tbuckley/cabot-search huggingface dataset:
Abstract 1720: Preclinical treatment of pancreatic ductal adenocarcinoma using targetable self-assembled gemcitabine nanoparticles
Authors: Zhang Fu
Journal: Cancer Research (2020)

Abstract The prognosis of pancreatic ductal adenocarcinoma (PDAC) patients remains poor, and new effective therapies are urgently needed. Cytotoxic gemcitabine (GEM) is currently used as a standard-of-care drug for PDAC treatment but its efficacy is greatly compromised mainly due to quick metabolism in the body and drug resistance. Here we introduce a new simple approach to effectively deliver GEM to PDAC-derived tumors through the combination of a prodrug strategy, nanoparticle formulation, and PDAC-specific targeting strategy. By covalently conjugating GEM with a hydrophobic moiety (i.e. linoleic acid) via amide linkage, the resulting GEM prodrug was conferred with an amphiphilic feature and showed spontaneously self-assembling behavior in aqueous solution. The self-assembled nanoparticles were spherical and monodispersed in water with a diameter less than 100 nm. To optimize the nanoparticles for the in vivo use, DSPE-PEG2k was used to co-assemble with the prodrug. A PDAC-specific peptide was further decorated on the particle surface to endow the nanoparticles with PDAC targeting effect. In vitro assays on PDAC cell lines showed that the modified GEM nanoparticles exhibited superior efficacy than free GEM, and the conjugation of the targeting peptide significantly facilitated the internalization of the nanoparticles into the targeted cancer cells. Furthermore, in vivo evaluation in xenograft-bearing animal models derived from either established cancer cells or patient tumor tissues showed that these GEM nanoparticles were remarkably effective to inhibit tumor growth with alleviated side effects. These data confirmed the effectiveness of our self-assembling GEM prodrug strategy. Moreover, this cost-effective strategy can potentially be applied broadly to many other chemotherapeutic drugs that are insufficiently effective because of pharmacologic obstacles. Citation Format: Zhang Fu. Preclinical treatment of pancreatic ductal adenocarcinoma using targetable self-assembled gemcitabine nanoparticles [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 1720.
Abstract 5460: Detecting somatic DNA copy number differences with cyclic shift testing
Authors: Vonn Walter, Hyo Young Choi, Xiaobei Zhao, Jose Zevallos, D. Neil Hayes
Journal: Cancer Research (2020)

Abstract The most basic differential expression analysis involves the identification of genes that exhibit distinct expression patterns in two cohorts. Surprisingly, even though there are numerous computational methods for detecting and assessing the statistical significance of somatic DNA copy number (CN) gains and losses in a single cohort, there are no tools for detecting and assessing the statistical significance of CN differences between two cohorts. Instead, typically each cohort is analyzed separately and distinct findings are presented as evidence of CN differences. Cyclic shift testing was originally introduced as a method to identify and assess the statistical significance of recurrent somatic CN gains and losses. Subsequent work explored theoretical statistical underpinnings of cyclic shift testing. Here we extend the previous results by showing that cyclic shift testing can be applied to detect and assess the statistical significance of CN differences between two cohorts. Human papilloma virus (HPV) infection is a risk factor for head and neck squamous cell carcinoma (HNSC), and it is known that HPV+ and HPV- HNSC have distinct mutational and gene expression profiles. We apply cyclic shift testing to detect and assess the statistical significance of CN differences between HPV+ and HPV- HNSC using data from The Cancer Genome Atlas HNSC cohort. Our approach detects statistically significant CN differences in regions that are known to contain HNSC drivers (7p, 9p21, 11q13, 11q14-qter), as well as regions of chr14, chr16, and others that are less well characterized. Citation Format: Vonn Walter, Hyo Young Choi, Xiaobei Zhao, Jose Zevallos, D. Neil Hayes. Detecting somatic DNA copy number differences with cyclic shift testing [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 5460.
Abstract 1622: Microsatellite instability causes colorectal cancer cell death to trigger anti-tumor immune response
Authors: Darleny Y. Lizardo, Yi-Jun Wang, Liheng Yang, Jian Yu, Lin Zhang
Journal: Cancer Research (2020)

