Genomic Findings Research Articles

Genomic discoveries advance the battle against black rot in crucifers

Xanthomonas campestris pv. campestris, the explanation for disease of crucifers, was one of the first bacterial plant pathogens ever identified. Over 130 years later, disease remains a threat to cabbage, cauliflower, and other Brassica crops around the world. Recent genomic and genetic data are informing our understanding of X. campestris taxonomy, dissemination, inoculum sources, and virulence factors. This new knowledge promises to positively impact resistance breeding of Brassica varieties and management of inoculum sources.

Lessons learned from the eMERGE Network: balancing genomics in discovery and practice

SummaryThe Electronic Medical Records and Genomics (eMERGE) Network, established in 2007, is a consortium of academic and integrated health systems conducting discovery and implementation research in translational genomics. Here, we outline the history of the network, highlight major impacts and lessons learned, and present the tools and resources developed for large-scale genomic analyses and translation into a clinical setting. The network developed methods to extract phenotypes from the electronic medical record to perform genome-wide and phenome-wide association studies. Recruited cohorts were clinically sequenced off a custom panel for targeted sequencing of variants and monogenic disease risks and returned to participants to investigate the impact of return of genomic results. After generating a 105,000 participant-imputed genome-wide association study (GWAS) dataset for discovery, the network enrolled and sequenced 24,998 participants. Integration of these results into the medical record and the effects of results on participants provided key lessons to the field. These learned lessons inform genetic research in diverse populations and provide insights into the clinical impact of return and implementation of genomic medicine using the electronic medical record. The lessons produced by the eMERGE Network can be utilized by other consortia as translational genomic medicine research evolves.

2020 Innovation-Based Optimism for Lung Cancer Outcomes.

Lung cancer is the leading cause of cancer death in both males and females in the U.S. and worldwide. Owing to advances in prevention, screening/early detection, and therapy, lung cancer mortality rates are decreasing and survival rates are increasing. These innovations are based on scientific discoveries in imaging, diagnostics, genomics, molecular therapy, and immunotherapy. Outcomes have improved in all histologies and stages. This review provides information on the clinical implications of these innovations that are practical for the practicing physicians, especially oncologists of all specialities who diagnose and treat patients with lung cancer. IMPLICATIONS FOR PRACTICE: Lung cancer survival rates have improved because of new prevention, screening, and therapy methods. This work provides a review of current standards for each of these areas, including targeted and immunotherapies. Treatment recommendations are provided for all stages of lung cancer.

Germline Variation and Somatic Alterations in Ewing Sarcoma.

Ewing sarcoma (EwS) is a rare bone or soft tissue tumor that occurs early in life and as such genetic variation is a major contributor to EwS risk. To date, genetic investigations have identified key somatic mutations and germline variants of importance for EwS risk. While substantial progress is being made in uncovering the genetic etiology of EwS, considerable gaps in knowledge remain. Herein, we provide a summary of methodological approaches for future genomic investigations of EwS. We anticipate this recommended analytical framework for germline and somatic investigations, along with genomic data from growing EwS case series, will aid in accelerating new genomic discoveries in EwS and expand knowledge of the genetic architecture of EwS.

PSVII-39 Late-Breaking Abstract: Enhancing production and Aleutian disease resilience in mink through advanced genomics

Abstract The fur industry is one of the oldest and the most historically significant industries in Canada. The industry has used American mink (Neovison vison) as the major source of fur for decades because of their high-quality fur and wide range of colours. This project will seek to (1) create the first accurate whole-genome sequence assembly of mink using next-generation sequencing technology to help understanding the biology and evolution of the order Carnivora, (2) design a robust and informative SNP assay for genomics discovery in mink, (3) discover genome structure and signature of selection as well as identify new genetic variants explaining variation in economically important traits, and (4) identify the genetic relationships among these traits including feed efficiency, Aleutian disease resilience, fur quality, reproductive performance, growth rate and pelt size. One hundred mink DNA samples from the Canadian Centre for Fur Animal Research at Dalhousie Agriculture Campus (Truro, Nova Scotia), and one breeding population (Millbank Fur Farm Limited, Rockwood, Ontario) were sequenced using next-generation whole-genome sequencing with more than 30x coverage to create the first SNP assay for American mink. A DNA panel composed of these sequenced mink from five color-types were assembled to identify the most homozygous individual as the reference animal for whole-genome sequence assembly development. The phenotypic data and DNA samples from 3,323 animals were collected and will be genotyped using the customized assay. The ultimate objective is to develop new tools for implementation of marker assisted selection or genomic selection in mink breeding programs for development of superior, highly efficient, and healthy animals. This approach will help improve the overall performance of the North American mink industry, which is now in difficulty due to several economic factors such as the high price of feed, declining price of fur and prevalence of diseases.

