A patient‐derived explant (<scp>PDE</scp>) model of hormone‐dependent cancer

Centenera, Margaret M.; Hickey, Theresa E.; Jindal, Shalini; Ryan, Natalie K.; Ravindranathan, Preethi; Mohammed, Hisham; Robinson, James C.; Schiewer, Matthew J.; Ma, Shihong; Kapur, Payal; Sutherland, Peter; Hoffmann, Clive E.; Roehrborn, Claus G.; Gomella, Leonard G.; Carroll, Jason S.; Birrell, Stephen N.; Knudsen, Karen E.; Raj, Ganesh V.; Butler, Lisa M.; Tilley, Wayne D.

doi:10.1002/1878-0261.12354

Cited by 108 publications

(99 citation statements)

References 48 publications

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“…21,23,28,29 As reported in these studies, maintenance of prostate or PCa tissue slices for a week could be achieved, but conservation of tissue structure and functionality was not always comprehensively reported with extensive variability in tissue origin and evaluation in the different studies. Application of the ex vivo culture system for drug testing was only reported in a few studies, describing reduced cell proliferation in response to genistein, 29 cisplatin combined with a BcL-2 antagonist, 30 heat shock protein 90 inhibitors 28 PARP-1 inhibitors, 31 and most recently published studies with bicalutamide 32 and docetaxel. 33 However detailed cell cycle progression (proliferation) of the tumor cells was not investigated, making direct comparison to our studies difficult.…”

Section: Discussionmentioning

confidence: 99%

Ex vivo treatment of prostate tumor tissue recapitulates in vivo therapy response

et al. 2018

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Background In vitro models of prostate cancer (PCa) are not always reliable to evaluate anticancer treatment efficacy. This limitation may be overcome by using viable tumor slice material. Here we report on the establishment of an optimized ex vivo method to culture tissue slices from patient‐derived xenografts (PDX) of prostate cancer (PCa), to assess responses to PCa treatments. Methods Three PDX models were used that are characterized by different androgen receptor (AR) expression and different homology directed DNA repair capacities, due to a breast cancer associated two ( BRCA2 ) wild‐type or mutated status. Tumors were removed from mice, sliced using a vibratome and cultured for a maximum of 6 days. To test the sensitivity to androgen antagonist, tumor slices from the AR‐expressing and AR‐negative PDX tumors were treated with the anti‐androgen enzalutamide. For sensitivity to DNA repair intervention, tumors slices from BRCA2 wild‐type and mutated PDXs were treated with the poly (ADP‐ribose) polymerase‐1 inhibitor olaparib. Treatment response in these tumor slices was determined by measuring slice morphology, cell proliferation, apoptosis, AR expression level, and secretion of prostate specific antigen (PSA). Results We compared various culture conditions (support materials, growth media, and use of a 3D smooth rocking platform) to define the optimal condition to maintain tissue viability and proliferative capacity up to least 6 days. Under optimized conditions, enzalutamide treatment significantly decreased proliferation, increased apoptosis, and reduced AR‐expression and PSA secretion of AR‐expressing tumor slices compared to AR‐negative slices, that did not respond to the intervention. Olaparib treatment significantly increased cell death in BRCA2 mutated tumors slices as compared to slices from BRCA2 wild type tumors. Conclusions Ex vivo treatment of PCa PDX tumor slices with enzalutamide and olaparib recapitulates responses previously observed in vivo. The faithful retention of tissue structure and function in this ex vivo model offers an ideal opportunity for treatment efficacy screening, thereby reducing costs and numbers of experimental animals.

