bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract LB-268: Assessment of flat dosing strategy for INCMGA00012 in patients with advanced tumors
Authors: chen Xuejun , Wang Phil , Kaul Sanjeev , Sumrow Bradley , Yeleswaram Swamy 
Published: August 2019

Abstract
Background: INCMGA00012, a humanized, hinge-stabilized, IgG4κ monoclonal antibody that recognizes human PD-1, is being developed for the treatment of multiple solid tumor types, both as monotherapy and in combination with other potentially immunoactive agents. Flat dosing is preferred to weight-based dosing for multiple reasons, including convenience of preparation and administration, reduced errors in preparation calculation, and minimization of drug waste. A modeling and simulation approach was employed to support flat doses for later phase studies.
Patients and Methods: INCMGA00012 has been administered to approximately 200 participants in a Phase 1 study (Study INCMGA 0012-101) at weight-based doses ranging from 1 to 10 mg/kg Q2W or Q4W and at flat doses of 500 mg Q4W and 750 mg Q4W. PK data from weight-based doses were used for population PK model development and data from flat doses were used for model validation. Simulations were performed to support the selection of RP2 flat dose.
Results: The concentrations of INCMGA00012 were adequately described by a 2-compartment model with first-order elimination. Higher clearance was estimated for 1 mg/kg (23.5 mL/h) than the other dose groups (13.5 mL/h). Body weight dependence of clearance and volume of distribution for central compartment were characterized by power relationships with exponents of 0.911 and 0.493, respectively. The model was validated using PK data from participants who received INCMGA00012 500 mg Q4W and 750 mg Q4W, respectively, in the cohort expansion phase. Median steady state trough concentrations of 500 mg Q4W and 750 mg Q4W exceeded the target value.
Conclusion: Modeling and simulation provide justification for 500 mg Q4W for further clinical development of INCMGA00012 based upon favorable safety, PK characteristics and presumed flat exposure-response relationships for efficacy.
Citation Format: Xuejun chen, Phil Wang, Sanjeev Kaul, Bradley Sumrow, Swamy Yeleswaram. Assessment of flat dosing strategy for INCMGA00012 in patients with advanced tumors [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 LB-268.
Abstract LB-277: Characterization of the anti-cancer and immunologic activity of RGX-019, a novel pre-clinical stage humanized monoclonal antibody targeting the MERTK receptor
Authors: Takeda Shugaku , Andreu-Agullo Celia , Sridhar Subhasree , Halberg Nils , Lorenz Ivo C. , Tavazoie Sohail , Kurth Isabel , Tavazoie Masoud 
Published: August 2019

Abstract
MERTK, a receptor tyrosine kinase of the TYRO3/AXL/MERTK (TAM) family, is expressed in innate immune cells including macrophages, dendritic cells and NK cells and is overexpressed in a wide variety of cancers, including leukemia and many solid cancers. Activation of MERTK on cancer cells via ligand binding results in activation of several tumor-promoting signaling pathways, which stimulate proliferation, migration and angiogenesis, and decrease apoptosis and chemosensitivity. Furthermore, activation of MERTK on macrophages drives immune evasion through the promotion of an immune-suppressive M2 phenotype. Pre-clinical and
clinical studies have shown promising emerging evidence of anti-tumor efficacy upon modulation of TAM receptor signaling. Herein, we report the pre-clinical characterization of RGX-019, a humanized IgG1 antibody with high affinity and specificity for human MERTK.
Surface Plasmon Resonance, cell-based binding assays and competition ELISA demonstrate high affinity/avidity binding for RGX-019 to human MERTK. In contrast, binding to human AXL, human TYRO3, or murine MERTK was not detected. Binding of RGX-019 to the MERTK receptor triggered its rapid internalization and degradation from the surface of human cancer cells within 4 hours and prevented Gas6 induced phosphorylation of AKT, a downstream signal transduction pathway that promotes cell growth and survival. RGX-019 treatment of SKMel5 melanoma cells effectively inhibited colony formation. RGX-019-induced degradation of MERTK in in vitro differentiated human M2 macrophages reduced AKT activation and promoted a pro-inflammatory cytokine signature. Furthermore, a related surrogate murine MERTK antibody significantly inhibited growth of MDA-MB-231 breast cancer tumors, demonstrating single agent anti-tumor efficacy in vivo. These findings demonstrate that RGX-019 is a potent and selective inhibitor of MERTK signaling with a unique mechanism-of-action that potently disrupts MERTK signaling in both cancer cells and immune-suppressive macrophages via MERTK receptor degradation. This activity results in robust repression of cancer cell growth both in vitro and in vivo. Overall, these data support further development of RGX-019 as a cancer therapeutic.
Citation Format: Shugaku Takeda, Celia Andreu-Agullo, Subhasree Sridhar, Nils Halberg, Ivo C. Lorenz, Sohail Tavazoie, Isabel Kurth, Masoud Tavazoie. Characterization of the anti-cancer and immunologic activity of RGX-019, a novel pre-clinical stage humanized monoclonal antibody targeting the MERTK receptor [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 LB-277.
Abstract LB-279: Artificial intelligence aided diagnosis of breast cancer molecular classification based on immunohistochemical images
Authors: Zhao Jean J. , Ruan Minzi , Cui Quancai 
Published: August 2019

