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Small-Molecule Targeted Therapies
Published in David E. Thurston, Ilona Pysz, Chemistry and Pharmacology of Anticancer Drugs, 2021
The Hedgehog (Hh) signaling pathway (Figure 6.67) plays a crucial role in human embryogenesis but is largely inactive in adult tissues under normal conditions. Diseases associated with the malfunction of this pathway include basal cell carcinoma and a number of other cancer types. The unusual name of this signaling pathway derives from the original observation that loss of the secreted Hedgehog signaling protein in Drosophila embryos causes them to develop as spiny spheres similar in appearance to Hedgehogs. Diagram of the Hedgehog signaling pathway (Taken from Wikipedia, “Illustration of sonic Hedgehog signaling based on published research” by Fred the Oyster, under the Creative Commons Attribution-Share Alike 4.0 International license (https://creativecommons.org/licenses/by-sa/4.0/legalcode)).
Non-Melanoma Skin Cancer
Published in Pat Price, Karol Sikora, Treatment of Cancer, 2020
Irene De Francesco, Sean Whittaker, Stephen L. Morris
Vismodegib is an oral drug that targets the hedgehog signaling pathway, and it was used in the United Kingdom until 2017 to treat patients with Gorlin syndrome. It acts as a cyclopamine-competitive antagonist of the smoothened receptor (SMO), which causes the transcription factors GLI1 and GLI2 to remain inactive, which prevents the expression of tumor mediating genes within the hedgehog pathway. A Phase II, randomized, placebo-controlled trial in Gorlin syndrome patients with BCC concluded that vismodegib was significantly better than placebo at reducing new BCC lesions (p < 0.001) and at decreasing the sum of the longest diameter of existing lesions (p = 0.003).37 The main reported side effects are loss of taste, muscle cramps, hair loss, weight loss, and rarely, liver dysfunction. Vismodegib was initially licensed in the United Kingdom in August 2013, but it is no longer available via the cancer drug fund since 2017, when National Institute for Health and Care Excellence (NICE) guidelines concluded they could not recommend the drug because of the uncertainty in the evidence and because it was not cost effective.
Basal Cell Nevus Syndrome
Published in Dongyou Liu, Handbook of Tumor Syndromes, 2020
Priyanka Chhadva, Pete Setabutr
While congenital malformations in BCNS are due likely to alterations in the concentration of the PTCH1 protein in the extremely dosage-sensitive hedgehog signaling pathway, evidence points to the loss of the normal PTCH1 allele in medulloblastoma in young patients (2 years of age) who have BCNS. It is estimated that patients with BCNS have a 90% risk of developing multiple basal cell skin cancers; and children with BCNS have about 5% risk of developing medulloblastoma. In addition, inactivation of the normal allele appears to be associated with jaw cysts.
The signature based on seven genomic instability-related genes could predict the prognosis of acute myeloid leukemia patients
Published in Hematology, 2022
Lirong Nie, Yuming Zhang, Yuchan You, Changmei Lin, Qinghua Li, Wenbo Deng, Jingzhi Ma, Wenying Luo, Honghua He
For the 114 DEGs identified, GO and KEGG enrichment analyses revealed more functional information related to AML patients with differential TMB. The 114 DEGs were significantly enriched in 429 GO terms and 13 KEGG pathways. Of note, some of the pathways have been revealed to involve AML in different ways. For instance, Natural killer (NK) cell mediated cytotoxicity pathway, a recent study showed that there was probably a positive correlation between NK cytotoxicity and OS of 5-azacytidine-treated AML patients [30]. The roles of NK cell functions are increasingly studied regarding novel immunotherapy for AML patients [31]. Besides, another prognostic research in AML revealed that the mRNAs in lncRNA-mRNA networks identified might regulate prognosis partly via the Fc epsilon RI signaling pathway [32]. The combined inhibition of focal adhesion kinase was reported to partly enhance the antileukemia activity in AML patients [33], which might be indirectly correlated with the Focal adhesion pathway. Ras signaling pathway has been suggested to contribute to various cancers’ predisposition, including AML, and somatic Ras pathway alterations have been observed in many pediatric malignancies [34]. Hedgehog signaling pathway inhibition was evidenced to be a therapeutic target in AML patients recently [35]. In short, the DEGs might indirectly or partly affect the prognosis of AML patients with differential TMB through multiple pathways involving immune, predisposition, and progression.
Overview and recent advances in the targeting of medulloblastoma cancer stem cells
Published in Expert Review of Anticancer Therapy, 2021
Hedgehog signaling is also key to medulloblastoma development, and Wang et al. elucidated a relationship between CD133 and the Hedgehog signaling pathway [93]. CD133+ Daoy cells showed an increase in expression of Hh receptor genes Smo and Ptch1, while CD133- cells showed increased expression of Shh [93]. Hh antagonist KAAD-cyclopamine decreased the Gli1 and Ptch1 expression in CD133+ but not CD133- cells and also led to reduced CD133 protein expression. Math1 and MYCN (a Hh target gene [94]) expression are also higher in CD133+ cells [93]. Bmi1 is downstream of Hh and is a key regulator of hematopoietic, neural, and brain tumor stem cell populations [93]. Incubating Daoy cultures with Shh ligand increased Bmi1 expression through preferential binding of Gli1 at the Bmi1 promoter, and a positive feedback loop exists where downstream effectors of Bmi1 further activates Shh pathway genes. Bmi1 expression is also seen at higher levels in tumors from groups 3 and 4 medulloblastoma.
Beyond JAK-2: potential targets for myeloproliferative neoplasm therapy
Published in Expert Review of Hematology, 2018
Patrick M. Harrington, Claire N. Harrison
The hedgehog signaling pathway plays an important, but not fully understood, role in cell proliferation and survival during embryonic development, as well as in hematopoietic stem cell maintenance in adults. It has been shown in a mouse model that overactive hedgehog signaling due to loss of PTCH receptors results in the development of an MPN-like phenotype [67]. Loss of PTCH receptors in mice was also associated with transformation from MPN to an acute leukemic state suggesting that hedgehog inhibitors could be investigated for the potential to prevent or treat this phenomenon [67]. Overactive hedgehog signaling has also been identified in the pathogenesis of some non-malignant fibrotic diseases, which may have relevance in their utilization in treatment of MF [68,69]. Combined inhibition of the JAK and hedgehog pathways in a mouse model of MF showed impressive results, with reduction in white cell count [WCC] and platelets, reduction in JAK2 allele burden and reversal of bone marrow fibrosis [70].