Abstract Colorectal cancer (CRC) is the second leading cause of cancer deaths in the western world. Approximately 15% of CRCs have defects in DNA mismatch repair (MMR) genes, which lead to frequent mutations in repetitive genomic sequences known as microsatellites. This kind of genomic instability, referred to as microsatellite instability (MSI), contributes to the emergence of highly immunogenic neoantigen peptides that can stimulate an antitumor response. As such, a subset of CRC patients with deficient MMR has a positive response to immune checkpoint blockade immunotherapy. However, the molecular basis of MSI-induced antitumor immune response is not well understood. To address this issue, we used CRISPR to genetically inactivate MutL homolog 1 (MLH1), a key MMR protein, in two microsatellite stable (MSS) murine colorectal cancer cell lines, CT26 and MC-38, which enabled us to directly compare isogenic MSI and MSS tumors in mice with an immuno-deficient or -competent microenvironment. The growth of MLH1-KO cells was comparable to the parental cells in immunocompromised mice. Upon transplantation into syngeneic, immunocompetent mice, the parental CT26 and MC-38 tumors rapidly proliferate. In contrast, the MLH1-KO tumors grew poorly under the same conditions, which was accompanied by apoptotic cell death, upregulation of inflammatory cytokines, and tumor infiltration of CD8+ T lymphocytes. Blocking apoptosis by caspase inhibition suppressed cytokine induction and T lymphocyte infiltration, suggesting a key role of apoptosis in triggering an antitumor immune response. Our current efforts are towards elucidating the mechanism of cell death and defining the associated immune signatures. Ultimately, a better understanding of the immunological consequences of MSI status in CRCs may help to develop more effective CRC therapies. Citation Format: Darleny Y. Lizardo, Yi-Jun Wang, Liheng Yang, Jian Yu, Lin Zhang. Microsatellite instability causes colorectal cancer cell death to trigger anti-tumor immune response [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 1622.
Abstract 3384: Characterization of the tumor microenvironment and liquid biopsy in head and neck and non-small cell lung cancer
Authors: Arutha Kulasinghe, Joanna Kapeleris, Liz Kenny, Brett Hughes, Majid Warkiani, Ian Vela, Jean-Paul Thiery, Ken O'Byrne, Chamindie Punyadeera
Journal: Cancer Research (2020)

Abstract Metastasis in cancer patients is reflected by measurable levels of circulating tumor cells (CTCs) in the blood of cancer patients. CTCs represent cancer cells from the primary and metastatic sites, thereby providing a comprehensive representation of the tumor burden of an individual patient. Recent advancements have shown that PD-1/PD-L1 immune checkpoint therapies have durable responses in a number of solid tumor types. Our study was designed to use multiple CTC enrichment platforms for the capture of CTCs and novel culture formulations for the ex vivo expansion of CTCs. Head and Neck cancer (n=350) and lung cancer (n=150) patients were recruited to investigate the prognostic role of CTCs. In parallel, a subset of HNC tumors were profiled using the NanoString GeoMx Digital Spatial Profiling (DSP) technology using a 44-plex antibody cocktail. We evaluated multiple CTC isolation technologies (CellSearch, filtration, CD45 depletion, Spiral, Straight and novel microfluidic chip technology) using matched patient samples which showed that epitope-independent CTC isolation captured a greater proportion of CTCs. Molecular alterations present in the primary tissue were confirmed in the CTCs by 3D-DNA FISH (EGFR-amplification, ALK-translocations). In HNC, the presence of CTC clusters associated with the development of distant metastatic disease (P=0.0313). HNC CTC-positive patients had shorter progression free survival (Hazard ratio [HR]: 4.946; 95% [CI]:1.571-15.57; P=0.0063) and PD-L1-positive CTCs were found to be significantly associated with worse outcome ([HR]:5.159; 95% [CI]:1.011-26.33; P=0.0485). In a proof of principle study, we were able to demonstrate for the first time, short-term patient derived CTC cultures outside the patient's body and exome sequencing of CTCs cultures confirmed the presence of mutational signatures consistent with The Cancer Genome Atlas (TCGA). Spatial characterization of the tumor microenvironment revealed immune subsets predictive of outcome to immunotherapy. Comprehensive characterization of the tumor microenvironment and liquid biopsy allows for the recapitulation of the molecular diversity present within the tumor, understanding of the disease progression and testing of therapies. Citation Format: Arutha Kulasinghe, Joanna Kapeleris, Liz Kenny, Brett Hughes, Majid Warkiani, Ian Vela, Jean-Paul Thiery, Ken O'Byrne, Chamindie Punyadeera. Characterization of the tumor microenvironment and liquid biopsy in head and neck and non-small cell lung 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 3384.
Abstract 3101: Utility of a new targeted next generation sequencing test for liquid biopsy samples from patients with NSCLC
Authors: Jordan Reese, Victoria Maxwell, Leisa Jackson, Gary Pestano, Hestia S. Mellert
Journal: Cancer Research (2020)