Abstract
Breast cancer has obvious heterogeneity. Molecular classification of breast cancer has been done through the study of gene expression profile. There were significant differences in gene expression, clinical characteristics, therapeutic response and prognosis among these molecular types, which were lumen A type, lumen B type, her-2 overexpression type and basal cell type, respectively. Compared with other nucleic acid level detection technologies, immunohistochemistry (IHC), as the most commonly used protein expression level detection method, has the advantages of low price, short cycle and more stable. IHC staining, including ER, PR, Ki-67, Her-2, CK5/6 and EGFR, can be used to classify breast cancer into different molecular subtypes and assist in the determination of treatment options. The application of artificial intelligence in pathological morphology is in the ascendant. Different algorithms can be used to evaluate both IHC staining and HE staining morphological evaluation of tumor tissues (including histological grading).In the molecular typing of breast cancer by IHC, the digital slide images obtained by scanning with software analysis can greatly reduce the subjectivity and instability of manual evaluation and improve the repeatability. Firstly, we scanned whole slide digital image of the HE staining slides and the six IHC slides of 200 surgical specimens of breast cancer with different molecular types (non-special types) from a medical center (Peking Union Medical College Hospital).Then compare the immunohistochemical results of each case obtained manually, adjust the algorithm, calibrate the parameters in the software, and finally get the fixed algorithm code and parameters. The algorithms used in study include image classification, nuclei segmentation, channel association and image registration. The algorithms were verified in the other surgical resection specimens of 400 cases of breast cancer with different molecular types (non-special types) from two other medical center, and was compared with the data obtained by manual reading. Finally, the results were encouraging, with the consistency of molecular classification reaching 100%. This study shows AI technology has great application prospect in pathological diagnosis of breast cancer.
Citation Format: Jean J. Zhao, Minzi Ruan, Quancai Cui. Artificial intelligence aided diagnosis of breast cancer molecular classification based on immunohistochemical images [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 LB-279.
Abstract LB-289: Genomic instability and the development of high-grade gliomas
Authors: Pribyl Lee J. , Downing Susanna M. , Camacho Cristel V. , Larson Jon D. , Baker Suzanne J. , McKinnon Peter J. 
Published: August 2019

Abstract
Genome stability is crucial for normal mammalian development. Broadly, genome maintenance is carried out by two distinct mechanisms; functional integration of DNA replication and DNA damage response signaling. Neural cells are particularly sensitive to DNA strand breaks and defective DNA damage responses can result in detrimental effects to the nervous system, including neurodegenerative disease and cancer. It remains unclear which DNA repair pathways are critical for preventing DNA damage accumulation in stem and progenitor cells. The same mechanisms that protect progenitor genomes also suppress DNA mutations that can result in cancer. A primary objective of the current study is delineation of key factors for genome stability that prevent tumorigenesis during cortical neurogenesis. We have compared the differential effects of inactivation of homologous recombination (HR) and non-homologous end-joining (NHEJ) towards tumorigenesis by directing their deletion specifically to early cortical progenitors in mouse models. We recently found that coincident loss of either of these repair pathways result in high-grade glioma formation. Furthermore, modelling histone H3 mutations found in human high-grade glioma, specifically the H3.3 K27M mutation, we found that gliomagenesis was accelerated after defective HR (Brca2 loss) or NHEJ (Lig4 loss), although the resultant cancers showed distinct differences in penetrance and diffusion throughout the cortex. Interestingly, gliomas resulting from NHEJ inhibition were more penetrant and diffuse than brain tumors subsequent from HR loss. Gene expression analysis through RNA sequencing is currently being used to identify causative events that drive these individual tumor identities. Embryonic analysis has further shown that inhibition of these repair pathways in combination with the H3.3 K27M mutation results in distinct spatiotemporal DNA damage early in cortical development. Our recent discoveries support cortical progenitor susceptibility to genomic damage is not only influenced by a critical early period of development but also the suppression of specific tumorigenic mutations involving DNA damage repair pathways and histone modifications during neurogenesis.
Citation Format: Lee J. Pribyl, Susanna M. Downing, Cristel V. Camacho, Jon D. Larson, Suzanne J. Baker, Peter J. McKinnon. Genomic instability and the development of high-grade gliomas [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 LB-289.
Abstract LB-303: Transposable element insertions impact the mutational landscape of breast cancer genomes and disease onset
Authors: Paul Robin , Radovich Milan , Solzak Jeffrey P. 
Published: August 2019

