The great escape: tumour cell plasticity in resistance to targeted therapy

Nature Reviews Drug Discovery, Journal Year: 2019, Volume and Issue: 19(1), P. 39 - 56

Published: Oct. 10, 2019

Language: Английский

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The dormant cancer cell life cycle

Nature reviews. Cancer, Journal Year: 2020, Volume and Issue: 20(7), P. 398 - 411

Published: June 2, 2020

Language: Английский

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Cycling cancer persister cells arise from lineages with distinct programs

Nature, Journal Year: 2021, Volume and Issue: 596(7873), P. 576 - 582

Published: Aug. 11, 2021

Language: Английский

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Challenges and Opportunities in Cancer Drug Resistance

Chemical Reviews, Journal Year: 2020, Volume and Issue: 121(6), P. 3297 - 3351

Published: July 21, 2020

There has been huge progress in the discovery of targeted cancer therapies recent years. However, even for most successful and impactful drugs which have approved, both innate acquired mechanisms resistance are commonplace. These emerging studied intensively, enabled drug scientists to learn how it may be possible overcome such subsequent generations treatments. In some cases, novel candidates able supersede previously approved agents; other cases they used sequentially or combinations with existing This review summarizes current field terms challenges opportunities that presents scientists, a focus on small molecule therapeutics. As part this review, common themes approaches identified utilized successfully target resistance. includes increase potency selectivity, alternative chemical scaffolds, change mechanism action (covalents, PROTACs), increases blood-brain barrier permeability (BBBP), targeting allosteric pockets. Finally, wider covered as monoclonal antibodies (mAbs), bispecific antibodies, antibody conjugates (ADCs), combination therapies.

Language: Английский

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Sarcoma treatment in the era of molecular medicine

EMBO Molecular Medicine, Journal Year: 2020, Volume and Issue: 12(11)

