Phase I study of oral sonidegib (LDE225) in pediatric brain and solid tumors and a phase II study in children and adults with relapsed medulloblastoma

Kieran, Mark W.; Chisholm, Julia; Casanova, Michela; Brandes, Alba Ariela; Aerts, Isabelle; Bouffet, Éric; Bailey, Simon; Leary, Sarah; MacDonald, Tobey J.; Méchinaud, Françoise; Cohen, Kenneth J.; Riccardi, Riccardo; Mason, Warren P.; Hargrave, Darren; Kalambakas, Stacey; Deshpande, Priya; Tian, Feng; Hurh, Eunju; Geoerger, Birgit

doi:10.1093/neuonc/nox109

Cited by 142 publications

(137 citation statements)

References 33 publications

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“…600 In a phase I study of a 3 + 3 dose escalation to treat small-cell lung cancer patients, sonidegib combined with cisplatin and etoposide sustained PFS in patients with Sox2 amplification. 224 These combinations in a phase II trial for patients with recurrent medulloblastoma resulted in a complete or partial response in 50% of patients 612 and have been used for other cancer treatments in phase I/II clinical trials, such as NCT02111187 for prostate cancer, NCT02027376 for breast cancer, and NCT02195973 for recurrent ovarian cancer.…”

Section: Agents Targeting Csc-associated Signaling Pathways In Clinicmentioning

confidence: 99%

Targeting cancer stem cell pathways for cancer therapy

Yang

Shi

Zhao

et al. 2020

Sig Transduct Target Ther

1,323

998

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Since cancer stem cells (CSCs) were first identified in leukemia in 1994, they have been considered promising therapeutic targets for cancer therapy. These cells have self-renewal capacity and differentiation potential and contribute to multiple tumor malignancies, such as recurrence, metastasis, heterogeneity, multidrug resistance, and radiation resistance. The biological activities of CSCs are regulated by several pluripotent transcription factors, such as OCT4, Sox2, Nanog, KLF4, and MYC. In addition, many intracellular signaling pathways, such as Wnt, NF-κB (nuclear factor-κB), Notch, Hedgehog, JAK-STAT (Janus kinase/signal transducers and activators of transcription), PI3K/AKT/mTOR (phosphoinositide 3-kinase/AKT/mammalian target of rapamycin), TGF (transforming growth factor)/SMAD, and PPAR (peroxisome proliferator-activated receptor), as well as extracellular factors, such as vascular niches, hypoxia, tumor-associated macrophages, cancer-associated fibroblasts, cancer-associated mesenchymal stem cells, extracellular matrix, and exosomes, have been shown to be very important regulators of CSCs. Molecules, vaccines, antibodies, and CAR-T (chimeric antigen receptor T cell) cells have been developed to specifically target CSCs, and some of these factors are already undergoing clinical trials. This review summarizes the characterization and identification of CSCs, depicts major factors and pathways that regulate CSC development, and discusses potential targeted therapy for CSCs.Signal Transduction and Targeted Therapy (2020) 5:8; https://doi.

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Section: Agents Targeting Csc-associated Signaling Pathways In Clinicmentioning

confidence: 99%

Targeting cancer stem cell pathways for cancer therapy

Yang

Shi

Zhao

et al. 2020

Sig Transduct Target Ther

1,323

998

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“…In a trial of adult and pediatric patients with medulloblastoma (and other tumors of the central nervous system [CNS]; NCT01125800; Table 2), a subset of patients without HH-driven tumors (determined by upregulation of GLI1, SHROOM2, sphingosine kinase-1, and PDLIM3, and the downregulation of orthodenticle homeobox 2) failed to respond to sonidegib. In total, 50% (5/10) of patients with HH-driven tumors had complete or partial responses to sonidegib; however, the prepubertal patients showed signs of premature growth plate closure [57]. In another trial of 31 patients with recurrent medulloblastoma, vismodegib was found to have activity only if the medulloblastoma was HH-driven (NCT00939484; Table 2) [58].…”

