tbuckley/cabot-search huggingface dataset:
Abstract 2968: BPM31510, a Coenzyme Q10 (CoQ10) containing lipid nanodispersion, enhances radiation effects to prolong survival in a rodent glioblastoma model
Authors: Jiaxin Sun, Milton Merchant, Anne R. Diers, Shiva Kazerounian, Stephane Gesta, Niven R. Narain, Rangaprasad Sarangarajan, Seema Nagpal, Lawrence Recht
Journal: Cancer Research (2020)

Abstract BPM31510 is a Coenzyme Q10 (CoQ10)-containing lipid nanodispersion in clinical development for the treatment of glioblastoma. Prior results demonstrate that high doses of CoQ10 delivered via BPM31510 differentially increases oxidative stress in glioblastoma relative to non-tumor cells in vitro and extends long-term survival (LTS) in an in vivo glioblastoma model. Since a primary consequences of tumor irradiation is induction of oxidative stress, we hypothesized that BPM31510 treatment would result in an enhanced radiation response and influence survival outcomes.1 x 106 luciferase labeled C6 cells were implanted into the right striatum of Sprague Dawley rats. 4 days post-implantation, rats were randomized into one of four groups: (i) Saline injection ip bid; (ii) BPM31510 50 mg/kg ip bid to continue up to 35 days; (iii) 12 Gy radiotherapy (RT) to be administered on Day 8 post-implant with saline injection; and (iv) BPM31510 + RT. Tumor-bearing rats were monitored until death or Day 50. Log rank survival analysis indicated a marked enhancement of median survival with the addition of BPM31510 to RT. While neither RT nor BPM31510 enhanced median survival relative to saline, the combination was markedly more effective (median survival of 17, 19, 24 and &amp;gt;50 days for saline, BPM31510, RT and combination, respectively, p &amp;lt; 0.001). This was also reflected in increase in frequency of LTS, which was over 70% (11 of 14 rats) in the combination group (p &amp;lt; 0.01 compared to control). BPM31510 significantly enhanced the therapeutic efficacy of radiation in this model of glioblastoma. Effects on median survival and an enhancement of LTS with combination treatment were observed. While the mechanistic underpinnings are under investigation, the low toxicity profile of BPM31510 and its potential protective effects on normal cells may offer a unique strategy with which to enhance radiation. Citation Format: Jiaxin Sun, Milton Merchant, Anne R. Diers, Shiva Kazerounian, Stephane Gesta, Niven R. Narain, Rangaprasad Sarangarajan, Seema Nagpal, Lawrence Recht. BPM31510, a Coenzyme Q10 (CoQ10) containing lipid nanodispersion, enhances radiation effects to prolong survival in a rodent glioblastoma model [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 2968.
Abstract 6073: The lipogenic regulator <i>SREBP</i> induces <i>Transferrin</i> in circulating melanoma cells, suppressing their susceptibility to ferroptosis
Authors: Xin Hong, Whijae Roh, Ryan J. Sullivan, Keith H. Wong, Ben S. Wittner, HongShan Guo, Taronish D. Dubash, Moshe Sade-Feldman, Ben K. Wesley, Genevieve M. Boland, Dieuwke L. Marvin, Todd Bonesteel, Chenyue Lu, Elad Horwitz, François Aguet, Samuel S. Freeman, Katherine Calhoun, Michelle K. Jewett, Linda T. Nieman, Nir Hacohen, Anders M. Näär, David T. Ting, Mehmet Toner, Shannon L. Stott, Gad Getz, Shyamala Maheswaran, Daniel A. Haber
Journal: Cancer Research (2020)

