bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2809: Role of c-Met in the development and progression of Tpl2-related skin cancer
Authors: Bonan Nicole F. , Kowalski David , Kudlac Kaitlin , Falkenberg Lauren G. , Maradiaga Erik , Flaherty Kira , Wiest Jonathan S. , DeCicco-Skinner Katie L. 
Published: July 2017

Abstract
Cutaneous squamous cell carcinoma (cSCC), a form of non-melanoma skin cancer, is the second most common form of cancer in the United States, with over one million cases diagnosed annually. Tpl2 (MAP3K8) is a serine threonine protein kinase in the mitogen-activated protein kinase (MAPK) signal transduction cascade. Tpl2 was identified by our laboratory as having a tumor suppressive function in skin carcinogenesis, with Tpl2 knockout mice developing significantly more papillomas and squamous cell carcinomas than matched wildtype (WT) controls. Cellular mesenchymal to epithelial transition factor (c-Met) is a receptor heightened in malignant skin cancers and involved in Tpl2 signaling. When bound to its ligand, hepatocyte growth factor (HGF), c-Met can regulate cell proliferation, survival, angiogenesis and invasion. The aim of this study was to ascertain whether c-Met signaling contributes to the heightened skin tumorigenesis in Tpl2-/- mice. Forty-four WT and Tpl2 -/- mice were subjected to a two-stage chemical carcinogenesis protocol for one year to induce skin tumors. Starting at the time of promotion, half of the WT and Tpl2 -/- mice were placed on normal diet and half received diet plus 30mg/kg Capmatinib, a pharmacological inihibitor of c-Met. This diet continued for the duration of the study. No adverse health effects were found in Capmatinib-treated mice. Similar to what we previously reported, Tpl2 -/- mice developed tumors earlier than WT controls and had statistically higher tumor incidence and overall tumor burden than WT mice. The number of tumor bearing Tpl2 -/- and Tpl2 -/- + Capmatinib fed mice was similar, although Capmatinib fed mice had a 60% reduction in overall tumor burden. Studies are underway to determine if Capmatinib affected the frequency of malignant conversion in Tpl2 -/- mice. In summary, our studies demonstrate that heightened c-Met signaling contributes to the higher tumor formation in Tpl2-/- mice and should be evaluated further as a possible therapeutic target in Tpl2-related skin cancers.
Citation Format: Nicole F. Bonan, David Kowalski, Kaitlin Kudlac, Lauren G. Falkenberg, Erik Maradiaga, Kira Flaherty, Jonathan S. Wiest, Katie L. DeCicco-Skinner. Role of c-Met in the development and progression of Tpl2-related skin cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2809. doi:10.1158/1538-7445.AM2017-2809
Abstract 2811: Comparative study of anti-PD1 and CSF1R inhibition on tumor-infiltrating lymphocytes and macrophage populations across a panel of syngeneic tumor models
Authors: Maves Yuki Kato , Izadi Hooman , Talaoc Elvira C. , Yan Deborah , Echegaray Charlene , Calinisan Andrew , Moya Krystal , Venant Heather , Garland Mitchell , Iyer Radhika , Gosh Shounak , Songco Stephanie , Thatte Jayant , Broudy Tommy 
Published: July 2017

Abstract
Immunotherapy represents an extremely promising treatment approach for cancer patients. The success in this field has been signified by multiple recent approvals of checkpoint inhibitors across a range of cancer types. Subsequently, there is an increasing need to understand why certain patients and diseases benefit from these treatments while others do not, as well as how to maximize the benefits from these treatments.
To address some of these questions, we used an in vivo screening platform, MuScreen, which allows for evaluation of multiple syngeneic models and treatment modalities.We have characterized baseline and treated tumor immune infiltrates for a panel of syngeneic models using flow cytometry. The correlation between responsiveness and effects of checkpoint inhibitors (e.g., anti-PD-1), and macrophage targeted agents (e.g., CSF1R inhibition) on immune infiltrates including tumor-associated macrophages (TAMs) were investigated in 6 syngeneic models. Furthermore, M1/M2 polarization of macrophages was investigated to explore the potential role of these cells in establishing an immunosuppressed tumor microenvironment that may affect response to therapy.
Here, we show that the baseline immune cell population varies across models, and that immune checkpoint inhibitors and macrophage-targeted agents had variable efficacy across different tumor models. We also present the correlation of immune cell infiltration, including tumor infiltrating lymphocytes (TILs), TAMs, and responsiveness to immunotherapy intervention.
Having an in-depth understanding of the immune make up of a model in which an immunomodulatory compound is screened is paramount for successful translation into the clinic. A well-characterized and fully profiled panel of syngeneic models such as the MuScreen platform allows for finding the right model for screening test compounds to be used alone or in combination with immunotherapy.
Citation Format: Yuki Kato Maves, Hooman Izadi, Elvira C. Talaoc, Deborah Yan, Charlene Echegaray, Andrew Calinisan, Krystal Moya, Heather Venant, Mitchell Garland, Radhika Iyer, Shounak Gosh, Stephanie Songco, Jayant Thatte, Tommy Broudy. Comparative study of anti-PD1 and CSF1R inhibition on tumor-infiltrating lymphocytes and macrophage populations across a panel of syngeneic tumor models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2811. doi:10.1158/1538-7445.AM2017-2811
Abstract 2853: Imaging tumor metabolism to guide treatment of breast cancer with drugs targeted at PI3K alpha
Authors: Ros Susana , D'Santos Paula , Hu De-en , Batra Ankita S. , Wright Alan J. , Mannion Elizabeth , Bruna Alejandra , Caldas Carlos , Brindle Kevin M. 
Published: July 2017

