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  • ||||||||||  Bylantra (devimistat) / Cornerstone Pharma
    Trial completion date, Combination therapy, Metastases:  CPI-613 and Combination Chemotherapy in Treating Patients With Metastatic Pancreatic Cancer (clinicaltrials.gov) -  Apr 22, 2021   
    P1,  N=21, Active, not recruiting, 
    To date, 5 of planned 20 pts enrolled on the phase 1b portion are without dose limiting toxicity. Trial completion date: Mar 2021 --> Jul 2021
  • ||||||||||  Bylantra (devimistat) / Rafael Pharma, Ono Pharma
    Journal:  TGF-β1 is a regulator of the pyruvate dehydrogenase complex in fibroblasts. (Pubmed Central) -  Apr 10, 2021   
    Over-expression of mutant PDH-E1α, resistant to phosphorylation, ameliorated effects of TGF-β1, while inhibition of PDC activity with CPI-613 was sufficient to induce αSMA and pro-collagen I expression, markers of myofibroblast differentiation and fibroblast activation...A reduction in acetyl-CoA, and therefore acetylation substrate, also resulted in a generalised loss of protein acetylation with TGF-β1. In conclusion, TGF-β1 in part regulates fibroblast activation via effects on PDC activity.
  • ||||||||||  Bylantra (devimistat) / Rafael Pharma, Ono Pharma
    Journal:  Neural signaling modulates metabolism of gastric cancer. (Pubmed Central) -  Feb 20, 2021   
    We demonstrate the efficacy of nerve-cancer metabolism therapy by intratumoral injection of BoNT-A (SNAP25 inhibitor) with systemic administration of RAD001 and CPI-613 but not cytotoxic drugs on overall survival in mice and show the feasibility in patients. These findings point to the importance of neural signaling in modulating the tumor metabolism and provide a rational basis for clinical translation of the potential strategy for gastric cancer.
  • ||||||||||  Bylantra (devimistat) / Rafael Pharma, Ono Pharma, Xenical (orlistat) / Roche, GSK, etomoxir (MIQ-001) - Meta / IQ
    Review, Journal:  Redox Homeostasis and Metabolism in Cancer: A Complex Mechanism and Potential Targeted Therapeutics. (Pubmed Central) -  Feb 3, 2021   
    In this review, we highlight the relation between ROS, the metabolic programing of cancer, and stromal and immune cells with emphasis on and the transcription machinery involved in redox homeostasis, metabolic programing and malignant phenotype. We also shed light on the therapeutic targeting of metabolic pathways generating ROS as we investigate: Orlistat, Biguandes, AICAR, 2 Deoxyglucose, CPI-613, and Etomoxir.
  • ||||||||||  Bylantra (devimistat) / Rafael Pharma, Ono Pharma
    Journal:  CPI-613 rewires lipid metabolism to enhance pancreatic cancer apoptosis via the AMPK-ACC signaling. (Pubmed Central) -  Jan 23, 2021   
    We also shed light on the therapeutic targeting of metabolic pathways generating ROS as we investigate: Orlistat, Biguandes, AICAR, 2 Deoxyglucose, CPI-613, and Etomoxir. These findings explore the critical role of lipid metabolism in apoptosis, providing new insights into the AMPK-ACC signaling axis in crosstalk between lipid metabolism and apoptosis in CPI-613 treatment.
