Increased sensitivity to SMAC mimetic LCL161 identified by longitudinal ex vivo pharmacogenomics of recurrent, KRAS mutated rectal cancer liver metastases

Kryeziu, Kushtrim; Moosavi, Seyed H.; Bergsland, Christian H.; Guren, Marianne G.; Eide, Peter W.; Totland, Max Z.; Lassen, Kristoffer; Abildgaard, Andreas; Nesbakken, Arild; Sveen, Anita; Lothe, Ragnhild A.

doi:10.1186/s12967-021-03062-3

Cited by 10 publications

(9 citation statements)

References 41 publications

(57 reference statements)

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“…Another study documented the feasibility of tumoroids in the accurate recapitulation of KRAS-mutant metastatic rectal cancer with microsatellite stability after hepatic resection and treatment with neoadjuvant combination chemotherapies of 5-FU, leucovorin, and oxaliplatin [114]. The histopathological differentiation phenotypes of these PDOs were consistent with liver metastases [114].…”

Section: Colorectal Cancermentioning

confidence: 98%

“…Organoids are also utilized to provide insights into possible therapeutic targets and facilitate the development of novel antitumor drugs, such as the SMAC mimetic LCL161 for liver metastatic rectal cancer organoids [114] and the novel CDK7 inhibitor YPN-005 for SCLC organoid lines [179]. A high-throughput screen based on the interaction of patient-derived BCOs and tumor-specific cytotoxic T cells identified three epigenetic inhibitors, BML-210, GSK-LSD1, and CUDC-101, with significant antitumor effects [180].…”

Section: Discovery Of Novel Anticancer Targets and Promising Drug Can...mentioning

confidence: 99%

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Tumor organoids: applications in cancer modeling and potentials in precision medicine

et al. 2022

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Cancer is a top-ranked life-threatening disease with intratumor heterogeneity. Tumor heterogeneity is associated with metastasis, relapse, and therapy resistance. These factors contribute to treatment failure and an unfavorable prognosis. Personalized tumor models faithfully capturing the tumor heterogeneity of individual patients are urgently needed for precision medicine. Advances in stem cell culture have given rise to powerful organoid technology for the generation of in vitro three-dimensional tissues that have been shown to more accurately recapitulate the structures, specific functions, molecular characteristics, genomic alterations, expression profiles, and tumor microenvironment of primary tumors. Tumoroids in vitro serve as an important component of the pipeline for the discovery of potential therapeutic targets and the identification of novel compounds. In this review, we will summarize recent advances in tumoroid cultures as an excellent tool for accurate cancer modeling. Additionally, vascularization and immune microenvironment modeling based on organoid technology will also be described. Furthermore, we will summarize the great potential of tumor organoids in predicting the therapeutic response, investigating resistance-related mechanisms, optimizing treatment strategies, and exploring potential therapies. In addition, the bottlenecks and challenges of current tumoroids will also be discussed in this review.

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Section: Colorectal Cancermentioning

confidence: 98%

Section: Discovery Of Novel Anticancer Targets and Promising Drug Can...mentioning

confidence: 99%

Tumor organoids: applications in cancer modeling and potentials in precision medicine

et al. 2022

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“…The advancement of in vitro tumor models has greatly accelerated, resulting in the creation of various model designs such as tumor spheroids, tumor organoids, and 3D bioprinted models. Organoids, in particular, are employed not only to gain insights into potential therapeutic targets but also to expedite the development of innovative anti-tumor medications [ 137 – 139 ]. For instance, liver metastatic rectal cancer organoids have been utilized to study the effects of the SMAC mimetic LCL161 [ 139 ], while SCLC organoid lines have facilitated research on the novel CDK7 inhibitor YPN-005 [ 137 ].…”

Section: Organoids For Clinical Applicationmentioning

confidence: 99%

Patient-derived organoids in human cancer: a platform for fundamental research and precision medicine

