Molecularly targeted cancer therapy: some lessons from the past decade

Trends in Pharmacological Sciences, Journal Year: 2013, Volume and Issue: 35(1), P. 41 - 50

Published: Dec. 19, 2013

Language: Английский

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Molecular and Cellular Heterogeneity in Breast Cancer

American Journal Of Pathology, Journal Year: 2013, Volume and Issue: 183(4), P. 1113 - 1124

Published: Aug. 28, 2013

Breast cancer is noted for disparate clinical behaviors and patient outcomes, despite common histopathological features at diagnosis. Molecular pathogenesis studies suggest that breast a collection of diseases with variable molecular underpinnings modulate therapeutic responses, disease-free intervals, long-term survival. Traditional strategies individual patients are guided by the expression status estrogen progesterone receptors (ER PR) human epidermal growth factor receptor 2 (HER2). Although such methods classification have utility in selection targeted therapies, short-term responses survival remain difficult to predict. signatures based on complex gene patterns prediction but not yet used guiding therapy. Examination correspondence between these reveals lack agreement affecting significant percentage cases. To realize true personalized therapy, more complete analysis evaluation characteristics disease required, together an understanding contributions specific genetic epigenetic alterations (and their combinations) management patient. Here, we discuss cellular heterogeneity cancer, impact this practical classification, challenges treatment.

Language: Английский

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Established breast cancer risk factors and risk of intrinsic tumor subtypes

Biochimica et Biophysica Acta (BBA) - Reviews on Cancer, Journal Year: 2015, Volume and Issue: 1856(1), P. 73 - 85

Published: June 13, 2015

Language: Английский

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Overview on Clinical Relevance of Intra-Tumor Heterogeneity

Frontiers in Medicine, Journal Year: 2018, Volume and Issue: 5

Published: April 6, 2018

Today clinical evaluation of tumor heterogeneity today is an emergent issue to improve oncology. In particular, intra-tumor (ITH) closely related cancer progression, resistance therapy, and recurrences. It interconnected with complex molecular mechanisms including spatial temporal phenomena, which are often peculiar for every single patient. This review tries describe all the types ITH morpho-histological ITH, at level clonal derived from genomic instability non-clonal micro-environment interaction. important consider different as a whole any patient investigate on prognosis treatment opportunities. From practical point view analytical methods that widely accessible today, or will be in near future, evaluated pattern reproducible way application.

Language: Английский

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Bioinformatics and Computational Tools for Next-Generation Sequencing Analysis in Clinical Genetics

Journal of Clinical Medicine, Journal Year: 2020, Volume and Issue: 9(1), P. 132 - 132

Published: Jan. 3, 2020

Clinical genetics has an important role in the healthcare system to provide a definitive diagnosis for many rare syndromes. It also can have influence over prevention, disease prognosis and assisting selection of best options care/treatment patients. Next-generation sequencing (NGS) transformed clinical making possible analyze hundreds genes at unprecedented speed lower price when comparing conventional Sanger sequencing. Despite growing literature concerning NGS setting, this review aims fill gap that exists among (bio)informaticians, molecular geneticists clinicians, by presenting general overview technology workflow. First, we will current platforms, focusing on two main platforms Illumina Ion Torrent, discussing major strong points weaknesses intrinsic each platform. Next, analytical bioinformatic pipelines are dissected, giving some emphasis algorithms commonly used generate process data sequence variants. Finally, challenges around bioinformatics placed perspective future developments. Even with huge achievements made bioinformatics, further improvements still required deal complex genetically heterogeneous disorders.

Language: Английский

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Functional and molecular characterisation of EO771.LMB tumours, a new C57BL/6-mouse-derived model of spontaneously metastatic mammary cancer

Disease Models & Mechanisms, Journal Year: 2015, Volume and Issue: unknown

Published: Jan. 1, 2015

Abstract The translation of basic research into improved therapies for breast cancer patients requires relevant preclinical models that incorporate spontaneous metastasis. We have completed a functional and molecular characterisation new isogenic C57BL/6 mouse model metastasis, comparing contrasting it with the established BALB/c 4T1 model. Metastatic EO771.LMB tumours were derived from poorly metastatic parental EO771 mammary tumours. Functional differences evaluated using both in vitro assays metastasis mice. Results compared to non-metastatic 67NR 4T1.2 Protein transcript levels markers human subtypes measured four tumour lines, as well p53 (Tp53) tumour-suppressor gene status responses tamoxifen vivo vitro. Array-based expression profiling whole identified genes pathways deregulated cells metastasised spontaneously lung mice displayed increased invasive capacity EO771. By immunohistochemical assessment, basal-like, was tumour, whereas had luminal phenotype. Primary all lines negative progesterone receptor, Erb-b2/Neu cytokeratin 5/6, but positive epidermal growth factor receptor (EGFR). Only nuclear estrogen alpha (ERα) positivity. expressed mutant p53, p53-null. Integrated analysis EO771/EO771.LMB 67NR/4T1.2 pairs indicated upregulation matrix metalloproteinase-3 (MMP-3), parathyroid hormone-like hormone (Pthlh) S100 calcium binding protein A8 (S100a8) downregulation thrombospondin (Cd36) might be causally involved dissemination cancer.

