|Title||Multimodal platform for assessing drug distribution and response in clinical trials.|
|Publication Type||Journal Article|
|Year of Publication||2022|
|Authors||Lopez BGC, Kohale IN, Du Z, Korsunsky I, Abdelmoula WM, Dai Y, Stopka SA, Gaglia G, Randall EC, Regan MS, Basu SS, Clark AR, Marin B-M, Mladek AC, Burgenske DM, Agar JN, Supko JG, Grossman SA, Nabors LB, Raychaudhuri S, Ligon KL, Wen PY, Alexander B, Lee EQ, Santagata S, Sarkaria J, White FM, Agar NYR|
|Date Published||2022 01 05|
|Keywords||Glioblastoma, Humans, Pharmaceutical Preparations|
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.
|Alternate Journal||Neuro Oncol|
|PubMed Central ID||PMC8730776|
|Grant List||P41 EB015898 / EB / NIBIB NIH HHS / United States |
R25 CA089017 / CA / NCI NIH HHS / United States
UM1 CA137443 / CA / NCI NIH HHS / United States
T32 GM007306 / GM / NIGMS NIH HHS / United States
U54 CA210180 / CA / NCI NIH HHS / United States
T32 EB025823 / EB / NIBIB NIH HHS / United States
U54 CA225088 / CA / NCI NIH HHS / United States
R01 CA201469 / CA / NCI NIH HHS / United States
T32 HL007627 / HL / NHLBI NIH HHS / United States