Section: Medulloblastomamentioning

confidence: 99%

Hedgehog signaling inhibitors in solid and hematological cancers

Cortes

Gutzmer

Kieran

et al. 2019

Cancer Treatment Reviews

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Background: The hedgehog signaling pathway is normally tightly regulated. Mutations in hedgehog pathway components may lead to abnormal activation. Aberrantly activated hedgehog signaling plays a major role in the development of solid and hematological cancer. In recent years, inhibitors have been developed that attenuate hedgehog signaling; 2 have been approved for use in basal cell carcinoma (BCC), while others are under development or in clinical trials. The aim of this review is to provide an overview of known hedgehog inhibitors (HHIs) and their potential for the treatment of hematological cancers and solid tumors beyond BCC. Design: Published literature was searched to identify articles relating to HHIs in noncutaneous cancer. Both preclinical and clinical research articles were included. In addition, relevant clinical trial results were identified from www.clinicaltrials.gov. Information on the pharmacology of HHIs is also included. Results: HHIs show activity in a variety of solid and hematological cancers. In preclinical studies, HHIs demonstrated efficacy in pancreatic cancer, rhabdomyosarcoma, breast cancer, and acute myeloid leukemia (AML). In clinical studies, HHIs showed activity in medulloblastoma, as well as prostate, pancreatic, and hematological cancers. Current clinical trials testing the efficacy of HHIs are underway for prostate, pancreatic, and breast cancers, as well as multiple myeloma and AML. Conclusions: As clinical trial results become available, it will be possible to discern which additional tumor types are suited to HHI mono-or combination therapy with other anticancer agents. The latter strategy may be useful for delaying or overcoming drug resistance. Dysregulated hedgehog signaling and the development of cancer The HH signaling pathway is normally tightly regulated; however, dysregulation due to mutations in Smo or Ptch1 plays a major role in

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“…SHH pathway inhibitors are attractive options for adult SHH medulloblastoma, as the toxicity of these compounds on growth plates is not a concern, and adult SHH medulloblastomas frequently harbor mutations upstream . Vismodegib and sonidegib have shown considerable efficacy in the relapsed setting and may be an option for upfront combination therapy . Future clinical trials need to address both the issue of addition of SMO inhibitors as well as the role and toxicity of adjuvant chemotherapy in this population.…”

Section: Epidemiologymentioning

confidence: 99%

“…96 Vismodegib and sonidegib have shown considerable efficacy in the relapsed setting and may be an option for upfront combination therapy. 97,98 Future clinical trials need to address both the issue of addition of SMO inhibitors as well as the role and toxicity of adjuvant chemotherapy in this population. Moreover, longer follow-up is mandatory for adult medulloblastoma studies due to the high frequency of late relapses.…”

Section: Medulloblastomamentioning

confidence: 99%

Adolescents and young adults with brain tumors in the context of molecular advances in neuro‐oncology

Zápotocký

Ramaswamy

Lassaletta

et al. 2017

Pediatric Blood & Cancer

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Adolescents and young adults (AYA) comprise a specific group of oncology patients with a distinct biological and epidemiological spectrum of central nervous system neoplasms. It has been well documented that they differ clinically, especially in relation to prognosis and chemotherapy tolerance; however, the underlying reasons for this are unclear. Recent advances in the genomics of both childhood and adult brain tumors have provided new explanations and insights into the previously described age-dependent heterogeneity. Herein, we summarize the current state of the AYA population in neuro-oncology, specifically how biological advances can help personalize therapy for this unique group of patients.

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Phase I study of oral sonidegib (LDE225) in pediatric brain and solid tumors and a phase II study in children and adults with relapsed medulloblastoma

Abstract: Sonidegib was well tolerated and the RP2D in pediatric patients was 680 mg/m2 once daily. Five of the 10 MB patients with activated Hh pathway demonstrated complete or partial responses.

Cited by 142 publications

References 33 publications

Targeting cancer stem cell pathways for cancer therapy

Targeting cancer stem cell pathways for cancer therapy

Hedgehog signaling inhibitors in solid and hematological cancers

Adolescents and young adults with brain tumors in the context of molecular advances in neuro‐oncology

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