Genomic Medicine Frontier in Human Solid Tumors: Prospects and Challenges

2013 ◽  
Vol 31 (15) ◽  
pp. 1874-1884 ◽  
Author(s):  
Rodrigo Dienstmann ◽  
Jordi Rodon ◽  
Jordi Barretina ◽  
Josep Tabernero
Keyword(s):  
Solid Tumors ◽  
Cancer Progression ◽  
Cancer Genomics ◽  
Genomic Medicine ◽  
Genomic Data ◽  
Cost Effective ◽  
Assessment Model ◽  
Historical View ◽  
Systemic Treatments ◽  
Human Solid Tumors

Recent discoveries of genomic alterations that underlie and promote the malignant phenotype, together with an expanded repertoire of targeted agents, have provided many opportunities to conduct hypothesis-driven clinical trials. The ability to profile each unique cancer for actionable aberrations by using high-throughput technologies in a cost-effective way provides unprecedented opportunities for using matched therapies in a selected patient population. The major challenges are to integrate and make biologic sense of the substantial genomic data derived from multiple platforms. We define two different approaches for the analysis, interpretation, and clinical applicability of genomic data: (1) the genomically stratified model originates from the “one test-one drug” paradigm and is currently being expanded with an upfront multicategorical approach following recent advances in multiplexed genotyping platforms; and (2) the comprehensive assessment model is based on whole-genome, -exome, and -transcriptome data and allows identification of novel drivers and subsequent therapies in the experimental setting. Tumor heterogeneity and evolution of the diverse populations of cancer cells during cancer progression, influenced by the effects of systemic treatments, will need to be addressed in the new scenario of early drug development. Logistical issues related to prescreening strategies and trial allocation, in addition to concerns in the economic and ethical domains, must be taken into consideration. Here we present a historical view of how increased understanding of cancer genomics has been translated to the clinic and discuss the prospects and challenges for further implementation of a personalized treatment strategy for human solid tumors.

scholarly journals Intravital Microscopy (IVM) in Human Solid Tumors: Novel Protocol to Examine Tumor-Associated Vessels (Preprint)

2019 ◽  
Author(s):  
Denslow Allerton Trumbull ◽  
Riccardo Lemini ◽  
Sanjay P Bagaria ◽  
Enrique F Elli ◽  
Dorin T Colibaseanu ◽  
...  
Keyword(s):  
Solid Tumors ◽  
Surgical Resection ◽  
Intravital Microscopy ◽  
Research Team ◽  
Patient Treatment ◽  
Direct Visualization ◽  
Open Label ◽  
Systemic Treatments ◽  
Human Solid Tumors ◽  
Improve Patient

BACKGROUND Intravital microscopy (IVM) allows the real-time, direct visualization of microscopic blood vessels. This pilot clinical trial will elucidate the physical and functional characteristics of vessels associated with solid tumors. OBJECTIVE The main objective of this study is to determine the feasibility of performing IVM in patients with solid tumors during the standard course of surgical resection. IVM will also be performed when vasopressors or fluid boluses are administered during the standard course of the operation. METHODS This is an open-label, nonrandomized, single-center, pilot study of IVM observation in subjects with solid tumors undergoing surgical resection. RESULTS This study was active on January 1, 2019 (NCT03823144) and funded by the Mayo Clinic Florida Cancer Focused Research Team Award. As of September 27, 2020, we had enrolled 20 patients. Accrual period is expected to end by December 31, 2021. CONCLUSIONS This trial will support the development of interventions to improve patient treatment by extending the application of IVM to the tumor microenvironment. IVM observations during volume and pressor management at the time of surgery may aid in the development of strategies to augment responses to systemic treatments. INTERNATIONAL REGISTERED REPORT PRR1-10.2196/15677

scholarly journals TET2 and DNMT3A mutations and exceptional response to 4′-thio-2′-deoxycytidine in human solid tumor models

2021 ◽  
Vol 14 (1) ◽  
Author(s):  
Sherry X. Yang ◽  
Melinda Hollingshead ◽  
Larry Rubinstein ◽  
Dat Nguyen ◽  
Angelo B. A. Larenjeira ◽  
...  
Keyword(s):  
Animal Models ◽  
Solid Tumors ◽  
Cell Lines ◽  
Cancer Cell ◽  
Cancer Genomics ◽  
Cancer Cell Lines ◽  
Histological Evaluation ◽  
Specific Gene ◽  
Xenograft Tumor ◽  
Human Solid Tumors

