Transcriptional Regulation and Therapeutic Modulation of Muscle CDKN1A in Cancer Cachexia - PROJECT SUMMARY Cancer cachexia is a debilitating syndrome characterized by muscle wasting, weight loss, and metabolic dysfunction, significantly reducing patient quality of life and survival. Affecting up to 80% of advanced cancer patients and responsible for approximately 20% of cancer-related deaths, effective treatments are lacking due to limited understanding of its molecular mechanisms. Elevated levels of cyclin-dependent kinase inhibitor 1A (CDKN1A) in muscle have been identified as a robust prognostic biomarker for cachexia severity and patient survival. Modulation of the transcriptional repressor B-cell lymphoma 6 (BCL6) directly regulates CDKN1A expression via transcriptional repression. Repressing CDKN1A, either through BCL6 overexpression or direct knockdown, ameliorates proinflammatory atrophy and improves metabolic parameters under cachexia conditions. These findings suggest that the BCL6-CDKN1A interaction plays a pivotal role in regulating muscle metabolism and inflammation, presenting a unique opportunity to develop integrated anti-cachexia therapies. This project aims to elucidate the role of muscle CDKN1A in cancer cachexia and develop novel therapeutic strategies targeting the BCL6-CDKN1A pathway to combat muscle wasting. Specifically, the research will: 1. Elucidate the role of muscle CDKN1A in muscle dysfunction during cancer cachexia by utilizing muscle-specific CDKN1A knockout mice to assess impacts on muscle function, body composition, metabolic parameters, and survival outcomes. 2. Define the temporal regulation of CDKN1A by BCL6 in response to nutrient availability by investigating the dynamics of BCL6-mediated repression of CDKN1A and its effects on muscle metabolism during fasting and cancer cachexia. 3. Assess immune modulation of muscle CDKN1A as a therapeutic strategy by dissecting the role of BCL6-mediated CDKN1A repression in muscle inflammation, identifying cancer-specific mechanisms of CDKN1A induction, and evaluating the translational potential of CDKN1A- modulating compounds. The research integrates advanced genetic tools, transgenic mouse models, next- generation sequencing, and high-throughput clinical compound screening to uncover molecular mechanisms driving muscle wasting in cancer cachexia. By targeting the BCL6-CDKN1A pathway, the project seeks to develop innovative therapies to improve muscle function and quality of life for cancer patients. The candidate's long-term career goal is to establish an independent research laboratory focused on understanding the mechanisms of muscle wasting in cancer cachexia and developing novel therapeutic strategies. The career development plan involves interdisciplinary training under the mentorship of Dr. Ronald Evans at the Salk Institute, an exceptional environment for research on tissue crosstalk and molecular endocrinology. The candidate will acquire expertise in advanced research tools, leadership skills, grant writing, and manuscript preparation, facilitating the transition to an independent investigator capable of leading a research team and securing funding.