TOA: A software package for automated functional annotation in non-model plant species.

The increase of sequencing capacity provided by high-throughput platforms has made it possible to routinely obtain large sets of genomic and transcriptomic sequences from model and non-model organisms. Subsequent genomic analysis and gene discovery in next-generation sequencing experiments are, however, bottlenecked by functional annotation. One common way to perform functional annotation of sets of sequences obtained from next-generation sequencing experiments, is by searching for homologous sequences and accessing the related functional information deposited in genomic databases. Functional annotation is especially challenging for non-model organisms, like many plant species. In such cases, existing free and commercial general-purpose applications may not offer complete and accurate results. We present TOA (Taxonomy-oriented annotation), a Python-based user-friendly open source application designed to establish functional annotation pipelines geared towards non-model plant species that can run in Linux/Mac computers, HPCs and cloud servers. TOA performs homology searches against proteins stored in the PLAZA databases, NCBI RefSeq Plant, Nucleotide Database and Non-Redundant Protein Sequence Database, and outputs functional information from several ontology systems: Gene Ontology, InterPro, EC, KEGG, Mapman and MetaCyc. The software performance was validated by comparing the runtimes, total number of annotated sequences and accuracy of the functional information obtained for several plant benchmark data sets with TOA and other functional annotation solutions. TOA outperformed the other software in terms of number of annotated sequences and accuracy of the annotation and constitutes a good alternative to improve functional annotation in plants. TOA is especially recommended for gymnosperms or for low quality sequence data sets of non-model plants.

Nonconserved Long Intergenic Noncoding RNAs Associate With Complex Cardiometabolic Disease Traits.

Transcriptome profiling of human tissues has revealed thousands of long intergenic noncoding RNAs (lincRNAs) at loci identified through large-scale genome-wide studies for complex cardiometabolic traits. This raises the question of whether genetic variation at nonconserved lincRNAs has any systematic association with complex disease, and if so, how different this pattern is from conserved lincRNAs. We evaluated whether the associations between nonconserved lincRNAs and 8 complex cardiometabolic traits resemble or differ from the pattern of association for conserved lincRNAs. Approach and Results: Our investigation of over 7000 lincRNA annotations from GENCODE Release 33-GRCh38.p13 for complex trait genetic associations leveraged several large, established meta-analyses genome-wide association study summary data resources, including GIANT (Genetic Investigation of Anthropometric Traits), UK Biobank, GLGC (Global Lipids Genetics Consortium), Cardiogram (Coronary Artery Disease Genome Wide Replication and Meta-Analysis), and DIAGRAM (Diabetes Genetics Replication and Meta-Analysis)/DIAMANTE (Diabetes Meta-Analysis of Trans-Ethnic Association Studies). These analyses revealed that (1) nonconserved lincRNAs associate with a range of cardiometabolic traits at a rate that is generally consistent with conserved lincRNAs; (2) these findings persist across different definitions of conservation; and (3) overall across all cardiometabolic traits, approximately one-third of genome-wide association study-associated lincRNAs are nonconserved, and this increases to about two-thirds using a more stringent definition of conservation. These findings suggest that the traditional notion of conservation driving prioritization for functional and translational follow-up of complex cardiometabolic genomic discoveries may need to be revised in the context of the abundance of nonconserved long noncoding RNAs in the human genome and their apparent predilection to associate with complex cardiometabolic traits.

