Targeting KLF10 to prevent cancer-associated muscle loss

Indiana University Indianapolis, Indianapolis IN

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Abstract

ABSTRACT Skeletal muscle wasting affects up to 80% of patients with advanced cancer and directly impacts surgical prognosis, chemotherapeutic response, morbidity, mortality, and quality of life. Treatment options for patients experiencing cancer-associated muscle wasting/cachexia are limited. Our long-term goal is to develop and leverage a detailed molecular understanding of skeletal muscle wasting to identify novel treatment paradigms that limit lean mass loss in cancer patients. TGF-β-associated signaling is a well-established driver of cancer cachexia, with many superfamily members (such as Activins A/B, Growth-Differentiation Factors (GDFs), and Myostatin) implicated in multiple cancer cachexia models as well as in humans. Despite clear links to the etiology of cancer cachexia, efforts to target the TGF-β pathway have not achieved great clinical success. This disconnect presents an opportunity to better define TGF-β-associated signaling in cancer cachexia, and in the process, identify better targets for therapeutic intervention. We present preliminary data implicating the TGF-β target gene KLF10 as a key mediator of cancer-associated muscle wasting. We show that KLF10 suppression/inactivation suppresses cancer-associated muscle wasting and further demonstrate that KLF10 is sufficient to drive the atrophy program. We directly link KLF10 to TGF-β-associated atrophy and show that KLF10 can bind to and regulate the atrophy-associated gene (atrogene) MuRF1. Considering these and other data, the central hypothesis of this proposal is that a TGF-β::KLF10::MuRF1/atrogene signaling axis promotes muscle wasting in tumor-bearing mice. We will test this hypothesis by completing the following objectives: 1) we will delineate TGF- β-associated inputs that drive muscle KLF10 expression and cancer-associated muscle wasting, 2) we will define KLF10 targets responsible for wasting-associated phenotypes, and 3) we will develop and test strategies to inhibit KLF10 in pre-clinical cancer cachexia models. Successful completion of these aims will address a critical mechanistic knowledge gap regarding a well-known atrophy-associated signaling pathway and will be a significant step towards developing novel therapies to combat cancer-associated muscle wasting.