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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.
Small-Molecule Targeted Therapies
Published in David E. Thurston, Ilona Pysz, Chemistry and Pharmacology of Anticancer Drugs, 2021
Aberrant activation of the Hedgehog pathway has been implicated in the genesis and progression of a number of cancer types including basal cell carcinoma and medulloblastoma, making it a potential target for therapeutic intervention. Cyclopamine (11-deoxojervine), a steroidal alkaloid, is a naturally occurring SMO antagonist and is a teratogen isolated from the corn lily (Veratrum californicum) that causes fatal birth defects. It prevents the embryonic brain from separating into two lobes which causes the development of a single eye (cyclopia), a phenomenon first observed in sheep in the 1950s due to grazing on the corn lily.
Steroidal Alkaloids
Published in Amritpal Singh Saroya, Contemporary Phytomedicines, 2017
Cycloposine (Fig. 21.19) is a polar, glycosidic alkaloid, isolated from Veratrum californicum (Durand) (Keeler 1968). Cycloposine is the glycoside of cyclopamine (Riet-Correa 2011). Jervine and cyclopamine are also identified in V. californicum.
Vascular and extracellular matrix remodeling by physical approaches to improve drug delivery at the tumor site
Published in Expert Opinion on Drug Delivery, 2020
Sara Gouarderes, Anne-Françoise Mingotaud, Patricia Vicendo, Laure Gibot
Hyperthermia is a multi-action therapeutic modality whose positive effects are the vascular permeability increase, moderate blood flow augmentation, remodeling of ECM, partly through disruption of collagen fibrils network. However, the necessity of limiting the temperature below 43°C to avoid severe irreversible damages as hemorrhage and stasis has impeded the development of hyperthermia as a standalone technique. Since the all-above-mentioned benefits prime the tumor environment, novel approach in contemporary oncology practice is to combine HT with other tumor care as radiotherapy or chemotherapy for a subsequent and improved tumor eradication [88]. Examining the recent literature proves that this is the current path followed. The strategy aims to destabilize ECM in a first step followed by adequate treatment to promote cancer cell death. In such protocols, hyperthermia can either be used as the first or the second step. In a study reported by Pang et al., the anti-cancer drug cyclopamine was administered to mice bearing pancreatic ductal adenocarcinoma for 3 weeks before injecting gold nanorods [103]. Cyclopamine led to ECM destructuration, improving the outcomes of the subsequent photothermal therapy.
An evaluation of glasdegib for the treatment of acute myelogenous leukemia
Published in Expert Opinion on Pharmacotherapy, 2020
Many Hh-signaling pathway inhibitors have been identified. These inhibitors exert their action at different point levels of the pathway. While the majority of them target SMO, mutations in SMO and PTCH/SMO-independent activation of the Hh pathway remain unaffected by these inhibitors. Only inhibitors acting downstream of these proteins are, therefore, of particular interest. Binding of SMO antagonists can prevent the downstream activation of the Hh-signaling cascade [53]. In this setting, cyclopamine was the first described compound. However, its characteristics including short half-life, low bioavailability, and chemical instability did not allow to retain it as a potential therapeutic agent [54]. Several other SMO antagonists with a higher potency were then developed, including sonidegib [55] and vismodegib [56]. Both agents displayed a similar safety profile but vismodegib revealed a lower therapeutic efficacy. However, those inhibitors are prone to develop drug resistances, especially by mutations arising in the drug-binding pocket. The main interest was, therefore, placed on SMO antagonists, such as glasdegib, that do not use the same binding site.
Cyclopamine treatment disrupts extracellular matrix and alleviates solid stress to improve nanomedicine delivery for pancreatic cancer
Published in Journal of Drug Targeting, 2018
Bo Zhang, Honglan Wang, Ting Jiang, Kai Jin, Zimiao Luo, Wei Shi, Heng Mei, Huafang Wang, Yu Hu, Zhiqing Pang, Xinguo Jiang
The excessive ECM in PDA can be regulated by several key signalling pathways including the Hedgehog (Hh) signalling pathway. The abnormal activation of Hh signalling pathway produces excess ECM [13,14]. More specifically, binding of tumour cell-derived Hh ligands to the patched 1 receptor in tumour stromal cells relieves inhibitor of the 12-transmembrane protein Smoothened (SMO), thereby activating the glioma-associated oncogene family zinc finger-1 (GLT-1) of transcription factor, leading to the expression of downstream genes and synthesis of abundant ECM proteins [15–17]. Cyclopamine is a kind of natural steroidal alkaloid, which can act on the SMO receptor to inhibit the Hh signalling pathway [16]. Thus, cyclopamine can be used to inhibit Hh signalling pathway to disrupt tumour ECM and alleviate solid stress in PDA.