First person profile: William Sellers, MD: Dr. Sellers has helped to shape the field of cancer genomics and, alongside his colleagues, is working toward its ultimate goal-to move from therapy to cure.

First person profile: William Sellers, MD: Dr. Sellers has helped to shape the field of cancer genomics and, alongside his colleagues, is working toward its ultimate goal-to move from therapy to cure.

The CLL-1100 Project: Towards Complete Genomic Characterization and Improved Prognostics for CLL

The CLL-1100 Project: Towards Complete Genomic Characterization and Improved Prognostics for CLL

Clinical Value of Next Generation Sequencing in the Detection of Recurring Structural Rearrangements and Copy Number Abnormalities in Acute Myeloid Leukemia

Purpose: Acute myeloid leukemia (AML) is the most common acute leukemia in adults, affecting approximately 20,000 patients annually in the United States. AML genetic subtypes, as defined by the World Health Organization (WHO), are identified through fluorescence in situ hybridization (FISH), conventional chromosome analysis, and sequencing techniques. Mate pair sequencing (MPseq) is a next generation sequencing (NGS) technology optimized to detect genome wide structural variants and copy number alterations at high resolution. Our study goal was to investigate the prognostic value of MPseq in comparison to FISH, chromosome, and sequencing studies in the evaluation of AML patients. Methods: We performed a prospective study using blood and bone marrow samples from 105 patients with a diagnosis of AML, using MPseq, along with chromosome, FISH, and NGS or PCR studies to detect small mutations. Cytogenetic and molecular genetic results were correlated with MPseq findings. We also analyzed the MPseq data for chromoplexy, chromothripsis, and progressive complexity. Junction and copy number burden, the incidence of structural variation in the genome and the percent of the genome with aberrant copy number, were evaluated. Overall survival statistics were stratified by AML subtypes and observed anomalies. Results: Although structural variants in AML were characterized at a high resolution using MPseq when compared to conventional cytogenetic methods, risk stratification using current European Leukemia Net (ELN) guidelines was not improved by MPseq. The cohorts involving 5q and/or 7q deletions exhibited high levels of genomic complexity when compared to normal karyotype AML (NK-AML). The incidence of copy number gains, losses and junctions was greatest in 5q and 7q co-deletions (5q/7q) (16.5, 25.0, 69.3) and 5q deletions (5q) (9.8, 16.7, 31.6) subtypes compared to 7q deletions (3.4, 7.0, 6.7) and NK-AML (2.6, 4.3, 3.8) (p<0.001) subtypes. Chromoplexy, chromothripsis, and progressive structural complexity were detected in most samples with 5q deletions and 5q/7q co-deletions, but absent in samples with 7q or NK-AML. Biallelic inactivation of TP53 by sequencing mutation and/or deletion was common in the 5q/7q co-deletion (14/18 cases) and 5q deletion cohorts (7/10 cases), rare in the 7q deletion cohort (1/11 cases), and absent in the NK-AML (n=44) cohort. The median OS was significantly worse for patients with 5q/7q deletions (122.5 days) and 5q deletions (248 days) compared to NK-AML (413.5 days; p<0.001 and p=0.017, respectively) and between 5q/7q deletions and 7q deletions (370.5 days; p<0.001). No significant difference was observed between 5q/7q and 5q deletion subtypes, between NK and 7q deletion subtypes and between 5q and 7q deletion subtypes. The median OS was also significantly shorter for patients with TP53 alterations compared to patients with normal TP53 status. Patients with chromoplexy, chromothripsis and/or progressive structural complexity identified by MPseq had a significantly shorter median OS compared to patients without these features. (p<0.0001) Discussion: Risk stratifications based on current guidelines using cytogenetic and sequencing results were not adjusted due to MPseq results, which is not surprising when primary abnormalities are observed by conventional cytogenetic methods. NK-AML cases did not appear to benefit from a high resolution genomic evaluation. However, MPseq added value when structural variation required additional characterization, detecting novel rearrangements, such as a KAT6A/SORBS3 fusion. Lastly, we recognized common mischaracterizations made by conventional chromosome studies - including missed TP53 deletions in 7 cases, 5q/7q deletions misinterpreted as monosomies, cryptic NUP98 rearrangements, and unappreciated genomic complexity correlating with poor OS. These mischaracterizations challenge the use of conventional chromosome studies as a gold standard without accompanying FISH or MPseq studies. MPseq, similar to other structural methodologies such as optical mapping and long read sequencing, should be considered important complements to standard cytologic techniques given the important additional genomic information obtained. The additional structural variant characterization will be critical in paving the way for genomic discovery with the overall goal of improving prognostication for patient care. Figure Disclosures Vasmatzis: WholeGenome LLC.: Other: Owner; Mayo Clinic: Membership on an entity's Board of Directors or advisory committees, Research Funding.

