tbuckley/cabot-search huggingface dataset:
Abstract 5137: Comprehensive analysis of POLE and POLD1 mutation in 9322 Chinese cancer patients
Authors: Hua Dong, Yuezong Bai, Xinkai Cao, Yanyan Wang, Lin Shi, Fugen Li, Yizhou Ye, Shuyang Sun
Journal: Cancer Research (2019)

Abstract POLE and POLD1 proofreading mutations can cause ultra-hypermutant-phenotype in cancer, but the distribution of POLE and POLD1 mutation frequency in Chinese population are not clear compared to microsatellite instability (MSI) and tumor mutation burden(TMB). Herein, we examined mutation profiles of POLE and POLD1 in 9322 Chinese cancer patients by two target sequencing panels including POLE and POLD1 gene. Tissue samples from 5866 patients were sequencing with a lab validated CP381 gene panel while plasma samples from 3155 patients were sequencing with a lab validated CT150 gene panel in a CAP certified lab 3DMed. Wet lab experiments and dry lab bioinformatics analysis were done by standard FFPE and ctDNA sample processing and analysis pipeline. POLE and POLD1 pathogenic mutation was defined by published research evidence. Of the 9322 cancer patients, 23 cases showed POLE and POLD1 pathogenic mutations (20 POLE and 3 POLD1), with the total mutation frequency 0.25% (0.35% for tumor sample and 0.006% for plasma sample). However, except for two Intrahepatic cholangiocarcinoma, one melanoma and one endometrial cancer patients, all the left mutation were from colon and rector cancer (CRC), account for a total mutation frequency 1.4% in CRC (19/1335). Although Endometrial cancer is reported with high POLE/POLD1 mutation, there were only 49 endometrial cancer patients in our cohort with mutation frequency 2%(1/49). POLE/POLD1 pathogenic mutations are micro satellite stable (MSS) in 20 cases while the left 3 were MSI-H. Eight cases have co-occurrence with MMR pathway gene loss of function mutation (any one of MSH2/MSH6/MLH1/PMS2), we infer those MMR gene mutations are not driver mutation but passenger mutation induced by POLE and POLD1 proofreading mutations as those eight cases are mostly MSS. Two patients with POLE pathogenic mutation with immune checkpoint inhibitor treatment were followed up for further response evaluation. POLE-and POLD1 pathogenic mutation are very rare in Chinese cancer patients, enrich in CRC type with 2.9% mutation frequency. POLE/POLD1 pathogenic mutations are usually exclusive to MSI-H patients, thus could expand the patient population in colon cancer which have potential to benefit from immune-therapy. Citation Format: Hua Dong, Yuezong Bai, Xinkai Cao, Yanyan Wang, Lin Shi, Fugen Li, Yizhou Ye, Shuyang Sun. Comprehensive analysis of POLE and POLD1 mutation in 9322 Chinese cancer patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 5137.
Abstract 246: Glioblastoma cell-modified cell membrane lipid-extracted nanoparticles (CLENs) for imaging and treatment: Influence of magnetic nanoparticle on physiochemical properties of CLENs, cellular uptake, and cytotoxicity
Authors: Woongjae Song, Robert Campbell
Journal: Cancer Research (2019)

