Towards a precision medicine approach to positive crossmatch transplantation: Impact on response to therapy

Malignant tumors are complex tissues composed of malignant cells, vascular cells, structural mesenchymal cells including pericytes and carcinoma-associated fibroblasts, infiltrating immune cells, and others, collectively called the tumor stroma. The number of stromal cells in a tumor is often much greater than the number of malignant cells. The physical associations among all these cell types are critical to tumor growth, survival, and response to therapy. Most cell-based screens for cancer drug discovery and precision medicine validation use malignant cells in isolation as monolayers, embedded in a matrix, or as spheroids in suspension. Medium- and high-throughput screening with multiple cell lines requires a scalable, reproducible, robust cell-based assay. Complex spheroids include malignant cells and two normal cell types, human umbilical vein endothelial cells and highly plastic mesenchymal stem cells, which rapidly adapt to the malignant cell microenvironment. The patient-derived pancreatic adenocarcinoma cell line, K24384-001-R, was used to explore complex spheroid structure and response to anticancer agents in a 96-well format. We describe the development of the complex spheroid assay as well as the growth and structure of complex spheroids over time. Subsequently, we demonstrate successful assay miniaturization to a 384-well format and robust performance in a high-throughput screen. Implementation of the complex spheroid assay was further demonstrated with 10 well-established pancreatic cell lines. By incorporating both human stromal and tumor components, complex spheroids might provide an improved model for tumor response in vivo.

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Explainable Transformer-Based Neural Network forthe Prediction of Survival Outcomes in Non-SmallCell Lung Cancer (NSCLC)

10.1101/2021.10.11.21264761 ◽

2021 ◽

Author(s):

Gustavo Arango ◽

Elly Kipkogei ◽

Etai Jacob ◽

Ioannis Kagiampakis ◽

Arijit Patra

Keyword(s):

Immune System ◽

Precision Medicine ◽

Cancer Patients ◽

Patient Survival ◽

Response To Therapy ◽

Survival Models ◽

Attractive Alternative ◽

Survival Prediction ◽

Molecular Features ◽

Clinical Measurements

In this paper, we introduce the Clinical Transformer - a recasting of the widely used transformer architecture as a method for precision medicine to model relations between molecular and clinical measurements, and the survival of cancer patients. Although the emergence of immunotherapy offers a new hope for cancer patients with dramatic and durable responses having been reported, only a subset of patients demonstrate benefit. Such treatments do not directly target the tumor but recruit the patient immune system to fight the disease. Therefore, the response to therapy is more complicated to understand as it is affected by the patients physical condition, immune system fitness and the tumor. As in text, where the semantics of a word is dependent on the context of the sentence it belongs to, in immuno-therapy a biomarker may have limited meaning if measured independent of other clinical or molecular features. Hence, we hypothesize that the transformer-inspired model may potentially enable effective modelling of the semantics of different biomarkers with respect to patient survival time. Herein, we demonstrate that this approach can offer an attractive alternative to the survival models utilized incurrent practices as follows: (1) We formulate an embedding strategy applied to molecular and clinical data obtained from the patients. (2) We propose a customized objective function to predict patient survival. (3) We show the applicability of our proposed method to bioinformatics and precision medicine. Applying the clinical transformer to several immuno-oncology clinical studies, we demonstrate how the clinical transformer outperforms other linear and non-linear methods used in current practice for survival prediction. We also show that when initializing the weights of a domain-specific transformer by the weights of a cross-domain transformer, we further improve the predictions. Lastly, we show how the attention mechanism successfully captures some of the known biology behind these therapies

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Patient-Derived Xenograft and Organoid Models for Precision Medicine Targeting of the Tumour Microenvironment in Head and Neck Cancer

Cancers ◽

10.3390/cancers12123743 ◽

2020 ◽

Vol 12 (12) ◽

pp. 3743

Author(s):

Tet Woo Lee ◽

Amy Lai ◽

Julia K. Harms ◽

Dean C. Singleton ◽

Benjamin D. Dickson ◽

...

