Ligand-dependent Hedgehog pathway activation in Rhabdomyosarcoma: the oncogenic role of the ligands

Almazán-Moga, Ana; Zarzosa, Patricia; Molist, Carla; Velasco, Pablo; Pyczek, Joanna; Simon-Keller, Katja; Giralt, Irina; Vidal, Isaac; Navarro, Natalia; Segura, Miguel F.; Soriano, Aroa; Navarro, Samuel; Tirado, Óscar M.; Ferreres, Joan Carles; Santamaría, Anna; Rota, Rossella; Hahn, Heidi; Toledo, Josep Sánchez de; Roma, Josep; Gallego, Soledad

doi:10.1038/bjc.2017.305

Cited by 24 publications

(22 citation statements)

References 44 publications

(54 reference statements)

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“…Ptch1 gene mutations were detected in trichoepitheliomas [116], esophageal carcinomas [117], and bladder carcinomas [118], whereas mutations of Ptch1 and Sufu have been found in a rare muscle tumor, rhabdomyosarcoma [119].…”

Section: Type I -Ligand-independent Signalingmentioning

confidence: 99%

The role of the Hedgehog signaling pathway in cancer: A comprehensive review

Škoda

Simovic

Karin

et al. 2018

Bosn J of Basic Med Sci

543

414

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The Hedgehog (Hh) signaling pathway was first identified in the common fruit fly. It is a highly conserved evolutionary pathway of signal transmission from the cell membrane to the nucleus. The Hh signaling pathway plays an important role in the embryonic development. It exerts its biological effects through a signaling cascade that culminates in a change of balance between activator and repressor forms of glioma-associated oncogene (Gli) transcription factors. The components of the Hh signaling pathway involved in the signaling transfer to the Gli transcription factors include Hedgehog ligands (Sonic Hh [SHh], Indian Hh [IHh], and Desert Hh [DHh]), Patched receptor (Ptch1, Ptch2), Smoothened receptor (Smo), Suppressor of fused homolog (Sufu), kinesin protein Kif7, protein kinase A (PKA), and cyclic adenosine monophosphate (cAMP). The activator form of Gli travels to the nucleus and stimulates the transcription of the target genes by binding to their promoters. The main target genes of the Hh signaling pathway are PTCH1, PTCH2, and GLI1. Deregulation of the Hh signaling pathway is associated with developmental anomalies and cancer, including Gorlin syndrome, and sporadic cancers, such as basal cell carcinoma, medulloblastoma, pancreatic, breast, colon, ovarian, and small-cell lung carcinomas. The aberrant activation of the Hh signaling pathway is caused by mutations in the related genes (ligand-independent signaling) or by the excessive expression of the Hh signaling molecules (ligand-dependent signaling - autocrine or paracrine). Several Hh signaling pathway inhibitors, such as vismodegib and sonidegib, have been developed for cancer treatment. These drugs are regarded as promising cancer therapies, especially for patients with refractory/advanced cancers.

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Section: Type I -Ligand-independent Signalingmentioning

confidence: 99%

The role of the Hedgehog signaling pathway in cancer: A comprehensive review

Škoda

Simovic

Karin

et al. 2018

Bosn J of Basic Med Sci

543

414

View full text Add to dashboard Cite

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“…Although HH activation is thought to play a role in its development, it is unclear how HH becomes activated in this disease. A series of studies examining the expression of HH ligands in specimens from children with rhabdomyosarcoma and in animal models showed that autocrine ligand-dependent activation of HH may drive the disease, therefore, the HH pathway may be a useful target for therapy [48].…”

Section: Rhabdomyosarcomamentioning

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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“…Hh signaling can be constitutively active in rhabdomyosarcoma and the GLI1/2 inhibitor GANT-61 significantly reduced cell growth in rhabdomyosarcoma xenograft models, although no complete responses (CR) were achieved. Combined treatment of GANT-61 with temsirolimus, rapamycin, or vincristine increased these effects, with a preference for temsirolimus over rapamycin (48,49). Similar effects were observed in primary rhabdomyosarcoma cells, in which multiple PI3K and/or mTOR inhibitors combined with GANT-61 led to enhanced apoptosis.…”

Section: Hedgehog Signalingmentioning

confidence: 60%

Targeted Therapy–based Combination Treatment in Rhabdomyosarcoma

Erp¹,

Graaf

Fleuren

2018

Molecular Cancer Therapeutics

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Targeted therapies have revolutionized cancer treatment; however, progress lags behind in alveolar (ARMS) and embryonal rhabdomyosarcoma (ERMS), a soft-tissue sarcoma mainly occurring at pediatric and young adult age. Insulin-like growth factor 1 receptor (IGF1R)-directed targeted therapy is one of the few single-agent treatments with clinical activity in these diseases. However, clinical effects only occur in a small subset of patients and are often of short duration due to treatment resistance. Rational selection of combination treatments of either multiple targeted therapies or targeted therapies with chemotherapy could hypothetically circumvent treatment resistance mechanisms and enhance clinical efficacy. Simultaneous targeting of distinct mechanisms might be of particular interest in this regard, as this affects multiple hallmarks of cancer at once. To determine the most promising and clinically relevant targeted therapy-based combination treatments for ARMS and ERMS, we provide an extensive overview of preclinical and (early) clinical data concerning a variety of targeted therapy-based combination treatments. We concentrated on the most common classes of targeted therapies investigated in rhabdomyosarcoma to date, including those directed against receptor tyrosine kinases and associated downstream signaling pathways, the Hedgehog signaling pathway, apoptosis pathway, DNA damage response, cell-cycle regulators, oncogenic fusion proteins, and epigenetic modifiers. .

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Ligand-dependent Hedgehog pathway activation in Rhabdomyosarcoma: the oncogenic role of the ligands

Cited by 24 publications

References 44 publications

The role of the Hedgehog signaling pathway in cancer: A comprehensive review

The role of the Hedgehog signaling pathway in cancer: A comprehensive review

Hedgehog signaling inhibitors in solid and hematological cancers

Targeted Therapy–based Combination Treatment in Rhabdomyosarcoma

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