Control of cancer cachexia via stimulation of resolution of inflammation

While cancer cachexia is a devastating syndrome characterized by progressive muscle wasting, inflammation, and metabolic disruption, the underlying mechanisms remain poorly characterized. There are currently no treatments for cachexia. Cancer cachexia is driven by systemic inflammation, pro-inflammatory cytokines, and apoptosis (“cellular debris”). A paradigm shift is emerging in understanding the resolution of inflammation as an active biochemical process with our discovery of novel specialized pro-resolving mediators (SPMs), such as resolvins and endogenous resolution programs. SPMs stimulate macrophage-mediated clearance of debris, promote tissue/muscle regeneration, and counter-regulate pro-inflammatory cytokines at nanogram doses without immunosuppression. Despite approaches to block systemic inflammation, there are no current “proresolving” therapies in cancer or cancer cachexia. Moreover, the impact of cancer cachexia on eicosanoids and the novel pro-resolving lipid mediators, both key endogenous regulators of initiation and resolution of inflammation, are unknown. This proposal builds on our recent finding that stimulating resolution of inflammation prevents tumor growth by counter-regulating pro-inflammatory cytokines/eicosanoids and clearing debris. Therefore, the overarching theme is to elucidate the underlying processes of failed resolution of inflammation that drive cancer cachexia. We will rely on a set of established experimental systems, including genetic and pharmacological manipulation of SPMs and their receptors in animal models and macrophages. We shall test this in a multi-pronged approach. In Specific Aim 1, the mechanisms of dysregulated resolution of inflammation in cachexia will be investigated. We will profile lipid autacoid mediators, including eicosanoids and SPMs, to test our innovative hypothesis that failed resolution of inflammation is necessary and sufficient to cause cachexia, which induces a rapid eicosanoid storm with dysregulated SPMs that leads to an uncontrolled cytokine storm. We will evaluate pro-resolving lipid mediators as interventional targets in cachexia. In Specific Aim 2, we will optimize the delivery of SPM mimetics and humanized nano-proresolving medicines (NPRMs) carrying SPM cargo to cachectic tissues and determine whether SPMs can prevent chemotherapy-induced cachexia. These studies will complement Specific Aim 3, which seeks to prevent cancer cachexia via stimulation of resolution by precision nutrition. Parabiosis studies will determine whether cancer-induced cachexia is caused by an effect on the primary tumor or the metastatic site as most patients with cachexia die from metastases. These studies can offer a new animal system to evaluate cachexia at an early stage. We will connect our preclinical findings to clinical disease phenotypes using a computational framework to understand failed inflammation resolution in cachexia. Since SPMs have proven safe and effective in human inflammatory disorders, these studies shall provide the basis for rapid translation of resolutiondirected treatments in humans as a new direction to potentially prevent and/or reverse cancer cachexia.