bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3744: Repurposing the neuroprotective agent dimethyl fumarate against white matter damage and cognitive decline after radiotherapy
Authors: Taraboletti Alexandra , Fornace Albert J. 
Published: August 2019

Abstract
Radiation therapy (RT) is a critical tool for the treatment of metastatic brain tumors, most commonly glioblastoma multiforme (GBM), however, patients can have significant cognitive impairment due to the exposure to ionizing radiation. Up to 50%-90% of adult patients that survive these brain tumors will develop radiation-induced cognitive dysfunction within 3-6 months. Brain injury from IR is characterized by white matter damage from the loss of myelin-producing oligodendrocyte cells, subsequent demyelination, and vascular inflammation. While neuro-oncology outcomes are often concerned with survival, strategies to ameliorate and understand radiation-induced demyelination after IR treatment are needed to preserve and improve patient quality of life (QOL). Here we investigate the ability of dimethyl fumarate (DMF), an established neuroprotective agent, to amend damage and demyelination caused by RT in oligodendrocyte cells versus glioma cells. Our in vitro study confirms that DMF acts opposingly in each cell type at lower doses (10 nM), but proves toxic in both the tumor and normal model at high concentrations (100 µM). DMF also increased survival rates in oligodendrocytes after radiation. Using metabolomics, we also noted that oligodendrocyte cells upregulated TCA cycle intermediates in response to DMF treatment with RT. This work provides a basis for in vivo dosing and timing strategies using DMF to cause cessation of ROS-driven oligodendrocyte loss and inflammation after RT. Ultimately, DMF is a promising therapy that could be used to ameliorate radiation-induced demyelination, promoting patient QOL.
Citation Format: Alexandra Taraboletti, Albert J. Fornace. Repurposing the neuroprotective agent dimethyl fumarate against white matter damage and cognitive decline after radiotherapy [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 3744.
Abstract 3745: Mechanisms of HIF2-mediated small intestine radioprotection
Authors: Garcia Carolina J. Garcia , Govindaraju Suman , Bonilla Marimar de la Cruz , Taniguchi Cullen M. 
Published: August 2019

Abstract
Pancreatic cancer is the fourth-leading cause of cancer-related deaths in the United States, and it is projected to become the second by 2030. The 5-year overall survival rate for locally advanced pancreatic cancer (LAPC) remains &lt; 5%. Chemotherapy regimens often fail due to poor drug delivery and penetration into the tumor. Because surgery is not feasible by definition in LAPC, radiation therapy (RT) is the only option to achieve local control. However, irradiating the pancreas is challenging because potentially curative doses are limited by the neighboring small intestine, which can only tolerate a maximum of 50Gy. A selective radioprotector of the intestinal tract could allow pancreatic cancer patients to receive a higher, and potentially definitive, dose of radiation by increasing the duodenum’s tolerance to survive radiation injury. The EGLN prolyl hydroxylases are cellular oxygen sensors that regulate cell survival and metabolism through the degradation of hypoxia-inducible factors (HIFs) in the presence of oxygen. Our group has shown that HIF2 stabilization through genetic or pharmacologic inhibition of the EGLN family prevents death from radiation-induced gastrointestinal toxicity in mice without protecting the primary tumor. To understand the mechanism by which HIF2 mediates this protection, we generated intestinal organoids from mice with a Cre-inducible allele that expresses a non-degradable form of human HIF1 or HIF2. Whole transcriptomic analysis revealed HIF1 and HIF2 have distinct gene responses in the small intestinal crypt. HIF2 induced the expression of known radiation modulators and genes involved in oxidative damage response, tissue healing, and intestinal homeostasis such as the non-canonical Wnt5a. We validated HIF2 drives Wnt5a expression in multiple organoid model systems. We then generated knockouts (KO) of Wnt5a or Ror2, its cognate receptor, using the Cre/lox system to test if Wnt5a is necessary and sufficient for radioprotection. By using the spheroid formation assay, a modified clonogenic assay, we found Wnt5a KO organoids had decreased crypt regeneration following RT. Our preliminary data suggest Wnt5a protects the duodenum from RT by increasing intestinal stem cell survival.
Citation Format: Carolina J. Garcia Garcia, Suman Govindaraju, Marimar de la Cruz Bonilla, Cullen M. Taniguchi. Mechanisms of HIF2-mediated small intestine radioprotection [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 3745.
Abstract 3746: Fasting in mice enables abdominal radiation dose escalation in the setting of pancreatic cancer by mitigating small intestinal toxicity
Authors: Bonilla Marimar de la Cruz , Stemler Kristina M. , Jeter-Jones Sabrina , Fujimoto Tara N. , Molkentine Jessica , Torres Gabriela M. Asencio , Taniguchi Cullen M. , Piwnica-Worms Helen 
Published: August 2019