Abstract Circulating tumor cells (CTCs) are shed by cancers into the bloodstream, where a viable subset overcomes oxidative stress to initiate metastatic outgrowth. Clonally derived cultured CTCs from patients with BRAF-mutant melanoma reveal upregulation of lipogenesis and iron homeostasis pathways, correlated with their baseline and acquired drug resistance. In CTCs, the lipogenesis regulator SREBP directly induces transcription of the iron carrier Transferrin (TF), thereby reducing intracellular reactive oxygen species (ROS) and lipid peroxidation, and conferring resistance to BRAF inhibitors and inducers of ferroptosis. Knockdown of endogenous TF impairs tumorigenesis by melanoma CTCs; their associated soft agar clonogenic defect is rescued by the lipophilic anti-oxidants Ferrostatin-1 or Vitamin E, and by cholesterol. Single cell RNA-seq of patient-derived melanoma CTCs identifies a subset with high lipogenic, iron metabolic and proliferative signatures, correlated with adverse clinical outcome. Together, the coordinated regulation of these SREBP-driven pathways contributes to cancer progression, drug resistance and metastasis. Citation Format: Xin Hong, Whijae Roh, Ryan J. Sullivan, Keith H. Wong, Ben S. Wittner, HongShan Guo, Taronish D. Dubash, Moshe Sade-Feldman, Ben K. Wesley, Genevieve M. Boland, Dieuwke L. Marvin, Todd Bonesteel, Chenyue Lu, Elad Horwitz, François Aguet, Samuel S. Freeman, Katherine Calhoun, Michelle K. Jewett, Linda T. Nieman, Nir Hacohen, Anders M. Näär, David T. Ting, Mehmet Toner, Shannon L. Stott, Gad Getz, Shyamala Maheswaran, Daniel A. Haber. The lipogenic regulator SREBP induces Transferrin in circulating melanoma cells, suppressing their susceptibility to ferroptosis [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 6073.
Abstract 1164: Targeted next generation sequencing microbiome assay design
Authors: Aren Ewing
Journal: Cancer Research (2020)

Abstract Background: Targeted Next Generation Sequencing may provide a lower cost approach for characterizing the Microbiome. Sequencing of 16S rRNA is one approach to characterize microbial diversity. However, 16S sequencing alone is often insufficient to gain species level information. Here we describe the design capabilities of targeted sequencing panels comprising both 16S and species-specific primers using Ion AmpliSeqTM technology. These types assay can be used to understand the composition and diversity of the microbiomes at the species level for human health and other applications. Method: Our assays include the capability to customize primers to multiple hypervariable regions of the 16S region. However, 16S alone can still be insufficient in distinguishing highly homologous organisms. To address this we can design species-specific primers that provide high strain coverage and high specificity performance. We have developed and tested example assays that include primers for a variety of species identification. With this approach, we can generate reads from sequencing to report taxonomic classifications and relative abundance for organisms in the sample with high specificity and sensitivity. Results: We designed many a multiplexed Ion AmpliSeqTM assays including 16S targets and species-specific markers targeting important microbial species that can be adapted to new species of interest. This approach is proven as example of our fixed panels including Ion AmpliSeq Microbiome Health research Panel, Pan Bacterial and Anti-Microbial Resistance (AMR) community panels using the Ion Genestudio S5™ system. With the data generated from the species-specific primers, we identified all the targeted species in the ATCC samples at the Species level. We also created mixed population pools using DNA from clonal isolates of different bacterial strains. We are able to identify most microbes at Genus level with 100% sensitivity using 16S alone. We improved the detection resolution to the Species level through the application of our species-specific primers. Conclusions: Using the Ion AmpliSeq™ technology, we can create highly sensitive and specific assays for robust characterization of microbiota customized to an individual labs needs. This highly multiplexed PCR approach enables an efficient and affordable means for conducting extensive analyses of the microbiomes having applications in the study of the etiology of phenotypic variability. For research use only. Not for use in diagnostic procedures. Citation Format: Aren Ewing. Targeted next generation sequencing microbiome assay design [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 1164.
Abstract LB-230: Nanotherapy targeting metastatic factor RHAMMB-positive pancreatic neuroendocrine tumors
Authors: Seung Koo Lee, Xiang Chen, Yi-Chieh Nancy Du, Ching-Hsuan Tung
Journal: Cancer Research (2020)