Abstract Background: Glioblastoma multiforme (GBM), located in the cerebral hemispheres of the brain, is the most aggressive form of cancer. Surgery associated with chemotherapy with radiation treatment is the defined way to treat the disease. The delivery of chemotherapeutic agents frequently result in serious side effects. To address this issue we have taken the first steps in the development of CLENs (cell membrane lipid-extracted nanoliposomes) to enhance selective delivery of drugs to the brain. Method: The CLENs used for the experiments were composed of various ratios of DOPC, DOTAP, cholesterol, and lipid extract (LE) material derived from the target cells (i.e., U87-MG), and DPPE-PEG5000 (PEG). Studies include the determination of drug (cisplatin) loading, magnetite (MAG-C) loading in CLENs, quantitative studies for particle size, zeta potential, SQUID (superconducting quantum interference device) measurements, and fluorescence detection to study cellular interactions. Results: The average size for the CLENs fell within the range of 130 to 190 nm. The zeta potential reported for CLENs was negatively-charged. The inclusion of 15mol % LE resulted in the most significant cellular uptake by target cell U87-MG. Overall, the uptake by these cells was less compared to CLENS previously published for other organ tissue environments such as with breast tissue. The inclusion of cationic lipid DOTAP in CLENs did not alter the size distribution; however, the values for zeta potential increased from -8 ± 5 to 12 ± 6 mv. The additional inclusion of DOTAP in CLENs increased cellular uptake approximately 4-fold compared to CLENs without DOTAP (fluorescence intensity (A.U) from 145 ± 52 to 525 ± 49)). The inclusion of DOTAP increased the efficiency of loading Cisplatin in CLENs by approximately 30%. Studies involving the incorporation of MAG-C in U87-MG CLENs are currently underway, as well magnetization studies involving SQUID. Conclusion: All CLENs demonstrated practical physicochemical properties similar to conventional liposomes. The cellular uptake results suggested that cellular uptake of CLENs in vitro, although relatively low overall, varied according to the total LE content. Furthermore, the inclusion of DOTAP in CLENs significantly increased uptake and the efficiency of drug loading. Citation Format: Woongjae Song, Robert Campbell. Glioblastoma cell-modified cell membrane lipid-extracted nanoparticles (CLENs) for imaging and treatment: Influence of magnetic nanoparticle on physiochemical properties of CLENs, cellular uptake, and cytotoxicity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 246.
Abstract 15469: Med10 Regulates the Formation of the Atrioventricular Canal by Controlling Tbx2b Expression in the Embryonic Zebrafish Heart
Authors: Ina M Berger, Steffen Just, Wolfgang Rottbauer
Journal: Circulation (2012)

The genetic and molecular mechanisms that guide valvulogenesis are mostly unknown but of immense importance for biomedical research since heart valve diseases account for up to 30% of all congenita...
E3A06: Randomized phase III trial of lenalidomide versus observation alone in patients with asymptomatic high-risk smoldering multiple myeloma.
Authors: Sagar Lonial, Susanna J. Jacobus, Matthias Weiss, Shaji Kumar, Robert Z. Orlowski, Jonathan L. Kaufman, Abdulraheem Yacoub, Francis Buadi, Timothy E. O'Brien, Jeffrey Matous, Daniel M. Anderson, Robert Emmons, Madhav V. Dhodapkar, Lynne I. Wagner, S. Vincent Rajkumar
Journal: Journal of Clinical Oncology (2019)

8001 Background: Smoldering multiple myeloma (SMM) is a precursor to myeloma, wherein current standard of care is observation (obs). Data from a randomized Spanish trial (Mateos et al, NEJM 2015) suggest that lenalidomide(len)/dexamethasone improves time to developing myeloma (TTP) and overall survival (OS) for patients (pts) with high risk (HR) SMM over obs. However, pts were not screened with advanced imaging techniques, used a HR definition that is not routinely available, and combination therapy limited the ability to isolate the effect of len, and thus has not become standard of care. Methods: E3A06 is a randomized phase III intergroup trial, testing the effect of single agent len compared with obs for pts with intermediate or high risk SMM. In an initial phase II run in all pts received len to demonstrate safety. Eligibility required ≥10% PCs and abnormal serum FLC ratio (&lt;0.26 or &gt;1.65). The primary endpoint was progression PFS was estimated by the Kaplan-Meier method and compared using the one-sided stratified log-rank test. Results: PII enrolled 44 pts and PIII randomized 182 pts to either len (n=90) or obs (n=92) [stratified on time since SMM diagnosis ≤1y vs &gt;1y]. Baseline characteristics were similar between the arms. 80% (PII) and 51% (PIII) are off len, primarily due to adverse events (AE) or pt withdrawal. Among the len treated pts, G3/4 non-hematologic AE occurred in 28% of PIII pts with fatigue being most common (n=5). G4 hematologic AE rate was 5.7%, primarily neutropenia (n=4). 3-year cumulative incidence of invasive SPMs was 5.2% (len) and 3.5% (obs). Overall response rate was 47.7% for the phase II study, and in phase III, 48.9% for the len arm, and 0% for the obs arm. Median follow up was 71 months (PII), and 28 months (PIII). 3-year PFS was 87% for the PII cohort. One, 2 and 3-year PFS was 98%, 93%, and 91% for len, and 89%, 76%, and 66% for the obs arm (HR 0.28, p=0.0005) favoring the len arm. No difference in QOL score was noted between arms. Conclusions: Overall, this trial represents the largest randomized trial in SMM to date. In conjunction with the Spanish data, this trial may support a change in clinical practice. Clinical trial information: NCT01169337. [Table: see text]
Abstract 2608: EGF signaling activates a TAZ-driven oncogenic program in glioblastoma
Authors: Minling Gao, Yi Fu, Laterra John, Mingyao Ying
Journal: Cancer Research (2019)

