bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract LB-012: US cancer centers of excellence coordination of operational strategies contribute to enhanced accrual of racial and ethnic minorities in clinical trials
Authors: Regnante Jeanne M. , Richie Nicole A. , Fashoyin-Aje Lola , Hall Laura Lee , Highsmith Quita , Louis J'Aimee A. , Turner Kenneth , Hoover Spencer C. , Lee Simon Craddock , Williams Erin L. , Adams Homer , Obasaju Coleman , Sargeant Ify , Geday Madeline , Gandee Marianne , Watson Rayneisha , Chen Moon S. 
Published: August 2019

Abstract
Background: Racial and ethnic minority groups (REMGs) have low rates of inclusion in cancer trials. With the rise of precision medicine, it is critical that study populations in clinical research reflect the changing US demographics.
Methods: Criteria were developed to identify cancer centers able to accrue a higher than average proportion of REMGs into clinical trials. Comprehensive interviews were conducted with leaders of identified cancer centers to ascertain operational strategies contributing to enhanced accrual of REMGs.
Results: Eight representative centers reported a REMG accrual rate range in cancer research between 10-50% in a 12-month reporting period and met other criteria for inclusion, and 14 leaders participated in this assessment. Key findings were that centers: had a metric collection and reporting approach; routinely captured race and ethnicity data within databases accessible to research staff; had operational standards to support access and inclusion; developed practices to facilitate sustained patient participation during clinical trials; had strategies to decrease recruitment time and optimize clinical study design; and identified low-resource strategies for improving accrual. There was also a commitment to establish processes that support the patient’s provider as the key influencer of patient recruitment into clinical trials.
Conclusion: Conduct of cancer research requires coordination of an operational framework governed by metrics in order to achieve high accrual of diverse populations in clinical trials. Leading US cancer centers have established key Operational Excellence practices and other notable practices which are critical for optimizing sustained inclusion of diverse populations in cancer clinical research.
Citation Format: Jeanne M. Regnante, Nicole A. Richie, Lola Fashoyin-Aje, Laura Lee Hall, Quita Highsmith, J'Aimee A. Louis, Kenneth Turner, Spencer C. Hoover, Simon Craddock Lee, Erin L. Williams, Homer Adams, Coleman Obasaju, Ify Sargeant, Madeline Geday, Marianne Gandee, Rayneisha Watson, Moon S. Chen. US cancer centers of excellence coordination of operational strategies contribute to enhanced accrual of racial and ethnic minorities in clinical trials [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-012.
Abstract LB-048: WRN helicase is a synthetic lethal target in microsatellite unstable cancers
Authors: Chan Edmond M. , Shibue Tsukasa , McFarland James , Gaeta Benjamin , Vazquez Francisca , Bass Adam J. 
Published: August 2019

Abstract
Microsatellite instability (MSI), a class of genetic hypermutability that arises from impaired DNA mismatch repair (MMR), contributes to the development of many malignancies including colon, endometrial, gastric, and ovarian cancers. While immune checkpoint blockade (ICB) has been an effective therapy for many patients with MSI cancers, numerous patients with MSI malignancies do not respond to ICB or the use of these agents are limited by their toxicity. Hence, there is still a pressing need to develop further therapies against MSI cancers. One approach to develop novel therapeutics is to leverage synthetic lethality, a phenomenon whereby the simultaneous occurrence of two or more genetic events lead to cell death but one event alone does not. DNA repair processes represent attractive synthetic lethal targets since many cancers exhibit an impaired DNA repair pathway, which can lead these cancers to become dependent on specific repair proteins. The success of poly (ADP ribose) polymerase (PARP) inhibitors in homologous recombination-deficient cancers highlights the potential of this approach. Hypothesizing that other DNA repair defects would give rise to alternative synthetic lethal relationships, we asked if there are specific dependencies in MSI cancers. Here, we analyzed data from large-scale CRISPR/Cas9 and RNA interference (RNAi) functional genomic screens and found that the RecQ DNA helicase WRN was selectively essential in MSI models in vitro and in vivo, but dispensable in microsatellite stable models. WRN silencing induced double-strand DNA breaks, activated a DNA-damage response, and promoted apoptosis and cell cycle arrest preferentially in MSI models. MSI cancer models specifically required WRN’s helicase activity, but not its exonuclease activity. These findings expose WRN as a synthetic lethal vulnerability and promising drug target for MSI cancers.
Citation Format: Edmond M. Chan, Tsukasa Shibue, James McFarland, Benjamin Gaeta, Francisca Vazquez, Adam J. Bass. WRN helicase is a synthetic lethal target in microsatellite unstable cancers [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-048.
Abstract LB-060: Characterization of the immune checkpoint inhibitor response in the MC38 murine colon cancer model
Authors: Fadden Patrick , Bui Thi , Hurtado David , Davis Kelli , Belle Ian , Krontz Kathrine , Hauser Jacob , Li Na , Takayama Kyle , Sokolowski Cristina , Wood Edgar 
Published: August 2019