Abstract
Surgical resection is the only potentially curative treatment for pancreatic cancer, but only 15-20% of patients have resectable tumors. In unresectable cases, stereotactic body radiotherapy (SBRT) may be used to give tumor-directed radiotherapy (RT). Unfortunately, this can cause severe gastrointestinal (GI) toxicity due to proximity of the pancreatic head to the duodenum. Protecting the intestine from the toxic side-effects of radiation may enable dose-escalation that could achieve more effective local control of disease. We and others have previously shown that a fast of 24 hours protects mice from lethal doses of the DNA-damaging agent etoposide. In this study, we demonstrate that a 24 hour fast also protects mice from lethal doses of total-abdominal radiation. Histologic analyses using the Withers-Elkind microcolony assay show that fasting protected small intestinal (SI) stem cells from radiation damage and promoted early regeneration. To show a proof-of-principle for the use of this radioporotective maneuver in cancer therapy, we used an orthotopic model of pancreatic cancer using KPC tumor cells syngeneic to C57BL/6. Here, we show that fasting-mediated intestinal protection enabled dose escalated SBRT for treatment of these orthotopic tumors. RT with fasting-mediated radioprotection delayed tumor growth and improved survival compared to controls. Given this robust phenotype, we developed a 3D culture ex vivo assay using intestinal stem cell-enriched epithelial spheroid cultures. We modified these intestinal spheroids with a bioluminescent reporter and used these cells to develop a modified clonogenic assay for 3D culture that can be used to identify novel radioprotectors, such as a fasting mimetic. Taken together, these results suggest that fasting protects small intestinal stem cells, allowing animals to receive potentially curative doses of abdominal radiation that would otherwise be lethal. Future work will aim to identifying the mechanisms by which fasting confers intestinal protection and drug candidates that can be used to mimic this fasting-mediated protection.
Citation Format: Marimar de la Cruz Bonilla, Kristina M. Stemler, Sabrina Jeter-Jones, Tara N. Fujimoto, Jessica Molkentine, Gabriela M. Asencio Torres, Cullen M. Taniguchi, Helen Piwnica-Worms. Fasting in mice enables abdominal radiation dose escalation in the setting of pancreatic cancer by mitigating small intestinal toxicity [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 3746.
Abstract 3758: Targeting ovarian cancer induced peritoneal carcinomatosis by inhibition of signaling axis between Interleukin-6 (IL-6) and serine protease inhibitor Kazal type 1 (SPINK1)
Authors: Mehner Christine , Miller Erin , Coban Mathew A. , Hockla Alexandra , Radisky Derek C. , Radisky Evette S. 
Published: August 2019