Abstract Glioblastoma multiforme (GBM) is the most aggressive and lethal primary brain tumor in humans. Hyperactivation of the signaling pathway driven by the epidermal growth factor (EGF) and its receptor (EGFR) are commonly occurring in GBM. The oncogenic transcriptional program driven by EGF signaling is still incompletely understood in GBM. Here, we found that EGF induces the upregulation and nuclear translocation of TAZ, an oncogenic transcriptional co-activator. TAZ and its paralog gene YAP are commonly known as downstream mediators of the Hippo signaling pathway. TAZ has been found as a driver of mesenchymal transition in GBM cells and promotes GBM radioresistance. Our results support that EGF induces TAZ transcription and the activation of TAZ gene targets, through the signaling axis including EGFR, STAT3 and ERK. EGFRvIII is the most frequently occurring EGFR mutation in GBM causing constitutively active EGFR. We found that EGFRvIII causes EGF-independent activation of TAZ and its downstream oncogenic targets. Next, we used next-generation sequencing to establish a genome-wide map of TAZ gene targets in GBM cells after EGF stimulation. The results suggest that EGF signaling activates a TAZ-driven oncogenic program including autocrine and paracrine factors that promote GBM growth, angiogenesis, stemness and immunoescape. Moreover, we found that TAZ targeting by shRNAs or the FDA-approved drug Verteporfin effectively inhibits the TAZ-driven oncogenic program activated by EGF stimulation or the EGFRvIII mutant. TAZ targeting also inhibits GBM cell growth and xenograft formation. In contrast, enforced TAZ induces the TAZ-driven oncogenic program and promotes GBM cell growth and xenograft formation. In conclusion, our results reveal a novel TAZ-driven oncogenic program that is activated by EGF signaling in GBM. Our discoveries strongly support TAZ as a therapeutic target for GBM and likely other human cancer with hyperactivation of EGF signaling. Our preclinical studies also provide a clinically translatable strategy for GBM therapy based on using the FDA-approved drug Verteporfin. Citation Format: Minling Gao, Yi Fu, Laterra John, Mingyao Ying. EGF signaling activates a TAZ-driven oncogenic program in glioblastoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2608.
Impact of ABL kinase domain mutations on the outcome of patients with chronic myeloid leukemia (CML).
Authors: Kendra Lynn Sweet, Rami S. Komrokji, Najla Al Ali, Robert M. Crescentini, Gelenis Domingo, Julio C. Chavez, Samir Dalia, Sara Tinsley, Jeffery Lancet, Ling Zhang, Javier Pinilla-Ibarz
Journal: Journal of Clinical Oncology (2012)

