Tumour stromal morphology impacts nanomedicine cytotoxicity in patient-derived xenografts.
It is challenging to evaluate how tumour pathophysiology influences nanomedicine therapeutic effect; however, this is a key question in drug delivery. An advanced analytical method was developed to quantify the spatial distribution of drug-induced effect in tumours with varied stromal morphologies. The analysis utilises standard immunohistochemistry images and quantifies the frequency of positive staining as a function of distance from the stroma. Two stromal morphologies - Estuary and Tumour Island - were classified in 28 tumours from a lung cancer explant model in mice treated with liposomal doxorubicin. Analysis demonstrated that Estuary-like tumours presented a highly convoluted tumour-stroma interface, with most tumour cells in close proximity to vessels; these tumours were 8.8-fold more responsive to liposomal doxorubicin than were Tumour Island-like tumours, which were nearly unresponsive to liposomal doxorubicin. SDARS analysis allows the relative treatment effect to be assessed in tumours individually, and enables investigation of nanomedicine delivery in complex tumour pathophysiologies.


BACKGROUND
Advances in nanotechnology have brought about many novel treatment modalities for cancer. Nonetheless, there is no standard evaluation technique for tumor cells' drug response. The authors here utilized patient-derived tumour xenograft (PDTX) models to have a more translatable pre-clinical evaluation platform for nanomedicine drugs. They then used advanced imaging acquisition technique to analyze tumor stromal morphology, which they named Spatial Distribution of Apoptosis Relative to Stroma (SDARS). The findings would have significant clinical impact as it would help predict the eventual clinical drug response.
Modelling & Simulation, Oncology DMPK, AstraZeneca, Macclesfield, UK; Physics Department, University of Aberdeen, Aberdeen, UK.
Juan A
JA
Delgado San Martin
Oncology iMed, AstraZeneca, Macclesfield, UK. Electronic address: Jennifer.Hare@astrazeneca.com.
Jennifer I
JI
Hare
Modelling & Simulation, Oncology DMPK, AstraZeneca, Macclesfield, UK.
James W T
JW
Yates
Oncology iMed, AstraZeneca, Macclesfield, UK.
Simon T
ST
Barry
D000465:Algorithms; D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D004317:Doxorubicin / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D005260:Female; D006801:Humans; D007091:Image Processing, Computer-Assisted / Q000379:methods; D007150:Immunohistochemistry / Q000379:methods; D008168:Lung / Q000187:drug effects / Q000473:pathology*; D008175:Lung Neoplasms / Q000188:drug therapy / Q000473:pathology*; D051379:Mice; D016513:Mice, SCID; D018307:Neoplasms, Squamous Cell / Q000188:drug therapy / Q000473:pathology*; D011092:Polyethylene Glycols / Q000494:pharmacology / Q000627:therapeutic use; D023041:Xenograft Model Antitumor Assays
D000903:Antibiotics, Antineoplastic; C506643:liposomal doxorubicin; D011092:Polyethylene Glycols; D004317:Doxorubicin
Image analysis; Immunohistochemistry; Microenvironment; Patient-derived tumour xenograft; Stroma; Tumour morphology