Abstract
Immune focused interventions remain a high priority for many drug discovery efforts, spurred on by the success of immune checkpoint therapies such as anti-PD-1, anti-PD-L1, and anti-CTLA-4 inhibitory antibodies. Preclinical efficacy assessments of novel immune-oncology therapies requires a functional immune system which limits the usefulness of traditional xenograft models and drive the use of humanized (human immune cell engrafted animals) and syngeneic model systems. Syngeneic mouse tumors are popular model systems in which to evaluate these novel therapies due the presence of fully intact mouse immune system and ease of accessibility. The MC38 mouse colon cancer model is popular for efficacy assessment studies due to its responsiveness to typical immune checkpoint inhibitors. We endeavored to characterize the immune response to checkpoint inhibitors in MC38 tumors using flow cytometry, gene expression analysis, and immunohistochemistry (IHC). Gene expression analysis provided a signature of gene changes that correlate to immune driven changes in tumor growth and may be used in preclinical pharmacodynamics studies as evidence of mode of action for other novel immune-oncology therapies. In addition, gene overrepresentation analysis highlighted the presence and involvement of B cell populations in the MC38 tumor environment which was supported by IHC data that show distinctive B cell staining in what resemble tumor associated tertiary lymph structures. These finding suggests that MC38 may provide a good model system for evaluating therapies that can modulate or impact tumor infiltrating B cell populations.
Citation Format: Patrick Fadden, Thi Bui, David Hurtado, Kelli Davis, Ian Belle, Kathrine Krontz, Jacob Hauser, Na Li, Kyle Takayama, Cristina Sokolowski, Edgar Wood. Characterization of the immune checkpoint inhibitor response in the MC38 murine colon cancer model [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-060.
Abstract LB-066: BiTE-armored CARs overcome antigen escape in EGFRvIII-targeted therapy for glioblastoma
Authors: Choi Bryan D. , Yu Xiaoling , Castano Ana P. , Bouffard Amanda A. , Curry William T. , Carter Bob S. , Maus Marcela V. 
Published: August 2019