Short RNA Universal Coding for Topological Transformation Nano-barcoding Application.

With the advent of innovative genomic discovery toolkits such as RT-PCR, genetic information can be quickly decrypted, and this has resulted in significant progress in overcoming diseases. However, RT-PCR has the serious problem of frequent errors, and the demand for a new gene diagnostic system is emerging. Herein, we propose a universal coding system for the effective detection of short single-stranded DNA or RNA by using a topological transformation-based nano-barcoding technique (TNT). Our goal was to develop a dedicated diagnostic device that unifies the other gene groups, thus resulting in minimum testing. In a universal coding system consisting of two separate circulation structures, different gene groups become generalized into specific single genes with the same sequence by a strand-displacement reaction and are then amplified, eventually being quickly detected in one TNT system. Simple gene diagnostic systems like this make high-speed, point-of-care diagnostic technologies, and we are very confident that these will provide clinical gene detection in the near future.

Abstract B28: A novel intestinal microbiome-derived peptide modulates immune cell activity and the tumor microenvironment

Abstract The composition of the gut microbiota affects cancer development, progression, and response to therapy. A number of commensal bacteria, including Bifidobacterium, have been associated with increased response to immune checkpoint inhibitors in mouse tumor models, as well as in melanoma patients. We hypothesized that secreted peptides or proteins contribute to the effects mediated by Bifidobacterium strains in vivo. We used our unique bioinformatics-driven discovery platform to nominate putatively secreted Bifidobacterium-derived peptides for evaluation in immune cell effector assays. We have previously described bacterial peptides that induce secretion of proinflammatory cytokines (e.g., IL-6, TNF) by in vitro-generated mouse and human dendritic cells, as well as effector cytokine secretion (e.g., IFNγ, IL-2) by mouse splenic T lymphocytes in vitro. To investigate the function of Bifidobacterium-derived peptides in the context of the tumor microenvironment, we injected a candidate peptide, termed SG-A, directly into the tumors of tumor-bearing mice. We then performed immune phenotyping via the Nanostring PanCancer Immune Profiling panel, as well as by flow cytometry. Both Nanostring and flow cytometry analysis demonstrated an increase in CD45+ lymphocytes within the tumors of mice treated with SG-A. Peptide SG-A also induced upregulation of dendritic cell function genes (CD40, CD83, and CD86) and multiple effector cytokines and chemokines. Restimulation of tumor-draining lymph node cells with a tumor-derived peptide antigen also increased induction of IFNγ in SG-A treated animals (vs. vehicle-treated controls). Collectively, our results demonstrate the utility of the Second Genome discovery platform for leveraging microbiome science to identify novel immunomodulatory factors. This platform offers the potential to identify agents that may complement or enhance efficacy of existing approaches to immunotherapy for melanoma and other cancers. Citation Format: Helena Kiefel, Dhwani Haria, Yuliya Katlinskaya, Divya Ravichandar, Sunit Jain, Thomas Weinmaier, Shoko Iwai, Todd DeSantis, Toshi Takeuchi, Karim Dabbagh, Kareem Graham. A novel intestinal microbiome-derived peptide modulates immune cell activity and the tumor microenvironment [abstract]. In: Proceedings of the AACR Special Conference on Melanoma: From Biology to Target; 2019 Jan 15-18; Houston, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(19 Suppl):Abstract nr B28.