Abstract Blood-based methods for profiling tumor-sourced nucleic acids have become increasingly important in the diagnostic workup for cancer patients, particularly in non-small cell lung cancer (NSCLC). Blood-based assays address several limitations of tissue-based testing approaches such as inaccessible lesions, limited tissue, extended time to results, and invasive specimen collection procedures. Broad-profiling next-generation sequencing (NGS) methods are used to detect rare variants in blood samples. Here we describe the utility of a newly developed 52 gene NGS test, which uses the GeneStudio S5 Prime platform. We report on performance verification of the assay using contrived specimens as well as studies which evaluated clinical specimens at diagnosis and during monitoring. Thirty-eight cell-free nucleic acid (cfNA) specimens were evaluated from donors previously diagnosed with NSCLC. Specimens were collected in blood collection tubes containing preservatives (Streck cfDNA BCT) and shipped at ambient temperature to our central testing Laboratory. cfNA was isolated from plasma and reverse transcribed. The sequencing metrics for these studies included an average of 15 million mapped reads, 94.4% of on target reads, and a mean sequencing depth of 52,000. Additionally, the average molecular coverage was 2400 reads per amplicon with 99.9% uniformity at 500x coverage. Detected variants and their allelic frequencies were compared with reference results from a validated ddPCR method. Eleven variants (6 EGFR and 5 KRAS) were detected in the cohort with allele frequencies ranging from 0.90 - 96.16%. Results were highly concordant between the two methods (R2=0.992) with 90.3% sensitivity and 100% specificity. In addition, we present a case study to further demonstrate clinical utility of NGS for longitudinal monitoring over 540 days for clearance followed by re-emergence of EGFR positive cfNA harboring the EGFR C797S resistance mutation. These studies add to the growing body of knowledge supporting the utility of molecular detection for actionable and emerging biomarkers in liquid biopsy. Citation Format: Jordan Reese, Victoria Maxwell, Leisa Jackson, Gary Pestano, Hestia S. Mellert. Utility of a new targeted next generation sequencing test for liquid biopsy samples from patients with NSCLC [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 3101.
Abstract LB-086: CD3 MOSPD2 bi specific antibody significantly prolongs survival in a model of metastatic human cervical cancer without any evidence of toxicity
Authors: Niva Yacov, Oshrat Propheta-Meiran, Pinhas Kafri, Yaniv Salem, Itzhak Mendel, EYAL BREITBART
Journal: Cancer Research (2020)