Abstract Pancreatic neuroendocrine tumors (PNETs) represent one-third of gastroenteropancreatic neuroendocrine tumors and are the second malignancy of the pancreas. The 5-year survival rate of metastatic PNETs is only about 15%. We have recently demonstrated that receptor for hyaluronic acid-mediated motility isoform B (RHAMMB) is upregulated in PNETs and promotes metastasis of PNETs. We have also reported that Bcl-xL accelerates the formation of PNETs with invasive properties. Here, we propose a RHAMM-targeted combination therapy (RCT), as a novel treatment for PNETs. RCT is designed to accomplish a synergistic apoptotic/anticancer effect, by aiming RHAMMB, a receptor for hyaluronic acid (HA), and codelivering Bcl-xL siRNA with mitochondria-fusing peptide to kill PNET cells. Yet, it is a substantial challenge to codeliver multiple drugs to RHAMM-expressing tumors. To simultaneously transport these unconventional therapeutics for a synergistic effect, a siRNA for Bcl-xL and a mitochondria-fusing peptide are layered onto a nanocore by charge-charge interaction, followed by a layer of HA for targeting RHAMMB. We showed that the prepared RCT is efficiently internalized by RHAMMB-positive cells, but not by RHAMMB-negative cells. We have found that the encapsulated Bcl-xL siRNA and the mitochondria-fusing peptide are released inside cells to silence Bcl-xL gene expression and induce apoptosis by fusing the mitochondrial membrane. A synergistic cell killing effect was achieved in vitro (&amp;gt; 83% cell death). In a preclinical mouse model, we demonstrated that systemically-injected RCT significantly reduced tumor burden (&amp;gt; 65% reduction) and sustained the blood glucose levels of mice bearing RHAMMB-positive PNETs. Together, the developed RCT can serve as a promising drug delivery system for RHAMMB-overexpressed cancer treatments. Citation Format: Seung Koo Lee, Xiang Chen, Yi-Chieh Nancy Du, Ching-Hsuan Tung. Nanotherapy targeting metastatic factor RHAMMB-positive pancreatic neuroendocrine tumors [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 LB-230.
Abstract 4378: Contribution of ERα/PR crosstalk to endocrine therapy resistance in breast cancer
Authors: Rosemary J. Huggins
Journal: Cancer Research (2020)

Abstract Half of estrogen receptor (ERα)-positive breast cancer patients treated with endocrine therapies display intrinsic or acquired therapy resistance. One-third of patients with acquired resistance present with metastatic tumors containing ERα-Y537S mutations. This mutation results in constitutive activity of ERα and altered ERα-associated gene expression. ERα/PR crosstalk, referring to the complex relationship of ERα and progesterone receptor (PR) interaction, offers therapeutic value in targeting both nuclear receptors simultaneously in ERα/PR-positive breast cancers. Previous research identified a synergistic effect of treating ERα-WT cancer cells with ERα/PR antagonism, where combined treatment results in tumor regression in vivo and increased cell death in vitro. Conversely, preliminary data suggests that treatment of ERα-Y537S-containing tumors with combined ERα and PR antagonists results in significantly increased proliferation in vivo and reduced cell death in vitro. My central hypothesis is that ERα-Y537S alters the transcription factor activity of ERα and PR, causing dysregulation of gene expression in SERM-resistant breast cancer. Using a three-dimensional culture system of patient-derived xenografts grown as organoids (PDxO), I have observed a synergistic effect of certain combinations of ERα/PR antagonists in the context of ERα-WT similar to previous results in two-dimensional cell culture. At the level of transcription, PR-associated transcriptional activity appears to be significantly altered in homozygous ERα-Y537S T47D cells compared to ERα-WT cells. Further understanding the role of ERα-Y537S in altering gene expression and reducing the response to SERM and SPRM treatment will provide understanding as to why these tumors are resistant to standard-of-care treatment and will suggest alternative targets for treatment as well. Citation Format: Rosemary J. Huggins. Contribution of ERα/PR crosstalk to endocrine therapy resistance in breast cancer [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 4378.
Effect of Multilevel Upper Airway Surgery vs Medical Management on the Apnea-Hypopnea Index and Patient-Reported Daytime Sleepiness Among Patients With Moderate or Severe Obstructive Sleep Apnea
Authors: Stuart MacKay, A. Simon Carney, Peter G. Catcheside, Ching Li Chai-Coetzer, Michael Chia, Peter A. Cistulli, John-Charles Hodge, Andrew Jones, Billingsley Kaambwa, Richard Lewis, Eng H. Ooi, Alison J. Pinczel, Nigel McArdle, Guy Rees, Bhajan Singh, Nicholas Stow, Edward M. Weaver, Richard J. Woodman, Charmaine M. Woods, Aeneas Yeo, R. Doug McEvoy
Journal: JAMA (2020)

