Journal ArticleDOI
Identification of resistance pathways and therapeutic targets in relapsed multiple myeloma patients through single-cell sequencing.
Yael C Cohen,Yael C Cohen,Mor Zada,Mor Zada,Shuang-Yin Wang,Chamutal Bornstein,Eyal David,Adi Moshe,Baoguo Li,Shir Shlomi-Loubaton,Moshe E. Gatt,Chamutal Gur,Chamutal Gur,Noa Lavi,Chezi Ganzel,Efrat Luttwak,Efrat Luttwak,Evgeni Chubar,Ory Rouvio,Iuliana Vaxman,Iuliana Vaxman,Oren Pasvolsky,Oren Pasvolsky,Mouna Ballan,Tamar Tadmor,Anatoly Nemets,Osnat Jarchowcky-Dolberg,Olga Shvetz,Meirav Laiba,Ofer Shpilberg,Najib Dally,Irit Avivi,Irit Avivi,Assaf Weiner,Ido Amit +34 more
TLDR
In this article, a prospective, multicenter, single-arm clinical trial (NCT04065789), combined with longitudinal single-cell RNA-sequencing (scRNA-seq) was conducted to study the molecular dynamics of MM resistance mechanisms.Abstract:
Multiple myeloma (MM) is a neoplastic plasma-cell disorder characterized by clonal proliferation of malignant plasma cells. Despite extensive research, disease heterogeneity within and between treatment-resistant patients is poorly characterized. In the present study, we conduct a prospective, multicenter, single-arm clinical trial (NCT04065789), combined with longitudinal single-cell RNA-sequencing (scRNA-seq) to study the molecular dynamics of MM resistance mechanisms. Newly diagnosed MM patients (41), who either failed to respond or experienced early relapse after a bortezomib-containing induction regimen, were enrolled to evaluate the safety and efficacy of a daratumumab, carfilzomib, lenalidomide and dexamethasone combination. The primary clinical endpoint was safety and tolerability. Secondary endpoints included overall response rate, progression-free survival and overall survival. Treatment was safe and well tolerated; deep and durable responses were achieved. In prespecified exploratory analyses, comparison of 41 primary refractory and early relapsed patients, with 11 healthy subjects and 15 newly diagnosed MM patients, revealed new MM molecular pathways of resistance, including hypoxia tolerance, protein folding and mitochondria respiration, which generalized to larger clinical cohorts (CoMMpass). We found peptidylprolyl isomerase A (PPIA), a central enzyme in the protein-folding response pathway, as a potential new target for resistant MM. CRISPR–Cas9 deletion of PPIA or inhibition of PPIA with a small molecule inhibitor (ciclosporin) significantly sensitizes MM tumor cells to proteasome inhibitors. Together, our study defines a roadmap for integrating scRNA-seq in clinical trials, identifies a signature of highly resistant MM patients and discovers PPIA as a potent therapeutic target for these tumors. Integration of longitudinal single-cell analysis of relapsed and refractory multiple myeloma patients in a prospective clinical trial uncovers new pathways of drug resistance and identifies potential actionable targets.read more
Citations
More filters
Journal ArticleDOI
Single-cell profiling of tumour evolution in multiple myeloma — opportunities for precision medicine
Ankit K. Dutta,Jean-Baptiste Alberge,Romanos Sklavenitis-Pistofidis,Elizabeth Lightbody,Gad Getz,Irene M. Ghobrial +5 more
TL;DR: How single-cell studies in individuals with multiple myeloma are enabling the mutational and phenotypic characterization of cells within the bone marrow tumour, immune microenvironment and peripheral blood to eventually guide early diagnosis, risk stratification and treatment strategies is discussed.
Journal ArticleDOI
Genomic Profiling for Clinical Decision Making in Lymphoid Neoplasms.
Laurence de Leval,Ash A. Alizadeh,P. Leif Bergsagel,Elias Campo,Andrew Davies,Ahmet Dogan,Jude Fitzgibbon,Steven M. Horwitz,Ari Melnick,William G. Morice,Ryan D. Morin,Bertrand Nadel,Stefano Pileri,Richard Rosenquist,Davide Rossi,Itziar Salaverria,Christian Steidl,Steven P. Treon,Andrew D. Zelenetz,Ranjana H. Advani,Carl E. Allen,Stephen M. Ansell,Wing C. Chan,James R. Cook,Lucy Cook,Francesco D'Amore,Stephan Dirnhofer,Martin Dreyling,Kieron Dunleavy,Andrew L. Feldman,Falko Fend,Philippe Gaulard,Paolo Ghia,John G. Gribben,Olivier Hermine,Daniel J. Hodson,Eric D. Hsi,Giorgio Inghirami,Elaine S. Jaffe,Kennosuke Karube,Keisuke Kataoka,Wolfram Klapper,Won Seog Kim,Rebecca L. King,Young Hyeh Ko,Ann S. LaCasce,Georg Lenz,Iñaki Martin-Subero,Miguel A. Piris,Stefania Pittaluga,Laura Pasqualucci,Leticia Quintanilla-Martinez,Scott J. Rodig,Andreas Rosenwald,Gilles Salles,Jesús F. San Miguel,Kerry J. Savage,Laurie H. Sehn,Gianpietro Semenzato,Louis M. Staudt,Steven H. Swerdlow,Constantine S. Tam,Judith Trotman,Julie M. Vose,Oliver Weigert,Wyndham H. Wilson,Jane N. Winter,Catherine J. Wu,Pier Luigi Zinzani,E. Zucca,Adam Bagg,David Scott +71 more
TL;DR: Established assays and newly developed technologies for molecular testing already complement clinical diagnoses and provide a novel lens on disease classification, and their contributions to diagnosis refinement, risk stratification and therapy prediction will be considered.
