Future Directions of Next-Generation Novel Therapies, Combination Approaches, and the Development of Personalized Medicine in Myeloma

2011 ◽  
Vol 29 (14) ◽  
pp. 1916-1923 ◽  
Author(s):  
Constantine S. Mitsiades ◽  
Faith E. Davies ◽  
Jacob P. Laubach ◽  
Douglas Joshua ◽  
Jesus San Miguel ◽  
...  
Keyword(s):  
Personalized Medicine ◽  
Molecular Heterogeneity ◽  
Clinical Safety ◽  
Resistant Disease ◽  
Molecular Features ◽  
Effective Combination ◽  
Profiling Techniques ◽  
Investigational Agents ◽  
Combination Regimens

Despite tangible progress in recent years, substantial therapeutic challenges remain in multiple myeloma (MM), particularly for patients at high risk for early relapse or death and for those with advanced multi-drug resistant disease and refractoriness to currently available combination regimens. Addressing these challenges requires identification of novel classes of anti-MM agents, their incorporation into safe and more effective combination regimens, and development of efficient algorithms to select the most appropriate therapeutic options for the clinical and molecular features of individual patients at a given time during their disease. Ideally, these goals can be facilitated by preclinical identification of the “driver” molecular lesions on which different myeloma subtypes exquisitely depend, and by informative preclinical models simulating the clinical setting(s) in which trials will be conducted. Large prospective studies of patients treated uniformly with contemporary clinical regimens are essential, but there is also a major need for flexibility in studying new regimens in the future. Long-term patient follow-up and integrated annotation of clinical (safety and efficacy) and correlative (molecular, biochemical, etc) data are also critical. Novel molecular profiling techniques will likely identify more clinically and biologically discrete subsets of patients with recurrent, even if infrequent, lesions. This molecular heterogeneity, combined with the increasing numbers of candidate therapeutic targets and respective investigational agents, may pose formidable challenges for the development and implementation of personalized medicine in MM. This review discusses these challenges, as well as potential strategies to address them, with the aim of making significant improvement in the clinical outcome of patients with MM.

Molecular profiling in cancer research and personalized medicine

2019 ◽  
pp. 347-362
Author(s):  
Pieter-Jan van Dam ◽  
Steven Van Laere
Keyword(s):  
Personalized Medicine ◽  
High Throughput ◽  
Cancer Biology ◽  
Complex Disease ◽  
Human Cancer ◽  
Molecular Profiling ◽  
Cancer Genome ◽  
The Cancer Genome Atlas ◽  
Molecular Heterogeneity ◽  
Profiling Techniques

Recent efforts by worldwide consortia such as The Cancer Genome Atlas and the International Cancer Genome Consortium have greatly accelerated our knowledge of human cancer biology. Nowadays, complete sets of human tumours that have been characterized at the genomic, epigenomic, transcriptomic, or proteomic level are available to the research community. The generation of these data was made possible thanks to the application of high-throughput molecular profiling techniques such as microarrays and next-generation sequencing. The primary conclusion from current profiling experiments is that human cancer is a complex disease characterized by extreme molecular heterogeneity, both between and within the classical, tissue-defined cancer types. This molecular variety necessitates a paradigm shift in patient management, away from generalized therapy schemes and towards more personalized treatments. This chapter provides an overview of how molecular cancer profiling can assist in facilitating this transition. First, the state-of-the-art of molecular breast cancer profiling is reviewed to provide a general background. Then, the most pertinent high-throughput molecular profiling techniques along with various data mining techniques (i.e. unsupervised clustering, statistical learning) are discussed. Finally, the challenges and perspectives with respect to molecular cancer profiling, also from the perspective of personalized medicine, are summarized.

Modern prevention and active longevity programs on the basis of disruptive domestic technologies: positive experience and prospects for application

2020 ◽  
pp. 66-73
Author(s):  
A. Simonova ◽  
S. Chudakov ◽  
R. Gorenkov ◽  
V. Egorov ◽  
A. Gostry ◽  
...  
Keyword(s):  
Personalized Medicine ◽  
Early Detection ◽  
Laboratory Diagnostics ◽  
Positive Experience ◽  
Practical Application ◽  
Wide Range ◽  
Integrated Program ◽  
Long Term Experience ◽  
Early Detection And Prevention

The article summarizes the long-term experience of practical application of domestic breakthrough technologies of preventive personalized medicine for laboratory diagnostics of a wide range of socially significant non-infectious diseases. Conceptual approaches to the formation of an integrated program for early detection and prevention of civilization diseases based on these technologies are given. A vision of the prospects for the development of this area in domestic and foreign medicine has been formed.