Many adults with obstructive sleep apnea (OSA) use device treatments inadequately and remain untreated.To determine whether combined palatal and tongue surgery to enlarge or stabilize the upper airway is an effective treatment for patients with OSA when conventional device treatment failed.Multicenter, parallel-group, open-label randomized clinical trial of upper airway surgery vs ongoing medical management. Adults with symptomatic moderate or severe OSA in whom conventional treatments had failed were enrolled between November 2014 and October 2017, with follow-up until August 2018.Multilevel surgery (modified uvulopalatopharyngoplasty and minimally invasive tongue volume reduction; n = 51) or ongoing medical management (eg, advice on sleep positioning, weight loss; n = 51).Primary outcome measures were the apnea-hypopnea index (AHI; ie, the number of apnea and hypopnea events/h; 15-30 indicates moderate and >30 indicates severe OSA) and the Epworth Sleepiness Scale (ESS; range, 0-24; >10 indicates pathological sleepiness). Baseline-adjusted differences between groups at 6 months were assessed. Minimal clinically important differences are 15 events per hour for AHI and 2 units for ESS.Among 102 participants who were randomized (mean [SD] age, 44.6 [12.8] years; 18 [18%] women), 91 (89%) completed the trial. The mean AHI was 47.9 at baseline and 20.8 at 6 months for the surgery group and 45.3 at baseline and 34.5 at 6 months for the medical management group (mean baseline-adjusted between-group difference at 6 mo, -17.6 events/h [95% CI, -26.8 to -8.4]; P < .001). The mean ESS was 12.4 at baseline and 5.3 at 6 months in the surgery group and 11.1 at baseline and 10.5 at 6 months in the medical management group (mean baseline-adjusted between-group difference at 6 mo, -6.7 [95% CI, -8.2 to -5.2]; P < .001). Two participants (4%) in the surgery group had serious adverse events (1 had a myocardial infarction on postoperative day 5 and 1 was hospitalized for observation following hematemesis of old blood).In this preliminary study of adults with moderate or severe OSA in whom conventional therapy had failed, combined palatal and tongue surgery, compared with medical management, reduced the number of apnea and hypopnea events and patient-reported sleepiness at 6 months. Further research is needed to confirm these findings in additional populations and to understand clinical utility, long-term efficacy, and safety of multilevel upper airway surgery for treatment of patients with OSA.Australian New Zealand Clinical Trials Registry: ACTRN12614000338662.
Abstract 3935: Runt related transcription factor-1 (runx1) plays a central role in vessel co-option of colorectal cancer liver metastases
Authors: Miran Rada, Audrey Kapelanski-Lamoureux, Stephanie Petrillo, Sébastien Tabariès, Peter Siegel, Anthoula Lazaris, Peter Metrakos
Journal: Cancer Research (2020)

Abstract Colorectal cancer liver metastasis (CRCLM) has two major morphological growth pattern subtypes including desmoplastic (DHGP) and replacement (RHGP). The DHGP tumors depend on angiogenesis for their growth. Conversely, RHGP tumors are non-angiogenic and obtain their blood supply through vessel co-option, which the cancer cells hijacking pre-existing blood vessels of the surrounding liver tissue. Therefore, anti-angiogenic therapies have shown modest efficacy in CRCLM patients with RHGP lesions. In this study, we found overexpression of Runt Related Transcription Factor-1 (RUNX1) in the cancer cells of RHGP lesions. Upregulation of RUNX1 is positively correlated with cancer cell motility and epithelial mesenchymal transition (EMT) in vitro. Our results also showed that RUNX1 regulated by Transforming Growth Factor Beta-1 (TGFβ1) through TGFβ Receptor II (TGFβRII). Significantly, RUNX1 knockdown induced conversion RHGP lesions to DHGP in vivo. Collectively, this study suggests RUNX1 as a potential target therapy to overcome resistance to anti-angiogenic therapy in CRCLM. Citation Format: Miran Rada, Audrey Kapelanski-Lamoureux, Stephanie Petrillo, Sébastien Tabariès, Peter Siegel, Anthoula Lazaris, Peter Metrakos. Runt related transcription factor-1 (runx1) plays a central role in vessel co-option of colorectal cancer liver metastases [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 3935.
Abstract 1274: Metformin, not γ-tocotrienol, increases gene methylation and decreases expression of genes responsible for cell signal transduction in prostate cancer cells
Authors: Christine Ann Moore, Janet Lightner, Michelle Duffourc, Koyamangalath Krishnan
Journal: Cancer Research (2020)

