Patient-Derived Cells to Guide Targeted Therapy for Advanced Lung Adenocarcinoma

Kim, Seok Young; Lee, Ji Yeon; Kim, Donghwi; Joo, Hyeong-Seok; Yun, Mi Ran; Jung, Dongmin; Yun, Jun-Won; Heo, Seong Gu; Park, Chae Won; Chun, Youngsub; Hong, Min Hee; Cho, Byoung Chul

doi:10.1038/s41598-019-56356-4

Cited by 24 publications

(35 citation statements)

References 61 publications

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“…EGFR activating mutations respond to 1 st generation EGFR-TKIs, while rare EGFR mutations exhibit differential sensitivity to the therapies (4,6,7). Clinical and preclinical data regarding an EGFR L747P mutation are sparse (37).…”

Section: Predictive Values Of Pdos In Diverse Clinical Settingsmentioning

confidence: 99%

“…IC 50 values were calculated from 3 biological replicates (3 technical replicates per biological replicate) using GraphPad Prism version 7. In vitro response to a targeted therapy was defined as sensitive (IC 50 value < 100 nmol/L) or resistant (IC 50 value > 100 nmol/L) (7).…”

Section: Cell Viability Assaymentioning

confidence: 99%

“…2D cultures have been widely used for translational research (7,11). To directly compare clinical relevance of 2D cultures and organoids, we attempted to generate 2D cultures from 9…”

Section: Comparison Of Clinical Relevance In 3d and 2d Culture Conditionsmentioning

confidence: 99%

“…Additionally, responses to targeted therapies are heterogeneous in patients harboring the identical driver mutation (3)(4)(5). Rarer molecular subtypes among the driver oncogenes display diverse clinical and biological characteristics, further complicating the clinical decision making for patients with advanced NSCLC (6)(7)(8)(9).…”

Section: Introductionmentioning

confidence: 99%

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Modeling Clinical Responses to Targeted Therapies by Patient-Derived Organoids of Advanced Lung Adenocarcinoma

Kim

Lim³

et al. 2021

Clinical Cancer Research

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We demonstrated that in vitro drug responses in patient-derived organoids (PDOs) are correlated to clinical responses to targeted therapies in individual patients with advanced lung adenocarcinoma and PDOs can be used to identify effective anti-cancer therapies for novel molecular targets. PDOs recapitulated progression-free survival and objective responses of NSCLC patients receiving clinically approved targeted agents. PDOs also predicted activity of therapeutic strategies under clinical investigation. YUO-071 harboring an EGFR exon 19 deletion and a BRAF G464A mutation and the matching patient responded to dabrafenib/trametinib combination therapy. YUO-004 and YUO-050 harboring an EGFR L747P mutation was sensitive to afatinib, consistent with the response in the matching patient of YUO-050. Furthermore, we utilized organoids to demonstrate preclinical efficacy of poziotinib against ERBB2 exon 20 insertions and pralsetinib against RET-fusions. Our findings suggest utility of PDOs in clinical decision making and development of therapeutic strategies.

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Section: Predictive Values Of Pdos In Diverse Clinical Settingsmentioning

confidence: 99%

Section: Cell Viability Assaymentioning

confidence: 99%

“…2D cultures have been widely used for translational research (7,11). To directly compare clinical relevance of 2D cultures and organoids, we attempted to generate 2D cultures from 9…”

Section: Comparison Of Clinical Relevance In 3d and 2d Culture Conditionsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Modeling Clinical Responses to Targeted Therapies by Patient-Derived Organoids of Advanced Lung Adenocarcinoma

Kim

Lim³

et al. 2021

Clinical Cancer Research

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“…Most are based upon a gene mutation, gene expression or protein analysis, and are limited by challenges in describing the broader phenotypic behavior resulting from the holistic interplay inherent in cellular processes that drive cancer biology. A system that recapitulates each patient's tumor as a model organism may enable this broad phenotypic assessment and facilitate rapid ex-vivo personalized drug testing 13,14 . Options for tumor modeling include two-dimensional cell lines, murine xenografts and three-dimensional patient-derived cultures, commonly termed organoids.…”