  • ||||||||||  Bylantra (devimistat) / Cornerstone Pharma
    Phase classification, Trial completion date, Trial primary completion date, Combination therapy, Metastases:  CPI-613 in Combination With Modified FOLFIRINOX in Locally Advanced Pancreatic Cancer (clinicaltrials.gov) -  Jan 8, 2021   
    P1/2,  N=33, Recruiting, 
    These findings explore the critical role of lipid metabolism in apoptosis, providing new insights into the AMPK-ACC signaling axis in crosstalk between lipid metabolism and apoptosis in CPI-613 treatment. Phase classification: P2 --> P1/2 | Trial completion date: Jan 2021 --> May 2021 | Trial primary completion date: Jan 2021 --> May 2021
  • ||||||||||  Bylantra (devimistat) / Cornerstone Pharma
    Trial completion date, Combination therapy, Metastases:  CPI-613 and Combination Chemotherapy in Treating Patients With Metastatic Pancreatic Cancer (clinicaltrials.gov) -  Nov 23, 2020   
    P1,  N=21, Active, not recruiting, 
    Phase classification: P2 --> P1/2 | Trial completion date: Jan 2021 --> May 2021 | Trial primary completion date: Jan 2021 --> May 2021 Trial completion date: Nov 2020 --> Mar 2021
  • ||||||||||  Bylantra (devimistat) / Cornerstone Pharma
    Trial completion date, Trial primary completion date:  CPI-613 in Treating Patients With Myelodysplastic Syndromes Who Failed Previous Therapy (clinicaltrials.gov) -  Nov 20, 2020   
    P2,  N=20, Suspended, 
    Trial completion date: Nov 2020 --> Mar 2021 Trial completion date: Oct 2020 --> Jan 2021 | Trial primary completion date: Oct 2020 --> Jan 2021
  • ||||||||||  Bylantra (devimistat) / Cornerstone Pharma, Ono Pharma
    Trial completion date, Trial primary completion date:  CPI-613 and Hydroxychloroquine for Patients With High Risk Myelodysplastic Syndrome (clinicaltrials.gov) -  Oct 1, 2020   
    P1/2,  N=35, Not yet recruiting, 
    These findings shed light on how these pharmaceutical agents interact and how treated cells augment metabolism to sustain viability. Trial completion date: Jul 2026 --> Jul 2027 | Trial primary completion date: Sep 2021 --> Sep 2022
  • ||||||||||  Bylantra (devimistat) / Rafael Pharma, Ono Pharma
    Preclinical, Journal:  Lactate dehydrogenase supports lactate oxidation in mitochondria isolated from different mouse tissues. (Pubmed Central) -  Sep 23, 2020   
    Inclusion of LDH (sodium oxamate or GSK 2837808A) and pyruvate dehydrogenase (PDH; CPI-613) inhibitors abolished respiration in mitochondria energized with lactate...Enzyme activity measurements conducted on permeabilized mitochondria revealed that LDH is localized in mitochondria. In aggregate, we can conclude that mitochondrial LDH fuels bioenergetics in several tissues by oxidizing lactate.
  • ||||||||||  Bylantra (devimistat) / Rafael Pharma, Ono Pharma
    [VIRTUAL] Devimistat induces reprogramming of glycolytic metabolism to augment its anticancer potency in head and neck cancer () -  Sep 7, 2020 - Abstract #AACRNCIEORTC2020AACR_NCI_EORTC_206;    
    In line with the in vitro data, devimistat treatment results in robust tumor growth inhibition coupled with reduced levels of PFKP and PDH in orthotopic mice of oral cancer, with no significant systemic toxicity, suggesting devimistat-mediated glycolytic reprogramming contributes to its cytotoxicity. Our study explores the critical role of glycolytic metabolism in apoptosis, providing new insights into the PFKP-PDH signaling axis in crosstalk between glycolysis and apoptosis in devimistat-mediated anti-mitochondrial treatment.
  • ||||||||||  Bylantra (devimistat) / Rafael Pharma, Ono Pharma
    [VIRTUAL] Devimistat induces reprogramming of glycolytic metabolism to augment its anticancer potency in head and neck cancer () -  Sep 7, 2020 - Abstract #AACRNCIEORTC2020AACR_NCI_EORTC_205;    
    In line with the in vitro data, devimistat treatment results in robust tumor growth inhibition coupled with reduced levels of PFKP and PDH in orthotopic mice of oral cancer, with no significant systemic toxicity, suggesting devimistat-mediated glycolytic reprogramming contributes to its cytotoxicity. Our study explores the critical role of glycolytic metabolism in apoptosis, providing new insights into the PFKP-PDH signaling axis in crosstalk between glycolysis and apoptosis in devimistat-mediated anti-mitochondrial treatment.
  • ||||||||||  Bylantra (devimistat) / Cornerstone Pharma
    Trial completion date, Trial primary completion date:  CPI-613 in Treating Patients With Myelodysplastic Syndromes Who Failed Previous Therapy (clinicaltrials.gov) -  Jun 11, 2020   
    P2,  N=20, Suspended, 
    Finally, we focus on the α-lipoic acid derivative CPI-613, an inhibitor of both PDC and KGDH, and delineate its anti-tumor effects for targeted therapy. Trial completion date: May 2020 --> Aug 2020 | Trial primary completion date: May 2020 --> Aug 2020
  • ||||||||||  Bylantra (devimistat) / Rafael
    Metabolic programming of bladder cancer: Vulnerabilities and opportunities (Virtual Meeting II: E-Posters) -  Jun 11, 2020 - Abstract #AACRII2020AACR-II_5405;    
    We found that each of these inhibitors exhibited significant dose-dependent inhibition on BCa cell survival and invasiveness in vitro. Together, our data provide evidence of metabolic plasticity BCa and dependence on multiple energy generating pathways that be exploited as potential therapeutic targets.
