tbuckley/cabot-search huggingface dataset:
Abstract 2426: Effects of MEN2 mutations on RET receptor localization and function
Authors: Eduardo Reyes-Alvarez, Brandy D. Hyndman, Lois M. Mulligan
Journal: Cancer Research (2021)

Abstract Multiple Endocrine Neoplasia type 2 (MEN2) is a cancer syndrome characterized by medullary thyroid carcinoma (MTC) and adrenal tumors. MEN2 is caused by activating point mutations of the REarranged during Transfection (RET) receptor tyrosine kinase, a protein essential for normal cell proliferation, migration, and differentiation in multiple tissues. MEN2 RET mutations can result in constitutive receptor dimerization (MEN2A) or in loss of receptor autoinhibition (MEN2B), which are associated with distinct disease courses and oncogenic potential. However, the specific cellular mechanisms contributing to these differences have not been well characterized. We have previously shown that RET maturation, cell surface localization and trafficking through the endolysosomal system modulate RET signaling and contribute to regulation of normal RET functions. Here, we have explored the contributions of these processes to MEN2A and MEN2B RET mutant activity. In preliminary studies using immunofluorescence (IF) microscopy and MTC cell lines endogenously expressing MEN2A (2ARET) or MEN2B (2BRET) RET mutant forms, we showed that RET mutants do not accumulate in pre-membrane compartments (ER, Golgi) at significant levels. Both 2ARET and 2BRET mutant receptors matured and reached the cell membrane efficiently. Using IF and cell surface protein labeling methods, we demonstrated that wildtype RET, 2ARET and 2BRET forms had differential patterns of plasma membrane distribution in the absence of ligand stimulation. Further, constitutive stimulation of wildtype RET receptors could not recapitulate the pattern observed for MEN2 RET mutants. We showed that, in the absence of ligand, 2ARET and 2BRET, but not wildtype RET, were constitutively phosphorylated, activated downstream signaling pathways and could localize to multiple endosomal compartments. We also showed different extents of protein turnover in 2ARET and 2BRET, which is important for sustained signals and suggests distinct endosomal sorting mechanisms for these receptors. Together, our data indicate that constitutive activation of MEN2 RET mutant receptors is not the only mechanism contributing to aberrant RET function in MEN2. Our results suggest that receptor localization at the membrane and trafficking through endosomal compartments is mutation-specific and may modulate RET signals that contribute to its roles in MEN2 oncogenicity. Citation Format: Eduardo Reyes-Alvarez, Brandy D. Hyndman, Lois M. Mulligan. Effects of MEN2 mutations on RET receptor localization and function [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2426.
Abstract 1001: Treatment of RB1-intact cancers with CDK4/6 inhibitor combination therapy
Authors: Chiaki Takahashi
Journal: Cancer Research (2021)

Abstract Synthetic CDK4/6 inhibitors exert anti-tumor effects by forcing RB1 in unphosphorylated status, causing not only cell cycle arrest but also cellular senescence, apoptosis and increased immunogenicity. These agents currently have an indication in advanced breast cancers, and are in clinical trials for many other solid tumors. Hepatocellular carcinoma (HCC) is one of promising targets of CDK4/6 inhibitors. RB family function is often aberrated in the initiation of HCC, however, this is revivable as RB family genes are rarely mutated or deleted in this malignancy. Loss of all Rb family members in Trp53-/- mouse liver resulted in hepatoma reminiscent of human HCC, and re-expression of RB1 sensitized these tumors to a CDK4/6 inhibitor, palbociclib. Introduction of an unphosphorylatable form of RB1 (RB7LP) into HepG2 cells induced effects similar to palbociclib. By screening for compounds that enhance the efficacy of RB7LP, we identified an IKKβ inhibitor. Consistently, RB7LP expression and treatment with palbociclib enhanced IKKα/β phosphorylation and NF-κB activation. Combination therapy using palbociclib with KKβ inhibitor was significantly more effective in HCC treatment than single administration. Moreover, blockade of IKK-NF-κB or AKT pathway enhanced effects of palbociclib on RB1-intact K-Ras mutated lung and colon cancers. These findings provide proof of principle for the treatment of a wide variety of RB1-intact cancers using CDK4/6 inhibitors in combination with an appropriate kinase inhibitor. In this presentation, we will propose a new therapeutic approach to RB1-intact solid tumors. Citation Format: Chiaki Takahashi. Treatment of RB1-intact cancers with CDK4/6 inhibitor combination therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1001.
Gene–Environment Interactions in Developmental Neurotoxicity: a Case Study of Synergy between Chlorpyrifos and CHD8 Knockout in Human BrainSpheres
Authors: Sergio Modafferi, Xiali Zhong, Andre Kleensang, Yohei Murata, Francesca Fagiani, David Pamies, Helena T. Hogberg, Vittorio Calabrese, Herbert Lachman, Thomas Hartung, Lena Smirnova
Journal: Environmental Health Perspectives (2021)

