- |||||||||| temozolomide / Generic mfg.
Targeting the circadian clock with small molecule compounds results in anti-tumor effects specifically in glioblastoma stem cells (Room 109-110) - Nov 11, 2023 - Abstract #SNO2023SNO_1502;
Treatment success remains challenging despite aggressive, multimodal current standard-of-care consisting of maximal surgical resection followed by concurrent temozolomide (TMZ) chemotherapy and radiation...Application of the CRY stabilizer SHP1705 in GBM PDX patient derived xenograft (PDX) models resulted in decreased tumor growth rate and increased survival time compared to vehicle control. These results highlight the therapeutic potential of circadian clock compounds as single agents, in combinations and as adjuvants to existing therapies by specifically targeting the GSC population in GBM.
- |||||||||| Journal: Dynamic regulation of the serine loop by distant mutations reveals allostery in cryptochrome1. (Pubmed Central) - Sep 14, 2023
Our findings highlighted the crucial roles of S44 and S45 in the dynamic behavior of the serine loop, specifically through their interactions with E382 in CRY1. Considering the clinical implications of altered CRY1 function, our study opens up new possibilities for the development of drugs that target the allosteric regulation of CRY1.Communicated by Ramaswamy H. Sarma.
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Small molecule circadian clock compounds display therapeutic potential in targeting glioblastoma stem cells (Section 18; Poster Board #5) - Mar 14, 2023 - Abstract #AACR2023AACR_2563;
One of the major challenges in treating GBM is the presence of GBM stem cells (GSCs) that are resistant to temozolomide (TMZ) chemotherapy and radiation, which is part of the current standard of care for GBM following maximal surgical resection...The clock compound SHP1705 increased over survival and delayed tumor growth in GBM PDX models. These results highlight the therapeutic potential small molecule circadian clock compounds have against GBM as both a single agent and adjuvant to existing therapies by specifically targeting the GSC population.
- |||||||||| Journal, IO biomarker: Nucleus-exported CLOCK acetylates PRPS to promote de novo nucleotide synthesis and liver tumour growth. (Pubmed Central) - Jan 17, 2023
Furthermore, CLOCK S106 phosphorylation and PRPS1/2 K29 acetylation are positively correlated in human HCC specimens and with HCC poor prognosis. These findings delineate a critical mechanism by which oncogenic signalling inhibits canonical CLOCK transcriptional activity and simultaneously confers CLOCK with instrumental moonlighting functions to promote nucleotide synthesis and tumour growth.
- |||||||||| fenofibrate / Generic mfg.
Journal: Down-regulation of hepatic CLOCK by PPARα is involved in inhibition of NAFLD. (Pubmed Central) - Dec 18, 2022
WT, KO, and PPARα-humanized (hPPARα) mice were treated with PPARα agonist fenofibrate to reveal the hPPARα dependence of circadian locomotor output cycles kaput (CLOCK) down-regulation...• Down-regulation of hepatic CLOCK by basal PPARα contributed to tolerance against development of NAFLD. • Inhibition of CLOCK by activated PPARα was involved in therapeutic actions against fatty liver diseases by PPARα agonists.
- |||||||||| Journal: Role of Wnt/β-catenin signaling pathway in ameloblast differentiation in relevance to dental fluorosis. (Pubmed Central) - Oct 13, 2022
Taken together, these findings suggested that excessive fluoride promoted ROS generation, leading to the inhibition of clock genes, which resulted in reduced PPARγ and activated Wnt/β-catenin signaling pathway, thus inhibiting ameloblast differentiation and matrix degradation. This study provides a better understanding of the molecular mechanism of enamel defects in dental fluorosis.
- |||||||||| Circadian Regulator CLOCK Drives Immunosuppression in Glioblastoma (West/Central Hall) - Sep 28, 2022 - Abstract #SNO2022SNO_1235;
In human GBM, the CLOCK-regulated LGMN signaling correlates positively with microglial level and poor prognosis. Together, these findings uncover the CLOCK–OLFML3–HIF1A–LGMN axis as a molecular switch that controls microglial biology and immunosuppression, thus revealing potential new therapeutic targets for GBM patients.
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