Development, validation and translational potential of novel anti-metastasis drug-screening strategie
Author
Zhu, LucíaAdvisor
Valiente Cortés, ManuelEntity
UAM. Departamento de Bioquímica; Centro Nacional de Investigaciones Oncológicas (CNIO)Date
2021-06-23Funded by
The work in thesis was supported by the La Caixa-Severo Ochoa International PhD fellowship (LCF/BQ/SO16/52270014) from October 2016 to January 2021.Subjects
Metástasis cerebrales - Fármacos - Inhibidores - Tesis doctorales; Biología y Biomedicina / Biología; MedicinaNote
Tesis Doctoral inédita leída en la Universidad Autónoma de Madrid, Facultad de Medicina, Departamento de Bioquímica. Fecha de Lectura: 23-06-2021Esta tesis tiene embargado el acceso al texto completo hasta el 23-12-2022
Esta obra está bajo una licencia de Creative Commons Reconocimiento-NoComercial-SinObraDerivada 4.0 Internacional.
Abstract
Systemic spread of cancer continues to be the key aspect associated with lethality. Specifically, patients with dissemination to the brain face dismal prognosis and limited therapeutic options. Here, we report a mediumthroughput drug-screening platform (METPlatform) based on organotypic cultures that allows to evaluate inhibitors against metastases growing in situ. By applying this approach to brain metastasis, we identified several hits from an anti-tumoral library of FDA-approved inhibitors and others being tested in clinical trials. A blood-brain barrier permeable HSP90 inhibitor showed high potency to treat and prevent mouse and human brain metastases at clinically relevant stages of the disease, including a novel model of local relapse after neurosurgery.
Furthermore, in situ proteomic analysis applied to organotypic cultures with metastases treated with the chaperone inhibitor revealed novel HSP90dependent targets as biomarkers in human brain metastasis with potential implications in the nuclear compartment. Our proteomic analysis also identified an actionable mechanism of resistance to the therapy driven by autophagy. Rationale combination targeting HSP90 and autophagy showed synergistic effects against brain metastases in situ compared to sublethal concentrations of the respective monotherapies. Our work validates METPlatform as a potent resource for metastasis research integrating drug-screening and unbiased omic approaches that is fully compatible with human samples.
Finally, METPlatform “avatars” predicted patient response in a proof-ofconcept using standard of care in human glioblastomas, even outperforming a clinically-accepted biomarker of response. We envision that METPlatform could be established as a clinically relevant strategy to personalize the management of difficult-to-treat cancers including metastatic disease in the brain or elsewhere.
Files in this item
Google Scholar:Zhu, Lucía
This item appears in the following Collection(s)
Related items
Showing items related by title, author, creator and subject.