CETSA-based target engagement of taxanes as biomarkers for efficacy and resistance

The use of taxanes has for decades been crucial for treatment of several cancers. A major limitation of these therapies is inherent or acquired drug resistance. A key to improved outcome of taxane-based therapies is to develop tools to predict and monitor drug efficacy and resistance in the clinical setting allowing for treatment and dose stratification for individual patients. To assess treatment efficacy up to the level of drug target engagement, we have established several formats of tubulin-specific Cellular Thermal Shift Assays (CETSAs). This technique was evaluated in breast and prostate cancer models and in a cohort of breast cancer patients. Here we show that taxanes induce significant CETSA shifts in cell lines as well as in animal models including patient-derived xenograft (PDX) models. Furthermore, isothermal dose response CETSA measurements allowed for drugs to be rapidly ranked according to their reported potency. Using multidrug resistant cancer cell lines and taxane-resistant PDX models we demonstrate that CETSA can identify taxane resistance up to the level of target engagement. An imaging-based CETSA format was also established, which in principle allows for taxane target engagement to be accessed in specific cell types in complex cell mixtures. Using a highly sensitive implementation of CETSA, we measured target engagement in fine needle aspirates from breast cancer patients, revealing a range of different sensitivities. Together, our data support that CETSA is a robust tool for assessing taxane target engagement in preclinical models and clinical material and therefore should be evaluated as a prognostic tool during taxane-based therapies

Incidence and surveillance of acute cardiovascular toxicities in paediatric acute lymphoblastic leukaemia: A retrospective population-based single-centre cohort study

Aim: Here, we studied the incidence of acute cardiovascular toxicities in children treated for acute lymphoblastic leukaemia (ALL). Methods: We performed a population-based single-centre longitudinal retrospective cohort study in 70 children diagnosed and treated with anthracycline-containing therapy against ALL at Karolinska University Hospital during 2015–2019 with a follow-up period of at least three months. Cardiovascular surveillance for these patients included echocardiography with measurements of left ventricular ejection fraction (LVEF) and shortening fraction (LVSF), electrocardiography and non-invasive blood pressure monitoring. Results: No patient experienced a significant decrease in LVEF or LVSF during or early after primary cancer treatment including anthracyclines. Surveillance with LVEF and LVSF was unable to predict the trajectory to severe clinical heart failure in one patient following treatment. Pericardial effusion prior to therapy initiation occurred in 13.6% of the patients. The incidence of intracardiac thrombosis and arterial hypertension was 8.5%, and 20%, respectively. Conclusion: Early cardiovascular toxicities were common in this paediatric ALL cohort. We confirm that early routine LVEF and LVSF assessments were insufficient to identify patients at risk of subsequent treatment-related heart failure. This underlines the unmet need of more sensitive methods for cardiovascular surveillance in children treated for cancer to reduce the burden of cardiovascular morbidity and mortality