Personalized Drug Sensitivity Screening for Bladder Cancer Using Conditionally Reprogrammed Patient-derived Cells

Kettunen, K; Boström, Peter J.; Lamminen, Tarja; Heinosalo, Taija; West, Gun; Saarinen, Irena; Kaipio, Katja; Rantala, Juha; Albanese, Chris; Poutanen, Matti; Taimen, Pekka

doi:10.1016/j.eururo.2019.06.016

Cited by 33 publications

(34 citation statements)

References 11 publications

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“…We collected 8 most widely used BCa cell lines and confirmed their identity by STR. Whole-exome sequencing (WES) of the 8 cell lines together with 2 conditionally reprogrammed cells (CRCs) [4] and 2 BCa tissues (Table S4) showed the CRCs have good consistency with tumor tissues, however, the cell lines showed significant deviation from genuine BCa by wide-the previous reports [5], we detected only a tiny fraction of the known driver FGFR3 fusion in SW780 ( Fig. 1E).…”

mentioning

confidence: 62%

Genomic profiling of cell lines reveals hidden research bias and caveats

Luo

Ju²,

Zhang

et al. 2020

Preprint

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Cancer cell lines are extremely valuable tools for carcinoma research. Biodiversity of cell lines and continuous random mutation in cell lines during passage, however, might result in phenotypic inconsistency and lead to biased experimental conclusions. Using statistics based on known and inferred protein interaction networks, as well as public research literature database, our study shows that essential driver genotypes of cell lines might have hidden impact on research results. Furthermore, by comprehensive genomic profiling of 8 most common used urothelial cell lines and comparing them to previous publications, we found that regardless of similar short tandem repeat (STR) profile, driver gene loss in cell lines could happen by random mutation. Our results suggest that clinical research using urothelial carcinoma cell lines might be influenced by cell line genotypes which could only be determined by next-generation sequencing. Meanwhile, this study indicates that the conditionally reprogrammed cells (CRCs), which closely resemble original tumor tissue, might represent a better alternative for in vitro research, which may be better used for personalized medicine.

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mentioning

confidence: 62%

Genomic profiling of cell lines reveals hidden research bias and caveats

Luo

Ju²,

Zhang

et al. 2020

Preprint

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“…Mutations and/or activation by other mechanism of any one of the upstream genes (such as KRAS, BRAF, EGFR or MET) may result in abnormal activation of the signaling pathway converting into sensitivity towards inhibition of the MAPK signaling pathway [34]. Comparison of the sensitivity of patient derived tumor cells with the sensitivity of primary cultures previously derived from three urothelial bladder carcinomas and one small-cell neuroendocrine bladder carcinoma with no known MAPK pathway activating mutations [1] confirmed the selective sensitivity of the urachal cancer cells to the mTORC1/2 inhibitor AZD2014, MEK inhibitor trametinib and EFGR inhibitor afatinib (Supplementary Figure 2). To assess the genetic background of the patient's tumor cells a targeted oncopanel DNA sequencing was performed from tumor cells kept in continuous Fig.…”

Section: Evaluation Of Targeted Drug Combinationsmentioning

confidence: 99%

“…The development of high-throughput screening technologies and cell culture methods has made it feasible to perform large-scale in vitro drug screens also using patient derived primary tumor cell cultures [1][2][3]. These techniques are collectively called as ex vivo drug screening methods.…”