6588 Background: Patients with CML who develop resistance to imatinib commonly have mutations in the BCR-ABL kinase domain (KDM). Studies looking at outcomes in patients with P-loop versus non-P-loop mutations within the ABL-Kinase Domain have produced conflicting results. Methods: The Total Cancer Care (TCC) database was used to identify patients with CML treated at Moffitt Cancer Center (MCC). Descriptive data were reported, chi square test was used for categorical variables, and Kaplan Meier curves were used for OS and PFS. Log rank test was used to compare survival times between groups. Results: Between 1992 and 2011, 540 CML patients were treated at MCC. Of those, 51% were male and 71% were under the age of 60. Sixty percent (n=322) were diagnosed after 2001. Of the 540 patients, 6.5% (n=35) were found to have mutations of which 26 were detected in patients diagnosed after 2001. Of the 35 patients, 74% (n=26) had single mutations and 26% (n=9) had compound mutations. P-loop mutations were seen in 17% (n=6) and 43% (n=15) had T315I mutations. Patients with KDM progressed to accelerated or blast phase in 46% (n=16) of cases compared to 27% (n=136) without mutations (p=0.03). Median OS was 126 months, 109 months, and not reached in patients with P-loop, T315I, and non-P-loop mutations respectively (p=0.17). The corresponding median PFS was 85 months, 89 months, and not reached (p=0.20). In patients with one mutation median OS was not reached compared to 105 months in patients with compound mutations (p=0.27). After 2001, patients with KDM had a median PFS of 75 months and OS of 126 months while neither was reached in the non-mutation cohort (p=0.007, p=0.26 respectively). Median PFS in patients with single mutations was 85 months versus 10 months in those with compound mutations (p=0.037). Patients with KDM had additional Ph+ clones on cytogenetics in 49% of cases compared with 19% of cases in the non-mutation group (P &lt; 0.005). Conclusions: T315I and P-loop KDM predict PFS and OS in CML patients, and convey a trend for worse prognosis. The presence of additional Ph+ clones in patients with BCR-ABL KDM indicates a higher level of genetic instability and clonal evolution, which may be the contributing factor to poor outcomes.
Abstract 3597: BAY 2402234: Preclinical evaluation of a novel, selective dihydroorotate dehydrogenase (DHODH) inhibitor for the treatment of diffuse large B-cell lymphoma (DLBCL)
Authors: Ashley Eheim, Sven Christian, Hanna Meyer, Detlef Stoeckigt, Claudia Merz, Katja Zimmermann, Marcus Bauser, Andrea Haegebarth, Steven Ferrara, David B. Sykes, David T. Scadden, Stefan Gradl, Andreas Janzer
Journal: Cancer Research (2019)

Abstract DLBCL is the most common type of non-Hodgkin lymphoma. It is an aggressive and fast growing tumor with two major molecular subtypes: germinal center (GCB) and activated B-cell like (ABC). While the majority of patients are 60 years or older, DLBCL can occur at any age. Despite a cure rate of around 50% the need for novel therapies remains high, especially for relapsed/refractory DLBCL patients not eligible for stem cell transplant. DHODH is a key enzyme in the de novo pyrimidine synthesis converting dihydroorotate to orotate. We recently discovered its role in AML differentiation (Sykes et al 2016, Cell) and we are investigating the novel DHODH inhibitor BAY 2402234 in an ongoing phase I study in myeloid malignancies (NCT03404726). Further screening of non-leukemia cancer types identified DLBCL as highly responsive to DHODH inhibition in preclinical studies. Here, we disclose for the first time the functional preclinical characterization of BAY 2402234 in DLBCL. BAY 2402234 is a selective low-nanomolar inhibitor of human DHODH enzymatic activity. In vitro it potently inhibits proliferation of DLBCL cell lines in the sub-nanomolar to low-nanomolar range. The anti-proliferative effects can be rescued by uridine supplementation which bypasses DHODH via the salvage pathway and demonstrates the on-target specificity of the inhibitor. In vivo, BAY 2402234 exhibits strong in vivo anti-tumor efficacy in monotherapy in subcutaneous models derived from patient-derived xenograft (PDX) and cell lines representing various DLBCL subtypes, including GCB and ABC. Dose dependent target engagement and drug exposure of BAY 2402234 could be observed by increases in plasma dihydroorotate levels and unbound plasma drug levels after treatment with the inhibitor. Based on preclinical data presented herein we plan to start clinical investigations of BAY 2402234 in patients with DLBCL in early 2019. Citation Format: Ashley Eheim, Sven Christian, Hanna Meyer, Detlef Stoeckigt, Claudia Merz, Katja Zimmermann, Marcus Bauser, Andrea Haegebarth, Steven Ferrara, David B. Sykes, David T. Scadden, Stefan Gradl, Andreas Janzer. BAY 2402234: Preclinical evaluation of a novel, selective dihydroorotate dehydrogenase (DHODH) inhibitor for the treatment of diffuse large B-cell lymphoma (DLBCL) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3597.
Abstract P099: Longitudinal Associations Between Plasma Levels of Perfluoroalkyl Substances and Cardiometabolic Risk Factors
Authors: Carolina Donat-Vargas, Ingvar A Bergdahl, Andreas Tornevi, Maria Wennberg, Johan Sommar, Hannu Kiviranta, Jani Koponen, Agneta Åkesson
Journal: Circulation (2018)

