scholarly journals Systems medicine dissection of chr1q-amp reveals a novel PBX1-FOXM1 axis for targeted therapy in multiple myeloma

Blood ◽  
2022 ◽  
Author(s):  
Nikolaos Trasanidis ◽  
Alexia Katsarou ◽  
Kanagaraju Ponnusamy ◽  
Yao-An Shen ◽  
Ioannis V Kostopoulos ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Targeted Therapy ◽  
Gene Signature ◽  
Systems Medicine ◽  
Chromosome 1Q ◽  
Oncogenic Pathways ◽  
Molecule Inhibitor ◽  
Cancer Multiple ◽  
Therapy Strategies ◽  
Genetic Amplification

Understanding the biological and clinical impact of copy number aberrations (CNA) for the development of precision therapies in cancer remains an unmet challenge. Genetic amplification of chromosome 1q (chr1q-amp) is a major CNA conferring adverse prognosis in several types of cancer, including in the blood cancer multiple myeloma (MM). Although several genes across chr1q portend high-risk MM disease, the underpinning molecular aetiology remains elusive. Here, with reference to the 3D chromatin structure, we integrate MM patient multi-omics datasets with genetic variables to obtain an associated clinical risk map across chr1q and to identify 103 adverse prognosis genes in chr1q-amp MM. Prominent amongst these genes, the transcription factor PBX1 is ectopically expressed by genetic amplification and epigenetic activation of its own preserved 3D regulatory domain. By binding to reprogrammed super-enhancers, PBX1 directly regulates critical oncogenic pathways and a FOXM1-dependent transcriptional programme. Together, PBX1 and FOXM1 activate a proliferative gene signature which predicts adverse prognosis across multiple types of cancer. Notably, pharmacological disruption of the PBX1-FOXM1 axis with existing agents (thiostrepton) and a novel PBX1 small-molecule inhibitor (T417) is selectively toxic against chr1q-amplified myeloma and solid tumour cells. Overall, our systems medicine approach successfully identifies CNA-driven oncogenic circuitries, links them to clinical phenotypes and proposes novel CNA-targeted therapy strategies in multiple myeloma and other types of cancer.

scholarly journals Systems medicine dissection of chromosome 1q amplification reveals oncogenic regulatory circuits and informs targeted therapy in cancer

2021 ◽  
Author(s):  
Nikolaos Trasanidis ◽  
Alexia Katsarou ◽  
Kanagaraju Ponnusamy ◽  
Yao-An Shen ◽  
Ioannis V Kostopoulos ◽  
...  
Keyword(s):  
Targeted Therapy ◽  
Gene Signature ◽  
Clinical Impact ◽  
Systems Medicine ◽  
Chromosome 1Q ◽  
Regulatory Circuits ◽  
Oncogenic Pathways ◽  
Cancer Multiple ◽  
Therapy Strategies ◽  
Genetic Amplification

Understanding the biological and clinical impact of copy number aberrations (CNA) in cancer remains an unmet challenge. Genetic amplification of chromosome 1q (chr1q-amp) is a major CNA conferring adverse prognosis in several cancers, including the blood cancer, multiple myeloma (MM). Although several chr1q genes portend high-risk MM disease, the underpinning molecular aetiology remains elusive. Here we integrate patient multi-omics datasets with genetic variables to identify 103 adverse prognosis genes in chr1q-amp MM. Amongst these, the transcription factor PBX1 is ectopically expressed by genetic amplification and epigenetic activation of its own preserved 3D regulatory domain. By binding to reprogrammed super-enhancers, PBX1 directly regulates critical oncogenic pathways, whilst in co-operation with FOXM1, activates a proliferative gene signature which predicts adverse prognosis across multiple cancers. Notably, pharmacological disruption of the PBX1-FOXM1 axis, including with a novel PBX1 inhibitor is selectively toxic against chr1q-amp cancer cells. Overall, our systems medicine approach successfully identifies CNA-driven oncogenic circuitries, links them to clinical phenotypes and proposes novel CNA-targeted therapy strategies in cancer.

