S100A9: emerging resistance biomarker and therapeutic target

Brain metastases (BM) presents a major challenge in clinical oncology. The high heterogeneity of BM patients, and the lack of durable responses to therapeutic approaches result in an overall poor prognosis. Despite the multidisciplinary treatment approach, some patients experience an early resistance to therapeutic strategies. Therefore, the identification of biomarkers predicting therapy resistance are an essential tool for rational treatment decisions. Unfortunately, our current knowledge on the specific escape mechanism leading to BM progression and personalized, actionable targets are limited. The group of Manuel Valiente recently identified the activation of the S100A9RAGE-NF-B JunB pathway in BM as a potential mediator of resistance to radiation therapy in preclinical and clinical models. Indeed, the S100- RAGE-complex contributes to the activation of various cellular pathways. Importantly, an increased expression of RAGE was found to be present in metastatic cancer, which was further significantly associated with an upregulation of S100A9 and S100A8. In the recent publication, the membranous expression of RAGE was shown to be increased in irradiated metastatic cancer cells rendering them susceptible to S100A9- mediated resistance to radiotherapy. As a result, a high expression of S100A9 was significantly associated with poor response to radiotherapy. Importantly, targeting this S100A9RAGE axis with a RAGE inhibitor, a reversion of the resistance to WBRT, and a further increase of the sensitivity to radiation therapy was observed in preclinical models. Although Valientes study was one of the first identifying the involvement of S100A9 in specific resistance pathways in BM, further investigation of these mechanisms in human samples is warranted to evaluate their potential clinical use as novel resistance biomarkers and treatment target. Indeed, detecting specific patient cohorts with activated S100A9- pathways and, therefore, a higher risk for relapses to specific therapeutic strategies is an essential step for a personalized treatment approach in BM patients. So far, the association between endogenous S100A9 levels and expression of S100A9 in BM tissue of human samples, as well as specific patients and molecular characteristics associated with activation of S100A9-pathways are unknown. In addition, the question whether S100A9 could also present an emerging resistance biomarker beyond the CNS remained unanswered. Considering these open questions, we aim to perform an in depth analysis on the role of S100A9 proteins in real-life human patient cohorts with the ultimate aim to establish S100A9 as an emerging non-invasive predictive stratification biomarker for treatment decision making in metastatic patients. In addition, preclinical analysis of brain organotypic cultures will help to further define the role of S100A9 in systemic therapeutic approaches for future prospective trial plannings.

In this post-doc project, we investigated peripheral blood, and tumor tissue from large real-life patient cohorts with CNS-metastatic cancer to evaluate S100A9-associated resistance mechanisms throughout radio- and systemic therapeutic approaches. The identification of pathways leading to therapy resistance and cancer progression was urgently needed to detect novel biomarkers and treatment targets for achieving durable responses in metastatic diseases. Additionally, identifying its expressions in different patient cohorts has enabled a more comprehensive selection of patients who could benefit from specific therapeutic approaches, thereby enhancing the personalized treatment of patients with and without BM.