Generating human prostate cancer organoids from leukapheresis enriched circulating tumour cells

Mout, Lisanne; Dessel, Lisanne F. van; Kraan, Jaco; Jong, Anouk C. de; Neves, Rui P.; Erkens-Schulze, Sigrun; Beaufort, Corine M.; Sieuwerts, Anieta M.; Riet, Job van; Woo, Thomas; Wit, Ronald de; Sleijfer, Stefan; Hamberg, Paul; Sandberg, Yorick; Boekhorst, Peter te; Werken, Harmen J.G. van de; Martens, John W.M.; Stoecklein, Nikolas H.; Weerden, Wytske M. van; Lolkema, Martijn P.

doi:10.1016/j.ejca.2021.03.023

Cited by 56 publications

(56 citation statements)

References 21 publications

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“…Measuring gene expression in single or a collection of pure CTCs (23) could give a more comprehensive and reliable sensitivity profile. Future research should also focus on diagnostic leukapheresis (DLA), since with this technique large amounts of CTCs can be obtained, and on generating organoids from CTCs to test drug sensitivity (24). Large amounts of patient derived and pure materials, in combination with techniques as single CTC genomics and transcriptomics, are promising tools to generate predictive sensitivity profiles.…”

Section: Discussionmentioning

confidence: 99%

Prospective Evaluation of a Circulating Tumor Cell Sensitivity Profile to Predict Response to Cisplatin Chemotherapy in Metastatic Breast Cancer Patients

et al. 2021

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BackgroundCisplatin (cDDP) has regained interest for metastatic breast cancer (MBC) patients, given the platinum sensitivity in subtypes and better manageable toxicity. Here, the primary aim was to determine whether molecular characteristics of circulating tumor cells (CTCs) could identify patients responding to cDDP and to describe the outcomes to cDDP monotherapy in a large group of MBC patients pretreated with anthracycline- and taxane-based treatments.MethodsBased on cell line data, a CTC-cDDP-sensitivity profile was generated. Applying an A’Herns single-stage phase II design, further investigation was considered worthwhile if 5/10 patients with a favorable profile responded to cDDP. Patients received 70mg/m2 cDDP every three weeks, CTCs were enumerated and the CTC-cDDP-sensitivity profile was determined. In total, 65 heavily pretreated MBC patients (77% received ≥2 lines of previous chemotherapy for MBC) were eligible for the per-protocol analysis. Primary endpoint was response rate, secondary endpoints included best observed response, progression-free survival (PFS) and overall survival (OS).ResultsThe best observed response during cDDP therapy was a partial response in 7% and stable disease in 56% of the patients. None of the patients with a favorable CTC-cDDP-sensitivity profile had a response. The median baseline CTC count was 8 (range 0-3254). Patients with <5 CTCs had a better PFS and OS than patients with ≥5 CTCs (median PFS 4.5 months (95%CI 2.38-6.62) vs. 2.1 months [(95%CI 1.34-2.80)(p=0.009)] and median OS 13.1 months (95%CI 9.89-16.33) vs. 5.6 months [(95%CI 3.60-7.64)(p=0.003)]. No other factors than CTC count were associated with outcome to cDDP therapy, including triple-negative breast cancer versus ER-positive tumors.ConclusionsThe CTC-cDDP-sensitivity profile was unable to select patients responding to cDDP monotherapy. In an unselected group of heavily pretreated MBC patients, cDDP yields outcomes comparable to other chemotherapeutic regimens for heavily pretreated MBC patients. CTC count was the only factor associated with outcome in these patients.Clinical Trial Registration(https://www.trialregister.nl/trial/3885, identifier NTR4046)

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Section: Discussionmentioning

confidence: 99%

Prospective Evaluation of a Circulating Tumor Cell Sensitivity Profile to Predict Response to Cisplatin Chemotherapy in Metastatic Breast Cancer Patients

et al. 2021

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“…Consequently, it has been found that tumor cells may disseminate, even when the tumor is still "confined", or before the detection of the primary tumor by imaging [39,40]. Moreover, the assessment of living tumor cells has the advantage of directly measuring the response to treatment compared with evaluation after tissue fixation [41,42]. Notwithstanding the potential of CTCs, their use is limited by their scarcity and the need for highly specialized techniques enabling their isolation.…”