scholarly journals Selinexor—A Drug Review

2021 ◽  
Vol 42 (04) ◽  
pp. 360-363
Author(s):  
Hridya Jayamohanan ◽  
Vaibhav Venniyoor ◽  
Keechilat Pavithran
Keyword(s):  
Multiple Myeloma ◽  
Mechanism Of Action ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Tumor Suppressor Proteins ◽  
Large B Cell Lymphoma ◽  
Oncogenic Pathways ◽  
Molecule Inhibitor ◽  
Drug Review ◽  
Large B Cell

AbstractSelinexor developed by Karyopharm Therapeutics is the first orally available small-molecule inhibitor of exportin-1 (XPO1). XPO-1 is a protein transporter responsible for the export of macromolecules such as tumor suppressor proteins and oncoprotein mRNAs from the nucleus to the cytoplasm; its inhibition results in blocking of multiple oncogenic pathways. Overexpression of XPO1 is seen in multiple myeloma and various other malignancies and is a poor prognostic marker. Pivotal positive trials have resulted in the approval of selinexor for use in refractory or relapsed diffuse large B cell lymphoma and multiple myeloma. In this review, we briefly cover the drug development, mechanism of action, indications, and toxicities of the drug, and the major pivotal trials.

DEVELOPMENT OF COMPOSITION AND PRODUCTION TECHNOLOGIES PAZOPANIB TABLET 400 MG

2021 ◽  
pp. 83-87
Author(s):  
А.Е. ЖУМАКАНОВА ◽  
А.Р. ИБРАГИМОВА ◽  
Г.О. УСТЕНОВА
Keyword(s):  
Targeted Therapy ◽  
Cancer Cells ◽  
Soft Tissue Sarcomas ◽  
Targeted Drugs ◽  
Cancer Treatments ◽  
Production Technologies ◽  
Cancer Multiple ◽  
Or Genes ◽  
Cancer Targeted Therapy ◽  
Better Than

Таргетные методы лечения рака - это лекарства, нацеленные на определенные части раковых клеток, такие как белки или гены, которые способствуют росту и распространению раковых клеток. Трагетная терапия при определенных типах раках является эффективной. При некоторых типах рака таргетная терапия может работать лучше, чем другие методы лечения. От английского target - цель, мишень. Природа таргетных лекарств очень специфична и при разработке они направляются под конкретный мутировавший ген раковой клетки определенного вида опухолевого новообразования. В настоящий момент разными странами разработаны эффективные таргетные препараты для лечения различных генетических форм рака молочной железы, множественной миеломы, лимфомы, рака предстательной железы, меланомы, сарком мягких тканей [1]. Targeted cancer treatments are medicaments that target specific parts of cancer cells, such as proteins or genes that growing power and spread of cancer cells. Targeted therapy for certain types of cancers is effective. For some types of cancer, targeted therapy may work better than other treatments. The nature of targeted drugs is very specific and when developed, they are directed to a specific mutated gene of a cancer cell of a certain type of tumor. Currently, different countries have developed effective targeted drugs for the treatment of various genetic forms of breast cancer, multiple myeloma, lymphoma, prostate cancer, melanoma, soft tissue sarcomas.

scholarly journals IL-32 is a metabolic regulator promoting survival and proliferation of malignant plasma cells

2021 ◽  
Author(s):  
Kristin Roseth Aass ◽  
Robin Mjelle ◽  
Martin H. Kastnes ◽  
Synne S. Tryggestad ◽  
Luca M. van den Brink ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Oxidative Phosphorylation ◽  
Plasma Cells ◽  
Inflammatory Diseases ◽  
Mitochondrial Respiratory Chain ◽  
Gene Signature ◽  
Growth And Survival ◽  
Novel Concept