scholarly journals ETMR-06. DISSECTING THE MOLECULAR AND DEVELOPMENTAL BASIS OF PINEOBLASTOMA THROUGH GENOMICS

2020 ◽  
Vol 22 (Supplement_3) ◽  
pp. iii323-iii324
Author(s):  
Brian Gudenas ◽  
Bernhard Englinger ◽  
Anthony P Y Liu ◽  
Yiai Tong ◽  
David Meredith ◽  
...  
Keyword(s):  
Pineal Gland ◽  
Single Cell ◽  
Outcome Data ◽  
Genetically Engineered ◽  
Developmental Trajectory ◽  
Transcriptional Analysis ◽  
Molecular Heterogeneity ◽  
Developmental Origins ◽  
Cell Of Origin ◽  
Molecular Features

Abstract Pineoblastoma (PB) is an aggressive embryonal brain tumor comprising 1% of pediatric CNS tumors. The clinico-molecular heterogeneity and developmental origins underlying PB are poorly understood; therefore, we have assembled a molecular cohort of histologically defined PBs (n=43) with corresponding outcome data. Methylation profiling revealed four molecularly and clinically distinct PB subgroups, including two novel entities. Mutational and transcriptional analysis identified characteristic molecular features of each subgroup, such as mutations in the miRNA processing pathway or FOXR2 proto-oncogene overexpression. Furthermore, subgroups exhibited differences in propensity for metastasis, cytogenetics, and clinical outcomes. To dissect PB developmental origins and resolve PB subgroup biology, we have employed a combination of single-cell genomics and genetically engineered mouse modeling. We created a single-cell transcriptional atlas of the developing murine pineal gland across 11 timepoints and are currently integrating these data with single nuclei RNA-seq data of human PB (n=25). Single-cell analysis of the developing pineal gland revealed three distinct populations of pinealocytes, referred to as early, mid and late pinealocytes, which segregate by developmental stage yet lie along a single developmental trajectory. Preliminary results implicate significant associations between PBs and the early pinealocyte population as well as subgroup-specific differences in intratumoral heterogeneity. Furthermore, this knowledge has informed the downstream generation of biologically faithful disease models, including a transgenic mouse model of the PB-RB subgroup. Remarkably, this model shows up-regulation of key markers of PB such as Crx, Asmt and Otx2 and substantiates early pinealocytes as the probable cell-of-origin for this PB subgroup.

scholarly journals Effective Combination of Photodynamic Therapy and Imiquimod 5% Cream in the Treatment of Actinic Keratoses: Three Cases

2013 ◽  
Vol 2013 ◽  
pp. 1-5 ◽  
Author(s):  
Laura Held ◽  
Thomas Kurt Eigentler ◽  
Ulrike Leiter ◽  
Claus Garbe ◽  
Mark-Jürgen Berneburg
Keyword(s):  
Photodynamic Therapy ◽  
Patient Adherence ◽  
Proof Of Concept ◽  
Treatment Area ◽  
Skin Reactions ◽  
Local Skin ◽  
Once Daily ◽  
Actinic Keratoses ◽  
Effective Combination

Background. The therapy for actinic keratoses includes photodynamic therapy (PDT) and imiquimod 5% cream. The sequential use of both could result in better clinical outcomes.Objectives. To enhance efficacy of therapies while improving tolerability, convenience, and patient adherence with a scheme combining two concomitant or sequential AK treatments.Methods. All patients underwent one session of conventional PDT. Two weeks after, the PDT imiquimod 5% cream was applied to the treatment area once daily for three days per week. One course continued for four weeks followed by a clinical evaluation and decision about further treatment. Patients who had not cleared all of their AK lesions in the treatment area in course 1 participated in a second 4-week course of treatment.Limitations. Small size of population.Results. Three participants were enrolled. Two patients showed complete clinical clearance of AKs. The effect was also noted after long-term followup, at months seven and eleven. No subject discontinued for an adverse event. There were severe local skin reactions in two participants which were severe erythema, scaling, and crusting. One patient showed no response to the therapy.Conclusions. Photodynamic therapy followed by imiquimod was well tolerated and improved reduction of actinic keratoses. This initial proof-of-concept should be studied in larger clinical trials.

