tbuckley/cabot-search huggingface dataset:
Abstract 1800: miR-376b and miR-4668 predict therapeutic response to sunitinib in metastatic renal cell carcinoma
Authors: Julia Kovacova, Jaroslav Juracek, Alexandr Poprach, Tomas Buchler, Ondrej Fiala, Lenka Radova, Marek Svoboda, Alena Kopkova, Marek Vecera, Ondrej Slaby
Journal: Cancer Research (2019)

Abstract Introduction: Metastatic renal cell carcinoma (mRCC) is routinely treated with sunitinib, a tyrosine kinase inhibitor (TKI) of VEGF signalisation. Although disease eventually progresses in most mRCC patients, length of progression-free survival (PFS) is ranging from few weeks up to more than 24 months. Patients with initial resistance to sunitinib could be redirected to other therapeutical options, as there are several other TKIs available for use in second and third line. However, without a reliable biomarker no result can be predicted. MicroRNAs (miRNAs) belong to class of short non-coding RNAs and could serve as biomarkers of therapy response due to their unique character and presence in tissues and body fluids. Their biomarker potential has been discussed concerning many diseases including mRCC, but current knowledge is very weak, has several discrepancies and is acquired on relatively small cohorts. Material and method: Candidate microRNAs have been chosen based on global expression profiling using Affymetrix GeneChip 4.0 in 47 samples of FFPE mRCC tissue of patients treated with sunitinib (good response n=25, PFS longer than 17 months; poor response n=22, PFS shorter than 9 months). Validation was performed using qRT-PCR TaqMan assays on an independent cohort of 136 FFPE samples from mRCC patients treated with sunitinib with variable length of PFS. Local ethical committees at all involved centres approved the study protocol. The study was performed according to the World Medical Association Declaration of Helsinki and all patients signed an informed consent. Results and discussion: Of all tested miRNAs, expression of miR-4668-5p and miR-376b was the most significantly deregulated in non-responding patients with high statistical significance (p&amp;gt;0,005) and combined AUC higher than 0,8. Although other independent validations are necessary, microRNAs presented here seem to be very promising as tools for therapy personalization. Conclusion: We have successfully validated miR-4668-5p and miR-376b to have predictive potential in estimation of therapeutical response to sunitinib. Further functional analyses could shed more light on their involvement in development of therapy resistance. This work was supported by Ministry of Health of the Czech Republic, grant nr. NV18-03-00554. All rights reserved. Citation Format: Julia Kovacova, Jaroslav Juracek, Alexandr Poprach, Tomas Buchler, Ondrej Fiala, Lenka Radova, Marek Svoboda, Alena Kopkova, Marek Vecera, Ondrej Slaby. miR-376b and miR-4668 predict therapeutic response to sunitinib in metastatic renal cell carcinoma [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 1800.
Abstract 126: Multidimensional gene expression models for characterizing response and metastasis in solid tumor samples
Authors: Walter P. Carney, Milan Bhagat, Natalie LaFranzo
Journal: Cancer Research (2019)

Abstract Predicting response to standard of care therapies and new immunotherapies is enabled by tools that quantitatively analyze the complex heterogeneity of the tumor microenvironment. Current methods to do so primarily rely either on single gene or protein markers, and often report solely on one feature of the multifaceted immune cycle. Unlike other molecular approaches, the ImmunoPrismTM Immune Profiling Assay has been built using multidimensional gene expression models validated to accurately identify immune cells in a complex mixture with high correlation to flow cytometry measurements, but accessible for formalin-fixed paraffin-embedded (FFPE) tissues. We will report results showing the assay is highly sensitive, capable of detecting immune cells present to as little as 2% of the specimen, important for critical immune cell types such as M1 and M2 macrophages and Tregs. Further, the assay requires as few as two sections of FFPE solid tumor tissue or as little as 20 ng of total RNA which enables the analysis of rare clinical archives. In this study, we apply the ImmunoPrism assay to cohorts of patients with indications including non-small cell lung carcinoma (NSCLC), triple-negative breast cancer (TNBC) and pancreatic adenocarcinoma (ADC) treated with standard of care therapies. Immune profile changes for pre vs. post treatment and primary vs. metastatic tissue are reported in the context of clinical data, such as therapy response. Resulting biomarkers, including a novel machine-learning based multidimensional marker are also reported with predictive accuracy, PPV, NPV, and selection thresholds. Citation Format: Walter P. Carney, Milan Bhagat, Natalie LaFranzo. Multidimensional gene expression models for characterizing response and metastasis in solid tumor samples [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 126.
Abstract 3830: Novel bromodomains and extra-terminal motif (BET) inhibitors developed against estrogen receptor positive, fulvestrant- and CDK4/6-resistant breast cancer models
Authors: Rui Xiong, Yangfeng Li, Jiong Zhao, Debra Tonetti, Gregory Thatcher
Journal: Cancer Research (2019)

