scholarly journals Precision Oncology Medicine: The Clinical Relevance of Patient-Specific Biomarkers Used to Optimize Cancer Treatment

2016 ◽  
Vol 56 (12) ◽  
pp. 1484-1499 ◽  
Author(s):  
Keith T. Schmidt ◽  
Cindy H. Chau ◽  
Douglas K. Price ◽  
William D. Figg
Keyword(s):  
Cancer Treatment ◽  
Clinical Relevance ◽  
Patient Specific ◽  
Precision Oncology

Functional precision medicine in colorectal cancer based on patient-derived tumoroids and in-vitro sensitivity drug testing.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e15567-e15567
Author(s):  
Lars Henrik Jensen ◽  
Anders Kristian Moeller Jakobsen ◽  
Birgitte Mayland Havelund ◽  
Cecilie Abildgaard ◽  
Chris Vagn-Hansen ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Clinical Trial ◽  
Primary Endpoint ◽  
Drug Testing ◽  
Progression Free Survival ◽  
Patient Specific ◽  
Precision Oncology ◽  
Sensitivity Testing ◽  
In Vitro Sensitivity

e15567 Background: Precision oncology based on in-vitro, functional assays has potential advantages compared to the much more common molecular approach, but the clinical benefit is unknown. We here report the results from the largest prospective interventional clinical trial testing the clinical outcome in colorectal cancer patients treated with drugs showing cytotoxic effect in matched patient-derived tumoroids. Methods: This single-center, phase II trial included patients with metastatic colorectal cancer previously exposed to all standard therapies. Specimens from one to three 18-16 G core needle biopsies were manually dissected, enzymatically treated, cultivated, and incubated to form 3D spherical microtumors, i.e. tumoroids. In the assay for in-vitro sensitivity testing, the tumoroids were challenged with single drugs and combinations thereof to determine patient-specific responses. Using tumoroid screening technology (IndiTreat, 2cureX, Copenhagen, Denmark), results were generated by comparing the sensitivity of the individual patient’s tumoroids with a reference panel from other patients. The testing included standard cytostatics and drugs with proven effect in previous early-phase clinical trials, a total of 15 drugs. The primary endpoint was the fraction of patients with progression-free survival (PFS) at two months. Based on placebo arms in randomized last-line trials, a minimal relevant difference of 20% (20% to 40%) was stated. Using Simon's two-stage design, a sample size of 45 patients was calculated with at least 14 PFS at two months (significance 5%, power 90%). Results: Ninety patients were enrolled from 9/2017 to 9/2020. Biopsies from 82 patients were obtained and sent for tumoroid formation of which 44 (54%, 95% CI 42-65) were successful and at least one treatment was suggested. Thirty-four patients initiated treatment according to the response obtained in the drug assays within a median of 51 days from inclusion (IQR 39-63). The primary endpoint, PFS at two months, was met in 17 of 34 patients (50%, 95%CI 32-68). There were no radiological responses. Median PFS was 81 days (95% CI 51-112) and median OS was 189 days (95% CI 103-277). Conclusions: Precision oncology using a functional approach with patient-derived tumoroids and in-vitro drug sensitivity testing seems feasible. The approach is limited by the fraction of patients with successful tumoroid development. The primary endpoint was met, as half of the patients were without progression at two months. Further clinical studies are justified. Clinical trial information: NCT03251612.

scholarly journals COMP-04. MODELING PRECISION ONCOLOGY FOR GLIOBLASTOMA THROUGH INTEGRATION OF DESCRIPTIVE, FUNCTIONAL, AND NETWORK-BASED GENOMICS

2019 ◽  
Vol 21 (Supplement_6) ◽  
pp. vi61-vi62
Author(s):  
Pia Hoellerbauer ◽  
Megan Kufeld ◽  
Sonali Arora ◽  
Emily Girard ◽  
James Olson ◽  
...  
Keyword(s):  
Membrane Trafficking ◽  
Mitochondrial Protein ◽  
Survival Rates ◽  
Mitotic Catastrophe ◽  
Patient Specific ◽  
Specific Gene ◽  
Precision Oncology ◽  
Genome Wide ◽  
F Box Protein ◽  
Phosphatidylinositol 4

