Cancer cachexia is a tumor-induced debilitating wasting condition that causes loss of white adipose tissue and muscle degradation, exacerbated, paradoxically, by the loss of appetite by unclear mechanisms. Preventing cancer cachexia is profoundly important as it can prevent deterioration of patient health allowing sustained treatment and improved outcome. Cancer cachexia likely results from a systemic metabolic imbalance where tumors outcompete host tissues for essential nutrients that drive a catabolic process within normal tissues. Defining the cause of the systemic metabolic imbalance that favors the tumor at the expense of the patient and reversing it will improve cancer treatment and patient health.
A major goal of the Ludwig Princeton Branch is to determine how tumors cause the metabolic imbalance that drives cancer cachexia. With an understanding of the metabolic deregulation responsible for cancer cachexia, we can then reverse the condition by targeting the signaling mechanisms of the tumor and by supplying nutrients to correct the metabolic imbalance. We specifically aim to determine if dietary, pharmacologic, or genetic intervention can prevent or reverse cancer cachexia to improve the health, well-being and survival of cancer patients.
A recent Cancer Grand Challenges award assembles a multinational consortium supported by the National Cancer Institute and Cancer Research UK to build upon and expand cachexia work at the Ludwig Princeton Branch.
Related Publications
Ferrer M, Mourikis N, Davidson EE, Kleeman SO, Zaccaria M, Habel J, Rubino R, Flint TR, Connell CM, Lukey M, White EP, Coll AP, Venkitaraman AR, Janowitz T. bioRxiv. 2023 Feb 18:2023.02.17.528937. doi: 10.1101/2023.02.17.528937. Preprint. PMID: 36824830
Glucose dependency of cancer cells can be targeted with a high-fat, low-carbohydrate ketogenic diet (KD). However, in IL-6-producing cancers, suppression of the hepatic ketogenic potential hinders the utilization of KD as energy for the organism. In IL-6-associated murine models of cancer cachexia, we describe delayed tumor growth but accelerated cachexia onset and shortened survival in mice fed KD. Mechanistically, this uncoupling is a consequence of the biochemical interaction of two NADPH-dependent pathways. Within the tumor, increased lipid peroxidation and, consequently, saturation of the glutathione (GSH) system lead to the ferroptotic death of cancer cells. Systemically, redox imbalance and NADPH depletion impair corticosterone biosynthesis. Administration of dexamethasone, a potent glucocorticoid, increases food intake, normalizes glucose levels and utilization of nutritional substrates, delays cachexia onset, and extends the survival of tumor-bearing mice fed KD while preserving reduced tumor growth. Our study emphasizes the need to investigate the effects of systemic interventions on both the tumor and the host to accurately assess therapeutic potential. These findings may be relevant to clinical research efforts that investigate nutritional interventions such as KD in patients with cancer.