Abstract Approximately 70% of breast cancer patients have estrogen receptor positive (ER+) tumors. Fulvestrant (FUL), a selective estrogen receptor degrader (SERD) able to ablate ER, was first introduced to clinical practice in 2002 as the second and third line treatment for ER+ metastatic breast cancer. In August 2017, FUL was added to first-line therapy in postmenopausal women by demonstrating superiority compared to first-line AI therapy, anastrozole, with improved progression-free-survival (PFS) and a 20% reduction in the risk of disease progression or death. However, acquisition of FUL-resistance in both first-line setting or as combination therapy with CDK4/6 inhibitor has been observed clinically, leaving patients and oncologists with chemotherapy as the only backup therapy. Little is known about resistance mechanisms to FUL alone or in combination with CDK4/6 inhibitors. Here, we showed that targeting epigenetic vulnerabilities in breast cancer using novel bromodomain and extra-terminal (BET) inhibitors can effectively inhibit growth of tamoxifen-, FUL- and CDK4/6- resistant breast cancer cells. We designed and developed a novel series of pyridinone-based BET inhibitors, optimized by growth inhibition in tamoxifen- and FUL- resistant breast cancer cell lines (MCF7:CFR) in both 2D and 3D cultures. Optimized compounds showed superior in vitro activity to BET inhibitors in clinical trials. Selected compounds were further evaluated for pharmacokinetics and shown efficacy in endocrine-resistant xenograft models. Citation Format: Rui Xiong, Yangfeng Li, Jiong Zhao, Debra Tonetti, Gregory Thatcher. Novel bromodomains and extra-terminal motif (BET) inhibitors developed against estrogen receptor positive, fulvestrant- and CDK4/6-resistant breast cancer models [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 3830.
Abstract 3523: A high-throughput screening strategy for the identification of novel lymphoproliferative elements
Authors: Laurence Jadin, Hiba Shaban, Anirban Kundu, Gregory Schreiber, Scooter Willis, Farzad Haerizadeh, James Onuffer, Gregory Frost
Journal: Cancer Research (2019)

Abstract Introduction - Chimeric Antigen Receptor (CAR) T-cell therapy is effective against certain leukemias and lymphomas and shows promise for other incurable malignancies. Considerable challenges remain however to expand this platform technology beyond transplant-oriented hospital care. Centralized manufacturing of genetically modified T cells, lymphodepleting chemotherapy and patient management of current CAR-T therapies are associated with significant costs and treatment complexity. As a first step to reduce this treatment complexity, the present study describes a high throughput combinatorial domain library screening method to identify synthetic lymphoproliferative elements capable of driving in vivo expansion and survival of CAR-T cells in a lymphoreplete host without the homeostatic proliferation signals generated by lymphodepleting chemotherapy. Methods - High-diversity semi-rationally-designed combinatorial libraries of putative lymphoproliferative protein subdomains were DNA barcoded and assembled into a lentiviral vector co-expressing a ROR2-targeted CAR. Human PBMC were transduced with the library and cultured in vitro for several days. Purified cells were injected into mice bearing xenograft tumors modified to express the ROR2 antigen and compared to unmodified xenograft controls. The expansion rate of integrated cells was monitored weekly by quantitative PCR and, after 21 days of exposure, genomic DNA was isolated from blood, spleen and xenograft tumor tissues. Enriched barcodes were amplified using PCR and amplicons were subjected to HiSeq Next-Generation Sequencing. Barcode decoding was achieved using PacBio long read sequencing analysis to align full-length construct sequences with barcode quantitation. Results - Using this approach, putative CAR-T cell driver candidates and common key protein subdomains were identified that support selective in vivo expansion and survival of human lymphocytes in a tumor-bearing mouse model. Conclusion - Taken together, these results demonstrate that a high throughput combinatorial screening strategy with quantitative bioinformatics is a viable method for identifying protein domain combinations capable of selectively driving human CAR-T cells in vivo. These small synthetic combinatorial protein domains may facilitate lymphodepleting chemotherapy-free regimens and lower CAR-T cell doses in the future. Citation Format: Laurence Jadin, Hiba Shaban, Anirban Kundu, Gregory Schreiber, Scooter Willis, Farzad Haerizadeh, James Onuffer, Gregory Frost. A high-throughput screening strategy for the identification of novel lymphoproliferative elements [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 3523.
Public health leaders slam Boris Johnson over “sin tax” review plan
Authors: Gareth Iacobucci
Journal: BMJ (2019)