Abstract
Ovarian cancer remains a challenging disease, with an average 5 year survival rate of 46%. At time of diagnosis, over 70% of patients have advanced metastatic disease, for which there are no effective treatment options. Of patients with metastatic disease, more than 70% of patients develop peritoneal carcinomatosis, making the peritoneum one of the main areas of dissemination.
We have previously found that expression of the serine protease inhibitor Kazal type 1 (SPINK1) by ovarian cancer cells drives anoikis resistance, allowing the tumor cells to circumvent apoptosis protocols and facilitating tumor cell metastasis. For this new study we focused on ovarian clear cell carcinoma (OCCC), a histotype of ovarian cancer that has particularly poor prognosis if diagnosed in late stage. Using OCCC cell lines, we found that knockdown of SPINK1 reduces cell survival and stimulates apoptotic pathways in OCCC cells, when cultured under attachment-free conditions to mimic metastatic disease. We then identified Interleukin-6 (IL-6) as an upstream regulator of SPINK1 expression and a potential therapeutic target for metastatic OCCC: we showed that IL-6 silencing reduced SPINK1 mRNA expression and cell survival, while treatment with recombinant IL-6 increased SPINK1 expression and attachment-free survival. We developed a new OCCC
mouse model and showed that knockdown of SPINK1 results in significant reduction of metastatic lesions, highlighting the impact of SPINK1 on OCCC metastasis. In ongoing studies we are testing intraperitoneal injections of FDA approved IL-6 inhibitors in a preclinical model to assess impact on abdominal dissemination of tumor cells.
By targeting the IL-6 – SPINK1 signaling axis, we aim to develop therapeutic approaches to reduce the metastatic burden and peritoneal carcinomatosis of late stage disease, resulting in better prognosis and survival of patients with ovarian clear cell carcinoma.
Citation Format: Christine Mehner, Erin Miller, Mathew A. Coban, Alexandra Hockla, Derek C. Radisky, Evette S. Radisky. Targeting ovarian cancer induced peritoneal carcinomatosis by inhibition of signaling axis between Interleukin-6 (IL-6) and serine protease inhibitor Kazal type 1 (SPINK1) [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 3758.
Abstract 376: Therapeutic role of ESR1-CCDC170 gene fusion in breast cancer endocrine resistance
Authors: Li Li , Veeraraghavan Jamunarani , Hu Yiheng , Wang Xian , Tan Ying , Schiff Rachel , Wang Xiaosong 
Published: August 2019

Abstract
Background: Gene fusions resulting from genomic rearrangements are important drivers for cancer initiation and progression. Estrogen receptor-positive (ER+) breast cancer is the most common type of breast cancer, and luminal B confers a more aggressive phenotype and higher risk of early relapse and prone to resistance to endocrine therapy. Identify new druggable genetic driver will be critical to improve clinical outcome of aggressive luminal B tumors. Our lab has identified a recurrent rearrangement between the estrogen receptor gene ESR1 and its neighbor gene CCDC170, in 6-8% of luminal B tumors. The exon 2 of ESR1 fused with the exon 6, 7, 8 or 10 of CCDC170, which enables the expression of different-sized N-terminally truncated CCDC170 (ΔCCDC170) under ESR1 promoter. Ectopic expression of ΔCCDC170 led to malignant transformation phenotypes in ER+ breast cancer cells, such as increase the cell migration, invasion and anchor-independent cell growth, as well as enhance xenograft tumor growth in mice.
Methods: The effect of ESR1-CCDC170 on endocrine resistance was examined by cologenic assay in vitro, and by xenograft mouse model in vivo. Bioinformatics approaches, Reverse Phase Protein Array (RPPA) analysis and Bimolecular Fluorescence Complementation assay were used to elucidate the potential molecular mechanism.
Results: This study aimed to determine the role of ESR1-CCDC170 in breast cancer endocrine resistance and elucidate the potential mechanisms as well as the therapeutic effect thereof. Our results show that ectopic expression of fusion variants in ER+ T47D cell line sustains the cell proliferation ability under estrogen deprivation (ED), and decreases the sensitivity to 4-OH Tamoxifen treatment. While silencing of ESR1-CCDC170 in fusion positive HCC1428 cell line increases the sensitivity to 4-OHTamoxifen and Fulvestrant treatment. Results from T47D xenograft tumor models show that ESR1-CCDC170 fusion induces endocrine resistance in vivo. Further mechanism studies show that ESR1-CCDC170 possesses a potential ATP binding pocket, has the ability to form homodimers.
Conclusion: These results demonstrate the important role of ESR1-CCDC170 fusions in breast cancer endocrine resistance, and suggest that ESR1-CCDC170 fusion could be a potential therapeutic target for the treatment of breast cancer.
Citation Format: Li Li, Jamunarani Veeraraghavan, Yiheng Hu, Xian Wang, Ying Tan, Rachel Schiff, Xiaosong Wang. Therapeutic role of ESR1-CCDC170 gene fusion in breast cancer endocrine 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 376.
Abstract 3760: Identifying site-specific disparities in the tumor microenvironment of primary and metastatic disease
Authors: Vance Krysten E. , Hollingsworth Micheal A. , Grandgenett Paul 
Published: August 2019

