Decode-And-Treat · Decoding and Treating Cancer-Induced Cachexia

One third of cancer death are due to cachexia, a metabolic syndrome characterized by fat and lean mass loss. The loss of muscle mass and strength is considered the most important clinical feature of cancer cachexia, and a key predictor of poor outcomes. We and others have shown that prevention of muscle wasting but not fat loss is beneficial for life span in tumour bearing animals. Despite several attempts to develop therapeutic approaches, cachexia is still orphan of any specific drug/treatment mainly because our understanding of the insights of this syndrome are largely unknown. We have started to approach the complexity of cancer cachexia by collecting blood plasma samples, muscle and fat biopsies from cancer patients and age-matched gender-balanced controls. By combining data from mouse models with human biopsies we have recently made exciting observations related to motoneurons involvement in cachexia and an unexpected neurotrophic action of Bone and Morphogenetic Proteins (BMPs) that inspired this application. By using interdisciplinary approaches and developing cutting edge technologies we have designed an experimental plan that will:1) define how gene networks and cellular landscapes in muscles are modified by tumour growth and dissect their relevance in cachexia onset and survival; 2) establish how much gene/chromatin signatures and cellular/cytokines landscapes overlap or diverge between humans and murine models, males and females cancer patients, colon and pancreatic cancer types; 3) develop patients derived organoids-on-chip to generate an in vitro pathology model that recapitulates the human cachexia complexity, 4) develop a personalized multi-target RNA-based therapeutic approach that will preserve muscle mass, force generation and survival. These ambitious objectives will pave the way for an innovative therapy that will match with the concept of precision and personalized medicine and could be broadly applied to many other muscle wasting diseases