Nuclear Receptors In Cancer Cachexia

Abstract public domain (NIH RePORTER)

PROJECT SUMMARY Cancer cachexia is a devastating muscle-wasting condition leading to poor quality of life and heightened mortality in cancer patients. While cachexia is responsible for nearly 30% of cancer deaths, there are currently no effective clinical interventions, highlighting a critical need for therapeutic target discovery for managing cachexia. We previously showed that estrogen-related receptors α and γ (ERRα/γ) are indispensable muscle fitness factors needed for skeletal muscle homeostasis, driving muscle mitochondrial biogenesis, vascularization and regeneration. However, their role in muscle wasting and atrophy is unknown. We postulated that ERRα/γ could play an anti-atrophy role in cachectic muscle wasting by virtue of its effects on mitochondrial and vascular homeostasis, and other potentially uncovered muscle size regulatory pathways. We have found that ERRα/γ protein and transcripts, as well as their mitochondrial and angiogenic gene targets are repressed in atrophic muscles isolated from murine models of cancer cachexia (pancreatic). Muscle C2C12 cells treated with conditioned media from KPC (KrasG12D/+; Trp53R712H/+; Pdx1-Cre) pancreatic cancer cells resulted in myofiber atrophy. Overexpression of ERRα/γ alone or in combination via adeno-associated virus (Ad-Esrra, Ad-Esrrg) prevented cancer cell-conditioned media induced atrophy and repressed cachexia-associated wasting genes. Conversely, an ERRα inverse agonist (XCT 790) in conjunction with cancer cell conditioned media worsened atrophy and expression of cachectic wasting markers. In KPC orthotopic murine pancreatic cancer model, which exhibits severe wasting, we found a deficit in ERRs and their metabolic-angiogenic gene signaling in cachectic muscles. Intramuscular injection of an adeno-associated virus (AAV9) carrying Esrra (ERRα) or Esrrg (ERR γ) gene neutralized the elevated expression of cachexia-related muscle wasting genes. Therefore, we will test the hypothesis that ERRs, along with their target metabolic and angiogenic genes, are repressed in cachectic muscles, and rescuing ERRα/γ pathways mitigates cachexia-associated muscle dysfunction. The hypothesis will be tested in two specific aims. In Aim 1, we will investigate whether ERRα/γ activation in skeletal muscle mitigates cancer-induced muscle wasting. In Aim 2, we will explore potential mechanism through which ERRα/γ protects against cancer-induced muscle atrophy. We will use pre-clinical pancreatic cancer cachexia model, as well as in vitro cachexia model, along with transgenic, gene therapy and pharmacological approaches to activate ERRs. We expect to identify a critical role for ERRs in muscle mass regulation, which could lead to advanced studies on these receptors as therapeutic target for cancer cachexia.

Public health relevance public domain (NIH RePORTER)

PROJECT NARRATIVE Cachexia is a weight loss and muscle wasting condition of cancer with no effective treatments resulting in increased morbidity and mortality. In this study we will test novel fitness factors to combat muscle wasting in cancer.