Experts in public health have condemned comments by the Tory leadership candidate Boris Johnson that he may halt the government’s sugar levy if he becomes the next prime minister.

The comments were made at a leadership campaign event where Johnson pledged to review taxes on sugar, salt, and fat that he argued unfairly punished poor people.

Johnson said, “The recent proposal for a tax on milkshakes seems to me to clobber those who can least afford it. If we want people to lose weight and live healthier lifestyles, we should encourage people to walk, cycle, and generally do more exercise. Rather than just taxing people more, we should look at how effective the so called sin taxes really are …
Twenty-five year anniversary of a successful rural, community hospital, comprehensive cancer screening program.
Authors: Shahid Waheed, Tonya A Linthacum
Journal: Journal of Clinical Oncology (2013)

e12569 Background: A 25 year successful comprehensive cancer screening program at a rural community hospital in Mexico, MO, USA, provides a multi-organ cancer detection clinic for asymptomatic women over age of 35. Methods: The Screening Program consists of a Medical Director, day to day oversight by a Family Nurse Practitioner, with nurse practitioner and specialty trained registered nurse examiners. This multi-organ screening program focuses on breast, colon, skin, cervical and prostate cancer early detection. One-hour screening exams for women include detailed cancer risk assessment, prevention education, head-to-toe physical exams including an examination of the skin, clinical breast exam, mammogram, pelvic and Pap test. Additionally, site-specific exams of the abdomen, thyroid, peripheral lymph nodes and rectum are conducted. Male exams include a physical examination of the skin, abdomen, peripheral lymph nodes, thyroid, external genital, digital rectal exam of the prostate and PSA blood education. For all tobacco users, the screening includes an oral examination. Extensive education is provided to participants on prevention modalities, current screening guidelines, and new research findings. Detected abnormalities are referred to the patient’s primary care physician for follow up. A phone call to the patient and the primary care provider four to six weeks after the initial exam obtains the results of the referral visit. Results: 25-year participation rates total 51,223 visits with a ratio of 1 male to 19 females. Return rates over the past year were 94%. 626 cancers have been detected since the inception of the program with 1 breast cancer for every 41 women participating, most identified at early stages. Over 2,500 participants, with a 95% satisfaction rating, from 48 Missouri counties, as well as 21 states of the nation are seen annually for cancer screening. Conclusions: Comprehensive screening programs are effective at decreasing cancer mortality and morbidity through education, prevention, and early detection. Nurse run clinics offer a satisfying, cost effective alternate approach, while continuing to provide competent expertise in the specialized field of cancer prevention.
Immune reactions after modern lamellar (DALK, DSAEK, DMEK) versus conventional penetrating corneal transplantation
Authors: Deniz Hos, Mario Matthaei, Felix Bock, Kazuichi Maruyama, Maria Notara, Thomas Clahsen, Yanhong Hou, Viet Nhat Hung Le, Ann-Charlott Salabarria, Jens Horstmann, Bjoern O. Bachmann, Claus Cursiefen
Journal: Progress in Retinal and Eye Research (2019)