A scoping review of social and behavioral science research to translate genomic discoveries into population health impact.

Since the completion of the Human Genome Project, progress toward translating genomic research discoveries to address population health issues has been limited. Several meetings of social and behavioral scientists have outlined priority research areas where advancement of translational research could increase population health benefits of genomic discoveries. In this review, we track the pace of progress, study size and design, and focus of genomics translational research from 2012 to 2018 and its concordance with five social and behavioral science recommended priorities. We conducted a review of the literature following the Preferred Reporting Items for Systematic Reviews and Meta-Analysis Guidelines for Scoping Reviews. Steps involved completing a search in five databases and a hand search of bibliographies of relevant literature. Our search (from 2012 to 2018) yielded 4,538 unique studies; 117 were included in the final analyses. Two coders extracted data including items from the PICOTS framework. Analysis included descriptive statistics to help identify trends in pace, study size and design, and translational priority area. Among the 117 studies included in our final sample, nearly half focused on genomics applications that have evidence to support translation or implementation into practice (Centers for Disease Control and Prevention Tier 1 applications). Common study designs were cross-sectional (40.2%) and qualitative (24.8%), with average sample sizes of 716 across all studies. Most often, studies addressed public understanding of genetics and genomics (33.3%), risk communication (29.1%), and intervention development and testing of interventions to promote behavior change (19.7%). The number of studies that address social and behavioral science priority areas is extremely limited and the pace of this research continues to lag behind basic science advances. Much of the research identified in this review is descriptive and related to public understanding, risk communication, and intervention development and testing of interventions to promote behavior change. The field has been slow to develop and evaluate public health-friendly interventions and test implementation approaches that could enable health benefits and equitable access to genomic discoveries. As the completion of the human genome approaches its 20th anniversary, full engagement of transdisciplinary efforts to address translation challenges will be required to close this gap.

Genomics, Computational Biology and Drug Discovery for Mycobacterial Infections: Fighting the Emergence of Resistance.

Tuberculosis (TB) and leprosy are mycobacterial infections caused by Mycobacterium tuberculosis and Mycobacterium leprae respectively. These diseases continue to be endemic in developing countries where the cost of new medicines presents major challenges. The situation is further exacerbated by the emergence of resistance to many front-line antibiotics. A priority now is to design new antimycobacterials that are not only effective in combatting the diseases but are also less likely to give rise to resistance. In both these respects understanding the structure of drug targets in M. tuberculosis and M. leprae is crucial. In this review we describe structure-guided approaches to understanding the impacts of mutations that give rise to antimycobacterial resistance and the use of this information in the design of new medicines.

Eco-evolutionary dynamics driven by fishing: From single species models to dynamic evolution within complex food webs.

Evidence of contemporary evolution across ecological time scales stimulated research on the eco‐evolutionary dynamics of natural populations. Aquatic systems provide a good setting to study eco‐evolutionary dynamics owing to a wealth of long‐term monitoring data and the detected trends in fish life‐history traits across intensively harvested marine and freshwater systems. In the present study, we focus on modelling approaches to simulate eco‐evolutionary dynamics of fishes and their ecosystems. Firstly, we review the development of modelling from single species to multispecies approaches. Secondly, we advance the current state‐of‐the‐art methodology by implementing evolution of life‐history traits of a top predator into the context of complex food web dynamics as described by the allometric trophic network (ATN) framework. The functioning of our newly developed eco‐evolutionary ATNE framework is illustrated using a well‐studied lake food web. Our simulations show how both natural selection arising from feeding interactions and size‐selective fishing cause evolutionary changes in the top predator and how those feed back to its prey species and further cascade down to lower trophic levels. Finally, we discuss future directions, particularly the need to integrate genomic discoveries into eco‐evolutionary projections.