Qu,

Xu,

et al. 2024

Mol Biomed

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Cancer is associated with a high degree of heterogeneity, encompassing both inter- and intra-tumor heterogeneity, along with considerable variability in clinical response to common treatments across patients. Conventional models for tumor research, such as in vitro cell cultures and in vivo animal models, demonstrate significant limitations that fall short of satisfying the research requisites. Patient-derived tumor organoids, which recapitulate the structures, specific functions, molecular characteristics, genomics alterations and expression profiles of primary tumors. They have been efficaciously implemented in illness portrayal, mechanism exploration, high-throughput drug screening and assessment, discovery of innovative therapeutic targets and potential compounds, and customized treatment regimen for cancer patients. In contrast to conventional models, tumor organoids offer an intuitive, dependable, and efficient in vitro research model by conserving the phenotypic, genetic diversity, and mutational attributes of the originating tumor. Nevertheless, the organoid technology also confronts the bottlenecks and challenges, such as how to comprehensively reflect intra-tumor heterogeneity, tumor microenvironment, tumor angiogenesis, reduce research costs, and establish standardized construction processes while retaining reliability. This review extensively examines the use of tumor organoid techniques in fundamental research and precision medicine. It emphasizes the importance of patient-derived tumor organoid biobanks for drug development, screening, safety evaluation, and personalized medicine. Additionally, it evaluates the application of organoid technology as an experimental tumor model to better understand the molecular mechanisms of tumor. The intent of this review is to explicate the significance of tumor organoids in cancer research and to present new avenues for the future of tumor research.

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“…Another observational coclinical study checked the standard combination of chemotherapy regimens in a PDO model generated from a patient with recurrent KRAS-mutated liver metastases from RC. They identified the SMAC mimetic as a unique therapeutic option in PDOs from the recurrent tumor tissue (51). Park et al developed a prediction model to analyze clinical and laboratory patients' radiotherapy response data by using a machine learning algorithm.…”

Section: Personalized Medicine Based On the Testing Of Individual Pdosmentioning

confidence: 99%

“…This case sets a great example for clinical application except for the small sample size. It is promising to conduct practice based on more large samples for evaluating the potential of PDOs in precision medicine ( 51 ).…”

Section: Drug Screening To Develop Novel Treatment Strategiesmentioning

confidence: 99%

Patient-derived rectal cancer organoids—applications in basic and translational cancer research

Yan

Cheong²,

Chen³

et al. 2022

Front. Oncol.

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Colorectal cancer (CRC) is one of the most commonly diagnosed cancers and among the leading causes of death in both men and women. Rectal cancer (RC) is particularly challenging compared with colon cancer as the treatment after diagnosis of RC is more complex on account of its narrow anatomical location in the pelvis adjacent to the urogenital organs. More and more existing studies have begun to refine the research on RC and colon cancer separately. Early diagnosis and multiple treatment strategies optimize outcomes for individual patients. However, the need for more accurate and precise models to facilitate RC research is underscored due to the heterogeneity of clinical response and morbidity interrelated with radical surgery. Organoids generated from biopsies of patients have developed as powerful models to recapitulate many aspects of their primary tissue, consisting of 3-D self-organizing structures, which shed great light on the applications in both biomedical and clinical research. As the preclinical research models for RC are usually confused with colon cancer, research on patient-derived RC organoid models enable personalized analysis of cancer pathobiology, organizational function, and tumor initiation and progression. In this review, we discuss the various applications of patient-derived RC organoids over the past two years in basic cancer biology and clinical translation, including sequencing analysis, drug screening, precision therapy practice, tumor microenvironment studies, and genetic engineering opportunities.

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Increased sensitivity to SMAC mimetic LCL161 identified by longitudinal ex vivo pharmacogenomics of recurrent, KRAS mutated rectal cancer liver metastases

Cited by 10 publications

References 41 publications

Tumor organoids: applications in cancer modeling and potentials in precision medicine

Tumor organoids: applications in cancer modeling and potentials in precision medicine

Patient-derived organoids in human cancer: a platform for fundamental research and precision medicine

Patient-derived rectal cancer organoids—applications in basic and translational cancer research

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