Chemoresistance of non-small-cell lung carcinoma (NSCLC) cells underlies the poor prognosis of patients with advanced disease. Hence, it seems plausible to combine the standard-of-care chemotherapy for NSCLC (typically a combination of platinum-based compounds and taxanes) with strategies that block the induction of chemoresistance.
Recent evidence illustrated that tumor-associated macrophages contribute to diminished therapy responsiveness and tumor relapse following irradiation, anti-angiogenic or vascular-disrupting therapies and chemotherapy in preclinical tumor models. Consequently, TAM or TAM-derived molecules are considered as novel and promising therapeutic targets. Our own data in preclinical NSCLC models demonstrate that IL-1beta is uniquely produced by TAM in the tumor microenvironment. Moreover, definciencies in the molecular machinery responsible for IL-1beta production, i.e. NLRP3 and NLRC4 inflammasomes and caspase-1, reduce tumor growth illustrating the tumor-promoting role of these molecules. Importantly, high levels of IL-1beta are also strongly correlated with worse outcome in advanced NSCLC patients.
Based on these observations, we propose in this study a combination of standard-of-care chemotherapy with the neutralization of inflammasome activity or the blockade of IL-1beta funcion. To achieve this goal, we will employ small-molecule inhibitors of NLRP3 (MCC950) and caspase-1 (pralnacasan and belnacasan), and recombinant IL-1 receptor antagonis (Anakinra) in comination with the chemotherapeutic compounds carboplatin or paclitaxel in two independent mouse models of NSCLC (transplantable LLC-OVA and transgenic KP mice). As a first objective, we will determine the most effective dosage of IL-1beta inhibiting compounds and assess their effect on multiple tumor characteristics. Secondly, we will combine inflammasome inhibition or IL-1beta blockade with chemotherapy, whereby the optimal sequence of administration (concurrent; first IL-1beta inhibition followed by chemotherapy; first chemotherapy followed by maintenance therapy of IL-1beta inhibition).
The ultimate deliverable of this study should be an optimized protocol for combining chemotherapy with inflammasome inhibition or IL-1beta blockade for the treatment of NSCLC in preclinical models, suitable for clinical translation.