Multimodal platform for assessing drug distribution and response in clinical trials
| Autor: | Giorgio Gaglia, Ziming Du, Louis B. Nabors, Yang Dai, Ishwar N. Kohale, Ilya Korsunsky, Brian M. Alexander, Jann N. Sarkaria, Eudocia Q. Lee, Patrick Y. Wen, Michael S. Regan, Sankha S. Basu, Soumya Raychaudhuri, Elizabeth C. Randall, Keith L. Ligon, Bianca-Maria Marin, Forest M. White, Ann C. Mladek, Sandro Santagata, Nathalie Y. R. Agar, Stuart A. Grossman, Danielle M. Burgenske, Jeffrey G. Supko, Jeffrey N. Agar, Amanda R Clark, Sylwia A. Stopka, Walid M. Abdelmoula, Begoña Gimenez-Cassina Lopez |
|---|---|
| Rok vydání: | 2021 |
| Předmět: |
Oncology
Cancer Research medicine.medical_specialty business.industry Clinical study design medicine.medical_treatment Phosphoproteomics Phases of clinical research Targeted therapy Clinical trial Efficacy Drug development Pharmaceutical Preparations Molecular Response Internal medicine Basic and Translational Investigations medicine Humans Neurology (clinical) business Glioblastoma |
| Zdroj: | Neuro Oncol |
| ISSN: | 1523-5866 |
| Popis: | Background Response to targeted therapy varies between patients for largely unknown reasons. Here, we developed and applied an integrative platform using mass spectrometry imaging (MSI), phosphoproteomics, and multiplexed tissue imaging for mapping drug distribution, target engagement, and adaptive response to gain insights into heterogeneous response to therapy. Methods Patient-derived xenograft (PDX) lines of glioblastoma were treated with adavosertib, a Wee1 inhibitor, and tissue drug distribution was measured with MALDI-MSI. Phosphoproteomics was measured in the same tumors to identify biomarkers of drug target engagement and cellular adaptive response. Multiplexed tissue imaging was performed on sister sections to evaluate spatial co-localization of drug and cellular response. The integrated platform was then applied on clinical specimens from glioblastoma patients enrolled in the phase 1 clinical trial. Results PDX tumors exposed to different doses of adavosertib revealed intra- and inter-tumoral heterogeneity of drug distribution and integration of the heterogeneous drug distribution with phosphoproteomics and multiplexed tissue imaging revealed new markers of molecular response to adavosertib. Analysis of paired clinical specimens from patients enrolled in the phase 1 clinical trial informed the translational potential of the identified biomarkers in studying patient’s response to adavosertib. Conclusions The multimodal platform identified a signature of drug efficacy and patient-specific adaptive responses applicable to preclinical and clinical drug development. The information generated by the approach may inform mechanisms of success and failure in future early phase clinical trials, providing information for optimizing clinical trial design and guiding future application into clinical practice. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|