Resolution of inflammation in chemical-induced cancer

PROJECT SUMMARY While exposure to toxic environmental chemicals can mutate DNA, causing cancer, the underlying non- genotoxic mechanisms that support malignant transformation remain largely uncharacterized. Transformed cells require growth factors to support and stimulate them in carcinogenesis, resulting in hyperinflammation and a cytokine storm. A paradigm shift is emerging in understanding the resolution of acute inflammation as an active biochemical process with our discovery of novel specialized pro-resolving mediators (SPMs), such as resolvins, and endogenous resolution programs. At nanogram doses, SPMs stimulate macrophage-mediated clearance of debris and counter-regulate pro-inflammatory cytokine (e.g., TNFα) production without immune suppression. Despite approaches to block systemic inflammation, there are no “pro-resolving” therapies for cancer treatment. Furthermore, the impact of carcinogens on eicosanoids and pro-resolving lipid media- tors, both critical regulators of the initiation and resolution of inflammation, is completely unknown. In response to NOSI-20-018 “Promoting Fundamental Research in Inflammation Resolution,” this proposal focuses on ad- vancing our recent results indicating that stimulating the resolution of inflammation prevents carcingogen- induced tumor growth by counter-regulating cytokine storms. Therefore, the overarching theme of this pro- posal is to elucidate the underlying processes of failed resolution of inflammation initiated by environmental chemicals. We will rely on a set of established experimental systems, including genetic and pharmacological manipulation of SPMs and their receptors in animal models and macrophage studies. In Specific Aim 1, we will profile lipid autacoid mediators, including eicosanoids (PGs, LTs) and SPMs, as well as cytokines to test our innovative hypothesis that environmental chemicals trigger dysregulation of SPMs that leads to an uncon- trolled cytokine & eicosanoid storm. We will evaluate pro-resolving lipid mediators as interventional targets in chemical-induced cancer. We will elucidate cellular, intracellular, and receptor-mediated pro-resolving and anti-tumor mechanisms of resolvins. In Specific Aim 2, the mechanisms that mediate failed resolution of in- flammation in chemical-induced cancer will be investigated. These studies will complement Specific Aim 3 in a multi-pronged approach that will evaluate SPM analog mimetics and humanized nano-pro-resolving medi- cines (NPRMs) carrying SPM cargo as novel targeted treatment approaches to prevent chemical-induced can- cer. These studies will offer new animal models to evaluate toxic chemicals and novel therapies to counter cancer. We will then connect our preclinical findings to clinical disease phenotypes using a new computational framework to understand failed resolution of inflammation in chemical-induced cancers. As SPMs are safe and effective in inflammatory disorders, the proposed studies shall provide the basis for rapid translation of resolution-directed treatments in humans as a new direction to prevent and/or reduce cancers that arise from environmental carcinogens.