Abstract Introduction: We have previously showed that motile sperm domain-containing protein 2 (MOSPD2), is highly expressed in multiple solid tumors and cancer cell lines but has low/undetectable levels in healthy tissues, implying that MOSPD2 can be an effective target for directed killing of tumor cells. We developed CD3xMOSPD2 bi-specific IgG antibodies (BsAb) that induced T-cell activation and yielded profound death of target tumor cells in-vitro. Experimental procedure: NSG mice were injected subcutaneously with the metastatic cervical cancer HeLa cell line (day 0). Freshly isolated human PBMC were transferred I.P when tumors volume reached an average of 150mm3 (day 29). Subsequently, mice were treated I.V with control IgG antibody or CD3xMOSPD2 BsAb and monitored for survival. To assess in-vivo T-cell activation, serum collected 6hr after first antibody treatment was analyzed for cytokines level. Results: Treatment with CD3xMOSPD2 BsAb, significantly increased serum concentration of IFN-γ, IL-6 and TNF-α compared with control IgG-treatment. Strikingly, by day 65, survival rate of CD3xMOSPD2 BsAb treated mice was 90% compared with only 10% in the control IgG-treated group (n=9-10; p=0.00106). No evidence of toxicity or off target activity was detected. Conclusions: Our data show that CD3xMOSPD2 bi-specific antibody induces T-cell activation in-vivo and significantly extends the survival of mice carrying established metastatic cervical cancer. These results highlight the potential of bi-specific mediated immuno-oncology therapy for the treatment of MOSPD2-positive metastatic solid tumors. Citation Format: Niva Yacov, Oshrat Propheta-Meiran, Pinhas Kafri, Yaniv Salem, Itzhak Mendel, EYAL BREITBART. CD3 MOSPD2 bi specific antibody significantly prolongs survival in a model of metastatic human cervical cancer without any evidence of toxicity [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-086.
Lesson of the month: novel method to quantify neutrophil uptake in early lung cancer using SPECT-CT
Authors: Neda Farahi, Daniel Gillett, Mark Southwood, Doris Rassl, Nicola Tregay, Uta Hill, Stephen Denis Preston, Chrystalla Loutsios, Laurence Si Chong Lok, Sarah Heard, John Buscombe, Robert Campbell Rintoul, A Michael Peters, Charlotte Summers, Edwin R Chilvers
Journal: Thorax (2020)

Neutrophils play an important role in the lung tumour microenvironment. We hypothesised that radiolabelled neutrophils coupled to single-photon emission CT (SPECT) may non-invasively quantify neutrophil uptake in tumours from patients with non-small cell lung cancer. We demonstrated increased uptake of radiolabelled neutrophils from the blood into tumours compared with non-specific uptake using radiolabelled transferrin. Moreover, indium-111-neutrophil activity in the tumour biopsies also correlated with myeloperoxidase (MPO)-positive neutrophils. Our data support the utility of imaging with In-111-labelled neutrophils and SPECT-CT to quantify neutrophil uptake in lung cancer.
Corrigendum re “Docetaxel Versus Surveillance After Radical Radiotherapy for Intermediate- or High-risk Prostate Cancer—Results from the Prospective, Randomised, Open-label Phase III SPCG-13 Trial” [Eur Urol 2019;76:823–30]
Authors: Pirkko-Liisa Kellokumpu-Lehtinen, Marie Hjälm-Eriksson, Camilla Thellenberg-Karlsson, Lennat Åström, Lars Franzen, Ann-Fofie Fransson, Markku J. Leskinen, Mihalj Zeke, Teppo Huttunen, Claes Ginman
Journal: European Urology (2020)
Dermot Patrick Byrnes
Authors: John Gray
Journal: BMJ (2020)

Dermot Patrick Byrnes was born in Dublin in 1939 into a well known medical family. His grandfather was a GP in County Limerick and his father was professor of surgery at the Royal College of Surgeons in Dublin. After completing his education at Clongowes Wood College in County Kildare, Byrnes studied medicine at University College Dublin where he graduated in 1963. He followed in his father’s footsteps by training in general surgery before turning to neurosurgery. He gained a very broad experience of this specialty in Dublin, Edinburgh, London, and Belfast. He was awarded fellowship of the Royal College of Surgeons of Edinburgh in 1967 and of the Royal College of Surgeons in Ireland in 1969. When working as a senior registrar in Belfast in 1974 at the height of Northern Irelands civil disturbances, he was the principal author of a landmark paper published in …
Abstract 4815: Differential expression profiling of long noncoding RNA establishes UCA1 as a hallmark of renal medullary carcinoma
Authors: Pavlos Msaouel, Gabriel G. Malouf, Xiaoping Su, Hui Yao, Durga N. Tripathi, Jianjun Gao, Priya Rao, Jean-Philippe Bertocchio, Jose Karam, Christopher G. Wood, Cheryl L. Walker, Giannicola Genovese, Nizar M. Tannir
Journal: Cancer Research (2020)