Keyword(s):

Head And Neck ◽

Precision Medicine ◽

Patient Survival ◽

Predictive Biomarkers ◽

Tumour Microenvironment ◽

Response To Therapy ◽

Preclinical Models ◽

Therapeutic Success ◽

Patient Derived Xenograft ◽

Individualise Therapy

Patient survival from head and neck squamous cell carcinoma (HNSCC), the seventh most common cause of cancer, has not markedly improved in recent years despite the approval of targeted therapies and immunotherapy agents. Precision medicine approaches that seek to individualise therapy through the use of predictive biomarkers and stratification strategies offer opportunities to improve therapeutic success in HNSCC. To enable precision medicine of HNSCC, an understanding of the microenvironment that influences tumour growth and response to therapy is required alongside research tools that recapitulate the features of human tumours. In this review, we highlight the importance of the tumour microenvironment in HNSCC, with a focus on tumour hypoxia, and discuss the fidelity of patient-derived xenograft and organoids for modelling human HNSCC and response to therapy. We describe the benefits of patient-derived models over alternative preclinical models and their limitations in clinical relevance and how these impact their utility in precision medicine in HNSCC for the discovery of new therapeutic agents, as well as predictive biomarkers to identify patients’ most likely to respond to therapy.

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Precision medicine in inflammatory bowel disease: concept, progress and challenges

F1000Research ◽

10.12688/f1000research.20928.1 ◽

2020 ◽

Vol 9 ◽

pp. 54 ◽

Cited By ~ 6

Author(s):

Simon P. Borg-Bartolo ◽

Ray Kiran Boyapati ◽

Jack Satsangi ◽

Rahul Kalla

Keyword(s):

Precision Medicine ◽

Clinical Decision Making ◽

Clinical Decision ◽

Underlying Disease ◽

Response To Therapy ◽

Current Evidence ◽

Disease Biology ◽

Bowel Diseases ◽

Inflammatory Bowel ◽

The Individual

Crohn’s disease and ulcerative colitis are increasingly prevalent, relapsing and remitting inflammatory bowel diseases (IBDs) with variable disease courses and complications. Their aetiology remains unclear but current evidence shows an increasingly complex pathophysiology broadly centring on the genome, exposome, microbiome and immunome. Our increased understanding of disease pathogenesis is providing an ever-expanding arsenal of therapeutic options, but these can be expensive and patients can lose response or never respond to certain therapies. Therefore, there is now a growing need to personalise therapies on the basis of the underlying disease biology and a desire to shift our approach from “reactive” management driven by disease complications to “proactive” care with an aim to prevent disease sequelae. Precision medicine is the tailoring of medical treatment to the individual patient, encompassing a multitude of data-driven (and multi-omic) approaches to foster accurate clinical decision-making. In IBD, precision medicine would have significant benefits, enabling timely therapy that is both effective and appropriate for the individual. In this review, we summarise some of the key areas of progress towards precision medicine, including predicting disease susceptibility and its course, personalising therapies in IBD and monitoring response to therapy. We also highlight some of the challenges to be overcome in order to deliver this approach.

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Results of the Seventh Scientific Workshop of ECCO: Precision medicine in IBD - disease outcome and response to therapy

Journal of Crohn s and Colitis ◽

10.1093/ecco-jcc/jjab050 ◽

2021 ◽

Author(s):

Bram Verstockt ◽

Nurulamin M Noor ◽

Urko M Marigorta ◽

Polychronis Pavlidis ◽

Parakkal Deepak ◽

...

Keyword(s):

Precision Medicine ◽

Response To Therapy ◽

Treatment Algorithms ◽

New Era ◽

Extreme Phenotypes ◽

Bowel Diseases ◽

Inflammatory Bowel ◽

Omic Data Integration ◽

Omic Data ◽

Prognostic And Predictive Markers

Abstract Inflammatory bowel diseases [IBD] are a heterogeneous spectrum with two extreme phenotypes, Crohn’s disease [CD] and ulcerative colitis [UC], which both represent numerous phenotypical variations. Hence, we should no longer approach all IBD patients similarly, but rather aim to rethink clinical classifications and modify treatment algorithms to usher in a new era of precision medicine in IBD. This scientific ECCO workshop aims to provide a state-of-the-art overview on prognostic and predictive markers, shed light on key questions in biomarker development, propose best practices in IBD biomarker development [including trial design], and discuss the potential for multi-omic data integration to help drive further advances to make precision medicine a reality in IBD.