Background: Autism spectrum disorder (ASD) is a major public health concern caused by complex genetic and environmental components. Mechanisms of gene–environment (G×E) interactions and reliable biomarkers associated with ASD are mostly unknown or controversial. Induced pluripotent stem cells (iPSCs) from patients or with clustered regularly interspaced short palindromic repeats and CRISPR-associated protein 9 (CRISPR/Cas9)-introduced mutations in candidate ASD genes provide an opportunity to study (G×E) interactions. Objectives: In this study, we aimed to identify a potential synergy between mutation in the high-risk autism gene encoding chromodomain helicase DNA binding protein 8 (CHD8) and environmental exposure to an organophosphate pesticide (chlorpyrifos; CPF) in an iPSC-derived human three-dimensional (3D) brain model. Methods: This study employed human iPSC-derived 3D brain organoids (BrainSpheres) carrying a heterozygote CRISPR/Cas9-introduced inactivating mutation in CHD8 and exposed to CPF or its oxon-metabolite (CPO). Neural differentiation, viability, oxidative stress, and neurite outgrowth were assessed, and levels of main neurotransmitters and selected metabolites were validated against human data on ASD metabolic derangements. Results: Expression of CHD8 protein was significantly lower in CHD8 heterozygous knockout (CHD8+/−) BrainSpheres compared with CHD8+/+ ones. Exposure to CPF/CPO treatment further reduced CHD8 protein levels, showing the potential (G×E) interaction synergy. A novel approach for validation of the model was chosen: from the literature, we identified a panel of metabolic biomarkers in patients and assessed them by targeted metabolomics in vitro. A synergistic effect was observed on the cholinergic system, S-adenosylmethionine, S-adenosylhomocysteine, lactic acid, tryptophan, kynurenic acid, and α-hydroxyglutaric acid levels. Neurite outgrowth was perturbed by CPF/CPO exposure. Heterozygous knockout of CHD8 in BrainSpheres led to an imbalance of excitatory/inhibitory neurotransmitters and lower levels of dopamine. Discussion: This study pioneered (G×E) interaction in iPSC-derived organoids. The experimental strategy enables biomonitoring and environmental risk assessment for ASD. Our findings reflected some metabolic perturbations and disruption of neurotransmitter systems involved in ASD. The increased susceptibility of CHD8+/− BrainSpheres to chemical insult establishes a possibly broader role of (G×E) interaction in ASD. https://doi.org/10.1289/EHP8580
Performance of a Machine Learning Algorithm Using Electronic Health Record Data to Identify and Estimate Survival in a Longitudinal Cohort of Patients With Lung Cancer
Authors: Qianyu Yuan, Tianrun Cai, Chuan Hong, Mulong Du, Bruce E. Johnson, Michael Lanuti, Tianxi Cai, David C. Christiani
Journal: JAMA Network Open (2021)