Section: Circulating Tumor Cellsmentioning

confidence: 99%

“…Indeed, following CTC isolation, several techniques can be used to investigate gene and protein expression [58]; genomic profiling can be carried out by sequencing; functional experiments can be conducted to evaluate metastasis, cell-cell communication, drug testing, and many other experiments [76] (Figure 1). Importantly, CTCs can be maintained in culture in vitro, either dissociated or as organoids, in which case they may be maintained for at least six weeks, as demonstrated by Mout et al [41]. Establishing PCa cell lines from liquid biopsy samples provides several advantages, including a lack of contaminant (and competing), normal epithelial and stromal cells, as well as the possibility of obtaining metastatic samples from patients with bone disease in a minimally invasive manner [41].…”

Section: Circulating Tumor Cellsmentioning

confidence: 99%

“…Importantly, CTCs can be maintained in culture in vitro, either dissociated or as organoids, in which case they may be maintained for at least six weeks, as demonstrated by Mout et al [41]. Establishing PCa cell lines from liquid biopsy samples provides several advantages, including a lack of contaminant (and competing), normal epithelial and stromal cells, as well as the possibility of obtaining metastatic samples from patients with bone disease in a minimally invasive manner [41].…”

Section: Circulating Tumor Cellsmentioning

confidence: 99%

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Bridging the Gaps between Circulating Tumor Cells and DNA Methylation in Prostate Cancer

Flores

Correia

Rodriguez

et al. 2021

Cancers

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Prostate cancer is the second most common male malignancy, with a highly variable clinical presentation and outcome. Therefore, diagnosis, prognostication, and management remain a challenge, as available clinical, imaging, and pathological parameters provide limited risk assessment. Thus, many biomarkers are under study to fill this critical gap, some of them based on epigenetic aberrations that might be detected in liquid biopsies. Herein, we provide a critical review of published data on the usefulness of DNA methylation and circulating tumor cells in diagnosis and treatment decisions in cases of prostate cancer, underlining key aspects and discussing the importance of these advances to the improvement of the management of prostate cancer patients. Using minimally invasive blood tests, the detection of highly specific biomarkers might be crucial for making therapeutic decisions, determining response to specific treatments, and allowing early diagnosis.

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“…Encouraging results from recent studies using patient-derived tumor organoids for personalized drug response profiling highlight the exceptional potential of these near-patient preclinical models in oncology research [ 5 , 6 , 7 , 8 ]. Additionally, in prostate cancer (PCa) research, organoids have been shown to be promising tools for preclinical drug testing and for studying emerging treatment resistant phenotypes [ 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 ].…”

Section: Introductionmentioning

confidence: 99%

Modeling Prostate Cancer Treatment Responses in the Organoid Era: 3D Environment Impacts Drug Testing

et al. 2021

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Organoid-based studies have revolutionized in vitro preclinical research and hold great promise for the cancer research field, including prostate cancer (PCa). However, experimental variability in organoid drug testing complicates reproducibility. For example, we observed PCa organoids to be less affected by cabazitaxel, abiraterone and enzalutamide as compared to corresponding single cells prior to organoid assembly. We hypothesized that three-dimensional (3D) organoid organization and the use of various 3D scaffolds impact treatment efficacy. Live-cell imaging of androgen-induced androgen receptor (AR) nuclear translocation and taxane-induced tubulin stabilization was used to investigate the impact of 3D scaffolds, spatial organoid distribution and organoid size on treatment effect. Scaffolds delayed AR translocation and tubulin stabilization, with Matrigel causing a more pronounced delay than synthetic hydrogel as well as incomplete tubulin stabilization. Drug effect was further attenuated the more centrally organoids were located in the scaffold dome. Moreover, cells in the organoid core revealed a delayed treatment effect compared to cells in the organoid periphery, underscoring the impact of organoid size. These findings indicate that analysis of organoid drug responses needs careful interpretation and requires dedicated read-outs with consideration of underlying technical aspects.

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Generating human prostate cancer organoids from leukapheresis enriched circulating tumour cells

Cited by 56 publications

References 21 publications

Prospective Evaluation of a Circulating Tumor Cell Sensitivity Profile to Predict Response to Cisplatin Chemotherapy in Metastatic Breast Cancer Patients

Prospective Evaluation of a Circulating Tumor Cell Sensitivity Profile to Predict Response to Cisplatin Chemotherapy in Metastatic Breast Cancer Patients

Bridging the Gaps between Circulating Tumor Cells and DNA Methylation in Prostate Cancer

Modeling Prostate Cancer Treatment Responses in the Organoid Era: 3D Environment Impacts Drug Testing

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