Abstract 1364: Spatially-resolved in situ expression profiling using the GeoMx™ Cancer Transcriptome Atlas panel in FFPE tissue

Abstract The emerging field of spatial genomics represents a significant advance for biology. To drive new discoveries in spatial genomics and immuno-oncology, we introduce the GeoMx Cancer Transcriptome Atlas (CTA) Panel for comprehensive spatial analysis of cancer pathways using the Nanostring GeoMx Digital Spatial Profiler (DSP). We demonstrate profiling of 1600+ immuno-oncology targets in the tumor, microenvironment, and immune compartments of archival FFPE tissue sections, coupled to downstream Next Generation Sequencing (NGS) readout to enable high-throughput workflows. High-plex spatial RNA molecular profiling with GeoMx CTA was performed as follows: 1. Photocleavable DNA oligonucleotides tags were coupled to 8000+ in situ hybridization probes targeting 1600+ genes. These reagents were allowed to bind targets directly on slide-mounted FFPE tissue sections. 2. ROIs were identified and selected using GeoMx DSP, and ROI-specific oligonucleotide tags were released using ultraviolet exposure. 3. Released oligonucleotide tags from each ROI were collected and deposited into designated wells on a microtiter plate, allowing well indexing of each ROI during NGS library preparation. 4. After indexing, the entire plate was pooled into a single tube for purification and then sequenced on an Illumina instrument. 5. NGS reads were processed into digital counts and mapped back to each ROI, generating a map of transcript activity within the tissue architecture. We compared data from experiments in which bulk RNA-seq and GeoMx DSP using the CTA Panel were performed on the same samples. Overall, we found good correlation between pseudo-bulk GeoMx CTA (sum of ROIs) and RNA-seq from the same tissue specimen. Individually, however, each ROI showed a distinct expression pattern from bulk, and ROI expression patterns clustered based on similar tissue morphology. Importantly, GeoMx CTA was able to detect a higher number of genes with low expression within the microenvironment and immune spatial compartment compared to bulk RNA-seq, providing a detailed look at the anti-tumor immune response. Lastly, we profiled similar tissues using a novel 18000+ gene whole transcriptome panel and found further enrichment of low-expressers relative to RNA-seq, revealing novel spatial biology previously masked by bulk assays. Together, these data demonstrate that GeoMx offers high sensitivity for genome-scale expression profiling while preserving critical information about tissue architecture. GeoMx DSP technology is for Research Use Only and not for use in diagnostic procedures. Citation Format: Margaret L. Hoang, Michelle Kriner, Zoey Zhou, Zach Norgaard, Kristina Sorg, Chris Merritt, Erin Piazza, Marty Ross, Robin Fropf, Nileshi Saraf, Patrick Danaher, Michael Rhodes, Joseph Beechem. Spatially-resolved in situ expression profiling using the GeoMx™ Cancer Transcriptome Atlas panel in FFPE tissue [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1364.

Biological nitrification inhibition in the rhizosphere: determining interactions and impact on microbially mediated processes and potential applications

Nitrification is the microbial conversion of reduced forms of nitrogen (N) to nitrate (NO3-), and in fertilized soils it can lead to substantial N losses via NO3- leaching or nitrous oxide (N2O) production. To limitsuch problems, synthetic nitrification inhibitors have been applied but their performance differs between soils. In recent years, there has been an increasing interest in the occurrence of biological nitrification inhibition (BNI), a natural phenomenon according to which certain plants can inhibit nitrification through the release of active compounds in root exudates. Here, we synthesize the current state of research but also unravel knowledge gaps in the field. The nitrification process is discussed considering recent discoveries in genomics, biochemistry and ecology of nitrifiers. Secondly, we focus on the 'where' and 'how' of BNI. The N transformations and their interconnections as they occur in, and are affected by, the rhizosphere, are also discussed. The NH4+ and NO3- retention pathways alternative to BNI are reviewed as well. We also provide hypotheses on how plant compounds with putative BNI ability can reach their targets inside the cell and inhibit ammonia oxidation. Finally, we discuss a set of techniques that can be successfully applied to solve unresearched questions in BNI studies.