Journal ArticleDOI
Single-cell immunology: Past, present, and future.
TL;DR: In this paper , the authors outline the past, present, and future applications of single-cell genomics in immunology and discuss how the integration of multi-omics at the singlecell level will pave the way for future advances in Immunology research and clinical translation.
Journal ArticleDOI
Big data in basic and translational cancer research
TL;DR: Jiang et al. as discussed by the authors reviewed the current state of the art and future challenges for harnessing big data to advance cancer research and treatment, and discussed considerations and strategies for wielding "big data" in basic research and for translational applications such as identifying biomarkers, informing clinical trials and developing new assays and treatments.
Journal ArticleDOI
LGR5 expressing skin fibroblasts define a major cellular hub perturbed in scleroderma
Chamutal Gur,Shuang-Yin Wang,Fadi Sheban,Mor Zada,Baoguo Li,Fadi Kharouf,H Peleg,Suhail Aamar,Adam Yalin,Daniel Kirschenbaum,Yolanda Braun-Moscovici,Diego Jaitin,Tomer meir-salame,Efrat Hagai,Bjørt K Kragesteen,Batia Avni,Sigal Grisariu,Chamutal Bornstein,Shir Shlomi-Loubaton,Eyal David,Rony Shreberk-Hassidim,Vered Molho-Pessach,Dalit Amar,Tomer Tzur,Rottem Kuint,Moshe Gross,Oren Barboy,Adi Moshe,Liat Fellus-Alyagor,Dana Hirsch,Yoseph Addadi,Shlomit Erenfeld,Moshe Biton,Tehila Tzemach,Anat Scheiman Elazary,Yaakov Naparstek,R. Tzemach,Assaf Weiner,Amir Giladi,Alexandra Balbir-Gurman,Ido Amit +40 more
TL;DR: In this paper , a population-scale single-cell genomic analysis of skin and blood samples of 56 healthy controls and 97 systemic sclerosis patients at different stages of the disease was conducted, which revealed ScAF-specific markers, pathways, regulatory elements, and transcription factors underlining disease development.
References
More filters
Journal ArticleDOI
A Unique Microglia Type Associated with Restricting Development of Alzheimer’s Disease
Hadas Keren-Shaul,Amit Spinrad,Assaf Weiner,Assaf Weiner,Orit Matcovitch-Natan,Raz Dvir-Szternfeld,Tyler K. Ulland,Eyal David,Kuti Baruch,David Lara-Astaiso,Beáta Tóth,Shalev Itzkovitz,Marco Colonna,Michal Schwartz,Ido Amit +14 more
TL;DR: A novel microglia type associated with neurodegenerative diseases (DAM) is described and it is revealed that the DAM program is activated in a two-step process that involves downregulation of microglian checkpoints, followed by activation of a Trem2-dependent program.
Journal ArticleDOI
Clonal evolution in cancer
Mel Greaves,Carlo C. Maley +1 more
TL;DR: The inherently Darwinian character of cancer is the primary reason for this therapeutic failure, but it may also hold the key to more effective control.
Journal ArticleDOI
Multiple myeloma
Noopur Raje,Kenneth C. Anderson +1 more
TL;DR: The use of bisphosphonates in patients with multiple myeloma (MM) has clearly demonstrated benefit and reduced morbidity associated with bone disease, but all patients with MM ultimately relapse and succumb to their disease.
Journal ArticleDOI
International Myeloma Working Group consensus criteria for response and minimal residual disease assessment in multiple myeloma
Shaji Kumar,Bruno Paiva,Kenneth C. Anderson,Brian G.M. Durie,Ola Landgren,Philippe Moreau,Nikhil C. Munshi,Sagar Lonial,Joan Bladé,Maria-Victoria Mateos,Meletios A. Dimopoulos,Efstathios Kastritis,Mario Boccadoro,Mario Boccadoro,Robert Z. Orlowski,Hartmut Goldschmidt,Andrew Spencer,Jian Hou,Wee Joo Chng,Saad Z. Usmani,Elena Zamagni,Kazuyuki Shimizu,Sundar Jagannath,Hans Erik Johnsen,Evangelos Terpos,Anthony Reiman,Robert A. Kyle,Pieter Sonneveld,Paul G. Richardson,Philip L. McCarthy,Heinz Ludwig,Wenming Chen,Michele Cavo,Jean Luc Harousseau,Suzanne Lentzsch,Jens Hillengass,Antonio Palumbo,Alberto Orfao,S. Vincent Rajkumar,Jesús F. San Miguel,Hervé Avet-Loiseau +40 more
TL;DR: Several aspects of disease response assessment are clarified, along with endpoints for clinical trials, and future directions for disease response assessments are highlighted, to allow uniform reporting within and outside clinical trials.
Journal ArticleDOI
Massively Parallel Single-Cell RNA-Seq for Marker-Free Decomposition of Tissues into Cell Types
Diego Jaitin,Ephraim Kenigsberg,Hadas Keren-Shaul,Naama Elefant,Franziska Paul,Irina Zaretsky,Alexander Mildner,Nadav Cohen,Steffen Jung,Amos Tanay,Ido Amit +10 more
TL;DR: An automated massively parallel single-cell RNA sequencing approach for analyzing in vivo transcriptional states in thousands of single cells is introduced and provides the ability to perform a bottom-up characterization of in vivo cell-type landscapes independent of cell markers or prior knowledge.