Section: Introductionmentioning

confidence: 99%

Patient-derived Organoid Pharmacotyping is a Clinically Tractable Strategy for Precision Medicine in Pancreatic Cancer

et al. 2020

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Objective: Patients with pancreatic cancer (PDAC) who undergo surgical resection and receive effective chemotherapy have the best chance of long-term survival. Unfortunately, we lack predictive biomarkers to guide optimal systemic treatment. Ex-vivo generation of patient-derived organoids (PDO) for pharmacotyping may serve as predictive biomarkers in PDAC. The goal of the current study was to demonstrate the clinical feasibility of a PDOguided precision medicine framework of care.Methods: PDO cultures were established from surgical specimens and endoscopic biopsies, expanded in Matrigel, and used for high-throughput drug testing (pharmacotyping).Efficacy of standard-of-care chemotherapeutics was assessed by measuring cell viability after drug exposure.Results: A framework for rapid pharmacotyping of PDOs was established across a multiinstitutional consortium of academic medical centers. Specimens obtained remotely and shipped to a central biorepository maintain viability and allowed generation of PDOs with 77% success. Early cultures maintain the clonal heterogeneity seen in PDAC with similar phenotypes (cystic-solid). Late cultures exhibit a dominant clone with a pharmacotyping profile similar to early passages. The biomass required for accurate pharmacotyping can be minimized by leveraging a high-throughput technology. Twenty-nine cultures were pharmacotyped to derive a population distribution of chemotherapeutic sensitivity at our center. Pharmacotyping rapidly-expanded PDOs was completed in a median of 48 (range 18-102) days.Conclusions: Rapid development of PDOs from patients undergoing surgery for PDAC is eminently feasible within the perioperative recovery period, enabling the potential for pharmacotyping to guide post-operative adjuvant chemotherapeutic selection. Studies validating PDOs as a promising predictive biomarker are ongoing.

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Soluble galectin‐3 as a microenvironment‐relevant immunoregulator with prognostic and predictive value in lung adenocarcinoma

Torres‐Martínez,

Calabuig‐Fariñas,

Moreno‐Manuel

et al. 2023

Molecular Oncology

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Despite the success of therapies in lung cancer, more studies of new biomarkers for patient selection are urgently needed. The present study aims to analyze the role of galectin‐3 (GAL‐3) in the lung tumor microenvironment (TME) using tumorspheres as a model and explore its potential role as a predictive and prognostic biomarker in non‐small cell lung cancer (NSCLC) patients. For in vitro studies, lung adenocarcinoma (LUAD) and lung squamous carcinoma (LUSC) primary cultures from early‐stage patients and commercial cell lines were cultured, using tumorsphere‐forming assays and adherent conditions for the control counterparts. We analyzed the pattern of secretion and expression of GAL‐3 using reverse transcription–quantitative real‐time PCR (RTqPCR), immunoblot, immunofluorescence, flow cytometry and immunoassay analysis. Our results using three‐dimensional (3D) models of lung tumor cells revealed that soluble GAL‐3 (sGAL‐3) is highly expressed and secreted. To more accurately mimic the TME, a co‐culture of tumorspheres and fibroblasts was used, revealing that GAL‐3 could be important as an immunomodulatory molecule expressed and secreted in the TME, modulating immunosuppression through regulatory T cells (TREGS). In the translational phase, we confirmed that patients with high expression levels of GAL‐3 had more TREGS, which suggests that tumors may be recruiting this population through GAL‐3. Next, we evaluated levels of sGAL‐3 before surgery in LUAD and LUSC patients, hypothesizing that sGAL‐3 could be used as an independent prognostic biomarker for overall survival and relapse‐free survival in early‐stage LUAD patients. Additionally, levels of sGAL‐3 at pretreatment and first response assessment from plasma to predict clinical outcomes in advanced LUAD and LUSC patients treated with first‐line pembrolizumab were evaluated, further supporting that sGAL‐3 has a high efficiency in predicting durable clinical response to pembrolizumab with an area under curve (AUC) of 0.801 (p=0.011). Moreover, high levels might predict decreased progression‐free survival and overall survival to anti‐PD‐1 therapy, with sGAL‐3 being a prognosis‐independent biomarker for advanced LUAD.

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Patient-Derived Cells to Guide Targeted Therapy for Advanced Lung Adenocarcinoma

Cited by 24 publications

References 61 publications

Modeling Clinical Responses to Targeted Therapies by Patient-Derived Organoids of Advanced Lung Adenocarcinoma

Modeling Clinical Responses to Targeted Therapies by Patient-Derived Organoids of Advanced Lung Adenocarcinoma

Patient-derived Organoid Pharmacotyping is a Clinically Tractable Strategy for Precision Medicine in Pancreatic Cancer

Soluble galectin‐3 as a microenvironment‐relevant immunoregulator with prognostic and predictive value in lung adenocarcinoma

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