<h3>Importance</h3> Electronic health records (EHRs) provide a low-cost means of accessing detailed longitudinal clinical data for large populations. A lung cancer cohort assembled from EHR data would be a powerful platform for clinical outcome studies. <h3>Objective</h3> To investigate whether a clinical cohort assembled from EHRs could be used in a lung cancer prognosis study. <h3>Design, Setting, and Participants</h3> In this cohort study, patients with lung cancer were identified among 76 643 patients with at least 1 lung cancer diagnostic code deposited in an EHR in Mass General Brigham health care system from July 1988 to October 2018. Patients were identified via a semisupervised machine learning algorithm, for which clinical information was extracted from structured and unstructured data via natural language processing tools. Data completeness and accuracy were assessed by comparing with the Boston Lung Cancer Study and against criterion standard EHR review results. A prognostic model for non–small cell lung cancer (NSCLC) overall survival was further developed for clinical application. Data were analyzed from March 2019 through July 2020. <h3>Exposures</h3> Clinical data deposited in EHRs for cohort construction and variables of interest for the prognostic model were collected. <h3>Main Outcomes and Measures</h3> The primary outcomes were the performance of the lung cancer classification model and the quality of the extracted variables; the secondary outcome was the performance of the prognostic model. <h3>Results</h3> Among 76 643 patients with at least 1 lung cancer diagnostic code, 42 069 patients were identified as having lung cancer, with a positive predictive value of 94.4%. The study cohort consisted of 35 375 patients (16 613 men [47.0%] and 18 756 women [53.0%]; 30 140 White individuals [85.2%], 1040 Black individuals [2.9%], and 857 Asian individuals [2.4%]) after excluding patients with lung cancer history and less than 14 days of follow-up after initial diagnosis. The median (interquartile range) age at diagnosis was 66.7 (58.4-74.1) years. The area under the receiver operating characteristic curves of the prognostic model for overall survival with NSCLC were 0.828 (95% CI, 0.815-0.842) for 1-year prediction, 0.825 (95% CI, 0.812-0.836) for 2-year prediction, 0.814 (95% CI, 0.800-0.826) for 3-year prediction, 0.814 (95% CI, 0.799-0.828) for 4-year prediction, and 0.812 (95% CI, 0.798-0.825) for 5-year prediction. <h3>Conclusions and Relevance</h3> These findings suggest the feasibility of assembling a large-scale EHR-based lung cancer cohort with detailed longitudinal clinical measurements and that EHR data may be applied in cancer progression with a set of generalizable approaches.
Abstract 168: Computational model for prediction of actionable drug combinations in cancer
Authors: Sairahul Pentaparthi, Brandon Burgman, S. Stephen Yi
Journal: Cancer Research (2021)

Abstract Synthetic essentiality presents an effective approach towards finding connected genetic targets in cancer by identifying genes that produce an inviable phenotype upon joint inactivation. However, it is less studied how synthetic lethal gene pairs may be contextualized with respect to deregulation of different cell functions and how these pairs act in different cell types and tissues. To study cancer-specific synthetic essentiality, we devised an integrated network-based algorithm to analyze relationships between tumor gene expression and patient survival in The Cancer Genome Atlas (TCGA) and expression data from the Genotype-Tissue Expression (GTEx) project. In particular, we identify gene pairs in each cancer cohort that exhibit upregulation in tumors but are associated with improved survival for patients whose tumors feature reduced expression of the gene pair. Our findings reveal variability in synthetic lethal pair activity across different cancer types, and the identified pairs connect distinct signaling and metabolic cellular pathways to different cancer types. Altogether, our findings present a pan-cancer reference for gene expression-based synthetic lethal gene pairs as well as a nuanced perspective on changes in synthetic essentiality across different cellular and tissue contexts, pointing to a new avenue for drug combination discovery oriented on targeting key pathways based on the cancer type. Citation Format: Sairahul Pentaparthi, Brandon Burgman, S. Stephen Yi. Computational model for prediction of actionable drug combinations in cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 168.
Elements of Wnt/β-catenin signaling pathway as prognostic biomarkers and therapeutic targets in penile squamous cell carcinoma
Authors: A. Thomas, P. Stenzel, K. Tagscherer, W. Roth, M. Schindeldecker, M. Albersen, O. Vakhrusheva, A. Haferkamp, E. Juengel, I. Tsaur
Journal: European Urology (2021)
NHS ignored women’s safety concerns for too long, says former prime minister
Authors: Clare Dyer
Journal: BMJ (2021)

The NHS “saw real pain and debilitation as women’s problems” and ignored concerns over safety for too many years, the UK’s former prime minister Theresa May has told MPs.

In a parliamentary debate on 8 July, May urged the government to accept in full the recommendations of the Cumberlege review into three health service scandals, which she put in train when she was in office.