Abstract Background Challenges remain on the selection of patients who potentially respond to a class of drugs that target epigenetics for cancer treatment. This study aims to investigate TET2/DNMT3A mutations and antitumor activity of a novel epigenetic agent in multiple human cancer cell lines and animal models. Methods Seventeen cancer cell lines and multiple xenograft models bearing representative human solid tumors were subjected to 4′-thio-2′-deoxycytidine (T-dCyd) or control treatment. Gene mutations in cell lines were examined by whole exome and/or Sanger sequencing. Specific gene expression was measured in cells and xenograft tumor samples by Western blotting and immunohistochemistry. TET2/DNMT3A mutation status in 47,571 human tumor samples was analyzed at cBioPortal for Cancer Genomics. Results Cell survival was significantly inhibited by T-dCyd in breast BT549, lung NCI-H23, melanoma SKMEL5 and renal ACHN cancer lines harboring deleterious TET2 and nonsynonymous DNMT3A mutations compared to 13 lines without such mutation pattern (P = 0.007). The treatment upregulated p21 and induced cell cycle arrest in NCI-H23 cells, and dramatically inhibited their xenograft tumor growth versus wildtype models. T-dCyd administrations led to a significant p21 increase and near eradication of tumor cells in the double-mutant xenografts by histological evaluation. TET2/DNMT3A was co-mutated in human lung, breast, skin and kidney cancers and frequently in angioimmunoblastic and peripheral T cell lymphomas and several types of leukemia. Conclusions Cell and animal models with concurrent mutations in TET2 and DNMT3A were sensitive to T-dCyd treatment. The mutations were detectable in human solid tumors and frequently occur in some hematological malignancies.

scholarly journals Intravital Microscopy (IVM) in Human Solid Tumors: Novel Protocol to Examine Tumor-Associated Vessels

10.2196/15677 ◽  
2020 ◽  
Vol 9 (10) ◽  
pp. e15677
Author(s):  
Denslow Allerton Trumbull ◽  
Riccardo Lemini ◽  
Sanjay P Bagaria ◽  
Enrique F Elli ◽  
Dorin T Colibaseanu ◽  
...  
Keyword(s):  
Solid Tumors ◽  
Surgical Resection ◽  
Intravital Microscopy ◽  
Research Team ◽  
Patient Treatment ◽  
Direct Visualization ◽  
Open Label ◽  
Systemic Treatments ◽  
Human Solid Tumors ◽  
Improve Patient

Background Intravital microscopy (IVM) allows the real-time, direct visualization of microscopic blood vessels. This pilot clinical trial will elucidate the physical and functional characteristics of vessels associated with solid tumors. Objective The main objective of this study is to determine the feasibility of performing IVM in patients with solid tumors during the standard course of surgical resection. IVM will also be performed when vasopressors or fluid boluses are administered during the standard course of the operation. Methods This is an open-label, nonrandomized, single-center, pilot study of IVM observation in subjects with solid tumors undergoing surgical resection. Results This study was active on January 1, 2019 (NCT03823144) and funded by the Mayo Clinic Florida Cancer Focused Research Team Award. As of September 27, 2020, we had enrolled 20 patients. Accrual period is expected to end by December 31, 2021. Conclusions This trial will support the development of interventions to improve patient treatment by extending the application of IVM to the tumor microenvironment. IVM observations during volume and pressor management at the time of surgery may aid in the development of strategies to augment responses to systemic treatments. International Registered Report Identifier (IRRID) PRR1-10.2196/15677

scholarly journals The Role of Cancer-Associated Fibroblasts in Tumor Progression

Cancers ◽  
2021 ◽  
Vol 13 (6) ◽  
pp. 1399
Author(s):  
Rushikesh S. Joshi ◽  
Samanvi S. Kanugula ◽  
Sweta Sudhir ◽  
Matheus P. Pereira ◽  
Saket Jain ◽  
...  
Keyword(s):  
Cancer Treatment ◽  
Tumor Progression ◽  
Cancer Progression ◽  
Immune Cell ◽  
Systemic Disease ◽  
Genomic Medicine ◽  
Therapeutic Targets ◽  
Therapy Resistance ◽  
Cancer Associated Fibroblasts ◽  
Breast Cancers

In the era of genomic medicine, cancer treatment has become more personalized as novel therapeutic targets and pathways are identified. Research over the past decade has shown the increasing importance of how the tumor microenvironment (TME) and the extracellular matrix (ECM), which is a major structural component of the TME, regulate oncogenic functions including tumor progression, metastasis, angiogenesis, therapy resistance, and immune cell modulation, amongst others. Within the TME, cancer-associated fibroblasts (CAFs) have been identified in several systemic cancers as critical regulators of the malignant cancer phenotype. This review of the literature comprehensively profiles the roles of CAFs implicated in gastrointestinal, endocrine, head and neck, skin, genitourinary, lung, and breast cancers. The ubiquitous presence of CAFs highlights their significance as modulators of cancer progression and has led to the subsequent characterization of potential therapeutic targets, which may help advance the cancer treatment paradigm to determine the next generation of cancer therapy. The aim of this review is to provide a detailed overview of the key roles that CAFs play in the scope of systemic disease, the mechanisms by which they enhance protumoral effects, and the primary CAF-related markers that may offer potential targets for novel therapeutics.