Abstract
More than 50% of the human genome consists of transposable elements (TE), which mostly remain inactive and relatively stable in healthy individuals. These elements, commonly known as “jumping genes,” are sequences of DNA that are mobile and can change positions in the genome. However, only certain classes of retrotransposons (ALU, SVA, ERV and L1) are believed to be active in the human genome. Most TEs transpose by a “copy-and-paste” mechanism via transcription from DNA to an RNA intermediate followed by reverse transcription back to DNA and subsequent insertion of the copied DNA into the genome. In healthy individuals, this mechanism is silenced by various epigenetic pathways such as the piRNA pathway which helps silence the transcribed TE RNA intermediates. However during cancer, some retrotransposons are believed to become active due to loss of this epigenetic silencing and DNA damage repair mechanisms. In this study, we analyzed somatic and germline TE insertions in 77 TCGA breast cancer whole genomes and performed association analysis with corresponding somatic and germline variants. In our analysis, we identified a subset of patients who harbored a high number of germline TE insertions. Statistical burden testing of germline TE insertions with germline genetic variants (SNPs and Indels), revealed an enrichment of deleterious variants in the NRDE2 and TNKS1BP1 genes. NRDE2 gene involved in the piRNA pathway is known to regulate TEs using RNA silencing whereas, TNKS1BP1 gene is known to be involved in DNA damage repair mechanisms and also helps maintain genomic integrity. Further, patients with high germline TE insertions had a lower median age of diagnosis (top quartile vs bottom 75%, p-value=0.019), suggesting a potential novel role of germline TE insertions in cancer predisposition. Lastly, comparison of somatic TE insertion burdenpattern against somatic tumor mutation burden revealed an inverse correlation, indicating that analysis of TE insertions is critical to breast cancer diagnosis in the clinic. Our results definitively argue that characterization of TEs is essential for elucidating the complete mutational profile of a breast cancer genome.
Citation Format: Robin Paul, Milan Radovich, Jeffrey P. Solzak. Transposable element insertions impact the mutational landscape of breast cancer genomes and disease onset [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 LB-303.
Abstract PL04-01: Screening for nasopharyngeal carcinoma using plasma Epstein-Barr virus DNA: Technological and clinical insights
Authors: Lo Yuk Ming Dennis 
Published: August 2019

Abstract
Epstein-Barr virus (EBV) DNA is released by a number of EBV-associated malignancies into the plasma. Examples of such malignancies include nasopharyngeal carcinoma (NPC), certain lymphomas and EBV-associated gastric carcinoma. Plasma EBV DNA in such malignancies exhibits a strong correlation with tumor stage, clinical progress and prognosis; and is thus an archetypal circulating tumor DNA species.
Our group is interested in exploring the use of plasma EBV DNA to screen for NPC. We have recently completed a prospective population screening project involving over 20,000 middle aged men in Hong Kong. Using plasma EBV DNA as a screening tool, NPC could be found at a much earlier stage than was normally possible. Furthermore, the prognosis of the NPC patients identified through such screening was much more favorable than those diagnosed without such screening. The positive predictive value of this approach was 11%.
False-positive results were observed a proportion of subjects without NPC. Factors that contributed to increased false-positive results included advancing age and surprisingly, the ambient temperature of the day when samples were collected. Hence, a higher percentage of false-positive results were observed when samples were collected in colder weather. We hypothesized that such results might be related to the fluctuations in the effectiveness of the immune system in certain individuals due to ambient temperature.
Since the reporting of the above-mentioned results, we have been exploring approaches for further enhancing the positive predictive value. Through the use of targeted massively parallel paired-end sequencing, we found that the size profiles of plasma EBV DNA in subjects with NPC and those without were different. Indeed, by combining such size profile and the concentration of plasma EBV DNA as measured by sequencing, the positive predictive value could be further enhanced.
Very recently, we investigated the epigenetic profile of plasma EBV DNA in subjects with NPC and those without cancer, in an attempt to further enhance the positive predictive value of the approach.
We believe that the development of a robust approach for NPC screening using circulating EBV DNA would have major public health impact, allowing the earlier detection and treatment of NPC in high prevalence areas. We also believe that such developments would also guide the development of other circulating tumor DNA markers for early cancer detection.
Citation Format: Yuk Ming Dennis Lo. Screening for nasopharyngeal carcinoma using plasma Epstein-Barr virus DNA: Technological and clinical insights [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 PL04-01.
Abstract SY17-02: Solid tumor cancer stem cells: From bench to bedside
Authors: Clarke Michael F. 
Published: August 2019