The review examined three medical interventions which harmed women or their babies—pelvic mesh, the anti-epileptic drug sodium valproate, and the hormone pregnancy test Primodos. Pelvic mesh, used to treat stress incontinence and pelvic organ prolapse, has caused crippling, life changing complications for some women. Sodium valproate has been definitively linked to autism and learning disabilities in children of mothers who took it during …
Plitidepsin for the management of a cancer patient infected with SARS-CoV-2 while receiving chemotherapy
Authors: P. Guisado-Vasco, L. González-Cortijo, G. D'Errico, A. Serrera-Alvarez, G. Sotres-Fernandez, M. García-Coca, J.M. Fernández-Sousa, X.E. Luepke-Estefan, J.A. López-Martín, J.M. Jimeno
Journal: Annals of Oncology (2021)
Abstract 1832: Development of a splicing modulator-based ADC payload class with immune stimulatory properties for cancer therapy
Authors: Satyajit K. Mitra, Vasu Jammalamadaka, Jeffrey Kang, Teodora Losic, Greg Tuffy, Tony W. Liang, Kim Tipton, Adriana Lopez, Scott Savage, William Monteith, William E. Haskins, Melissa S. Jurica, Sanjeev Satyal, Mary Do
Journal: Cancer Research (2021)

Abstract Background: Thailanstatins are naturally occurring anti-proliferative compounds that target spliceosomes and modulate pre-mRNA splicing. Alterations in splicing machinery and mRNA splicing is common in cancer and represents a potential susceptibility that can be exploited by targeted delivery of a splicing modulator to tumors with antibody drug conjugates (ADCs). Results: PH1 payload is a novel derivative of Thailanstatin optimized for metabolic stability and anti-tumor activity. PH1 is an efficient modulator of splicing in vitro and in vivo and a poor substrate for the MDR1 transporter. Transcriptome analysis of PH1- treated NCI-N87 cells revealed multiple classes of mis-splicing events including elevated expression of transcripts with skipped exons (3364 genes/4x change) and retained introns (332 genes/2.5x change). Translation of transcripts with retained introns and novel exon-exon junctions results in generation of neoepitopes. Upon conjugation to Trastuzumab, Tras PH1 ADC exhibited nanomolar potency specific to HER2-expressing cancer cells, with durable anti-tumor response in vivo and favorable pharmacokinetic exposure in mice. Due to the potential for generation of neoepitopes, combination studies of Tras PH1 with a checkpoint inhibitor antibody was performed in a syngeneic MC38-HuHer2 model. Single agent and combination treatments induced tumor recruitment of CD11b+ positive myeloid cell subsets. While the combination treatment eradicated tumors, the treated animals also developed tumor-specific immunity. A toxicology study performed in cynomolgus monkeys confirmed favorable PK profile and a wide safety margin for Tras PH1 ADC. Conclusions: We present the development of a splicing modulator-based payload class with the ability to target tumor mRNA splicing, induce tumor neoepitopes, recruit myeloid cells and generate anti-tumor immunity. These findings support the development of ADCs using this novel class of immunostimulatory payload. Citation Format: Satyajit K. Mitra, Vasu Jammalamadaka, Jeffrey Kang, Teodora Losic, Greg Tuffy, Tony W. Liang, Kim Tipton, Adriana Lopez, Scott Savage, William Monteith, William E. Haskins, Melissa S. Jurica, Sanjeev Satyal, Mary Do. Development of a splicing modulator-based ADC payload class with immune stimulatory properties for cancer therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1832.
Prenatal tobacco exposure and risk of asthma and allergy outcomes in childhood
Authors: Rikke Bjersand Sunde, Jonathan Thorsen, Casper-Emil Tingskov Pedersen, Jakob Stokholm, Klaus Bønnelykke, Bo Chawes, Hans Bisgaard
Journal: European Respiratory Journal (2021)