Abstract
Glioblastoma (GBM) is a devastating disease with an extremely poor prognosis. Immune therapy with T cells engineered to express chimeric antigen receptors (CARs), represents a promising alternative to conventional therapy, but responses have been limited to date due to heterogeneous target antigen expression and the emergence of immune escape following treatment with CAR T cells directed at a single target. This was observed in clinical studies with CART-EGFRvIII, wherein EGFRvIII-targeted T cells successfully localized to the brain tumor microenvironment, but ultimately failed to prevent disease progression—with post-treatment specimens demonstrating high levels of wild-type EGFR despite reduced expression of EGFRvIII. To help address this therapeutic barrier, we developed a novel CAR construct engineered for local delivery of bispecific T-cell engagers (BiTEs) that target residual tumor. Specifically, EGFRvIII-targeted CAR T cells were engineered to secrete BiTEs against wild-type EGFR, which is not expressed in normal brain but frequently amplified in GBM, recurrent disease and other cancers. Our results demonstrate that human T cells are efficiently transduced with the dual CART.BiTE transgene, and that modified cells successfully secrete biologically active EGFR-specific BiTEs that not only redirect CAR T cells but also recruit and activate untransduced bystander T cells against wild-type EGFR. Recapitulating clinical data, EGFRvIII CAR T cells were unable to completely treat tumors with heterogenous EGFRvIII expression, leading to outgrowth of EGFRvIII-negative, EGFR-positive recurrence. Conversely, CART.BiTE cells mediated potent antitumor efficacy in the setting of heterogeneous tumors and EGFRvIII antigen loss. In these models, infusion of CART.BiTE cells yielded extended survival and cured mice with even late-stage, established intracerebral tumors, including those derived from glioma cell lines and patient-derived glioma neurosphere cultures. Unlike CAR T cells directly targeting EGFR, which caused on-target toxicity against human skin grafts in vivo, secreted BiTE-EGFR was locally effective at exceedingly low concentrations that did not mediate immune responses against healthy human tissue. These results demonstrate that CARs and BiTEs can be combined strategically to mitigate the impact of antigen heterogeneity in GBM, and also provide a unique T-cell-based delivery method for BiTEs to tumors in the brain.
Citation Format: Bryan D. Choi, Xiaoling Yu, Ana P. Castano, Amanda A. Bouffard, William T. Curry, Bob S. Carter, Marcela V. Maus. BiTE-armored CARs overcome antigen escape in EGFRvIII-targeted therapy for glioblastoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr LB-066.
Abstract LB-076: Personal neoantigen immunotherapy in hepatocellular carcinoma
Authors: Peng Sui , Peng Zhenwei , Xu Lixia , Mei Jie , Tang Longqing , Han Yanyan , Kuang Ming 
Published: August 2019

Abstract
Hepatocellular carcinoma (HCC) is one of the most common cancers and the leading causes of mortality in China with limited therapeutic options. To investigate whether neoantigens could induce tumor specific immune responses in patients with HCC, neoantigen stimulating cellular therapy (neo-MASCT) was applied after radical resection. Neo-MASCT was a cell-based immunotherapy with injections of mature dendritic cells (DCs) loaded with a peptide pool of multiple shared tumor associated antigens (TAAs) and several personalized neoantigens followed by autologous T cells stimulated by these DCs. To obtain neoantigens, fresh tumor samples were acquired immediately after biopsy or surgery for subsequently WES and RNAseq. All mutations including SNV, non-frame shift insert/deletion (Indel), and neoORF were detected by comparing NGS data from tumors to normal tissues. All neo-epitope candidates were predicted by our own proprietary algorithm MASNEO according to the patient’s HLA class I genotypes. Long neoantigen peptides containing 25-31 amino acids with higher affinities were selected for further synthesis and treatment. Peptides containing multiple neo-epitopes were preferred. Until now, eight patients had received neo-MASCT, and seven of them were tested for specific immune responses against both TAAs and neoantigens using IFNγ Elispot assay. The results showed that Neo-MASCT induced TAA-specific immune responses in five patients (5/7, 71%), and induced neoantigen-specific immune responses in six patients (6/7, 86%), respectively. One patient demonstrated specific T cell responses against all the five neoantigen peptides (5/5, 100%) after neo-MASCT treatment. The average responsive rate of neoantigens was 65% (22/34 peptides) in the six responding patients. In conclusion, our results demonstrate that neo-MASCT is well-tolerated in HCC patients and elicits immune responses against multiple tumor antigens, especially personalized neoantigens. We will continuously monitor the immune responses against neoantigens, and use the results to train and optimize our predicting algorithm. We will also evaluate the clinical benefit of neo-MASCT in further clinical trials with more patients.
Citation Format: Sui Peng, Zhenwei Peng, Lixia Xu, Jie Mei, Longqing Tang, Yanyan Han, Ming Kuang. Personal neoantigen immunotherapy in hepatocellular 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 LB-076.
Abstract LB-084: Human T-cell lymphoma invasion and metastasis 2 promotes chronic inflammation mediated tumorigenicity
Authors: Chan Ya-Lin , Lai Wei-Chung , Tsai Shaw-Jenq , Sun H. Sunny 
Published: August 2019

