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Oral AMXT 1501 Dicaprate in Combination With IV DFMO

ABSTRACT: A Phase 1B/2A study will be conducted to establish safety and dose level of AMXT 1501 dicaprate in combination with IV DFMO, in cancer patients.

DISEASE(S): Endometrial Cancer,Ovary Cancer,Dipg Brain Tumor,Glioma, Malignant,Colorectal Cancer,Mesothelioma,Endometrial Neoplasms,Nsclc,Diffuse Midline Glioma, H3 K27m-mutant,Gastric Cancer,Diffuse Intrinsic Pontine Glioma,Ovarian Neoplasms,Solid Tumor,Cervical Cancer,Melanoma,Papillary Thyroid Cancer,Advanced Cancer,Breast Cancer,Thyroid Cancer, Papillary,Glioma,Mesothelioma Peritoneum,Mesotheliomas Pleural,Esophageal Cancer,Head And Neck Cancer,Solid Carcinoma,Mesothelioma, Malignant,Cancer

PROVIDER: 2745148 | ecrin-mdr-crc |

REPOSITORIES: ECRIN MDR

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Project description:It is well known that rennin-angiotensin-aldosterone system (RAAS) plays a critical role in the development of diabetic cardiomyopathy. The present study was aimed to clarify the role of a novel member of RAAS, angiotensin IV (Ang IV) and its downstream mediator forkhead box protein O1 (FoxO1), in the pathogenesis of diabetic cardiomyopathy. In vivo, diabetic mice were treated with low-, medium- and high-dose Ang IV, AT4R antagonist divalinal, FoxO1 inhibitor AS1842856 (AS), or their combinations. In vitro, cardiomyocytes and cardiofibroblasts were treated with different concentrations of glucose, low-, medium- and high-dose Ang IV, divalinal, FoxO1-overexpression plasmid (FoxO1-OE), AS or their combinations. The results showed that Ang IV treatment dose-dependently attenuated left ventricular dysfunction, fibrosis, and myocyte apoptosis in diabetic mice. Besides, enhanced autophagy and FoxO1 protein expression by diabetes were dose-dependently suppressed by Ang IV treatment. However, these cardioprotective effects of Ang IV were completely abolished by divalinal administration. Bioinformatics analysis revealed that the differentially expressed genes were enriched in autophagy, apoptosis, and FoxO signaling pathways among control, diabetes, and diabetes+high-dose Ang IV groups. Similar to Ang IV, AS treatment ameliorated diabetic cardiomyopathy in mice. In vitro, high glucose stimulation increased collagen expression, apoptosis, overactive autophagy flux and FoxO1 nuclear translocation in cardiomyocytes, and upregulated collagen and FoxO1 expression in cardiofibroblasts, which were substantially attenuated by Ang IV treatment. However, these protective effects of Ang IV were completely blocked by the use of divalinal or FoxO1-OE, and these detrimental effects were reversed by the additional administration of AS. In summary, Ang IV treatment dose-dependently attenuated left ventricular dysfunction and remodeling in a mouse model of diabetic cardiomyopathy, and the mechanisms involved stimulation of AT4R and suppression of FoxO1-mediated fibrosis, apoptosis, and overactive autophagy.

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Oral AMXT 1501 Dicaprate in Combination With IV DFMO

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