AbstractIL-32 is a non-classical cytokine expressed in cancers, inflammatory diseases and infections. IL-32 can have both extracellular and intracellular functions, and its receptor is not identified. We here demonstrate that endogenously expressed, intracellular IL-32 binds to components of the mitochondrial respiratory chain and promotes oxidative phosphorylation. Knocking out IL-32 in malignant plasma cells significantly reduced survival and proliferation in vitro and in vivo. High throughput transcriptomic and MS-metabolomic profiling of IL-32 KO cells revealed that loss of IL-32 leads to profound perturbations in metabolic pathways, with accumulation of lipids, pyruvate precursors and citrate, indicative of reduced mitochondrial function. IL-32 is expressed in a subgroup of multiple myeloma patients with an inferior prognosis. Primary myeloma cells expressing IL-32 were characterized by a plasma cell gene signature associated with immune activation, proliferation and oxidative phosphorylation. We propose a novel concept for regulation of metabolism by an intracellular cytokine and identify IL-32 as an endogenous growth and survival factor for malignant plasma cells. IL-32 is a potential prognostic biomarker and a treatment target in multiple myeloma.

scholarly journals TP-064, a potent and selective small molecule inhibitor of PRMT4 for multiple myeloma

Oncotarget ◽  
2018 ◽  
Vol 9 (26) ◽  
pp. 18480-18493 ◽  
Author(s):  
Kazuhide Nakayama ◽  
Magdalena M. Szewczyk ◽  
Carlo dela Sena ◽  
Hong Wu ◽  
Aiping Dong ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Small Molecule ◽  
Small Molecule Inhibitor ◽  
Molecule Inhibitor

Another Targeted Therapy for Patients With Multiple Myeloma

JAMA ◽  
2020 ◽  
Vol 323 (13) ◽  
pp. 1236
Author(s):  
Rebecca Voelker
Keyword(s):  
Multiple Myeloma ◽  
Targeted Therapy

scholarly journals Jumping Translocations of Chromosome 1q in Multiple Myeloma: Evidence for a Mechanism Involving Decondensation of Pericentromeric Heterochromatin

Blood ◽  
1998 ◽  
Vol 91 (5) ◽  
pp. 1732-1741 ◽  
Author(s):  
Jeffrey R. Sawyer ◽  
Guido Tricot ◽  
Sandy Mattox ◽  
Sundar Jagannath ◽  
Bart Barlogie
Keyword(s):  
Multiple Myeloma ◽  
Clonal Evolution ◽  
Chromosome 1 ◽  
Pericentromeric Heterochromatin ◽  
Chromosome 1Q ◽  
Numerical Aberrations ◽  
Cytogenetic Evidence ◽  
Acrocentric Chromosomes ◽  
Cytogenetic Evolution ◽  
Proliferative Advantage

Abstract Karyotypes in multiple myeloma (MM) are complex and exhibit numerous structural and numerical aberrations. The largest subset of structural chromosome anomalies in clinical specimens and cell lines involves aberrations of chromosome 1. Unbalanced translocations and duplications involving all or part of the whole long arm of chromosome 1 presumably occur as secondary aberrations and are associated with tumor progression and advanced disease. Unfortunately, cytogenetic evidence is scarce as to how these unstable whole-arm rearrangements may take place. We report nonrandom, unbalanced whole-arm translocations of 1q in the cytogenetic evolution of patients with aggressive MM. Whole-arm or “jumping translocations” of 1q were found in 36 of 158 successive patients with abnormal karyotypes. Recurring whole-arm translocations of 1q involved chromosomes 5,8,12,14,15,16,17,19,21, and 22. A newly delineated breakpoint present in three patients involved a whole-arm translocation of 1q to band 5q15. Three recurrent translocations of 1q10 to the short arms of different acrocentric chromosomes have also been identified, including three patients with der(15)t(1;15)(q10;p10) and two patients each with der(21)t(1;21)(q10;p13) and der(22)t(1;22) (q10;p10). Whole-arm translocations of 1q10 to telomeric regions of nonacrocentric chromosomes included der(12)t(1;12) (q10;q24.3) and der(19)t(1;19)(q10;q13.4) in three and two patients, respectively. Recurrent whole-arm translocations of 1q to centromeric regions included der(16)t(1;16)(q10;q10) and der(19)t(1;19)(q10;p10). The mechanisms involved in the 1q instability in MM may be associated with highly decondensed pericentromeric heterochromatin, which may permit recombination and formation of unstable translocations of chromosome 1q. The clonal evolution of cells with extra copies of 1q suggests that this aberration directly or indirectly provides a proliferative advantage.

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