Published: Oct. 13, 2020

Review13 October 2020Open Access Sarcoma treatment in the era of molecular medicine Thomas GP Grünewald Corresponding Author [email protected] orcid.org/0000-0003-0920-7377 Max-Eder Research Group for Pediatric Biology, Institute Pathology, Faculty Medicine, LMU Munich, Germany Division Translational Research, German Cancer Center (DKFZ), Hopp Children's (KiTZ), Consortium (DKTK), Heidelberg, Heidelberg University Hospital, Search more papers by this author Marta Alonso orcid.org/0000-0002-7520-7351 Program Solid Tumors and Biomarkers, Foundation Applied Medical Navarra Pamplona, Spain Sofia Avnet Orthopedic Pathophysiology Regenerative Medicine Unit, IRCCS Istituto Ortopedico Rizzoli, Bologna, Italy Ana Banito Soft Tissue Group, Stefan Burdach Department Pediatrics (CCRC), Technische Universität München, Florencia Cidre-Aranaz orcid.org/0000-0002-0246-7179 Gemma Di Pompo Martin Distel Institute, Vienna, Austria Heathcliff Dorado-Garcia Oncology/Hematology, Charité-Universitätsmedizin Berlin, Javier Garcia-Castro Cellular Biotechnology Instituto de Salud Carlos III, Madrid, Laura González-González Agamemnon E Grigoriadis Centre Craniofacial King's College London, UK Merve Kasan Christian Koelsche Manuela Krumbholz Pediatrics, Erlangen, Fernando Lecanda Oncology, Adhesion Metastasis Laboratory, Navarra, Silvia Lemma Dario L Longo Biostructures Bioimaging (IBB), Italian National Council (CNR), Turin, Claudia Madrigal-Esquivel Oncology Metabolism, Sheffield, Álvaro Morales-Molina Julian Musa General, Visceral Transplantation Surgery, Shunya Ohmura Benjamin Ory Université Nantes, Inserm, U1238, France Miguel Pereira-Silva Pharmaceutical Technology, Pharmacy, Coimbra, Portugal Francesca Perut Rene Rodriguez orcid.org/0000-0002-0768-7306 Investigación Sanitaria del Principado Asturias, Oviedo, CIBER en oncología (CIBERONC), Carolin Seeling Ulm University, Ulm, Nada Al Shaaili Shabnam Shaabani Drug Design, Groningen, The Netherlands Kristina Shiavone Snehadri Sinha Oral Maxillofacial Diseases, Helsinki, Finland Eleni M Tomazou Marcel Trautmann orcid.org/0000-0002-5842-1196 Gerhard-Domagk-Institute Münster Münster, Maria Vela Hospital La Paz Health (IdiPAZ), Yvonne MH Versleijen-Jonkers Radboud Center, Nijmegen, Julia Visgauss Duke Durham, NC, USA Zalacain Sebastian J Schober Andrej Lissat Children′s Zurich – Eleonoren Foundation, Kanton Zürich, Switzerland William R English Nicola Baldini orcid.org/0000-0003-2228-3833 Biomedical Neuromotor Sciences, Dominique Heymann orcid.org/0000-0001-7777-0669 Institut Cancérologie l'Ouest, Tumor Heterogeneity Precision Saint-Herblain, Information *,1,2,3, Alonso4, Avnet5, Banito6, Burdach7, Cidre-Aranaz1, Pompo5, Distel8, Dorado-Garcia9, Garcia-Castro10, González-González10, Grigoriadis11, Kasan1, Koelsche3, Krumbholz12, Lecanda13, Lemma5, Longo14, Madrigal-Esquivel15, Morales-Molina10, Musa1,16, Ohmura1, Ory17, Pereira-Silva18, Perut5, Rodriguez19,20, Seeling21, Shaaili15, Shaabani22, Shiavone15, Sinha23, Tomazou8, Trautmann24, Vela25, Versleijen-Jonkers26, Visgauss27, Zalacain14, Schober7, Lissat28, English15, *,5,29 *,15,30 1Max-Eder 2Division 3Institute 4Program 5Orthopedic 6Pediatric 7Department 8Children's 9Department 10Cellular 11Centre 12Department 13Division 14Institute 15Department 16Department 17Université 18Department 19Instituto 20CIBER 21Institute 22Department 23Department 24Division 25Hospital 26Department 27Medical 28University 29Department 30Université *Corresponding author. Tel: +49 6221 42 3718; E-mail: +39 (0) 516 366 549; +33 240 679 841; EMBO Mol Med (2020)12:e11131https://doi.org/10.15252/emmm.201911131 See Glossary abbreviations used article. PDFDownload PDF article text main figures. ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinked InMendeleyWechatReddit Figures & Info Abstract Sarcomas are heterogeneous clinically challenging soft tissue bone cancers. Although constituting only 1% all human malignancies, sarcomas represent second most common type solid tumors children adolescents comprise an important group secondary malignancies. More than 100 histological subtypes have been characterized date, many being discovered due profiling. Owing their mostly aggressive biological behavior, relative rarity, occurrence at virtually every anatomical site, sarcoma particular difficult-to-treat categories. Current multimodal concepts combine surgery, polychemotherapy (with/without local hyperthermia), irradiation, immunotherapy, and/or targeted therapeutics. Recent scientific advancements enabled a precise characterization revealed novel therapeutic targets prognostic/predictive biomarkers. This review aims providing comprehensive overview latest advances biology effects on clinical oncology; it is meant broad readership ranging from novices experts field sarcoma. stem cells (CSCs) Cells within tumor found very small fractions that thought be responsible resistance cancer treatments thus relapse. Cell dormancy Stage progression during which cease dividing but survive quiescent state while waiting appropriate environmental conditions. Chorioallantoic Membrane (CAM) models Chick embryo CAM study formation, angiogenesis, metastasis. Circulating (CTCs) leak into vasculature or lymphatics primary carried around body blood circulation. Epigenomic alterations Heritable change does not affect DNA sequence results gene expression. Extracellular vesicles (EVs) Heterogeneous family generated different subcellular compartments released extracellular space Genomic Permanent modifications including somatic mutations, copy-number variations (CNVs), fusions. Immunotherapy Type aids immune system fight tumors. Oncolytic viruses Viruses that, intrinsic properties through genetic engineering, specifically replicate kill cells. Orthotopic xenografts Animal based injection cell lines location where typically appear humans. Patient-derived (PDXs) model transplantation biopsies encompass TME immunodeficient animals. arise between 0–14 years age. Approach patient care allows physicians select likely help patients understanding disease. Malignant neoplasms originate skeleton tissues. microenvironment (TME) environment reside encompassing matrix stromal (endothelial cells, fibroblasts, cells) Epidemiology rare among adult they 12–15% pediatric (Stiller et al, 2013). Despite implementation continuous optimization therapies, one-third still succumb Historically, clustered two large subgroups, according site occurrence—sarcomas tissues (hereafter referred as "bone sarcomas" "soft [STSs], respectively). Both subgroups variety subtypes, recent technological decipher constantly increasing number level (Fig 1; Baldauf 2018a; Watson 2018; Weidema 2020). Table 1 summarizes major discussed features. Figure 1. Diversity highlighted methylation profilingt-distributed stochastic neighbor embedding (t-SNE) plot n = 18 genome-wide profiling Illumina EPIC arrays (Koelsche 2018a,b). Web-link classifier: www.molecularsarcomapathology.org. Download figure PowerPoint Main characteristics subtype Abbreviation features Bone Chondrosarcomaa CHS Localization: Cartilage, surface, centrally Histopathology: Lobules composed malignant chondrocytes entrapped chondroid with calcified foci Identified mutations IDH1/2, EXT1/2 Ewing sarcomaa EwS Long flat bones (˜85%), extraskeletal sites (˜15%) Undifferentiated round cells; strong membranous CD99 immunoreactivity PAS-positive cytoplasm Harbor FET-ETS translocations (˜85% EWSR1-FLI1; ˜10% EWSR1-ERG; ˜5% subtypes) Osteosarcomaa OS surface Neoplastic mesenchymal morphology frequent polymorphism (epithelioid, fusiform, round, spindled, etc.) associated osteoid Various telangiectatic numerous hemorrhagic areas Complex highly aneuploidy karyotypes multiple chromosomal aberrations (numerical structural) Frequent TP53 RB other defining "BRCAness" signature (STSs) Fibrosarcomaa Deep extremities, trunk, head neck Composed monomorphic fibroblastic collagenous GastroIntestinal Stromal GIST Gastrointestinal track (main site: stomach intestine) morphological spectrum mainly spindle epithelioid (˜20% cases) mixed histology differentiation toward interstitial Cajal. Usually immunopositive CD117 (KIT) DOG1 activating KIT PDGFRA Leiomyosarcoma LMS Most commonly detected peritoneum uterus (rarely bone) Mesenchymal, spindle-shaped smooth muscle (SMA, desmin h-Caldesmon positivity) Highly complex genomic instability Liposarcomaa LPS Variable (most retroperitoneal space) variable adipocytic heterogenous embedded vascularized stroma (in case myxoid stroma) Rhabdomyosarcoma RMS Mesenchymal phenotype myogenic (usually positive myogenin MYOD) pleomorphic UPS frequently extremities high degree cellular atypia pleomorphism Synovial SS Mostly deep Spindle epithelial (i.e., monophasic/biphasic SS) specific SS18-SSX1/2/4 fusion oncogenes STS (WHO Classification Tumours: Tumours, Among sarcomas, osteosarcoma (OS) (Heymann, 2014). primarily affects young adults, first largest peak incidence age ~10–14 years. Coinciding pubertal growth spurt, rate 4 (3.5–4.6) range 5 (4.6–5.6) 0–19 per year million persons (Ottaviani Jaffe, 2009). current standard was introduced late 1970s remains largely unaltered despite efforts improve outcomes (Rosen 1976). Nowadays, localized disease face 5-year overall survival rates < 70%, 20% who develop metastatic relapse > 3 (Roberts 2019). (EwS) included because both (~85% (~15% cases), has similar OS. subgroup comprises ~70–80% 70 STSs cancers, highest Overall, estimated ~57–62% can vary widely depending stage interplay (Lyu Unfortunately, epidemiological data limited incomplete. initiatives ongoing databases, will benefit use "big data"