Section: Introductionmentioning

confidence: 99%

Ex vivo modelling of drug efficacy in a rare metastatic urachal carcinoma

et al. 2020

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Background: Ex vivo drug screening refers to the out-of-body assessment of drug efficacy in patient derived vital tumor cells. The purpose of these methods is to enable functional testing of patient specific efficacy of anti-cancer therapeutics and personalized treatment strategies. Such approaches could prove powerful especially in context of rare cancers for which demonstration of novel therapies is difficult due to the low numbers of patients. Here, we report comparison of different ex vivo drug screening methods in a metastatic urachal adenocarcinoma, a rare and aggressive non-urothelial bladder malignancy that arises from the remnant embryologic urachus in adults. Methods: To compare the feasibility and results obtained with alternative ex vivo drug screening techniques, we used three different approaches; enzymatic cell viability assay of 2D cell cultures and image-based cytometry of 2D and 3D cell cultures in parallel. Vital tumor cells isolated from a biopsy obtained in context of a surgical debulking procedure were used for screening of 1160 drugs with the aim to evaluate patterns of efficacy in the urachal cancer cells. Results: Dose response data from the enzymatic cell viability assay and the image-based assay of 2D cell cultures showed the best consistency. With 3D cell culture conditions, the proliferation rate of the tumor cells was slower and potency of several drugs was reduced even following growth rate normalization of the responses. MEK, mTOR, and MET inhibitors were identified as the most cytotoxic targeted drugs. Secondary validation analyses confirmed the efficacy of these drugs also with the new human urachal adenocarcinoma cell line (MISB18) established from the patient's tumor. Conclusions: All the tested ex vivo drug screening methods captured the patient's tumor cells' sensitivity to drugs that could be associated with the oncogenic KRAS G12V mutation found in the patient's tumor cells. Specific drug classes however resulted in differential dose response profiles dependent on the used cell culture method indicating that the choice of assay could bias results from ex vivo drug screening assays for selected drug classes.

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“…In this study, we report an image-based ex vivo screen to assess drug efficacy on metastatic thymoma cells and to inform treatment of the patient after the standard treatments had been exhausted. Highthroughput drug screening with vital patient derived cell cultures makes it possible to assess therapeutic efficacy of hundreds of drugs in parallel [14,15]. It is thus an attractive application for biomarker discovery and assessment of patient and tumor type specific therapy sensitivity especially in context of rare cancers such as metastatic thymoma, for which alternative approaches to better stratify patients to matched targeted therapies are currently unavailable [16].…”

Section: Introductionmentioning

confidence: 99%

Image-based ex vivo drug screen to assess targeted therapies in recurrent thymoma

Arjonen¹,

Mäkelä²,

Härmä

et al. 2020

Lung Cancer

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Thymoma is a rare malignancy derived from the thymic epithelial cells. No standard salvage treatments are available for recurrent thymoma and due to the low number of cases, alternative treatment regimens have been assessed only in small case series with varying success. The aim of this study was to use an imagebased ex vivo drug screening strategy to assess efficacy of a large panel of anti-cancer agents for thymoma using patient derived tumor cells. Materials and Methods: Vital tumor and tumor associated cells were used to assess the efficacy of 147 anti-cancer drugs including approved and experimental agents. Drug efficacy was analyzed at single cell resolution using image-based high content drug screening to assess tumor cell specific responses. Molecular profiling and histopathology was used to confirm the drug targets identified by the screen. Results: The ex vivo drug screen identified selective sensitivity of the cancerous epithelial thymoma cells to EGFR-, HDAC-and mTOR-inhibition. Histopathology confirmed high protein level expression of EGFR in the patient's tumor. Patient was initiated treatment with Cetuximab resulting in stable disease after relapse on five different chemotherapy regimens. Conclusion: The results show that the image-based ex vivo therapy efficacy screening strategy can be used to identify patient and tumor relevant drug sensitivity patterns in thymoma. The results also warrant continued research on EGFR as a biomarker and therapy target in recurrent thymomas.

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Personalized Drug Sensitivity Screening for Bladder Cancer Using Conditionally Reprogrammed Patient-derived Cells

Cited by 33 publications

References 11 publications

Genomic profiling of cell lines reveals hidden research bias and caveats

Genomic profiling of cell lines reveals hidden research bias and caveats

Ex vivo modelling of drug efficacy in a rare metastatic urachal carcinoma

Image-based ex vivo drug screen to assess targeted therapies in recurrent thymoma

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