Articular Cartilage Development
Kyriacos A. Athanasiou, Eric M. Darling, Grayson D. DuRaine, Jerry C. Hu, A. Hari Reddi in Articular Cartilage, 2017
Hedgehog Proteins: The hedgehog proteins are signaling molecules initially identified in classic genetic screens in fruit flies, Drosophila melanogaster (Nusslein-Volhard and Wieschaus 1980). Homologous genes were subsequently isolated in mice and humans and named sonic hedgehog (Shh), Indian hedgehog (Ihh), and desert hedgehog (Dhh). Members of the hedgehog family bind to their cognate receptors patched (PTC) and also bind transmembrane protein smoothened (Smo) (Figure 2.3). Activation of the hedgehog signaling pathway results in functional activation of the Gli family of transcription factors. The sonic and Indian hedgehog proteins have been implicated in prehypertrophic chondrocytes in the epiphyseal growth plate, and, therefore, in chondrogenesis and longitudinal growth of mammals (Beachy et al. 2010).
Small-Molecule Targeted Therapies
David E. Thurston, Ilona Pysz in 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)).
Acute Lymphoblastic Leukaemia
Tariq I. Mughal in Precision Haematological Cancer Medicine, 2018
Following the description of the hedgehog signalling pathway having a role in a subset of T-ALL patients, several clinical trials are now assessing the use of hedgehog-inhibitory drugs. Drug combinations targeting NOTCH1, which is activated in about 65% of T-ALL patients, are also being tested. In this regard, there has been interest in developing RO4929097, a γ-secretase inhibitor (GSI), with modest activity so far. Drugs are also being developed for the very rare MEF2D-BCL9 fusion associated with high-risk B-ALL. A report suggests successful targeting of the tumour-specific junction sequence produced by the BCR-ABL1 fusion with infusions of P190BCR-ABL1 neo-antigen-specific T-cells in three patients with BCR-ABL1 positive ALL. There is also interest in a novel-Fc-engineered CD19 antibody which has demonstrated activity in murine models of MLL-rearranged ALL.
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].
Long-Term Glucose Restriction with or without β-Hydroxybutyrate Enrichment Distinctively Alters Epithelial-Mesenchymal Transition-Related Signalings in Ovarian Cancer Cells
Published in Nutrition and Cancer, 2021
Hossein Ghahremani, Saeedeh Nabati, Hanieh Tahmori, Tahmineh Peirouvi, Majid Sirati-Sabet, Siamak Salami
Changes in the Hedgehog signaling pathway were studied by measuring the expression profile of chief genes including SMO, SUFU, and GLI1. The findings did not reveal significant changes among the three groups of A2780CP cells (Figure 3c). However, as shown in Figure 4c, the expression of GLI1 in both of GLC-RES and bHB-ENR SK-OV-3 cells were significantly lower than controls (fold:-3.89 with p = 0.008 and fold: −2.60 with p = 0.008, respectively), but there was no significant change between bHB-ENR and GLC-RES cells (p = 0.365). Also, a significant decrease of the SMO expression was solely observed in the bHB-ENR cells (fold: −3.40 and p = 0.016), and in comparison to control cells, no significant changes were observed in the GLC-RES and bHB-ENR cells (p = 0.17 and 0.167, respectively).
Emerging drugs for the treatment of Myelofibrosis
Published in Expert Opinion on Emerging Drugs, 2018
Aditya Shreenivas, John Mascarenhas
Second mitochondria-derived activator of caspases (SMAC) mimetics induces cancer cell apoptosis through inhibition of a family of cellular proteins, termed the Inhibitor of Apoptosis Proteins. This pathway is particularly relevant target in the setting of elevated TNF-α expression, making it an attractive therapeutic target in MF. LCL-161 (Novartis) is an oral SMAC mimetic that has been tested in a phase II study of MF patients [82]. In this study, 5 out of 13 patients treated with this agent achieved CI by IWG criteria (spleen, symptom, anemia). Grade 2 fatigue was the most common treatment-related AEs noted. Further results of this ongoing trial are eagerly anticipated. Another potential therapeutic target is the hedgehog signaling pathway, which is known to play a crucial role in maintenance, proliferation, and differentiation of hematopoietic stem cells. Sonidegib (LDE225, Novartis), a smoothened inhibitor, has murine data to suggest efficacy when combined with ruxolitinib, but limited clinical data are available currently [83].
Related Knowledge Centers
- Cell Signaling
- Ligand
- Metamorphosis
- Peptide
- Embryo
- Cellular Differentiation
- Cancer
- Segment Polarity Gene
- Body Plan
- Indian Hedgehog