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Section: Discussionmentioning

confidence: 99%

Ex vivo treatment of prostate tumor tissue recapitulates in vivo therapy response

et al. 2018

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“…82,83 In the breast cancer study, PDE responses to the targeted therapy TRAIL were found to be more consistent with clinical trial data than 2D tumour model systems. 80,84 The gelatine-sponge approach has proved successful for the culture of explants derived from breast and prostate tumours, 85 and has been applied to the testing of novel anti-cancer agents, 66,67,86,87 development of biomarkers 87,88 and for monitoring changes in the tumour microenvironment. 89 In these studies, the PDE approach contributed important information to show the effect of the PARP inhibitor ABT888 in suppressing tumour cell proliferation in human prostate cancers 86 and the effect of progesterone in inhibiting the proliferation of the oestrogenmediated growth of ERα + breast cancers.…”

Section: Recent Advances In Pde-based Platformsmentioning

confidence: 99%

Patient-derived explants (PDEs) as a powerful preclinical platform for anti-cancer drug and biomarker discovery

et al. 2020

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Preclinical models that can accurately predict outcomes in the clinic are much sought after in the field of cancer drug discovery and development. Existing models such as organoids and patient-derived xenografts have many advantages, but they suffer from the drawback of not contextually preserving human tumour architecture. This is a particular problem for the preclinical testing of immunotherapies, as these agents require an intact tumour human-specific microenvironment for them to be effective. In this review, we explore the potential of patient-derived explants (PDEs) for fulfilling this need. PDEs involve the ex vivo culture of fragments of freshly resected human tumours that retain the histological features of original tumours. PDE methodology for anti-cancer drug testing has been in existence for many years, but the platform has not been widely adopted in translational research facilities, despite strong evidence for its clinical predictivity. By modifying PDE endpoint analysis to include the spatial profiling of key biomarkers by using multispectral imaging, we argue that PDEs offer many advantages, including the ability to correlate drug responses with tumour pathology, tumour heterogeneity and changes in the tumour microenvironment. As such, PDEs are a powerful model of choice for cancer drug and biomarker discovery programmes.

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“…4a). PDXDE models have been shown to accurately predict patient-specific responses to multiple drugs and to mimic in vivo results in breast cancer 44,45 . We first established the appropriate culture conditions to maintain TNBC PDXDEs.…”

Section: Pharmacological Inhibition Of Glut1 Impedes Tnbc Cancer Growmentioning

confidence: 99%

GLUT1 inhibition blocks growth of RB1-positive Triple Negative Breast Cancer

Ba-Alawi

Deblois

et al. 2019

Preprint

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Triple negative breast cancer (TNBC) is a deadly form of breast cancer due to the development of resistance to chemotherapy affecting over 30% of patients. New therapeutics and companion biomarkers are urgently needed. Recognizing the elevated expression of glucose transporter 1 (GLUT1, encoded by SLC2A1) and associated metabolic dependencies in TNBC, we investigated the vulnerability of TNBC cell lines and patient-derived samples to GLUT1 inhibition. We report that genetic or pharmacological inhibition of GLUT1 with BAY-876 impairs the growth of a subset of TNBC cells displaying high glycolytic and lower oxidative phosphorylation (OXPHOS) rates. Pathway enrichment analysis of gene expression data implicates E2F Targets pathway activity as a surrogate of OXPHOS activity. Furthermore, the protein levels of retinoblastoma tumor suppressor (RB1) are strongly correlated with the degree of sensitivity to GLUT1 inhibition in TNBC, where RB1-negative cells are insensitive to GLUT1 inhibition. Collectively, our results highlight a strong and targetable RB1-GLUT1 metabolic axis in TNBC and warrant clinical evaluation of GLUT1 inhibition in TNBC patients stratified according to RB1 protein expression levels.

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A patient‐derived explant (PDE) model of hormone‐dependent cancer

Cited by 108 publications

References 48 publications

Ex vivo treatment of prostate tumor tissue recapitulates in vivo therapy response

Ex vivo treatment of prostate tumor tissue recapitulates in vivo therapy response

Patient-derived explants (PDEs) as a powerful preclinical platform for anti-cancer drug and biomarker discovery

GLUT1 inhibition blocks growth of RB1-positive Triple Negative Breast Cancer

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