Abstract Renal medullary carcinoma (RMC) is a rare but highly lethal renal cell carcinoma (RCC) that predominantly afflicts young African Americans with sickle cell hemoglobinopathies. There are currently no approved targeted therapies for RMC and the median survival from diagnosis is 13 months despite best available treatments. New biomarkers and therapeutic targets are therefore urgently needed for this very aggressive disease. No studies to date have profiled the long noncoding RNA landscape of RMC. We performed RNA sequencing in untreated primary tumor samples obtained from 11 patients with RMC. The lncRNA expression profile of RMC was compared to that of adjacent normal kidney (n = 6 patients with RMC), upper tract urothelial carcinoma (UTUC), and closely related RCCs including collecting duct carcinoma (CDC), clear cell renal cell carcinoma (ccRCC), papillary renal cell carcinoma (pRCC), and chromophobe renal cell carcinoma (chRCC). We performed principal component analyses as well as hierarchical clustering of the lncRNA expression levels using the Pearson correlation coefficient as the distance metric and the ward's linkage rule. The read counts of each lncRNA were fitted using a negative binomial model and a Wald test was used in DESeq2 to compare expression levels. The false discovery rate (FDR) was controlled using the Benjamini and Hochberg method. We found that the lncRNA signature of RMC is clearly distinct from that of ccRCC, pRCC, and chRCC, but substantially overlaps with CDC. Urothelial cancer associated 1 (UCA1) was the highest upregulated lncRNA (305-fold increase, FDR &amp;lt; 0.001) in RMC compared with adjacent normal kidney. This dramatic upregulation of UCA1 was similar to that seen in UTUC and not found in any of the other RCCs, including CDC. UCA1 is known to be associated with chemotherapy resistance and was previously considered to be highly specific for urothelial carcinoma. Our findings now suggest that UCA1 is also a hallmark of RMC. Future studies will focus on elucidating the functional consequences of UCA1 expression in RMC pathobiology. Citation Format: Pavlos Msaouel, Gabriel G. Malouf, Xiaoping Su, Hui Yao, Durga N. Tripathi, Jianjun Gao, Priya Rao, Jean-Philippe Bertocchio, Jose Karam, Christopher G. Wood, Cheryl L. Walker, Giannicola Genovese, Nizar M. Tannir. Differential expression profiling of long noncoding RNA establishes UCA1 as a hallmark of renal medullary carcinoma [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 4815.
Abstract 6000: eIF3A regulate the Warburg effect via ENO1 in cervical cancer cells
Authors: Pengfei Xu, Dake Li
Journal: Cancer Research (2020)

Abstract Eukaryotic translation initiation factor 3A (eIF3A) is one of the core subunits of the translation initiation complex eIF3. eIF3A is critical for ribosomal subunit joining and recruiting mRNA to the ribosome, as well as for the regulation of various gene products. However, the function of eif3A have not been reported in cervical cancer (CC). Here we reported that Eif3A protein was overexpressed in CC tissues and the higher expression of Eif3A predicted a worse prognosis. Further experiments showed that eIF3A knockdown inhibited CC cells' proliferation and migration and promoted apoptosis in vitro and in vivo. eIF3A silencing accelerated acidification of the culture medium of CC cells. Seahorse results showed that the decreased expression of eIF3A significantly reduced glycolysis flux in CC cells. Mass spectrometry suggested that eIF3A knockdown could significantly repressed the expression of ENO1, which is a famous glycolytic protein. Western blot assay indicated that eIF3A silencing significant decreased the expression of ENO1. Therefore, our results indicated that eIF3A could enhance the warburg effect in cervical cancer by regulating ENO1. Citation Format: Pengfei Xu, Dake Li. eIF3A regulate the Warburg effect via ENO1 in cervical 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 6000.