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Novel Methods in Pulmonary Hypertension Phenotyping in the Age of Precision Medicine (2015 Grover Conference Series)

Pulmonary Circulation ◽

10.1086/688847 ◽

2016 ◽

Vol 6 (4) ◽

pp. 439-447 ◽

Cited By ~ 4

Author(s):

Jarrod W. Barnes ◽

Adriano R. Tonelli ◽

Gustavo A. Heresi ◽

Jennie E. Newman ◽

Noël E. Mellor ◽

...

Keyword(s):

Pulmonary Hypertension ◽

Precision Medicine ◽

Relevant Literature ◽

Vascular Diseases ◽

Peripheral Circulation ◽

Response To Therapy ◽

Protein Glycosylation ◽

Exhaled Breath ◽

Peripheral Vasculature ◽

Novel Methods

Among pulmonary vascular diseases, pulmonary hypertension (PH) is the best studied and has been the focus of our work. The current classification of PH is based on a relatively simple combination of patient characteristics and hemodynamics. This leads to inherent limitations, including the inability to customize treatment and the lack of clarity from a more granular identification based on individual patient phenotypes. Accurate phenotyping of PH can be used in the clinic to select therapies and determine prognosis and in research to increase the homogeneity of study cohorts. Rapid advances in the mechanistic understanding of the disease, improved imaging methods, and innovative biomarkers now provide an opportunity to define novel PH phenotypes. We have recently shown that altered metabolism may affect nitric oxide levels and protein glycosylation, the peripheral circulation (which may provide insights into the response to therapy), and exhaled-breath analysis (which may be useful in disease evaluation). This review is based on a talk presented during the 2015 Grover Conference and highlights the relevant literature describing novel methods to phenotype pulmonary arterial hypertension patients by using approaches that involve the pulmonary and systemic (peripheral) vasculature. In particular, abnormalities in metabolism, the pulmonary and peripheral circulation, and exhaled breath in PH may help identify phenotypes that can be the basis for a precision-medicine approach to PH management. These approaches may also have a broader scope and may contribute to a better understanding of other diseases, such as asthma, diabetes, and cancer.

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Precision medicine applications in prostate cancer

Therapeutic Advances in Medical Oncology ◽

10.1177/1758835918776920 ◽

2018 ◽

Vol 10 ◽

pp. 175883591877692 ◽

Cited By ~ 4

Author(s):

Edel M. McCrea ◽

Daniel K. Lee ◽

Tristan M. Sissung ◽

William D. Figg

Keyword(s):

Prostate Cancer ◽

Precision Medicine ◽

Resistance Mechanisms ◽

Response To Therapy ◽

Cancer Management ◽

Integral Component ◽

Prostate Cancer Management

Aided by developments in diagnostics and therapeutics, healthcare is increasingly moving toward precision medicine, in which treatment is customized to each individual. We discuss the relevance of precision medicine in prostate cancer, including gene targets, therapeutics and resistance mechanisms. We foresee precision medicine becoming an integral component of prostate cancer management to increase response to therapy and prolong survival.

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The overexpression of DNA repair genes in invasive ductal and lobular breast carcinomas: Insights on individual variations and precision medicine

PLoS ONE ◽

10.1371/journal.pone.0247837 ◽

2021 ◽

Vol 16 (3) ◽

pp. e0247837

Author(s):

Ruwaa I. Mohamed ◽

Salma A. Bargal ◽

Asmaa S. Mekawy ◽

Iman El-Shiekh ◽

Nurcan Tuncbag ◽

...

Keyword(s):

Dna Repair ◽

Precision Medicine ◽

Differentially Expressed Genes ◽

Cancer Diagnostics ◽

Response To Therapy ◽

Differentially Expressed ◽

Dna Repair Genes ◽

Individual Variations ◽

Cancer Subtype ◽

Repair Genes

In the era of precision medicine, analyzing the transcriptomic profile of patients is essential to tailor the appropriate therapy. In this study, we explored transcriptional differences between two invasive breast cancer subtypes; infiltrating ductal carcinoma (IDC) and lobular carcinoma (LC) using RNA-Seq data deposited in the TCGA-BRCA project. We revealed 3854 differentially expressed genes between normal ductal tissues and IDC. In addition, IDC to LC comparison resulted in 663 differentially expressed genes. We then focused on DNA repair genes because of their known effects on patients’ response to therapy and resistance. We here report that 36 DNA repair genes are overexpressed in a significant number of both IDC and LC patients’ samples. Despite the upregulation in a significant number of samples, we observed a noticeable variation in the expression levels of the repair genes across patients of the same cancer subtype. The same trend is valid for the expression of miRNAs, where remarkable variations between patients’ samples of the same cancer subtype are also observed. These individual variations could lie behind the differential response of patients to treatment. The future of cancer diagnostics and therapy will inevitably depend on high-throughput genomic and transcriptomic data analysis. However, we propose that performing analysis on individual patients rather than a big set of patients’ samples will be necessary to ensure that the best treatment is determined, and therapy resistance is reduced.

