Abstract:Background
Radiotherapy is one of the cornerstones of the treatment of Head and Neck Squamous Cell Carcinomas (HNSCC). However, radioresistance is associated with a high risk of recurrence. To propose strategies (such as combinations with drugs) that could over intrinsic radioresistance, it is crucial to predict the response to treatment. Patient-Derived Tumor Organoids (PDTO) are in vitro tridimensional microtumors obtained from patient’ own cancer samples. They have been shown to serve as rel… Show more
“…The TRIPLEX study and this manuscript have been written in accordance with standard protocol items, namely recommendations for interventional trials (SPIRIT). The method and design of this study is based on the ORGAVADS study described by Perréard et al [ 30 ]. Fig.…”
Section: Method/designmentioning
confidence: 99%
“…RNA analysis will be performed according to the protocol described in Perréard et al [ 30 ]. Briefly, total RNA will be extracted using the Nucleospin RNA kit (Macherey Nagel, Hoerdt) and libraries will be made with the QuantSeq 3’RNA Library Kitto.…”
Section: Method/designmentioning
confidence: 99%
“…Analysis of intra reproducibility and differences between original tumors and PDTO will be assessed by PCA and unsupervised hierarchical clustering as described in Perréard et al [ 30 ].…”
Background
Triple negative breast cancers (TNBC) account for approximately 15% of all breast cancers and are associated with a shorter median survival mainly due to locally advanced tumor and high risk of metastasis. The current neoadjuvant treatment for TNBC consists of a regimen of immune checkpoint blocker and chemotherapy (chemo-ICB). Despite the frequent use of this combination for TNBC treatment, moderate results are observed and its clinical benefit in TNBC remains difficult to predict. Patient-derived tumor organoids (PDTO) are 3D in vitro cellular structures obtained from patient’s tumor samples. More and more evidence suggest that these models could predict the response of the tumor from which they are derived. PDTO may thus be used as a tool to predict chemo-ICB efficacy in TNBC patients.
Method
The TRIPLEX study is a single-center observational study conducted to investigate the feasibility of generating PDTO from TNBC and to evaluate their ability to predict clinical response. PDTO will be obtained after the dissociation of biopsies and embedding into extra cellular matrix. PDTO will be cultured in a medium supplemented with growth factors and signal pathway inhibitors. Molecular and histological analyses will be performed on established PDTO lines to validate their phenotypic proximity with the original tumor. Response of PDTO to chemo-ICB will be assessed using co-cultures with autologous immune cells collected from patient blood samples. PDTO response will finally be compared with the response of the patient to evaluate the predictive potential of the model.
Discussion
This study will allow to assess the feasibility of using PDTO as predictive tools for the evaluation of the response of TNBC patients to treatments. In the event that PDTO could faithfully predict patient response in clinically relevant time frames, a prospective clinical trial could be designed to use PDTO to guide clinical decision. This study will also permit the establishment of a living biobank of TNBC PDTO usable for future innovative strategies evaluation.
Trial registration
The clinical trial (version 1.2) has been validated by local research ethic committee on December 30th 2021 and registered at ClinicalTrials.gov with the identifier NCT05404321 on June 3rd 2022, version 1.2.
“…The TRIPLEX study and this manuscript have been written in accordance with standard protocol items, namely recommendations for interventional trials (SPIRIT). The method and design of this study is based on the ORGAVADS study described by Perréard et al [ 30 ]. Fig.…”
Section: Method/designmentioning
confidence: 99%
“…RNA analysis will be performed according to the protocol described in Perréard et al [ 30 ]. Briefly, total RNA will be extracted using the Nucleospin RNA kit (Macherey Nagel, Hoerdt) and libraries will be made with the QuantSeq 3’RNA Library Kitto.…”
Section: Method/designmentioning
confidence: 99%
“…Analysis of intra reproducibility and differences between original tumors and PDTO will be assessed by PCA and unsupervised hierarchical clustering as described in Perréard et al [ 30 ].…”
Background
Triple negative breast cancers (TNBC) account for approximately 15% of all breast cancers and are associated with a shorter median survival mainly due to locally advanced tumor and high risk of metastasis. The current neoadjuvant treatment for TNBC consists of a regimen of immune checkpoint blocker and chemotherapy (chemo-ICB). Despite the frequent use of this combination for TNBC treatment, moderate results are observed and its clinical benefit in TNBC remains difficult to predict. Patient-derived tumor organoids (PDTO) are 3D in vitro cellular structures obtained from patient’s tumor samples. More and more evidence suggest that these models could predict the response of the tumor from which they are derived. PDTO may thus be used as a tool to predict chemo-ICB efficacy in TNBC patients.
