Phenotype-driven precision oncology in patient-derived tumor models predict therapeutic response in squamous cell carcinoma
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE84676 | GEO | 2017/07/21
SECONDARY ACCESSION(S): PRJNA330817
REPOSITORIES: GEO
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Project description:Phenotype-driven precision oncology in patient-derived tumor models predict therapeutic response in squamous cell carcinoma
| PRJNA330817 | ENA
Project description:Genomics-driven cancer therapeutics has gained prominence in personalized cancer treatment. However, its utility in indications lacking biomarker-driven treatment strategies remains limited. Here we present a "phenotype-driven precision-oncology" approach, based on the notion that biological response to perturbations, chemical or genetic, in ex vivo patient-individualized models can serve as predictive biomarkers for therapeutic response in the clinic. We generated a library of "screenable" patient-derived primary cultures (PDCs) for head and neck squamous cell carcinomas that reproducibly predicted treatment response in matched patient-derived-xenograft models. Importantly, PDCs could guide clinical practice and predict tumour progression in two n = 1 co-clinical trials. Comprehensive "-omics" interrogation of PDCs derived from one of these models revealed YAP1 as a putative biomarker for treatment response and survival in ~24% of oral squamous cell carcinoma. We envision that scaling of the proposed PDC approach could uncover biomarkers for therapeutic stratification and guide real-time therapeutic decisions in the future.Treatment response in patient-derived models may serve as a biomarker for response in the clinic. Here, the authors use paired patient-derived mouse xenografts and patient-derived primary culture models from head and neck squamous cell carcinomas, including metastasis, as models for high-throughput screening of anti-cancer drugs.
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Project description:Patient-derived xenografts (PDX) and organoids (PDO) have been shown to model clinical response to cancer therapy. However, it remains challenging to use these models to guide timely clinical decisions for cancer patients. Here we used droplet emulsion microfluidics with temperature control and dead-volume minimization to rapidly generate thousands of Micro- Organospheres (MOS) from low-volume patient tissues, which serve as an ideal patient-derived model for clinical precision oncology. A clinical study of newly diagnosed metastatic colorectal cancer (CRC) patients using a MOS-based precision oncology pipeline reliably predicted patient treatment outcome within 14 days, a timeline suitable for guiding treatment decisions in clinic. Furthermore, MOS capture original stromal cells and allow T cell penetration, providing a clinical assay for testing immuno-oncology (IO) therapies such as PD-1 blockade, bispecific antibodies, and T cell therapies on patient tumors.
2022-09-01 | GSE184242 | GEO
Project description:BackgroundEarly-stage oral squamous cell carcinoma (OSCC) patients have a one-in-four risk of regional metastasis (LN+), which is also the most significant prognostic factor for survival. As there are no validated biomarkers for predicting LN+ in early-stage OSCC, elective neck dissection often leads to over-treatment and under-treatment. We present a machine-learning-based model using the quantitative nuclear phenotype of cancer cells from the primary tumor to predict the risk of nodal disease.Methods and findingsTumor specimens were obtained from 35 patients diagnosed with primary OSCC and received surgery with curative intent. Of the 35 patients, 29 had well (G1) or moderately (G2) differentiated tumors, and six had poorly differentiated tumors. From each, two consecutive sections were stained for hematoxylin & eosin and Feulgen-thionin staining. The slides were scanned, and images were processed to curate nuclear morphometric features for each nucleus, measuring nuclear morphology, DNA amount, and chromatin texture/organization. The nuclei (n = 384,041) from 15 G1 and 14 G2 tumors were randomly split into 80% training and 20% test set to build the predictive model by using Random Forest (RF) analysis which give each tumor cell a score, NRS. The area under ROC curve (AUC) was 99.6% and 90.7% for the training and test sets, respectively. At the cutoff score of 0.5 as the median NRS of each region of interest (n = 481), the AUC was 95.1%. We then developed a patient-level model based on the percentage of cells with an NRS ≥ 0.5. The prediction performance showed AUC of 97.7% among the 80% (n = 23 patient) training set and with the cutoff of 61% positive cells achieved 100% sensitivity and 91.7% specificity. When applying the 61% cutoff to the 20% test set patients, the model achieved 100% accuracy.ConclusionsOur findings may have a clinical impact with an easy, accurate, and objective biomarker from routine pathology tissue, providing an unprecedented opportunity to improve neck management decisions in early-stage OSCC patients.
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Project description:BackgroundGlioblastoma (GBM) remains associated with a dismal prognoses despite standard therapies. While population-level survival statistics are established, generating individualized prognosis remains challenging. We aim to develop machine learning (ML) models that generate personalized survival predictions for GBM patients to enhance prognostication.MethodsAdult patients with histologically confirmed IDH-wildtype GBM from the National Cancer Database (NCDB) were analyzed. ML models were developed with TabPFN, TabNet, XGBoost, LightGBM, and Random Forest algorithms to predict mortality at 6, 12, 18, and 24 months postdiagnosis. SHapley Additive exPlanations (SHAP) were employed to enhance the interpretability of the models. Models were primarily evaluated using the area under the receiver operating characteristic (AUROC) values, and the top-performing models indicated by the highest AUROCs for each outcome were deployed in a web application that was created for individualized predictions.ResultsA total of 7537 patients were retrieved from the NCDB. Performance evaluation revealed the top-performing models for each outcome were built using the TabPFN algorithm. The TabPFN models yielded mean AUROCs of 0.836, 0.78, 0.732, and 0.724 in predicting 6, 12, 18, and 24 month mortality, respectively.ConclusionsThis study establishes ML models tailored to individual patients to enhance GBM prognostication. Future work should focus on external validation and dynamic updating as new data emerge.
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Project description:Prioritizing molecular alterations that act as drivers of cancer remains a crucial bottleneck in therapeutic development. Here we introduce HIT'nDRIVE, a computational method that integrates genomic and transcriptomic data to identify a set of patient-specific, sequence-altered genes, with sufficient collective influence over dysregulated transcripts. HIT'nDRIVE aims to solve the "random walk facility location" (RWFL) problem in a gene (or protein) interaction network, which differs from the standard facility location problem by its use of an alternative distance measure: "multihitting time," the expected length of the shortest random walk from any one of the set of sequence-altered genes to an expression-altered target gene. When applied to 2200 tumors from four major cancer types, HIT'nDRIVE revealed many potentially clinically actionable driver genes. We also demonstrated that it is possible to perform accurate phenotype prediction for tumor samples by only using HIT'nDRIVE-seeded driver gene modules from gene interaction networks. In addition, we identified a number of breast cancer subtype-specific driver modules that are associated with patients' survival outcome. Furthermore, HIT'nDRIVE, when applied to a large panel of pan-cancer cell lines, accurately predicted drug efficacy using the driver genes and their seeded gene modules. Overall, HIT'nDRIVE may help clinicians contextualize massive multiomics data in therapeutic decision making, enabling widespread implementation of precision oncology.
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