Assessment of bone marrow stem cell reserve and function and stromal cell function in patients with autoimmune cytopenias

Blood ◽  
2000 ◽  
Vol 96 (9) ◽  
pp. 3272-3275 ◽  
Author(s):  
Helen A. Papadaki ◽  
Frances M. Gibson ◽  
Sian Rizzo ◽  
Edward C. Gordon-Smith ◽  
Judith C. W. Marsh
Keyword(s):  
Bone Marrow ◽  
Stem Cell ◽  
Stromal Cell ◽  
Cell Function ◽  
Resistant Disease ◽  
Cell Assays ◽  
Factor Data ◽  
Autoimmune Cytopenias ◽  
And Function

Abstract To investigate whether bone marrow (BM) stem cell compartment and/or BM microenvironment are affected by the immune insult in autoimmune cytopenias (AICs), BM stem cell reserve and function and BM stromal function were studied in 15 AIC patients. Stem cells were evaluated by means of flow cytometry, clonogenic progenitor cell assays, long-term BM cultures (LTBMCs), and limiting dilution assay for quantification of long-term–culture initiating cells (LTC-ICs). Stromal cell function was assessed with the use of preformed irradiated LTBMCs from patients and normal controls, recharged with normal CD34+ cells. AIC patients exhibited a high number of CD34+, CD34+/CD38+, and CD34+/CD38− cells; high frequency of granulocyte-macrophage colony forming units in the BM mononuclear cell fraction; high colony recovery in LTBMCs; and normal LTC-IC frequency. Patient BM stromal layers displayed normal hematopoietic-supporting capacity and increased production of granulocyte-colony stimulating factor. Data from this study support the concept that AIC patients with severe, resistant disease might be appropriate candidates for autologous stem cell transplantation.

scholarly journals Future therapeutic strategies for metastatic prostate cancer

2019 ◽  
Vol 9 (6-7) ◽  
pp. 117-130 ◽  
Author(s):  
Minke Smits ◽  
Winald Gerritsen ◽  
Niven Mehra
Keyword(s):  
Prostate Cancer ◽  
Metastatic Prostate Cancer ◽  
Predictive Biomarkers ◽  
Parp Inhibition ◽  
Oncological Patient ◽  
Damage Repair ◽  
Repair Deficiency ◽  
Disease Stabilization ◽  
Combination Regimens

Abstract During the last decade several new therapies have been investigated and approved for metastatic prostate cancer that greatly impacts patients’ quality of life and outcome. Nevertheless, optimal sequencing algorithms are still lacking, as are combinatory strategies that deliver long-term disease stabilization. Precision medicine, utilizing molecular profiles from tissue biopsies, will help us deliver optimal patient care by identifying patients that may benefit from targeted- and immunotherapy, and help guide treatment decisions by use of predictive biomarkers. Here, we present an overview of predictive biomarkers in prostate cancer, including mismatch repair and DNA damage repair deficiency, and promising novel targeted- and immunotherapies regimens, such as PSMA-radioligand therapy, PARP inhibition and PD-1/PD-L1 and CTLA‑4 checkpoint therapy. We anticipate that these agents in monotherapy and in combination regimens will alter uro-oncological patient management within the next ten years.

scholarly journals Germ Cell Tumor Molecular Heterogeneity Revealed Through Analysis of Primary and Metastasis Pairs

2020 ◽  
pp. 1307-1320
Author(s):  
Michael L. Cheng ◽  
Mark T.A. Donoghue ◽  
François Audenet ◽  
Nathan C. Wong ◽  
Eugene J. Pietzak ◽  
...  
Keyword(s):  
Germ Cell ◽  
Somatic Mutations ◽  
Germ Cell Tumors ◽  
Molecular Heterogeneity ◽  
Targeted Next Generation Sequencing ◽  
Variants Of Unknown Significance ◽  
Resistant Disease ◽  
Oncogenic Mutations ◽  
Dna Copy Number Alterations ◽  
Metastatic Sites