Method
The TRIPLEX study is a single-center observational study conducted to investigate the feasibility of generating PDTO from TNBC and to evaluate their ability to predict clinical response. PDTO will be obtained after the dissociation of biopsies and embedding into extra cellular matrix. PDTO will be cultured in a medium supplemented with growth factors and signal pathway inhibitors. Molecular and histological analyses will be performed on established PDTO lines to validate their phenotypic proximity with the original tumor. Response of PDTO to chemo-ICB will be assessed using co-cultures with autologous immune cells collected from patient blood samples. PDTO response will finally be compared with the response of the patient to evaluate the predictive potential of the model.
Discussion
This study will allow to assess the feasibility of using PDTO as predictive tools for the evaluation of the response of TNBC patients to treatments. In the event that PDTO could faithfully predict patient response in clinically relevant time frames, a prospective clinical trial could be designed to use PDTO to guide clinical decision. This study will also permit the establishment of a living biobank of TNBC PDTO usable for future innovative strategies evaluation.
Trial registration
The clinical trial (version 1.2) has been validated by local research ethic committee on December 30th 2021 and registered at ClinicalTrials.gov with the identifier NCT05404321 on June 3rd 2022, version 1.2.
“…9 Moreover, patient-derived tumoroids from HNC facilitate treatment stratification and serve as an indispensable tool for the validation and identification of biomarkers. 20 Perréard et al (2023) successfully developed organoids from HNSCC to assess their sensitivity to different novel therapeutic approaches and demonstrated that these organoids are reliable surrogates for predicting tumor response in patients. 21…”
Section: Opportunities For Patient-derived Organoid Cultures In Head ...mentioning
confidence: 99%
“…20 Perréard et al (2023) successfully developed organoids from HNSCC to assess their sensitivity to different novel therapeutic approaches and demonstrated that these organoids are reliable surrogates for predicting tumor response in patients. 21…”
Section: Opportunities For Patient-derived Organoid Cultures In Head ...mentioning
Patient‐derived organoid models hold promise for advancing clinical cancer research, including diagnosis and personalized and precision medicine approaches, and cytology, in particular, plays a pivotal role in this process. These three‐dimensional multicellular structures are heterogeneous, potentially maintain the cancer phenotype, and conserve the genomic, transcriptomic, and epigenomic patterns of the parental tumors. To ensure that only tumor tissue is used for organoid development, cytologic validation is necessary before initiating the process of organoid generation. Here, we explore the technology of tumor organoids and discuss the fundamental application of cytology as a simple and cost‐effective approach toward organoid development. We also underscore the potential application of organoid development in drug efficacy studies for lung cancer and head and neck tumors. Additionally, we stress the importance of using fine‐needle aspiration to generate tumoroids.
BackgroundHead and neck malignancy, and in particular squamous cell carcinoma (SCC), is responsible for a significant disease burden globally. The lack of an optimal in vitro model system to accurately recapitulate in vivo response to therapy in HNSCC remains a challenge. The development of patient‐derived three‐dimensional tumour cultures, or tumoroids, has enabled improved modelling of the tumour microenvironment through simulation of important characteristics such as tumour hypoxia, cell–cell interactions and nutrient diffusion characteristics.MethodsWe performed a comprehensive English‐language literature review of current methods of tumoroid development utilising Matrigel and Cultrex Basement Membrane Extract 2 (key terms: tumour organoids, tumoroids, hydrogels, Matrigel, Cultrex, squamous cell carcinoma, head and neck)—two common proprietary murine‐derived hydrogels containing extracellular matrix proteins. Nascent literature on the establishment of a novel hydrogel‐free platform for tumoroid development as distinct from these existing methods was also explored.ResultsWhilst useful for facilitating cell‐matrix interactions and providing a scaffold for three‐dimensional cell growth and organisation, murine‐derived cell matrix methods were noted to have notable limitations including temperature sensitivity and the medium forming a barrier to analysis of the supernatant. A novel hydrogel‐free method of establishing in vitro tumoroid cultures has been subject to experimentation in colorectal but not head and neck malignancy. The absence of a hydrogel provides for the de novo synthesis of extracellular matrix native to the tumour and self‐organisation of cells within this scaffold through the use of ultralow attachment plates. This model demonstrates similar structural and physiological properties to native tissue, whilst enabling more accurate biomimicry of the tumour microenvironment for drug testing.ConclusionsIn the absence of prior experimentation on a hydrogel‐free method for establishing HNSCC tumoroids, and comparisons between hydrogel and hydrogel‐free models, the future development of a comparative protocol encompassing recruitment, collection, processing and analysis represents a valuable opportunity.
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