Abstract Precision oncology is largely based on the notion that identification and targeting of oncogenic drivers will lead to improved clinical outcomes. However, the promise of precision oncology awaits to be fulfilled for many cancers, including Glioblastoma (GBM), where identification of oncogenic drivers has yet to improve survival rates. Here, we have attempted to systematically identify GBM vulnerabilities by performing genome-wide CRISRP-Cas9 lethality screens in patient-derived GBM stem-like cells (GSCs). In validation studies, we comprehensively retested GSC-specific hits in multiple GSC isolates, which were also genomically profiled (e.g. RNA-seq, exome-seq, CNV), and further integrated these data with CRISPR-Cas9 lethality screens from over 500 human cell lines from the Broad Institute’s CRISPR Avana dataset. As a result, we have begun making GBM dependency predictions and functional associations for top scoring hits, including: tumor developmental subtype; loss of functional redundancy with other genes/proteins; cancer-specific subnetworks of genes involved in mitochondrial protein turnover and membrane trafficking; and genes of unknown function essential for subset of GBMs. A few examples of these categories include the following scenarios. We find ADAR (Adenosine Deaminase RNA Specific) gene dependency is associated with the mesenchymal GBM subtype. The EFR3Agene, which has roles in maintaining active pools of phosphatidylinositol 4-kinase, appears required when the expression of its paralog EFR3Bis low or absent in tumor cells. The F-box protein-encoding gene FBXO42appears non-essential to most human cells lines and neural stem cells, but when knocked out in sensitive GSCs causes mitotic arrest, mitotic catastrophe, and cell death. While still a work in progress, we hope to use these results as a foundation for exploring and illuminating patient-specific molecular vulnerabilities for brain tumors. The results also underscore the need for integration of functional genetic approaches, where gene activities are inhibited, into precision oncology paradigms.

scholarly journals Thirty Years of Cancer Nanomedicine: Success, Frustration, and Hope

Cancers ◽  
2019 ◽  
Vol 11 (12) ◽  
pp. 1855 ◽  
Author(s):  
Lucia Salvioni ◽  
Maria Antonietta Rizzuto ◽  
Jessica Armida Bertolini ◽  
Laura Pandolfi ◽  
Miriam Colombo ◽  
...  
Keyword(s):  
Cancer Treatment ◽  
Safety Profile ◽  
Crucial Role ◽  
Clinical Relevance ◽  
Scientific Community ◽  
Design Development ◽  
Manufacturing Costs ◽  
Epr Effect ◽  
Enhanced Permeability And Retention ◽  
Cancer Nanomedicine

Starting with the enhanced permeability and retention (EPR) effect discovery, nanomedicine has gained a crucial role in cancer treatment. The advances in the field have led to the approval of nanodrugs with improved safety profile and still inspire the ongoing investigations. However, several restrictions, such as high manufacturing costs, technical challenges, and effectiveness below expectations, raised skeptical opinions within the scientific community about the clinical relevance of nanomedicine. In this review, we aim to give an overall vision of the current hurdles encountered by nanotherapeutics along with their design, development, and translation, and we offer a prospective view on possible strategies to overcome such limitations.

scholarly journals Prediction formulas to determine breast cancer treatment related lymphedema do have a clinical relevance

2018 ◽  
Vol 225 ◽  
pp. 256-257
Author(s):  
Nick Gebruers ◽  
Hanne Verbelen ◽  
Tessa De Vrieze ◽  
Lore Vos ◽  
Nele Devoogdt ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Treatment ◽  
Clinical Relevance ◽  
Breast Cancer Treatment

scholarly journals Three-Dimensional Printed Molds for Image-Guided Surgical Biopsies: An Open Source Computational Platform

2020 ◽  
pp. 736-748
Author(s):  
Mireia Crispin-Ortuzar ◽  
Marcel Gehrung ◽  
Stephan Ursprung ◽  
Andrew B. Gill ◽  
Anne Y. Warren ◽  
...  
Keyword(s):  
Open Source ◽  
Tumor Heterogeneity ◽  
Spatial Scales ◽  
Three Dimensional ◽  
Patient Specific ◽  
Sampling Location ◽  
Precision Oncology ◽  
Similarity Coefficients ◽  
Tissue Samples ◽  
Manual Intervention

PURPOSE Spatial heterogeneity of tumors is a major challenge in precision oncology. The relationship between molecular and imaging heterogeneity is still poorly understood because it relies on the accurate coregistration of medical images and tissue biopsies. Tumor molds can guide the localization of biopsies, but their creation is time consuming, technologically challenging, and difficult to interface with routine clinical practice. These hurdles have so far hindered the progress in the area of multiscale integration of tumor heterogeneity data. METHODS We have developed an open-source computational framework to automatically produce patient-specific 3-dimensional–printed molds that can be used in the clinical setting. Our approach achieves accurate coregistration of sampling location between tissue and imaging, and integrates seamlessly with clinical, imaging, and pathology workflows. RESULTS We applied our framework to patients with renal cancer undergoing radical nephrectomy. We created personalized molds for 6 patients, obtaining Dice similarity coefficients between imaging and tissue sections ranging from 0.86 to 0.96 for tumor regions and between 0.70 and 0.76 for healthy kidneys. The framework required minimal manual intervention, producing the final mold design in just minutes, while automatically taking into account clinical considerations such as a preference for specific cutting planes. CONCLUSION Our work provides a robust and automated interface between imaging and tissue samples, enabling the development of clinical studies to probe tumor heterogeneity on multiple spatial scales.

