophthalmic Plast Reconstr Surg)
In this large cohort of a relatively uncommon variant of BCC, the clinicopathological features and tumor behavior of PBCC was similar to periocular non-PBCC. The somatic mutation spectrum of PBCC resembles that reported in nonperiocular cutaneous BCC with novel drivers identified. We identified several potential actionable mutations that could be targeted with molecular therapy.
Journal
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TERT (Telomerase Reverse Transcriptase) • PTCH1 (Patched 1) • CREBBP (CREB binding protein) • SMO (Smoothened Frizzled Class Receptor) • FANCD2 (FA Complementation Group D2)
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PTCH1 mutation • CREBBP mutation • TERT mutation • SMO mutation