Abstract
Cancer development is a very complex, multi-step process with mechanisms largely unknown. Despites numerous efforts in identifying many oncogenes and tumor suppressor genes that contribute to the development of cancers, the etiology of cancer remains poorly understood. Our previous studies showed the ectopic expression of human T-Cell Lymphoma Invasion and Metastasis 2, variant b (TIAM2S) in liver cells promotes liver cancer tumorigenesis. Nevertheless, the mechanism that underlies its oncogenic effect remains unclear. This study aims to investigate the role of TIAM2S in spontaneous and carcinogen-induced tumorigenesis. We established TIAM2-overexpressing transgenic (TG) mouse lines and characterize the genotypes and phenotypes of these transgenic mice in great details. In addition, we apply azoxymethane (AOM)-induced colon cancer model to examine the tumor susceptibility in these TG mice. We found that TIAM2S expressed murine model developed chronic inflammation and resulted in high incidence of lymphocytic infiltration in various organs. Furthermore, AOM-induced colon tumor developing in younger age of TG mice compared to the WT. Through the examination of immune cells and cytokine/chemokine profiles, we found that serotonin-mediated chronic inflammation, especially IL-23+/IL-17+/CD8+ T lymphocytes were characterized in the tertiary lymphoid organs in the TG mic. Altogether, this study demonstrate that TIAM2S mediates chronic inflammation and increases the susceptibility of colon cells to environmental hit and lead to the development of colon cancer.
Citation Format: Ya-Lin Chan, Wei-Chung Lai, Shaw-Jenq Tsai, H. Sunny Sun. Human T-cell lymphoma invasion and metastasis 2 promotes chronic inflammation mediated tumorigenicity [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-084.
Abstract LB-089: Direct BAX activation effectively induces apoptosis in anaplastic thyroid cancer cells
Authors: Shanja-Grabarz Xhesika , Cristofano Francesca Di , Gavathiotis Evripidis , Cristofano Antonio Di 
Published: August 2019

Abstract
Despite recent advancements in chemotherapy and radiation, anaplastic thyroid cancer (ATC) remains an almost invariably lethal disease with an average life expectancy of 2-6 months. Current interventions, including surgery are palliative, underlining the urgent need for novel, effective approaches.
Targeting the apoptosis pathway using BH3 mimetics is effective in hematologic malignancies. However, in solid tumors, the response to these compounds is usually limited and short-lived. In addition, most ATCs have lost p53, resulting in a significant dampening of the pro-apoptotic signals deriving from chemotherapy or radiation.
We hypothesized that a small molecule that directly binds to and activates BAX, bypassing the need for upstream activating signals, might effectively induce apoptosis in ATC cells.
We used a novel activator, EGAV1, that is derived from the previously described BTSA1 molecule, and a panel of 10 ATC cell lines, representing the entire mutation spectrum observed in patients.
We generated dose-response profiles of these cell lines both in traditional 2D cell cultures and in 3D spheroid cultures, and found that EGAV1 induces prompt apoptosis in all cell lines. However, co-immunoprecipitation assays showed that EGAV1-activated BAX can still be sequestered by BCL-XL, which may reduce its efficacy.
Thus, we tested the ability of the BH3 mimetic Navitoclax (ABT-263) to increase EGAV1 efficacy by inhibiting BCL-XL and BCL2.
In fact, we found a dramatic decrease in the EGAV1 IC50 in the presence of a low dose of Navitoclax that has no effect as single agent. Also, we found that the efficacy of Navitoclax was equally amplified by a low dose of EGAV1.
Time-course analysis of caspase 3/7 activity confirmed that these compounds induce prompt apoptosis, peaking between four and eight hours after treatment.
Taken together these data suggest that there is an important therapeutic opportunity in targeting the apoptosis pathway in ATC with a BAX activator accompanied by a BH3 mimetic.
Citation Format: Xhesika Shanja-Grabarz, Francesca Di Cristofano, Evripidis Gavathiotis, Antonio Di Cristofano. Direct BAX activation effectively induces apoptosis in anaplastic thyroid cancer cells [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-089.
Abstract LB-090: Molecular and pharmacological characterization of mutant NRAS dependency in melanoma cell lines
Authors: Mehta Anita K. , Hua Kevin , Gadrey Jayant , Fuller Angelina , Singh Anurag 
Published: August 2019

