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NIH grant 1R21AR088832-01: Nuclear Receptors In Cancer Cachexia
Institute: {'code': 'AR', 'abbreviation': 'NIAMS', 'name': 'National Institute of Arthritis and Musculoskeletal and Skin Diseases', 'admin_org_id': '12500006', 'admin_funding_url': ''}. PI: VIHANG A NARKAR. Award: $200604.
Start: 2026-09-25T00:00:00.
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.document fetched 2026-10-04 02:43