In the past decade, novel lamellar keratoplasty techniques such as Deep Anterior Lamellar Keratoplasty (DALK) for anterior keratoplasty and Descemet stripping automated endothelial keratoplasty (DSAEK)/Descemet membrane endothelial keratoplasty (DMEK) for posterior keratoplasty have been developed. DALK eliminates the possibility of endothelial allograft rejection, which is the main reason for graft failure after penetrating keratoplasty (PK). Compared to PK, the risk of endothelial graft rejection is significantly reduced after DSAEK/DMEK. Thus, with modern lamellar techniques, the clinical problem of endothelial graft rejection seems to be nearly solved in the low-risk situation. However, even with lamellar grafts there are epithelial, subepithelial and stromal immune reactions in DALK and endothelial immune reactions in DSAEK/DMEK, and not all keratoplasties can be performed in a lamellar fashion. Therefore, endothelial graft rejection in PK is still highly relevant, especially in the "high-risk" setting, where the cornea's (lymph)angiogenic and immune privilege is lost due to severe inflammation and pathological neovascularization. For these eyes, currently available treatment options are still unsatisfactory. In this review, we will describe currently used keratoplasty techniques, namely PK, DALK, DSAEK, and DMEK. We will summarize their indications, provide surgical descriptions, and comment on their complications and outcomes. Furthermore, we will give an overview on corneal transplant immunology. A specific focus will be placed on endothelial graft rejection and we will report on its incidence, clinical presentation, and current/future treatment and prevention options. Finally, we will speculate how the field of keratoplasty and prevention of corneal allograft rejection will develop in the future.
Abstract 2760: Photoinducible detection of the oncometabolite fumarate
Authors: Chloe Briney, Sarah Bergholtz, Rhushikesh Kulkarni, Daniel Crooks, Chandrasekhar Mushti, Stephen Lockett, Rolf Swenson, W. Marston Linehan, Jordan Meier
Journal: Cancer Research (2019)

Abstract Dysregulated metabolism is an important marker of many disease states, including cancer. For example, in hereditary leiomyomatosis and renal cell cancer (HLRCC), inactivating mutations in fumarate hydratase (FH) lead to accumulation of high levels of fumarate, a so-called “oncometabolite.” Substantial evidence indicates that fumarate stimulates various oncogenic signaling pathways, necessitating sensitive methods to detect the oncometabolite in order to more rapidly diagnose HLRCC as well as to identify new disease settings in which fumarate may play a signaling role. Here, we report development of novel photoactivatable, fluorogenic chemical probes for detection and profiling of fumarate in biological systems. These chemical probes, diaryl tetrazoles, are by themselves inert towards fumarate. However, upon irradiation with UV light, they release nitrileimines that can form fluorescent cycloadducts with fumarate. We have demonstrated that diaryl tetrazoles can sensitively detect FH activity as well as low micromolar levels of fumarate in complex biological samples. We have also shown that diaryl tetrazoles can be used to monitor changes in intracellular fumarate levels in biological samples by live-cell imaging and flow cytometry. Moreover, these compounds are capable of visualizing differences between patient-derived primary HLRCC tumors lacking FH activity and the adjacent normal kidney, highlighting their potential utility in clinical diagnostics. By offering new insights into fumarate reactivity, our studies provide the chemical basis for novel approaches to therapy and diagnosis in cancers driven by oncometabolite accumulation. Citation Format: Chloe Briney, Sarah Bergholtz, Rhushikesh Kulkarni, Daniel Crooks, Chandrasekhar Mushti, Stephen Lockett, Rolf Swenson, W. Marston Linehan, Jordan Meier. Photoinducible detection of the oncometabolite fumarate [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 2760.
Abstract 1265: Validation of the interaction between a candidate compound and the intended drug target by a phenotypic rescue approach
Authors: Lieke Geerts, Laure Grandmoursel, Jamil Aarbiou, Jeroen DeGroot, Julia Schüler, Ian Waddell, Anne-Marie Zuurmond
Journal: Cancer Research (2019)