Abstract
Stem cells are essential for maintenance of multiple tissues including the intestine, skin, brain and breast. Remarkably, cancers invariably arise in tissues that contain stem cells whose function is to maintain and repair tissues for the life of the animal. Self renewal, the mechanisms by which stem cells regenerate themselves, is the fundamental property by which stem cells maintain themselves. Our laboratory investigates the fundamental molecular mechanisms of self renewal. Our studies have found that stem cells can be identified by the expression of genes required for self renewal AND by the lack of expression of genes that suppress self renewal. The specific components of self renewal pathways in normal and malignant colon and mammary gland stem cells will be discussed. Stem cell pathways contribute to minimal residual disease after cancer therapy will be discussed. Finally, the application of stem cell biology to cancer therapy will be described. Approximately 4-7% of stage 2 colon cancers consist of homogeneous populations of undiffentiated CDX2- cancer cells. Stage 2 colon cancer patients are generally not thought to benefit from adjuvant chemotherapy. However, stage 2 colon cancer patients with CDX 2- cancer do appear to benefit.
Citation Format: Michael F. Clarke. Solid tumor cancer stem cells: From bench to bedside [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 SY17-02.
Abstract SY18-03: Single cells and therapy resistance in cancer
Authors: Raj Arjun 
Published: August 2019

Abstract
Cancer is a disease that originates from single cells, and the treatment of cancer also is a problem of single cells: anti-cancer therapies can often kill the vast majority of tumor cells but a few rare cells remain and grow despite treatment. Often, it is thought that the underlying basis for the behavior of these rare cells is a genetic difference. However, we and others have shown that non-genetic differences may be a key driver of rare, drug resistant cells, yet the precise molecular nature of these differences often remains mysterious. We here describe the development of a cellular “time machine” that allows us to link the ultimate cellular fate to the initial cellular state on a single cell basis, thus revealing markers for pre-resistant cells in the population. Further, we use genetic screening technologies to elucidate the pathways that control the formation of these rare cells and discuss their therapeutic implications.
Citation Format: Arjun Raj. Single cells and therapy resistance in cancer [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 SY18-03.
Abstract SY20-02: The SIRT3-MnSOD-Ac axis in carcinogenesis and tumor resistance
Authors: Gius David R. , Zhu Yueming 
Published: August 2019

Abstract
ABSTRACT The molecular mechanism by which acetylation regulates manganese superoxide dismutase (MnSOD) activity, and its oncogenic and/or physiological significance, is unclear. Here we show that expression of the MnSOD-K68 acetylation (Ac) mimic mutant (MnSODK68Q) transformed wild-type primary mouse embryonic fibroblasts (pMEFs) when co-infected with either c-Myc or Ras, as measured by in vitro transformation assays and xenograft formation. Immortalized MnSOD-/- mouse embryonic fibroblasts (MEFs) infected with lenti-MnSODK68Q also exhibited an in vitro transformation permissive phenotype. In addition, MCF7 and T47D cells expressing MnSODK68Q demonstrated increased in vitro and xenograft oncogenic properties. These findings collectively identify MnSODK68Q as a tumor promoter. MCF7, T47D, and MnSOD-/- cells expressing MnSODK68Q displayed a monomeric form of MnSOD, distinct from the well-established homotetramer, and MnSOD-K68-Ac functions as a peroxidase, determined using a bacterial system for site-specific incorporation of N-(ε)-acetyl-l-lysine. Finally, tamoxifen resistant MCF7 and T47D cells, and a subgroup of human breast malignancies, displayed a MnSOD-K68-Ac signature.
Citation Format: David R. Gius, Yueming Zhu. The SIRT3-MnSOD-Ac axis in carcinogenesis and tumor resistance [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 SY20-02.
Abstract SY23-02: Actions of the EMT Program in fostering malignant progression
Authors: Weinberg Robert A. 
Published: August 2019

Abstract
The cell-biological program commonly termed the epithelial-mesenchymal transition (EMT) confers a variety of distinct traits on epithelial cells that express it, including many that enable primary carcinoma cells to complete most of the steps of the invasion-metastasis cascade. Among other traits, it confers increased resistance to various forms of therapy and a stem-cell phenotype, which appears to be tightly linked to tumor-initiating ability. In addition, mammary carcinoma cells expressing an EMT program show a reduced susceptibility to elimination by anti-CTLA4 checkpoint blockade relative to their more mesenchymal counterparts. Carcinoma cells rarely if ever execute a complete EMT program but instead venture only partway toward the mesenchymal state, resulting in cells that co-express both epithelial and mesenchymal traits. Moreover, tumor-initiating cells appear to co-express both epithelial and mesenchymal traits, indicating that cells that have moved too far into the mesenchymal state actually lose stemness and thus tumor-initiating powers.
Citation Format: Robert A. Weinberg. Actions of the EMT Program in fostering malignant 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 SY23-02.