Abstract
The tumor microenvironment (TME), or all cellular and molecular components in and around the tumor, has a well-documented impact on cancer cell proliferation, chemoresistance, and overall patient survival. However much of the research into the TME has been limited to the primary site. How the TME of metastases compares to the primary lesions remains poorly characterized, even though metastasis is responsible for 90% of all cancer deaths. Understanding these differences is critical to treating advanced cancer patients. To study this our lab examined the TME in 22 matched sets primary pancreatic tumors and liver metastasis obtained from end-stage pancreatic cancer patients via our rapid autopsy program. We used a multiplex-immunofluorescent technique that allows staining of a single slide with up to 35 antigens and characterized the presence, position and functional statues of cells that comprise the pancreatic TME. These included: tumor cells, vasculature, fibroblasts, macrophages, mast cells, basophils, eosinophils, B cells, T cells, and NK cells, along with multiple subtypes of these. Based on our preliminary data from this, we hypothesize that the organ determines the features of the TME. Analyzing primary tumors and metastases revealed that both the composition and spatial distribution of different cell types are distinct between the primary tumor and liver metastases. PAM clustering of the cellular featured grouped primary tumor with primary and metastasis with metastatis 87% of the time. As the TME has been shown to impact chemotherapeutic response, we further examined chemotherapeutic effect between sites. Comparing gemcitabine (standard of care) and untreated patients, we observed distinct site-based responses. In the primary tumors with gemcitabine treatment there was a significant increase in inflammatory cells (neutrophils and macrophages) in comparison to untreated patients, while in the liver gemcitabine induced an increase in desmoplasia (SMA). Combined this data indicates that the distinct TME’s exist within the same patient in an organ specific manner which can impact chemotherapeutic response. Understand these differences is therapeutically critical to patients whose therapeutic strategies involve targeting the TME to improve drug delivery, modulate immune suppression or otherwise modulate the microenvironment.
Citation Format: Krysten E. Vance, Micheal A. Hollingsworth, Paul Grandgenett. Identifying site-specific disparities in the tumor microenvironment of primary and metastatic disease [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 3760.
Abstract 3763: Effect of cancer-associated fibroblasts on lymphatic vessel formation in malignant melanoma
Authors: Maeda Shusaku , Yashiro Masakazu , Motomura Hisashi , Hatano Takaharu , Fujikawa Heishiro 
Published: August 2019

Abstract
Introduction: It has been reported that cancer-associated fibroblasts (CAFs) in tumor microenvironment may play an important role for the progression and metastasis of cancer cells. Some reports suggested that CAFs may promote tumor lymphangiogenesis. In malignant melanoma, lymph node metastasis is one of important prognostic factors. Tumor lymphangiogenesis may be controlled not only by tumor cells but also tumor microenvironment such as CAFs, however no study about the interaction between CAFs and human lymphatic endothelial cells (HLECs) was found. Then, we evaluated the effect of CAFs on lymphatic vessel formation in malignant melanoma.
Materials and methods: We used CAFs, normal tissue associated fibroblasts (NAFs) established from a patient of malignant melanoma, and HLECs. Serum-free conditioned medium was obtained from NAFs (NAF-CM) or CAFs (CAFs-CM). CAFs and NAFs were cultured with or without supernatant from malignant melanoma cells. HLECs were cultured by EBM with 50% of NAF-CM or CAFs-CM. Control group was cultured with 50% EBM and 50% of serum-free medium. The effect of each CM on the proliferation of HLECs was examined by CCK assay and tube formation assay. Tube formation was assessed at 12 hours of incubation by fluorescence microscope.
Result: CAFs-CM significantly decreased the proliferation of HLECs in comparison with NAFs-CM after 48, 72 and 96 hours of incubation by CCK assay. In tube formation assay, tube length and number of tubes and junctions were also significantly shorter and smaller in CAFs group, in compared with the control and NAFs group.
Conclusion: CAFs might have a suppressive effect on HLECs, resulting in inhibition of lymphangiogenesis.
Citation Format: Shusaku Maeda, Masakazu Yashiro, Hisashi Motomura, Takaharu Hatano, Heishiro Fujikawa. Effect of cancer-associated fibroblasts on lymphatic vessel formation in malignant melanoma [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 3763.
Abstract 3777: Exploring phenotypic mosaicism in a mouse model of glioma towards understanding intratumoral heterogeneity
Authors: Hara Toshiro 
Published: August 2019

