PROJECT SUMMARY
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 “pro-
resolving” 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 inflamma-
tion 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 inflamma-
tion 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 in-
flammation 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 un-
controlled cytokine storm. We will evaluate pro-resolving lipid mediators as interventional targets in ca-
chexia. In Specific Aim 2, we will optimize the delivery of SPM mimetics and humanized nano-pro-
resolving 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 pre-
vent 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 effec-
tive in human inflammatory disorders, these studies shall provide the basis for rapid translation of resolution-
directed treatments in humans as a new direction to potentially prevent and/or reverse cancer cachexia.