  • ||||||||||  Bylantra (devimistat) / Rafael
    Journal:  Changes in acetyl-CoA mediate Sik3-induced maturation of chondrocytes in endochondral bone formation. (Pubmed Central) -  Jun 4, 2020   
    Inhibition of Pdh by treatment with CPI613 delayed chondrocyte maturation in metatarsal primordial cartilage in organ culture...Blocking ATP synthesis in the TCA cycle by treatment with rotenone also delayed chondrocyte maturation in metatarsal primordial cartilage in organ culture, suggesting the possibility that depriving acetyl-CoA as a substrate for the TCA cycle is responsible for the delayed maturation. Our finding of acetyl-CoA as a regulator of chondrocyte maturation could contribute to understanding the regulatory mechanisms controlling endochondral bone formation by metabolites.
  • ||||||||||  Bylantra (devimistat) / Rafael
    Disruption of mitochondrial metabolism underlies the efficacy of devimistat in acute myeloid leukemia (Virtual Meeting II: All Session Times Are U.S. EDT) -  May 16, 2020 - Abstract #AACRII2020AACR-II_4716;    
    Comprehensive metabolite profiling reveals that devimistat targets KADH enzymes and reduces mitochondrial metabolism in humans. Furthermore, these metabolic changes are quantitatively associated with clinical outcomes, posing a potential opportunity for biomarker development and precision metabolic therapy.
  • ||||||||||  Bylantra (devimistat) / Rafael
    SIRT6 PROTEIN CONTRIBUTES TO INTESTINAL CELL DIFFERENTIATION () -  May 4, 2020 - Abstract #DDW2020DDW_6726;    
    HT29 cells were treated with CPI-613, a pyruvate dehydrogenase (PDH) inhibitor; intestinal cell differentiation markers were detected...We provide evidence showing that SIRT6 protein contributes to intestinal cell differentiation. Importantly, our results suggest that SIRT6 regulation of differentiation may be mediated by alterations in OXPHOS
  • ||||||||||  Bylantra (devimistat) / Cornerstone Pharma
    Trial completion date, Combination therapy, Metastases:  CPI-613 and Combination Chemotherapy in Treating Patients With Metastatic Pancreatic Cancer (clinicaltrials.gov) -  Apr 28, 2020   
    P1,  N=21, Active, not recruiting, 
    Importantly, our results suggest that SIRT6 regulation of differentiation may be mediated by alterations in OXPHOS Trial completion date: Apr 2020 --> Jul 2020
  • ||||||||||  Bylantra (devimistat) / Rafael
    Journal:  Development of a Tumor-Responsive Nanopolyplex Targeting Pancreatic Cancer Cells and Stroma. (Pubmed Central) -  Apr 14, 2020   
    Here, we report a novel biodegradable copolymer to codeliver LY2109761 (a TGF-β receptor I/II inhibitor) and CPI-613 (a novel chemotherapy agent) to desmoplastic stroma and tumor cells, respectively, in the tumor microenvironment...Moreover, the targeted nanopolyplex markedly inhibits tumor growth in an orthotopic pancreatic cancer mouse model by dual-targeting tumor cells and stroma. Overall, the multifunctional nanopolyplex is a promising platform for pancreatic cancer therapy.
  • ||||||||||  Bylantra (devimistat) / Cornerstone Pharma
    Trial completion date, Trial primary completion date:  CPI-613 in Treating Patients With Myelodysplastic Syndromes Who Failed Previous Therapy (clinicaltrials.gov) -  Mar 27, 2020   
    P2,  N=20, Suspended, 
    Clinical trial registration: NCT#03504410. Trial completion date: Feb 2020 --> May 2020 | Trial primary completion date: Feb 2020 --> May 2020
  • ||||||||||  Bylantra (devimistat) / Cornerstone Pharma
    Trial completion date, Combination therapy, Metastases:  CPI-613 and Combination Chemotherapy in Treating Patients With Metastatic Pancreatic Cancer (clinicaltrials.gov) -  Jan 30, 2020   
    P1,  N=21, Active, not recruiting, 
    Further clinical studies of CPI-613 efficacy in pancreatic cancer are in progress. Trial completion date: Jan 2020 --> Apr 2020