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Precision Therapy of Head and Neck Squamous Cell Carcinoma

Journal of Dental Research ◽

10.1177/0022034518769645 ◽

2018 ◽

Vol 97 (6) ◽

pp. 614-621 ◽

Cited By ~ 18

Author(s):

P.J. Polverini ◽

N.J. D’Silva ◽

Y.L. Lei

Keyword(s):

Squamous Cell Carcinoma ◽

Cell Carcinoma ◽

Head And Neck ◽

Precision Medicine ◽

Squamous Cell ◽

Response To Therapy ◽

Neck Squamous Cell Carcinoma ◽

Great Promise ◽

Prevention And Treatment ◽

Precision Therapy

Precision medicine is an approach to disease prevention and treatment that takes into account genetic variability and environmental and lifestyle influences that are unique to each patient. It facilitates stratification of patient populations that vary in their susceptibility to disease and response to therapy. Shared databases and the implementation of new technology systems designed to advance the integration of this information will enable health care providers to more accurately predict and customize prevention and treatment strategies for patients. Although precision medicine has had a limited impact in most areas of medicine, it has been shown to be an increasingly successful approach to cancer therapy. Despite early promising results targeting aberrant signaling pathways or inhibitors designed to block tumor-driven processes such as angiogenesis, limited success emphasizes the need to discover new biomarkers and treatment targets that are more reliable in predicting response to therapy and result in better health outcomes. Recent successes in the use of immunity-inducing antibodies have stimulated increased interest in the use of precision immunotherapy of head and neck squamous cell carcinoma. Using next-generation sequencing, the precise profiling of tumor-infiltrating lymphocytes has great promise to identify hypoimmunogenic cancer that would benefit from a rationally designed combinatorial approach. Continued interrogation of tumors will reveal new actionable targets with increasing therapeutic efficacy and fulfill the promise of precision therapy of head and neck cancer.

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Results of the Seventh Scientific Workshop of ECCO: Precision medicine in IBD - what, why, and how

Journal of Crohn s and Colitis ◽

10.1093/ecco-jcc/jjab051 ◽

2021 ◽

Author(s):

Claudio Fiocchi ◽

Gabriele Dragoni ◽

Dimitrios Iliopoulos ◽

Konstantinos Katsanos ◽

Vicent Hernandez Ramirez ◽

...

Keyword(s):

Precision Medicine ◽

Complex Disease ◽

Complex Diseases ◽

Clinical Information ◽

Response To Therapy ◽

Or Groups ◽

Pathogenic Factors ◽

Prediction And Prevention ◽

Number Of Patients ◽

Definition Of

Abstract Many diseases that affect modern humans fall in the category of complex diseases, thus called because they result from a combination of multiple aetiological and pathogenic factors. Regardless of the organ or system affected, complex diseases present major challenges in diagnosis, classification, and management. Current forms of therapy are usually applied in an indiscriminate fashion based on clinical information, but even the most advanced drugs only benefit a limited number of patients and to a variable and unpredictable degree. This ‘one measure does not fit all’ situation has spurred the notion that therapy for complex disease should be tailored to individual patients or groups of patients, giving rise to the notion of ‘precision medicine’ [PM]. Inflammatory bowel disease [IBD] is a prototypical complex disease where the need for PM has become increasingly clear. This prompted the European Crohn’s and Colitis Organisation to focus the 7 th Scientific Workshop on this emerging theme. The articles in this special issue of the Journal address the various complementary aspects of PM in IBD, including what is PM; why it is needed and how it can be used; how PM can contribute to prediction and prevention of IBD; how IBD PM can aid in prognosis and improve response to therapy; and the challenges and future directions of PM in IBD. This first article of this series is structured on three simple concepts [what, why, and how] and addresses the definition of PM, discusses the rationale for the need of PM in IBD, and outlines the methodology required to implement PM in IBD in a correct and clinically meaningful way.

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