Abstract
The lethality of glioblastoma multiforme (GBM) and the failure of treatment is largely attributable to the heterogeneous properties of this cancer. We aim specifically to characterize the driving event for GBMs to acquire a heterogeneous phenotype during progression. Central to achieving this goal is the ability to interrogate possible sources of heterogeneity that guide cellular states that are similar to those identified in human patients. We therefore employ a mouse model of glioma that recapitulates the pathophysiology and gene expression signatures of human GBM. While initiated with identical oncogenic drivers, this mouse model unexpectedly displays heterogeneous phenotypes between animals. Our preliminary data using time-series single-cell transcriptomics approach shows that transformed cells, even without acquiring additional genetic alterations, switch cellular states at the beginning of tumor formation and one population commit themselves to expand to establish gliomas that are mainly comprised of one cell type. We further observe the strong association of microenvironmental cues with glioma cell populations and their roles in the state transitioning of glioma cells. Through the characterization of mechanisms that drive phenotypic mosaicism, we hope to uncover general principles that govern tumor progression and heterogeneity, and then ultimately provide novel therapeutic strategies to cure GBM.
Citation Format: Toshiro Hara. Exploring phenotypic mosaicism in a mouse model of glioma towards understanding intratumoral heterogeneity [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 3777.
Abstract 3784: Role of HPV-human fusion transcripts in oropharyngeal cancer development
Authors: Pinatti Lisa , Walline Heather , Carey Thomas 
Published: August 2019

Abstract
Human papillomavirus (HPV) genomic integration is frequently seen in oropharyngeal squamous cell carcinoma (OPSCC). Integration into cellular genes can cause the generation of HPV-host fusion transcripts, which have been associated with worse survival in OPSCC patients, but their functional consequences are unknown, as HPV alone is capable of transformation. The forced expression of fusion transcripts versus HPV transcripts in spontaneously immortalized human oral keratinocytes (NOKSI) could demonstrate their effects on cell behavior. Our research focuses on characterizing HPV integration sites and fusion transcripts in cell lines and tumors, followed by in vitro analysis of fusion transcript function. By Detection of Integrated Papillomavirus Sequences (DIPS-PCR) and RT-PCR, we have identified integration events and fusion transcripts in a subset of samples in both intergenic and genic regions of the genome. We began our analysis with a fusion transcript reading from HPV16 E6-E7-E1 into the tumor suppressor gene TP63 from UM-SCC-47. The full fusion transcript and the HPV portion only were cloned into lentiviral vectors, and stable NOKSI populations expressing these transcripts were selected. These cultures, as well as control cultures, were subjected to proliferation, migration and invasion assays. Subsequent in-depth molecular characterization and in vivo studies will help clarify their effects on cancer formation and metastasis. These studies will advance our understanding of how fusion transcripts lead to worse patient survival and help develop new therapies for these patients.
Citation Format: Lisa Pinatti, Heather Walline, Thomas Carey. Role of HPV-human fusion transcripts in oropharyngeal cancer development [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 3784.