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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
Among medulloblastoma subtypes, SHH medulloblastoma has been the most well studied and well defined subgroup. SHH signaling plays a crucial role in central nervous system development, including neuronal precursor proliferation, dorso-ventral patterning, specification of oligodendrocytes, and axonal growth control [41]. Aberrant activation of SHH pathway is not exclusive to medulloblastoma but has also been noted in basal cell carcinoma (BCC), pancreatic cancer, ovarian cancer, and colorectal cancer [42-44]. Constitutive activation of SHH signaling due to mutations in PTCH1/2, SUFU (suppressor-of-fused) and SMO (smoothened) leads to activation of GLI1 and GLI2 favoring transcription of pro-proliferative, pro-survival and pro-angiogenic genes leading to enhanced tumor growth, metastasis and therapeutic resistance [45]. Thus, targeting the key molecules of canonical SHH signaling pathway could yield better therapeutic options against SHH medulloblastoma.
Small-Molecule Targeted Therapies
Published in David E. Thurston, Ilona Pysz, Chemistry and Pharmacology of Anticancer Drugs, 2021
Antitumor activity has also been observed in sonic Hedgehog expressing human primary pancreatic and ovarian cancer xenografts. In these mouse models, the expression of tumor-associated stromal Gli1 mRNA was markedly decreased following TAK-441 treatment, suggesting that Hh signaling in these tumors was driven by a paracrine mode of action. A combination of TAK-441 and rapamycin in human primary pancreatic cancer xenograft models has also been investigated, the results demonstrating a significantly greater antitumor activity than for either agent alone. As a result of promising preclinical studies, TAK-441 entered Phase I clinical studies in solid tumors; however, development was discontinued in 2013.
Soft Tissue Sarcomas
Published in Pat Price, Karol Sikora, Treatment of Cancer, 2020
Thomas F. DeLaney, David C. Harmon, Karol Sikora, Francis J. Hornicek
Other chromosomal changes characteristic of specific sarcoma type include the reciprocal exchange t(11:22)(q24;ql2) seen in approximately 85%–90% of Ewing’s sarcoma and primitive peripheral neuro-ectodermal tumor (PNET). In this translocation, the EWS (Ewing sarcoma breakpoint region 1) gene from chromosome 22q12 is covalently linked to the erythroblast transformation-specific (ETS) family member, FLI-1, to form the EWS–FLI-1 fusion gene.15 The chimeric proteins that result from this translocation may alter transcription of a number of genes including upregulation of the transcription factor Gli1 that promotes the oncogenic potential of the Hedgehog pathway. A less common translocation t(21;22)(q22;q12) has also been identified and links EWS to a different ETS family member, ETS-related gene (ERG). Myxoid and round cell subtypes of liposarcomas display a reciprocal translocation t(12;16) (q13;p11). In this translocation, the CHOP (induced by DNA damage) gene is inserted adjacent to a novel gene called TLS. The fusion gene, called TLS–CHOP, shows sequence homology to the Ewing’s fusion gene. It fails to induce G1/S arrest, which is one of the functions of the non-oncogenic form of CHOP (GADD153). Identification of the fusion gene has been used as a diagnostic aid for these subtypes of liposarcoma.
Treatment update for vitiligo based on autoimmune inhibition and melanocyte protection
Published in Expert Opinion on Therapeutic Targets, 2023
Bo Xie, Yuqi Zhu, Yuqing Shen, Wen Xu, Xiuzu Song
In addition to NB-UVB, research has shown that excimer light (308 nm) could promote melanoblast differentiation in vitro by activating the aryl hydrocarbon receptor and epidermal growth factor receptor [220]. According to current knowledge, the p53 and Wnt/β-catenin pathways are the main signals for the activation of repigmentation after phototherapy [221,222]. After melanocytes are activated by NB-UVB, p53 and its downstream effectors promote the secretion of α-MSH, which further activates MITF expression by acting on MC1R [221–225]. In mouse models, UVB irradiation induced robust expression of Wnt7a, which further triggered β-catenin translocation into the nucleus of melanocyte stem cells [211,226]. Goldstein NB et al. explored the signature changes of melanocytes in hair follicle bulge of vitiligo patients after NB-UVB treatment and found that the expressions of GLI1, TNC, GJB6 and THBS1 were significantly increased, which may be potential participants in melanocyte precursors activation. GLI1, a candidate stem cell-associated gene, may play a key role in this process and could serve as a therapeutic target to promote melanocyte regeneration [227].
Patched 1 and C-C Motif Chemokine Receptor 6 Distinguish Heterogeneous T Helper 17 Subsets in Colitic Lamina Propria
Published in Immunological Investigations, 2023
Shengli Pei, Chao Ke, Jiantao Han, Xingwang Xie
The present study first unveiled the expression of important Hedgehog signaling components in Th17 cells in colitis development. The frequency of Th17 cells was boosted in both mLN and LP CD4+ T lymphocytes after colitis induction, indicating that Th17 response was initiated and promoted during the development of colitis. The transcripts of PTCH1, SMO, and Gli1 were not significantly altered in mLN Th17 cells after the onset of colitis, suggesting that the differentiation and activation of Th17 cells do not influence the transcription of these molecules. In contrast, the changes in PTCH1, SMO, and Gli1 in LP Th17 cells suggest that LP-specific factors, perhaps inflammatory mediators, enhance the transcription of these molecules. Interestingly, Gli3 was increased in both mLN Th17 cells and LP Th17 cells after the onset of colitis, signifying the activation of the hedgehog signaling in colitis-responsive Th17 cells. Therefore, our study might support the conclusion of the latest study showing that the Hedgehog signaling particularly Gli3 controls Th17 differentiation (Hanna et al. 2022). Because Gli1 itself is the target gene of the Hedgehog signaling (Carballo et al. 2018), the remarkable increase in Gli1 implies the activation of the Hedgehog signaling in LP Th17 cells.
T-cell acute lymphoblastic leukemia: promising experimental drugs in clinical development
Published in Expert Opinion on Investigational Drugs, 2023
Novel drugs are currently emerging from promising preclinical studies. Inhibition of GLI1, a Hedgehog pathway transcription factor, resulted in improved survival in T-ALL preclinical models [98]. Selinexor (KPT-330), a selective inhibitor of nuclear export compound and an exportin-1 XPO1 antagonist, has shown preclinical efficacy in T-ALL [99], and is currently under investigation in relapsed pediatric ALL (NCT02091245). Eltanexor (KPT-8602), a second-generation XPO1 inhibitor, enhances the efficacy of dexamethasone therapy [100]. TYK2 pathway, chaperoned by heat shock proteins, acts to upregulate BCL2 and its inhibition by the drug Luminespib triggers apoptosis in vitro in T-ALL [101,102]. The aurora kinase-A inhibitor alisertib (MLN8237) and the aurora kinase-B inhibitor barasertib (AZD1152) have demonstrated promising results in ALL [103,104]. Alisertib is currently under investigation in combination with vorinostat in R/R T-ALL (NCT01567709). AZD1152 has shown synergy with vincristine [105]. Bortezomib, a proteasome inhibitor, has also shown encouraging data in relapsed T-ALL with 68% of CR when combined with chemotherapy [106] and is currently under clinical investigation in trials including T-ALL (NCT03117751, NCT01769209, NCT02518750, and NCT02112916). Preclinical models using the Nedd8-activating enzyme pevonedistat (MLN4924) has demonstrated cell-cycle arrest and apoptosis [107]. OBI-3424 has shown cytotoxic activity in preclinical models in T-ALL that express the Aldo-Keto Reductase 1 C3 (AKR1C3) enzyme [108].