scholarly journals The Interplay between Oxidative Phosphorylation and Glycolysis as a Potential Marker of Bladder Cancer Progression

2020 ◽  
Vol 21 (21) ◽  
pp. 8107 ◽  
Author(s):  
Greta Petrella ◽  
Giorgia Ciufolini ◽  
Riccardo Vago ◽  
Daniel Oscar Cicero
Keyword(s):  
Bladder Cancer ◽  
Oxidative Phosphorylation ◽  
Cell Lines ◽  
Cancer Progression ◽  
Cancer Genomics ◽  
Low Grade ◽  
Metabolic State ◽  
Extracellular Medium ◽  
Potential Marker ◽  
Risk Of Progression

Urothelial bladder cancer (UBC) is the most common tumor of the urinary system. One of the biggest problems related to this disease is the lack of markers that can anticipate the progression of the cancer. Genomics and transcriptomics have greatly improved the prediction of risk of recurrence and progression. Further progress can be expected including information from other omics sciences such as metabolomics. In this study, we used 1H-NMR to characterize the intake of nutrients and the excretion of products in the extracellular medium of three UBC cell lines, which are representatives of low-grade tumors, RT4, high-grade, 5637, and a cell line that shares genotypic features with both, RT112. We have observed that RT4 cells show an activated oxidative phosphorylation, 5637 cells depend mostly on glycolysis to grow, while RT112 cells show a mixed metabolic state. Our results reveal the relative importance of glycolysis and oxidative phosphorylation in the growth and maintenance of different UBC cell lines, and the relationship with their genomic signatures. They suggest that cell lines associated with a low risk of progression present an activated oxidative metabolic state, while those associated with a high risk present a non-oxidative state and high glycolytic activity.

scholarly journals Large hypomethylated blocks as a universal defining epigenetic alteration in human solid tumors

2014 ◽  
Vol 6 (8) ◽  
Author(s):  
Winston Timp ◽  
Hector Corrada Bravo ◽  
Oliver G McDonald ◽  
Michael Goggins ◽  
Chris Umbricht ◽  
...  
Keyword(s):  
Solid Tumors ◽  
Epigenetic Alteration ◽  
Human Solid Tumors

scholarly journals Identifying Aspects of Public Attitudes Toward Whole Genome Sequencing to Inform the Integration of Genomics into Care

2021 ◽  
pp. 1-12
Author(s):  
Holly Etchegary ◽  
Daryl Pullman ◽  
Charlene Simmonds ◽  
Zoha Rabie ◽  
Proton Rahman
Keyword(s):  
Whole Genome Sequencing ◽  
Genome Sequencing ◽  
Online Survey ◽  
Public Attitudes ◽  
Genetic Counselor ◽  
Genomic Medicine ◽  
Genomic Data ◽  
Whole Genome ◽  
The Public ◽  
Genomic Test

<b><i>Introduction:</i></b> The growth of global sequencing initiatives and commercial genomic test offerings suggests the public will increasingly be confronted with decisions about sequencing. Understanding public attitudes can assist efforts to integrate sequencing into care and inform the development of public education and outreach strategies. <b><i>Methods:</i></b> A 48-item online survey was advertised on Facebook in Eastern Canada and hosted on SurveyMonkey in late 2018. The survey measured public interest in whole genome sequencing and attitudes toward various aspects of sequencing using vignettes, scaled, and open-ended items. <b><i>Results:</i></b> While interest in sequencing was high, critical attitudes were observed. In particular, items measuring features of patient control and choice regarding genomic data were strongly endorsed by respondents. Majority wanted to specify upfront how their data could be used, retain the ability to withdraw their sample at a later date, sign a written consent form, and speak to a genetic counselor prior to sequencing. Concerns about privacy and unauthorized access to data were frequently observed. Education level was the sociodemographic variable most often related to attitude statements such that those with higher levels of education generally displayed more critical attitudes. <b><i>Conclusions:</i></b> Attitudes identified here could be used to inform the development of implementation strategies for genomic medicine. Findings suggest health systems must address patient concerns about privacy, consent practices, and the strong desire to control what happens to their genomic data through public outreach and education. Specific oversight procedures and policies that are clearly communicated to the public will be required.

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