Project Portugal 2030

Summary

The importance of preventing BM in HER2+ BC patients cannot be overstated. Up to 50% of patients develop BM and with the best supportive care, the estimated median survival after initial diagnosis is less than 1 year (7). Despite its devastating impact and significant economic burden on healthcare systems, screening for BM is not currently recommended due to a lack of data supporting its benefit in terms of overall survival. Identifying prognostic biomarkers and developing targeted therapies specifically tailored to high-risk HER2-positive BC is essential for improving outcomes in this challenging clinical scenario. Our preliminary data suggest a novel mechanism by which ENPP1, a protein found exclusively in the secretome of HER2+ brain metastasis-prone cells, disrupts brain endothelial cell barrier function to facilitate tumor cell transmigration into the brain parenchyma (Annex 1, Figs. 1, 2 and 3). Notably, the knockdown of ENPP1 effectively prevented endothelial dysfunction (Annex 1, Fig. 4) and reduced metastatic burden (Annex 1, Fig. 5) in preclinical models, highlighting its potential as a therapeutic target. In addition, our findings suggest that ENPP1 may serve as a prognostic biomarker for BM, as it was detected in the plasma of mice with HER2+ metastatic breast tumors before BM formation. Recent research has linked ENPP1 expression to poor prognosis in several cancers, attributed to its role in suppressing antitumor immunity (8). However, its relevance as a risk factor for BM has not been investigated. Alternatively, ENPP1 is a negative regulator of the insulin signaling pathway at the receptor level, inducing an insulin resistance syndrome (5) that may further compromise the BBB, as already observed in Alzheimer's disease and type 2 diabetes (6). Given these compelling findings, we are committed to uncovering the role of ENPP1 in driving BM and exploring its translational potential in real-world scenarios. Our ultimate goal is to establish ENPP1 as a prognostic biomarker for the risk of BM in HER2+ BC patients and as a druggable target to delay or prevent BM recurrence. To achieve this goal, we have outlined the following research objectives: 1. Understand the mechanisms underlying ENPP1-induced endothelial dysfunction with emphasis on insulin signaling and downstream pathways. 2. Evaluate how tumor-derived ENPP1 affects the innate and adaptive immune responses of the host to ascertain whether cancer cells exploit this immune evasive mechanism to enhance their survival and progression alongside inducing endothelial cell dysfunction. 3. Explore ENPP1 as a therapeutic target by evaluating the effectiveness of specific ENPP1 inhibitors in preventing BM formation and enhancing survival rates in preclinical models. 4. Evaluate ENPP1 as a prognostic biomarker for BM risk in a cohort of HER2+ breast cancer patients. 5. Explore the prognostic value of ENPP1 in melanoma patients, given the high incidence of BM in this malignancy. Establishing ENPP1 as both a biomarker for BM risk and a therapeutic target holds great promise for improving patient outcomes. By deepening our understanding of the mechanisms driving BM formation and exploring targeted interventions, we aim to pave the way for personalized treatment strategies. These strategies could effectively mitigate the devastating consequences of BM in HER2+ BC and other cancers with similar metastatic propensities.