Abstract New targets for cancer treatment frequently emerge in literature, but the thorough target validation required to consider these targets for a drug discovery program is often lacking. In pharmacological or genetic perturbation studies using complex biological assays, undesired off-target effects cannot be easily distinguished from the intended mode of action at the desired target. This is especially evident in cancer drug development where it is important to discriminate on-target effects on cell viability from off-target effects resulting in non-specific loss of cellular fitness. Neglecting the possibility of being deceived by off-target effects can have tremendous scientific and financial impact on a drug discovery program. Ideally confidence in a preclinical drug target and a modulating compound is boosted in an early stage by more extensive analysis and validation of the actual drug-target relationship. Rescue of a disease-relevant phenotype by genetic restoration of a target mutation is a gold standard approach in drug discovery by which target validation can be achieved. We aim to follow this approach targeting the BRAF V600E mutation in a number of well described melanoma lines as well as the MAP2K1 Q56P mutation in non-small cell lung cancer cell line H1437. Target validation for both BRAF and MAP2K1 will be addressed by assessing viability, phenotypic changes and sensitivity to compound modulation upon CRISPR/Cas9 repair of the target mutation or by exogenous re-expression of the wildtype variant. Compounds tested will be Vemurafenib for BRAF and Trametinib for MAP2K1. Further investigation into target validity will be done using a physiologically relevant 3D spheroid based co-culture system. Mimicking the tumor microenvironment increases the knowledge about “drug-ability” of a target and sustainability of the target modulation at an early time point in the development process. Such early in-depth validation of the relationship between a compound and the drug target is vital to mitigate the risk of failure at later steps of drug development. Citation Format: Lieke Geerts, Laure Grandmoursel, Jamil Aarbiou, Jeroen DeGroot, Julia Schüler, Ian Waddell, Anne-Marie Zuurmond. Validation of the interaction between a candidate compound and the intended drug target by a phenotypic rescue approach [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 1265.
Abstract 4856: Suppression of PRKCI gene-amplified ovarian cancer using aptamer-delivered siRNA
Authors: Hina Rehmani
Journal: Cancer Research (2019)

Abstract Ranked fifth in cancer death among women, ovarian cancer cure rates have remained at 30% over the past two decades. Treatment options have steadily followed the same methodology, surgery and then first-line chemotherapy. With a 70% relapse rate within the first two years of diagnosis and limited secondary options, acquiring more targeted treatments is imperative. Copy number aberrations, more than mutations, are commonly found in high grade serous ovarian cancer. Copy number gains of the Protein Kinase C iota (PRKCI) gene are found in over 33% of ovarian cancer patients. According to the TCGA database, patients with PRKCI gene amplification have a significantly poor overall survival than those that do not. With this information and the fact that it is a previously identified oncogene in ovarian cancer, Protein Kinase C iota (PKCi) serves as an excellent target. Unfortunately, the Protein Kinase C iota isoform shares an overall homology of 72% with the Protein Kinase C zeta isoform which makes selective targeting of the iota form a challenge. Previous publications have used gold-based compounds to block atypical PKC family members from interactions that are crucial for apical-basal polarity. We found, however, that these compounds exhibit no specific selectivity for PRKCI gene amplified ovarian cancer cell lines.To specifically target PKCi, we have created an RNA-based aptamer that contains a siRNA sequence against the PRKCI mRNA and EpCAM moieties on either end. The aptamer efficiently becomes internalized after binding to the cell surface EpCAM via clathrin-dependent endocytosis. Once inside, the aptamer is processed by Dicer to release the two unique siRNA duplex intermediates. The guide strand of the siRNA loads into the RNA-induced silencing complex (RISC) complex and Argonaute (Ago) protein family members mediate PRKCI mRNA silencing.We hypothesize that PRKCI gene amplification status offers a unique opportunity to stratify patients into different risk categories and RNA-aptamer targeting of PRKCI can provide therapeutic benefits, by impairing ovarian cancer cell proliferation and tumorigenesis. We expect this approach to provide potent and selective anti-tumor and anti-metastasis activity compared to targeting using other pharmaceutical options. Citation Format: Hina Rehmani. Suppression of PRKCI gene-amplified ovarian cancer using aptamer-delivered siRNA [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 4856.