Abstract IA17: From functional genomics to new targets in pediatric oncology

Abstract The sequencing of human genomes harkened a new era of pediatric cancer investigations. Indeed, genomic discoveries, such as the identification of ALK mutations in neuroblastoma, Philadelphia-like fusions in acute B-cell acute lymphoblastic leukemia (B-ALL), and NTRK fusions in infantile fibrosarcoma, have led to early successes in the application of genomically informed, targeted therapy for children with cancer. While these new drugs have become an important part of the pediatric cancer armamentarium, many children with cancer still lack targeted therapies. Thus, new therapeutic approaches are still needed. Approaches such as RNA interference and CRISPR-Cas9 have transformed the functionalizing of the genome and offer promise for identifying new cancer therapeutic targets. We have applied genome-scale CRISPR-CAS9 screening to identify novel therapeutic targets in pediatric malignancies through the development of a Pediatric Cancer Dependency Map. We screened the Broad Institute’s Avana library in over 100 pediatric cancer cell lines and compared their dependencies to over 600 nonpediatric cell lines. Novel targets emerging from these efforts will be discussed. Citation Format: Kimberly Stegmaier. From functional genomics to new targets in pediatric oncology [abstract]. In: Proceedings of the AACR Special Conference on the Advances in Pediatric Cancer Research; 2019 Sep 17-20; Montreal, QC, Canada. Philadelphia (PA): AACR; Cancer Res 2020;80(14 Suppl):Abstract nr IA17.

An evaluation of Ibrutinib for the treatment of Waldenstrom macroglobulinaemia

ABSTRACT Introduction Waldenstrom Macroglobulinaemia (WM) is a heterogenous condition which poses a challenge to manage. Novel therapies such as Ibrutinib have been shown to be efficacious in treating WM. The landscape of Ibrutinib’s role in treating WM is everchanging with new discoveries in disease genomics and evolution together as well as through new findings in clinical trials. Areas covered A systematic literature review was carried out using two databases ‘Medline’ and ‘Embase’ from 2009 to July 2019. Keywords used included ‘Ibrutinib,’ ‘Waldenstrom Macroglobulinaemia,’ and ‘lymphoma.’ There were four major clinical trials identified primarily describing outcomes of Ibrutinib in managing WM which this paper evaluates in detail. The authors present evidence of the role of Ibrutinib in the management of specific complications associated with WM. They also explore the recently discovered genomics of the disease affecting response to therapy. Expert opinion The evidence for the use of Ibrutinib as a treatment option for relapsed/refractory WM is compelling in MYD88 mutated WM with the response and survival rates potentially better than conventional salvage chemoimmunotherapy. There is also a case for it to be used in the frontline setting in patients unfit for conventional frontline chemoimmunotherapy.

Genomic discovery of an evolutionarily programmed modality for small-molecule targeting of an intractable protein surface

The vast majority of intracellular protein targets are refractory toward small-molecule therapeutic engagement, and additional therapeutic modalities are needed to overcome this deficiency. Here, the identification and characterization of a natural product, WDB002, reveals a therapeutic modality that dramatically expands the currently accepted limits of druggability. WDB002, in complex with the FK506-binding protein (FKBP12), potently and selectively binds the human centrosomal protein 250 (CEP250), resulting in disruption of CEP250 function in cells. The recognition mode is unprecedented in that the targeted domain of CEP250 is a coiled coil and is topologically featureless, embodying both a structural motif and surface topology previously considered on the extreme limits of "undruggability" for an intracellular target. Structural studies reveal extensive protein-WDB002 and protein-protein contacts, with the latter being distinct from those seen in FKBP12 ternary complexes formed by FK506 and rapamycin. Outward-facing structural changes in a bound small molecule can thus reprogram FKBP12 to engage diverse, otherwise "undruggable" targets. The flat-targeting modality demonstrated here has the potential to expand the druggable target range of small-molecule therapeutics. As CEP250 was recently found to be an interaction partner with the Nsp13 protein of the SARS-CoV-2 virus that causes COVID-19 disease, it is possible that WDB002 or an analog may exert useful antiviral activity through its ability to form high-affinity ternary complexes containing CEP250 and FKBP12.