Abstract
Oncogenic NRAS mutations are found in 20 percent of sporadic melanoma cases. Mutant NRAS activates the RAF/MEK/ERK mitogen-activated protein kinase (MAPK), PI3K/AKT and RAC1/PAK kinase signaling pathways, which cooperate to drive melanomagenesis. The complexity of the NRAS signaling network presents a challenge to develop effective therapeutics for NRAS mutant melanoma. Many inhibitors of NRAS-regulated signaling pathways, such as BRAF and MEK/ERK inhibitors are ineffective in this setting. Furthermore, direct NRAS inhibition is pharmacologically challenging. It is likely that combined inhibition of two or more nodes in the NRAS signaling network will be effective in treating NRASmutant melanoma. We have used whole-genome transcriptional profiling coupled with phenotypic characterization of NRAS dependency to derive an NRAS dependency gene expression signature. The signature reveals two key features: (1) NRAS dependency is associated with an kinase-regulated inflammatory gene expression program and (2) expression of the melanocyte lineage factor MITF is strongly associated with NRAS-independent cell proliferation. Based on this knowledge, we have identified combinatorial therapeutic modalities to target either NRAS-dependent or NRAS-independent melanoma subtypes. NRAS-dependent melanoma cell lines undergo apoptotic cell death upon combined inhibition of PAK kinases and Bcl2/Bcl-XL proteins. Conversely, NRAS-independent cell lines are sensitive to the apoptotic effects of combined CDK2 and ERK kinase inhibition. Notably, CDK2 is an MITF transcriptional target gene that mediates a feed-forward loop to potentiate MITF activation. Taken together, our studies highlight phenotypic variations in NRAS mutant melanomas that can be exploited to identify subtype-specific therapeutic targets for NRAS mutant melanoma.
Citation Format: Anita K. Mehta, Kevin Hua, Jayant Gadrey, Angelina Fuller, Anurag Singh. Molecular and pharmacological characterization of mutant NRAS dependency in melanoma cell lines [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-090.
Abstract LB-091: Tumor suppressor WW domain-containing oxidoreductase controls epidermal keratinocyte growth
Authors: Hsu Li-Jin 
Published: August 2019

Abstract
Human fragile WWOX gene encodes a candidate tumor suppressor WW domain-containing oxidoreductase. Ectopically overexpressed WWOX protein induces apoptosis in cancer cells and suppresses tumor growth both in vitro and in vivo. Functional suppression of WWOX by antisense mRNA, dominant negatives, and small interfering RNA protects cells from apoptosis induced by tumor necrosis factor, anticancer drugs, UV light, and ectopic p53 in vitro. Interestingly, substantial studies have revealed that progression of various cancers to a pre-metastatic stage positively correlates with upregulation of WWOX protein expression, suggesting that WWOX may act more than a tumor suppressor. In normal human epidermis, WWOX is abundant in proliferating epithelial cells of the skin, and its expression is increased in intensity toward the superficial layers. In this study, we determined a reduced number of Ki67-positive proliferating keratinocytes in the epidermis of our newly developed Wwox gene knockout (Wwox-/-) mice. A marked reduction in the basal (K5-positive) and suprabasal (K10-positive) keratinocyte numbers was examined in the keratinized squamous epithelium of the Wwox-/- mouse skin. Apparent decreases in Wwox-/- epidermal and dermal thickness were found. To further verify whether WWOX regulates keratinocyte growth, we detected significantly decreased cell proliferation in both Wwox-/- primary keratinocyte cultures and WWOX-knockdown HaCaT cells as compared to the control cells. No significant increases in the number of TUNEL-positive cells were observed in the Wwox-/- epidermal tissues. Taken together, our results clearly demonstrated a crucial role of tumor suppressor WWOX in regulating normal keratinocyte proliferation for maintaining skin homeostasis.
Note: This abstract was not presented at the meeting.
Citation Format: Li-Jin Hsu. Tumor suppressor WW domain-containing oxidoreductase controls epidermal keratinocyte growth [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-091.