Language: Английский

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Breast Cancer: A Molecularly Heterogenous Disease Needing Subtype-Specific Treatments

Medical Sciences, Journal Year: 2020, Volume and Issue: 8(1), P. 18 - 18

Published: March 23, 2020

Breast cancer is the most commonly occurring in women. There were over two-million new cases world 2018. It second leading cause of death from western countries. At molecular level, breast a heterogeneous disease, which characterized by high genomic instability evidenced somatic gene mutations, copy number alterations, and chromosome structural rearrangements. The caused defects DNA damage repair, transcription, replication, telomere maintenance mitotic segregation. According to features, cancers are subdivided subtypes, according activation hormone receptors (estrogen receptor progesterone receptor), human epidermal growth factors 2 (HER2), or BRCA mutations. In-depth analyses features primary metastatic have shown great heterogeneity genetic alterations their clonal evolution during disease development. These studies contributed identify repertoire numerous disease-causing genes that altered through different mutational processes. While early-stage curable about 70% patients, advanced largely incurable. However, develop therapeutic approaches targeting HER2, CDK4/6, PI3K, involving poly(ADP-ribose) polymerase inhibitors for mutation carriers immunotherapy.

Language: Английский

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High intratumor genetic heterogeneity is related to worse outcome in patients with head and neck squamous cell carcinoma

Cancer, Journal Year: 2013, Volume and Issue: 119(16), P. 3034 - 3042

Published: May 20, 2013

BACKGROUND Although the presence of genetic heterogeneity within tumors individual patients is established, it unclear whether greater predicts a worse outcome. A quantitative measure based on next‐generation sequencing (NGS) data, mutant‐allele tumor (MATH), was previously developed and applied to data set head neck squamous cell carcinoma (HNSCC). Whether this correlates with clinical outcome not assessed. METHODS The authors examined association between MATH clinical, pathologic, overall survival for 74 HNSCC whom exome completed. RESULTS High (a value above median) found be significantly associated shorter (hazards ratio, 2.5; 95% confidence interval, 1.3‐4.8). similarly adverse outcomes in clinically high‐risk an advanced stage disease, those classified as high risk basis validated biomarkers including that were negative human papillomavirus or having disruptive protein p53 mutations. In who received chemotherapy, hazards ratio 4.1 (95% 1.6‐10.2). CONCLUSIONS This novel progression treatment outcomes, thereby supporting hypothesis higher portends HNSCC. prognostic some known may result their heterogeneity. provides useful prospectively NGS from homogeneously treated patient cohorts become available Cancer 2013;119:3034—3042 . © 2013 American Society

Language: Английский

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Emerging targeted agents in metastatic breast cancer

Nature Reviews Clinical Oncology, Journal Year: 2013, Volume and Issue: 10(4), P. 191 - 210

Published: March 5, 2013

Language: Английский

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Molecular characterization and targeted therapeutic approaches in breast cancer

Breast Cancer Research, Journal Year: 2015, Volume and Issue: 17(1)

Published: April 22, 2015

Despite the wide improvements in breast cancer (BC) detection and adjuvant treatment, BC is still responsible for approximately 40,000 deaths annually United States. Novel biomarkers are fundamental to assist clinicians detection, risk stratification, disease subtyping, prediction of treatment response, surveillance, allowing a more tailored approach therapy both primary metastatic settings. In BC, development molecular profiling techniques has added prognostic predictive information conventional - estrogen receptor, progesterone human epidermal growth factor receptor 2. Moreover, application next-generation sequencing reverse-phase protein microarray methods setting holds promise further advance toward personalized management cancer. The improvement our understanding on biology associated with study genomic aberrations characterizing most common subtypes allows us explore new targets drug development. Finally, integration stem cell-targeted therapies immune future combination regimens increases chances successfully treat larger proportion women aggressive resistant disease. This article reviews current state novel biological markers evidence demonstrate their clinical validity utility, implication therapeutic targeting.

Language: Английский

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