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Targeting Subgroup-specific Cancer Epitopes for Effective Treatment of Pediatric Medulloblastoma
Published in Surinder K. Batra, Moorthy P. Ponnusamy, Gene Regulation and Therapeutics for Cancer, 2021
Sidharth Mahapatra, Naveenkumar Perumall
Several natural and synthetic antagonists for SMO and GLI have been studied in medulloblastoma. The steroidal alkaloid cyclopamine and its derivatives have been the best studied due to their ability to selectively bind SMO and exert inhibitory action on the SHH pathway [46, 47]. Cyclopamine treatment, for example, inhibits proliferation and induces neuronal differentiation with subsequent loss of neuronal stem cell-like character both in vitro and in murine tumor allografts [48]. Cyclopamine derivatives with superior potency and bioavailability that were later developed include vismodegib (GDC-0449), sodinegib (LDE-225), saridegib (IPI-926), and PF-5274857. All have shown efficacy in tumor reduction and prolonged survival in a SHH-driven medulloblastoma mouse models [49-53]. Moreover, Phase I and II trials of vismodegib showed significant tumor regression in both pediatric and adult patients with refractory or relapsed SHH pathway-driven medulloblastoma [52, 54, 55]. Similarly, Novartis has recently completed a phase II trial on the safety and efficacy of oral sodinegib in patients with Hh-pathway activated, relapsed medulloblastoma (NCT01708174) [56]. Given the success of these inhibitors in both pre-clinical and clinical trials, SMO-inhibitors may mark the first successful signaling pathway-specific therapeutic option for patients with SHH subgroup MB.
An update on current and future treatment options for chondrosarcoma
Published in Expert Review of Anticancer Therapy, 2019
Iona J MacDonald, Chih-Yang Lin, Shu-Jui Kuo, Chen-Ming Su, Chih-Hsin Tang
The Hedgehog (Hh) signaling pathway is crucial for many developmental processes, including pattern formation, differentiation, proliferation and apoptosis [49]. CS is characterized by ligand-dependent activation of Hh signaling; upregulation of ligand Indian hedgehog (Ihh) is associated with increased activity of the transcription factor glioma-associated oncogene 1 (Gli1) homolog [50,51]. Inhibiting Gli1 suppressed cell proliferation and promoted cell cycle arrest, induced apoptosis by downregulating Bcl2 and Bcl-xl expression, and induced autophagy by altering mTOR phosphorylation [49]. Other researchers have reported that treating human CS SW1353 cells with the Hh pathway inhibitor-4 (HPI-4) significantly decreased cell proliferation, invasion and migration capacity [52], while in mice bearing primary human CS xenografts, Hh pathway inhibition with saridegib (IPI-926) downregulated expression of the Hh target genes GLI1 and PTCH1, and inhibited tumor growth [50]. However, the encouraging results of these studies did not effectively translate into a phase II clinical trial in which patients with metastatic or locally advanced, inoperable CS were treated with saridegib or placebo [53]. The trial was discontinued early after a planned futility analysis of data concluded that treatment with saridegib was not superior to placebo and that the trial would therefore fail to meet its primary endpoint of progression-free survival.
Therapeutic trends in pancreatic ductal adenocarcinoma (PDAC)
Published in Expert Opinion on Investigational Drugs, 2019
Sreenivasa Chandana, Hani M. Babiker, Daruka Mahadevan
Targeting the stroma in PDAC has been a challenge due to inadequate models representing human disease. In a mouse model, SMO inhibition had a similar effect to SHh deletion leading to a reduced stroma, but tumors grew faster with increased metastasis and mortality. It was concluded that Hh signaling associated stromal constituents may act to restrain, rather than promote tumor progression [179]. However, stroma genesis in human PDAC is complex and mouse modeling may not adequately address cell adhesion-mediated anoikis (e.g. CEACAM6) as a mechanism for reshaping the fibrotic DR [180,181] rather than disruption per se. In clinical trials, inhibitors targeting TGF-b, galunisertib (LY2157299), Hh signaling pathway, cyclopamine, saridegib, and vismodegib, and matrix metalloproteinase, marimastat all showed minimal efficacy and in some instances increased toxicities in early phase clinical trials [182–184]. Conversely, PEGPH20 when combined with gemcitabine plus nab-paclitaxel in a randomized phase II trial demonstrated improved PFS, although a SWOG trial demonstrated detrimental outcomes when combined with FOLFIRINOX [120,121]. Hence, perhaps targeting new stromal drivers such as CEACAM6 and the JAK-STAT pathway are potentially exciting new therapeutic opportunities.
Beyond JAK-2: potential targets for myeloproliferative neoplasm therapy
Published in Expert Review of Hematology, 2018
Patrick M. Harrington, Claire N. Harrison
A phase II study has reported on the use of the hedgehog inhibitor saridegib [IPI-296] in 14 patients with MF; however, results were disappointing with 9 patients discontinuing therapy due to a lack of response [71]. There was minimal improvement in symptoms but the majority of patients had a slight spleen response [<50% reduction] and one patient achieved transfusion independence for a period of 9 months. Recently reported results of a phase I study evaluating the hedgehog inhibitor vismodegib in combination with ruxolitinib showed no evidence of disease-modifying activity and the study was terminated [72]. However, combination therapy with sonidegib showed more promising results with 44.4% of MF patients achieving a >35% reduction in splenic volume at 24 weeks and evidence of some disease modifying activity with a mean reduction in JAK2 allele burden of −9% [range −56.5% to –7%] [73]. Combination therapy was well tolerated as indicated by 74% of patients remaining on treatment at data cut off.