Abstract Metformin and γ-tocotrienol (GT3) are promising chemopreventative agents with studies showing improved patient outcomes with metformin use in several cancer types, including prostate cancer. However, the cellular mechanisms underlying the improved survival rates in cancer patients treated with these drugs are incompletely understood. Inhibition of mammalian target of rapamycin (mTOR), alteration of p-c-JUN and p-ERK signaling pathways and inhibition of mitochondrial complex 1 have all been implicated as part of metformin's anti-tumorigenesis activities. More recently, metformin was shown to influence the activity of epigenetic modifying enzymes resulting in genome-wide alterations in DNA methylation patterns in breast cancer cell lines. In this study, we investigated whether GT3 and metformin treatment would alter methylation pathways in prostate cancer cells.The prostate cancer cell line PC-3 (androgen independent) and normal prostate control cell line RWPE-1 were treated with varying concentrations of either GT3, metformin, the methylation inhibitor azacitidine, or metformin plus azacitidine for 6 hours. Genomic DNA was isolated, and methylation assessed using the Illumina Infinium methylation EPIC BeadChip array. Analysis revealed treatment of PC-3 cells with metformin promoted hypermethylation of CC2D2B, GHDC, LINC01377, PLPP2, and PTK2 and decreased methylation of TSPY4 as compared to normal prostate controls. qRT-PCR experiments confirmed decreased expression of PTK2 mRNA, consistent with hypermethylation of PTK2. In contrast, GT3 did not affect methylation of any identifiable recognizable genes. This study suggests metformin, but not GT3, may inhibit prostate cancer proliferation partially through epigenetic changes which disrupt downstream focal adhesion kinase (FAK) signaling pathways. Metformin is a promising chemopreventive agent; studies investigating the impact of metformin on cellular adhesion and FAK pathways are ongoing in our laboratory. Citation Format: Christine Ann Moore, Janet Lightner, Michelle Duffourc, Koyamangalath Krishnan. Metformin, not γ-tocotrienol, increases gene methylation and decreases expression of genes responsible for cell signal transduction in prostate cancer cells [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 1274.
Abstract 166: Absolute quantification of DNA methylation markers using methylation-sensitive restriction enzymes and multiplex digital PCR
Authors: Rogier J. Nell, Pieter A. Van der Velden
Journal: Cancer Research (2020)

Abstract Aberrant DNA methylation plays important roles in the initiation and progression of cancer. Therefore, DNA methylation markers have important diagnostic and prognostic potential. However, accurate quantification of these markers remains challenging in clinical samples of limited quality or quantity. We introduce a novel, digital approach for the absolute quantification of the amount, density and allele-specificity of DNA methylation. We designed an experimental setup combining efficient methylation-sensitive restriction enzymes with quantitative digital PCR. This allowed to measure a targeted density of DNA methylation independent of bisulphite conversion. In-silico simulations were performed to demonstrate the mathematical validity of the setup. A practical validation was carried out by quantifying RASSF1A promotor methylation in a variety of healthy and malignant reference samples and in an innovative calibration curve. Furthermore, we extended our setup to a multiplex digital PCR experiment. Hereby, methylation markers may be analyzed together with physically linked genetic markers to determine the allele-specificity of the methylation. Overall, our results show an accurate quantification of DNA methylation markers with digital PCR, independent of bisulphite conversion. Effective measurements with high precision could be obtained, even in minute amounts of DNA. Moreover, as the context-density and allele-specificity of methylation can also be determined, mechanisms in cancer biology can now be quantitatively assessed in a digital experiment. Citation Format: Rogier J. Nell, Pieter A. Van der Velden. Absolute quantification of DNA methylation markers using methylation-sensitive restriction enzymes and multiplex digital PCR [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 166.