Practical guidelines for fabricating mandibular guide flange prostheses: A new technique for measuring the flange angulation

2015 ◽  
Vol 40 (4) ◽  
pp. 528-531
Author(s):  
Farideh Geramipanah ◽  
Saman Fallahi Sichani ◽  
Susan Mirmohammadrezaei ◽  
Safoura Ghodsi
Keyword(s):  
Clinical Relevance ◽  
New Technique ◽  
Patient Specific ◽  
Posterior Teeth ◽  
Vertical Distance ◽  
Patient Will ◽  
Practical Guidelines ◽  
A New Technique

Background and aim: When a mandibulectomy causes discontinuity, the patient will need a rehabilitative prosthesis to achieve a proper occlusal relationship. Technique: This article describes step-by-step guidelines for measuring the patient-specific mandibular guide flange angulation. In the presented technique, the flange angulation is determined by dividing the horizontal overlap of the maxillary posterior teeth plus the maxillary buccal clasp thickness by the vertical distance of the mandibular continuous clasp up to the maxillary buccal clasp. Discussion: The mandibular guiding flange prosthesis must achieve an angulation that is appropriate for the particular circumstances of each patient to minimize the complications with mandibular deviation. Clinical relevance The introduced method for measuring the patient-specific mandibular guide flange angulation can help prosthodontists to prepare the mandibular guiding flange prosthesis with higher accuracy and predictability.

scholarly journals X Chromosome-Linked CNVs in Male Infertility: Discovery of Overall Duplication Load and Recurrent, Patient-Specific Gains with Potential Clinical Relevance

PLoS ONE ◽  
2014 ◽  
Vol 9 (6) ◽  
pp. e97746 ◽  
Author(s):  
Chiara Chianese ◽  
Adam C. Gunning ◽  
Claudia Giachini ◽  
Fabrice Daguin ◽  
Giancarlo Balercia ◽  
...  
Keyword(s):  
Male Infertility ◽  
X Chromosome ◽  
Clinical Relevance ◽  
Patient Specific

scholarly journals ORN: Extracting Latent Pathway Activities in Cancer with OR-gate Network

2020 ◽  
Author(s):  
Lifan Liang ◽  
Kunju Zhu ◽  
Songjian Lu
Keyword(s):  
Somatic Mutations ◽  
Expression Profiles ◽  
Patient Specific ◽  
Lower Grade ◽  
Precision Oncology ◽  
Cell Cycles ◽  
Functional Relationships ◽  
Lower Grade Glioma ◽  
Specific Pathway ◽  
Or Gate

ABSTRACTPathway level understanding of cancer plays a key role in precision oncology. In this study, we developed a novel data-driven model, called the OR-gate Network (ORN), to simultaneously infer functional relationships among mutations, patient-specific pathway activities, and gene co-expression. In principle, logical OR gates agree with mutual exclusivity patterns in somatic mutations and bicluster patterns in transcriptomic profiles. In a trained ORN, the differential expression profiles of tumours can be explained by somatic mutations perturbing signalling pathways. We applied ORN to lower grade glioma (LLG) samples in TCGA and breast cancer samples from METABRIC. Both datasets have shown pathway patterns related to immune response and cell cycles. In LLG samples, ORN identified multiple metabolic pathways closely related to glioma development and revealed two pathways closely related to patient survival. Additional results from the METABRIC datasets showed that ORN could characterize key mechanisms of cancer and connect them to less studied somatic mutations (e.g., BAP1, MIR604, MICAL3, and telomere activities), which may generate novel hypothesis for targeted therapy.

scholarly journals Multiobjective Optimization Identifies Cancer-Selective Combination Therapies

2020 ◽  
Author(s):  
Otto I. Pulkkinen ◽  
Prson Gautam ◽  
Ville Mustonen ◽  
Tero Aittokallio
Keyword(s):  
Multiobjective Optimization ◽  
Cost Effective ◽  
Selective Inhibition ◽  
Search Space ◽  
Optimization Method ◽  
Drug Combinations ◽  
Braf V600e ◽  
Patient Specific ◽  
Precision Oncology ◽  
Massive Number

ABSTRACTCombinatorial therapies are required to treat patients with advanced cancers that have become resistant to monotherapies through rewiring of redundant pathways. Due to a massive number of potential drug combinations, there is a need for systematic approaches to identify safe and effective combinations for each patient, using cost-effective methods. Here, we developed an exact multiobjective optimization method for identifying pairwise or higher-order combinations that show maximal cancer-selectivity. The prioritization of patient-specific combinations is based on Pareto-optimization in the search space spanned by the therapeutic and nonselective effects of combinations. We demonstrate the performance of the method in the context of BRAF-V600E melanoma treatment, where the optimal solutions predicted a number of co-inhibition partners for vemurafenib, a selective BRAF-V600E inhibitor, approved for advanced melanoma. We experimentally validated many of the predictions in BRAF-V600E melanoma cell line, and the results suggest that one can improve selective inhibition of BRAF-V600E melanoma cells by combinatorial targeting of MAPK/ERK and other compensatory pathways using pairwise and third-order drug combinations. Our mechanism-agnostic optimization method is widely applicable to various cancer types, and it takes as input only measurements of a subset of pairwise drug combinations, without requiring target information or genomic profiles. Such data-driven approaches may become useful for functional precision oncology applications that go beyond the cancer genetic dependency paradigm to optimize cancer-selective combinatorial treatments.

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