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JRF 2024
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Metabolomic profiling of cardiac tissue to understand increased doxorubicin cardiotoxicity in early-life chronic moderate protein-deficiency malnutrition
Malnutrition significantly complicates the treatment of pediatric oncology patients, often leading to poor prognosis. Understanding the underlying molecular mechanisms can inform therapeutic strategies to improve outcomes. Previous research in our lab has demonstrated increased doxorubicin accumulation in moderately protein-deficient juvenile animals compared to controls. Proteomic analysis revealed pronounced effects on metabolic pathways, particularly fatty acid and glucose metabolism, with greater impact in malnourished animals. These pathways are crucial for cardiac function, and disruptions can lead to severe complications such as heart failure and cardiomyopathy.
This study aims to conduct targeted metabolomic analysis to quantify metabolite levels in doxorubicin-treated animals, providing insights into pathway modulation. Subsequently, therapeutic interventions will be tested, including dietary protein supplementation, combined with pathway inhibitors/enhancers, or standalone pathway modulation. Given the developmental stage of young rats, chronic protein deficiency-induced changes may be irreversible, necessitating early intervention strategies.
These findings are expected to enhance treatment outcomes for pediatric malnourished patients undergoing doxorubicin therapy.
Screening and development of mitochondria-targeted drug candidates for the treatment of therapy resistant cancers
Mitochondria plays a vital role in cell survival through various cellular pathways such as redox homeostasis, biogenesis & mitophagy, metabolism, and apoptosis. However, key oncogenic drivers and suppressors associated with mitochondrial functions are modulated during tumor formation and progression. Hence, targeting these oncogenic pathways with suitable ligands can be a potential strategy for the treatment of advanced cancers. In this study, potential hits will be identified from the mitochondria-targeted compound library through screening against various cancer cell lines. The therapeutic efficacy of the hits will be established in vitro and in vivo using several preclinical models such as organoids, xenograft and PDX, sequentially, eliminating the less active molecules at each step. A few lead compounds will be selected for pharmacokinetics and toxicology studies. The most potent molecule with a favorable safety and pharmacokinetic profile will be taken up for a comprehensive investigation of its anti-tumor mechanism of action, including several unbiased global approaches such as total RNA transcriptomics and proteomics.