Harmful effects of prenatal tobacco exposure and possible interaction with 17q12-21 genetic variants have been shown for some asthma outcomes in childhood, whereas findings related to allergy outcomes are more inconsistent. This study aimed to examine the effect of prenatal tobacco exposure and relation to 17q12-21 genotype on a wide array of asthma and allergy-related outcomes in early childhood.Prenatal tobacco exposure was determined by maternal smoking during the third trimester (yes/no) in 411 children from the phenotyped Copenhagen Prospective Studies on Asthma in Childhood 2000 (COPSAC2000) birth cohort with clinical follow-up to age 7 years. The rs7216389 single nucleotide polymorphism was used as main representative of the 17q12-21 locus. Asthma end-points included asthma diagnosis, exacerbations, episodes with troublesome lung symptoms and lower respiratory tract infections, spirometry, plethysmography, bronchial responsiveness to methacholine, exercise and cold dry air. Allergy-related endpoints included aeroallergen sensitisation, allergic rhinitis, fractional exhaled nitric oxide, blood eosinophil count and urine eosinophil protein X levels. Statistical analyses were done using Cox regression, linear regression, logistic regression and quasi-Poisson regression.Prenatal tobacco exposure increased the risk of asthma (adjusted hazard ratio (aHR) 2.05, 95% CI 1.13-3.73; p=0.02), exacerbations (aHR 3.76, 95% CI 2.05-6.91; p<0.001), number of LRTIs (adjusted incidence rate ratio 1.87, 95% CI 1.34-2.55; p<0.001), and was associated with decreased spirometry indices (forced expiratory volume in 1 s (FEV1) adjusted mean difference (aMD) -0.07 L, 95% CI -0.13- -0.005 L, p=0.03; maximal mid-expiratory flow aMD -0.19 L·s-1, -0.34- -0.04 L·s-1, p=0.01) and increased bronchial responsiveness to methacholine (provocative dose of methacholine causing a 20% drop in FEV1 adjusted geometric mean ratio 0.55, 95% CI 0.31-0.96; p=0.04). In contrast, there was no association with any allergy-related end-points. The effect on asthma depended on 17q12-21 genotype with an increased risk only among children without risk alleles.Prenatal tobacco exposure was associated with asthma dependent on 17q12-21 genotype and with exacerbations, lung function and bronchial responsiveness, but not with any allergy-related outcomes. This suggests that tobacco exposure in utero leads to adverse lung developmental/structural effects rather than susceptibility to develop allergy and type 2 inflammation.
Abstract 1961: Cyclin-dependent kinase inhibition in mesothelioma
Authors: Marian Kratzke, Betsy Kren, Stephen Porter, George Scaria, Mark A. Klein
Journal: Cancer Research (2021)

Abstract Background: Mesothelioma is a cancer that arises out of the pleura or the peritoneum and is considered incurable in the majority of patients afflicted. Abnormalities of the cell cycle pathway are among the most common molecular alterations in mesothelioma. Previously, we have demonstrated that inhibition of CDK4/6 by abemaciclib or palbociclib is effective against mesothelioma in vitro. Increased expression of Cyclin E has been demonstrated to be one mechanism of resistance to CDK4/6 inhibition in other cancers. We hypothesized that select cell cycle-related proteins may compensate for inhibition of one part of the cell cycle machinery and that the CDK2 inhibitor dinaciclib may act synergistically in combination with abemaciclib. Methods: Dinaciclib was evaluated for activity against mesothelioma cells in vitro with regard to cell proliferation and colony formation. In addition, dinaciclib was evaluated in combination with abemaciclib at several concentration combinations in a cell proliferation assay to determine if the combination may be additive or synergistic. Combination indices (CI) were calculated via the Chou-Talalay method. Immunoblotting was used to evaluate for expression of key survival proteins after treatment with abemaciclib. Results: The IC50 of dinaciclib was determined to be 18 nM, 23 nM, 32 nM, and 33 nM in mesothelioma cell lines H2373, H2052, H2452, and H2461, respectively. Colony formation was decreased significantly after 72 hours incubation with 50 nM or 100 nM dinaciclib in Bap1-expressing (35.1 ± 2%; 22.8 ± 2%) and Bap1-null cell lines (14.5 ± 3%; 8.1 ± 2%) versus untreated controls. CI &amp;lt; 1 (denoting synergism) was identified for several combinations of varied concentrations of abemaciclib and dinaciclib for both cell lines evaluated. Further, treatment with abemaciclib for 72 hrs in both Bap1-expressing and Bap 1-null cells at 1x the IC50 resulted in complete loss of FoxM1 expression and pro-survival survivin and significantly decreased the expression of Mcl-1 and XIAP. Conclusions: Dinaciclib is a potent inhibitor of mesothelioma cell growth. The combination of abemaciclib and dinaciclib is synergistic across a spectrum of concentrations in vitro. Further experiments are currently underway to determine which CDKs and related proteins may be more effectively targeted in mesothelioma. As the cell cycle is altered in the vast majority of mesothelioma tumors, select combinations of CDK inhibition may be a feasible future therapeutic strategy against mesothelioma. Citation Format: Marian Kratzke, Betsy Kren, Stephen Porter, George Scaria, Mark A. Klein. Cyclin-dependent kinase inhibition in mesothelioma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1961.