PURPOSE Although primary germ cell tumors (GCTs) have been extensively characterized, molecular analysis of metastatic sites has been limited. We performed whole-exome sequencing and targeted next-generation sequencing on paired primary and metastatic GCT samples in a patient cohort enriched for cisplatin-resistant disease. PATIENTS AND METHODS Tissue sequencing was performed on 100 tumor specimens from 50 patients with metastatic GCT, and sequencing of plasma cell-free DNA was performed for a subset of patients. RESULTS The mutational landscape of primary and metastatic pairs from GCT patients was highly discordant (68% of all somatic mutations were discordant). Whereas genome duplication was common and highly concordant between primary and metastatic samples, only 25% of primary-metastasis pairs had ≥ 50% concordance at the level of DNA copy number alterations (CNAs). Evolutionary-based analyses revealed that most mutations arose after CNAs at the respective loci in both primary and metastatic samples, with oncogenic mutations enriched in the set of early-occurring mutations versus variants of unknown significance (VUSs). TP53 pathway alterations were identified in nine cisplatin-resistant patients and had the highest degree of concordance in primary and metastatic specimens, consistent with their association with this treatment-resistant phenotype. CONCLUSION Analysis of paired primary and metastatic GCT specimens revealed significant molecular heterogeneity for both CNAs and somatic mutations. Among loci demonstrating serial genetic evolution, most somatic mutations arose after CNAs, but oncogenic mutations were enriched in the set of early-occurring mutations as compared with VUSs. Alterations in TP53 were clonal when present and shared among primary-metastasis pairs.

scholarly journals Transcriptional Characterization of Stage I Epithelial Ovarian Cancer: A Multicentric Study

Cells ◽  
2019 ◽  
Vol 8 (12) ◽  
pp. 1554
Author(s):  
Enrica Calura ◽  
Matteo Ciciani ◽  
Andrea Sambugaro ◽  
Lara Paracchini ◽  
Giuseppe Benvenuto ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Epithelial Ovarian Cancer ◽  
Stage I ◽  
Molecular Heterogeneity ◽  
Low Grade ◽  
Multicentric Study ◽  
Molecular Alterations ◽  
Molecular Features ◽  
Signaling Axis ◽  
Tumor Biopsies

Stage I epithelial ovarian cancer (EOC) represents about 10% of all EOCs. It is characterized by a complex histopathological and molecular heterogeneity, and it is composed of five main histological subtypes (mucinous, endometrioid, clear cell and high, and low grade serous), which have peculiar genetic, molecular, and clinical characteristics. As it occurs less frequently than advanced-stage EOC, its molecular features have not been thoroughly investigated. In this study, using in silico approaches and gene expression data, on a multicentric cohort composed of 208 snap-frozen tumor biopsies, we explored the subtype-specific molecular alterations that regulate tumor aggressiveness in stage I EOC. We found that single genes rather than pathways are responsible for histotype specificities and that a cAMP-PKA-CREB1 signaling axis seems to play a central role in histotype differentiation. Moreover, our results indicate that immune response seems to be, at least in part, involved in histotype differences, as a higher immune-reactive behavior of serous and mucinous samples was observed with respect to other histotypes.

scholarly journals Apolipoprotein E mimetic peptide CN-105 improves outcome in a murine model of SAH

2018 ◽  
Vol 3 (4) ◽  
pp. 222-230 ◽  
Author(s):  
Ji Liu ◽  
Guanen Zhou ◽  
Bradley J Kolls ◽  
Yanli Tan ◽  
Chuan Fang ◽  
...  
Keyword(s):  
Brain Injury ◽  
Apolipoprotein E ◽  
Murine Model ◽  
Neuronal Degeneration ◽  
Pharmacokinetic Profile ◽  
Clinical Safety ◽  
Mimetic Peptide ◽  
Intravenous Injections ◽  
Central Nervous System Penetration

ObjectiveSubarachnoid haemorrhage (SAH) accounts for 3% of all strokes, and is associated with significant morbidity and mortality. There is growing evidence implicating apolipoprotein E (apoE) in mediating adaptive anti-inflammatory and neuroprotective responses following ischaemic and traumatic brain injury. In the current study, we test the efficacy of a small apoE mimetic peptide, CN-105 in a murine model of SAH.MethodsMice subjected to SAH received repeated intravenous injections of CN-105 every 12 hours for 3 days, with the first dose given 2 hours after injury. Daily functional outcomes were assessed by rotarod and neurological severity score. Haemorrhage grade and cerebral vascular diameters were measured at 5 days post-SAH. Cerebral microgliosis, neuronal degeneration and survival were analysed at 5 and 35 days post-SAH, respectively.ResultsCN-105 reduces histological evidence of inflammation, reduces vasospasm and neuronal injury and is associated with improved long-term behavioural outcomes in a murine model of SAH.ConclusionsGiven its favourable pharmacokinetic profile, central nervous system penetration and demonstration of clinical safety, CN-105 represents an attractive therapeutic candidate for treatment of brain injury associated with SAH.

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