Language: Английский

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Emerging role of tumor cell plasticity in modifying therapeutic response

Signal Transduction and Targeted Therapy, Journal Year: 2020, Volume and Issue: 5(1)

Published: Oct. 7, 2020

Abstract Resistance to cancer therapy is a major barrier management. Conventional views have proposed that acquisition of resistance may result from genetic mutations. However, accumulating evidence implicates key role non-mutational mechanisms underlying drug tolerance, the latter which focus will be discussed here. Such processes are largely driven by tumor cell plasticity, renders cells insusceptible drug-targeted pathway, thereby facilitating survival and growth. The concept plasticity highlights significance re-activation developmental programs closely correlated with epithelial–mesenchymal transition, properties stem cells, trans-differentiation potential during exposure. From observations in various cancers, this provides an opportunity for investigating nature anticancer resistance. Over years, our understanding emerging phenotype switching modifying therapeutic response has considerably increased. This expanded knowledge contributes developing novel strategies or combination regimens using available drugs, likely improve patient outcomes clinical practice.

Language: Английский

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Functional precision oncology: Testing tumors with drugs to identify vulnerabilities and novel combinations

Cancer Cell, Journal Year: 2021, Volume and Issue: 40(1), P. 26 - 35

Published: Dec. 23, 2021

Functional precision medicine is a strategy whereby live tumor cells from affected individuals are directly perturbed with drugs to provide immediately translatable, personalized information guide therapy. The heterogeneity of human cancer has led the realization that approaches needed improve treatment outcomes. Precision oncology traditionally used static features dictate which therapies should be used. Static can include expression key targets or genomic analysis mutations identify therapeutically targetable "drivers." Although surprisingly small proportion derive clinical benefit approach, functional additional regarding vulnerabilities. We discuss emerging technologies for as well limitations and challenges in using these assays trials will necessary determine whether outcomes eventually become standard tool oncology.

Language: Английский

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Paradoxical effects of chemotherapy on tumor relapse and metastasis promotion

Seminars in Cancer Biology, Journal Year: 2019, Volume and Issue: 60, P. 351 - 361

Published: Aug. 24, 2019

Several lines of compelling pre-clinical evidence identify chemotherapy as a potentially double-edged sword: therapeutic efficacy on the primary tumor may in fact be counterbalanced by induction tumor/host reactive responses supportive for survival and dissemination cancer cell subpopulations. This paradoxical effect can affect different districts such tumor, circulation distant organs simultaneously shaping properties composition stromal cells. At site, has been reported to promote selection chemoresistant disseminating cells endowed with stem (CSCs) through activation autocrine paracrine self-renewing/survival pathways promoted jointly therapy-selected Resistant CSCs represent seeds relapse increased infiltration immune cells, together enhanced vascular permeability induced chemotherapy, facilitates intravasation, first step metastatic cascade. As consequence tumor/metastasis re-shaping circulating (CTCs) detected during therapy display shift towards more mesenchymal stem-like phenotype, conductive ability survive seed organs. host activate inflammatory that ultimately facilitate extravasation colonization. Finally, cooperation endothelial at perivascular niches favors high potential metastasis initiation protects them from chemotherapy. review highlights pro-metastatic effects linking treatment formation remodeling generation favorable niche.

Language: Английский

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Stem Cell Plasticity and Dormancy in the Development of Cancer Therapy Resistance

Frontiers in Oncology, Journal Year: 2019, Volume and Issue: 9

Published: July 10, 2019

Cancer treatment with either standard chemotherapy or targeted agents often results in the emergence of drug-refractory cell populations, ultimately leading to therapy failure. The biological features drug resistant cells are largely overlapping those cancer stem and include heterogeneity, plasticity, self-renewal ability tumor-initiating capacity. Moreover, resistance is usually characterized by a suppression proliferation that can manifest as quiescence, dormancy, senescence proliferative slowdown. Alterations key cellular pathways such autophagy, unfolded protein response redox signaling, well metabolic adaptations also contribute establishment resistance, thus representing attractive therapeutic targets. complex interplay micro/macroenvironment immune system plays role dictating maintaining phenotype. Recent studies have challenged traditional views providing innovative perspectives, establishing new connections between their environment indicating unexpected strategies. In this review we discuss recent advancements understanding mechanisms underlying report novel targeting able overcome status, particular focus on strategies directed against dormant cells. Research will take us one step forward towards development approaches improvement relapse-free survival solid hematological patients.

Language: Английский

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Three-dimensional in vitro culture models in oncology research

Cell & Bioscience, Journal Year: 2022, Volume and Issue: 12(1)

Published: Sept. 11, 2022

Abstract Cancer is a multifactorial disease that responsible for 10 million deaths per year. The intra- and inter-heterogeneity of malignant tumors make it difficult to develop single targeted approaches. Similarly, their diversity requires various models investigate the mechanisms involved in cancer initiation, progression, drug resistance recurrence. Of vitro cell-based models, monolayer adherent (also known as 2D culture) cell cultures have been used longest time. However, appears they are often less appropriate than three-dimensional (3D) culture approach mimicking biological behavior tumor cells, particular leading therapeutic escape resistance. Multicellular spheroids widely study cancers 3D, can be generated by multiplicity techniques, such liquid-based scaffold-based 3D cultures, microfluidics bioprinting. Organoids more complex multicellular because from stem cells isolated patients considered powerful tools reproduce development vitro. present review provides an overview set up response. advantages compared limitations, fields application these techniques production also discussed.

Language: Английский

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