Background: Perfluoroalkyl substances (PFAS) are highly persistent synthetic chemicals with high global demand. Although PFAS may affect different components of cardiometabolic risk through the peroxisome proliferator-activated receptor (a master regulator of lipid and glucose metabolism), evidence remains scarce and inconsistent. Objective: Our aim was to evaluate plasma levels of six PFAS in association with cardiometabolic risk factors in a longitudinal setting among 40-50 year old women and men. Methods: Participants in the Västerbotten Intervention Programme visited their health center twice, 10 years apart: during 1990 to 2003 (baseline) and during 2001 to 2013 (follow-up). Participant underwent a medical examination, and measurements of systolic and diastolic blood pressure, total cholesterol and triglycerides were performed twice 10 years apart. PFAS were measured in 374 participants. The PFAS analysed were perfluorooctanoic acid (PFOA), perfluorooctanesulfonic acid (PFOS), perfluorononanoic acid (PFNA), perfluorohexanesulfonic acid (PFHxS), perfluorodecanoic acid (PFDA), and perfluoroundecanoic acid (PFUnA). A generalized estimated equations method was used to assess repeated measurements and to provide beta coefficients (β) with their 95% confidence intervals (CI). Results: Overall, we observed little or no evidence of associations between PFAS and cardiometabolic risk factors. Exceptions were statistically significant inverse associations between PFOS and PFHxS with total cholesterol (β~- 0.30 ; mmol/L, comparing 3 rd tertile vs 1 st ) and PFOS, PFOA and PFDA with triglycerides (β from -0.17 to -0.26 mmol/L, comparing 3 rd tertile vs 1 st ), when analysis were restricted to those who did not develop diabetes during the follow-up. Conclusions: Our findings did not support the emerging premise that PFAS might increase cardiovascular risk through disrupting lipid metabolism and/or vascular system.
Abstract 3752: Fabrication and validation of an <i>in vitro</i> bone marrow microenvironment for the study of prostate cancer progression
Authors: Molly Kozminsky, Lydia Sohn
Journal: Cancer Research (2019)

Abstract Metastasis is responsible for the vast majority of cancer deaths, motivating the investigation of how the disease progresses in the face of each obstacle put forth by the body. While disseminated tumor cells (DTCs) are detected in the bone marrow of many prostate cancer patients, only 1% of DTCs yield macrometastases. There is pressing need for an in vitro system to study the characteristics of the interactions with the microenvironment that influence prostate cancer progression. High-throughput DNA-directed single-cell patterning was used to create an in vitro bone-marrow microenvironment that provides replicates of these miniature systems within an easy-to-images conventional chamber slide. This system enables the study of the contributions of several cell types present in the bone marrow microenvironment. Cell types in the in vitro system to be represented by cell lines include bone cells (osteoblasts and osteoclasts), cells of hematopoietic lineage (macrophages, osteoclasts), and endothelial cells. Optimization strategies for cell culture conditions, pattern design, and fabrication parameters will be described as well the incorporation of prostate cancer cells to study cell-cell interactions. Applying high-throughput DNA-directed cell-patterning system yielded a highly complex cellular system that can be used to answer open questions about prostate cancer metastasis. Citation Format: Molly Kozminsky, Lydia Sohn. Fabrication and validation of an in vitro bone marrow microenvironment for the study of prostate cancer progression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3752.