Abstract
PI3KCA (which encodes the phosphoinositide-3 kinase alpha isoform) is the most frequently mutated oncogene in breast cancer. Recently, several alpha isoform-specific PI3K inhibitors have been developed and have entered into early-phase clinical trials. However, intrinsic and acquired resistance limits their utility. Non-invasive imaging methods could be used to guide treatment by not only allowing selection of the most effective drug in individual patients, but also by detecting intrinsic and acquired resistance.
We have been evaluating the effectiveness of a selective PI3K alpha inhibitor, Taselisib (GDC-0032 Genentech S.A.), by monitoring the rate of [1-13C]lactate production after injection of hyperpolarized [1-13C]pyruvate in cell lines and patient-derived xenografts (PDX) models of breast cancer using 13C magnetic resonance spectroscopic imaging. Hyperpolarization of the 13C nucleus increases its sensitivity to detection in the MR experiment by 104 - 105x, thus allowing real time imaging of tumor metabolism. Preliminary data suggest that labeled lactate production can distinguish sensitive and resistant breast cancer models to Taselisib a few days after treatment. We are currently broadening the panel of PDXs analyzed and also including genetically engineered mechanistic-models of drug resistance.
The present study highlights the effectiveness of hyperpolarized 13C spectroscopy/spectroscopic imaging for detecting early response or resistance to next generation PI3K inhibitors. This clinically applicable technique can provide insights into in vivo response in real-time and identify new strategies to increase the efficacy of therapy in individual patients.
Citation Format: Susana Ros, Paula D'Santos, De-en Hu, Ankita S. Batra, Alan J. Wright, Elizabeth Mannion, Alejandra Bruna, Carlos Caldas, Kevin M. Brindle. Imaging tumor metabolism to guide treatment of breast cancer with drugs targeted at PI3K alpha [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2853. doi:10.1158/1538-7445.AM2017-2853
Abstract 2886: CD44/SMURF1 signaling maintains cancer stem cell-like invasive cells in head and neck squamous cell carcinoma
Authors: Khammanivong Ali , Gopalakrishnan Raj , Dickerson Erin B. 
Published: July 2017

Abstract
Head and neck squamous cell carcinoma (HNSCC) is highly invasive and resistant to therapies, where treatments often result in high rates of failure and disease recurrence. A subpopulation of tumor-initiating cancer stem cells (CSC) is thought to be responsible for metastatic invasion and drug resistance in many types of cancer, including HNSCC. CD44 is a known CSC marker in HNSCC but its role in maintaining CSC populations is not well understood. We previously reported that SMAD specific E3 ubiquitin protein ligase 1 (SMURF1) inhibition of bone morphogenetic protein (BMP) signaling is essential for maintaining a CD44-high CSC-like population in HNSCC. In this study, we sought to determine how CD44, a receptor for hyaluronic acid (HA) that constitutes a major component of the tumor stroma, is involved in the regulation of SMURF1 and the maintenance of a HNSCC CSC phenotype. CSC-like cells were enriched from HNSCC cell lines as CD44-high cells. CD44 signaling was stimulated by exogenous HA treatment and inhibited by CD44 knockout (KO) using an inducible CRISPR/Cas9 system. We then assessed changes in SMURF1 protein level, BMP signaling, transwell migration, Matrigel colony formation, and invasion through three-dimensional organotypic culture (OTC) following CD44 modulation. CD44-high cells were found to have increased extracellular HA production. Treatment with exogenous HA reduced BMP signaling, as determined by a reduction in phospho-SMAD1/5/8 levels, and increased transwell migration of CD44-high cells. CD44-KO reduced SMURF1 protein expression and inhibited Matrigel colony formation of an invasive and recurrent HNSCC-derived CD44-high cells but only partially reduced colony formation of a less-invasive cell line derived from a primary HNSCC. Knockout of CD44 expression showed a slight reduction in transwell migration of invasive cells. CD44-high cells also recapitulated an invasive and CSC-like growth pattern in OTC assays. In contrast, CD44-KO inhibited OTC invasion and the epithelial-to-mesenchymal transition (EMT) phenotype, resulting in increased apical epithelial growth and differentiation. CD44 reconstitution appeared to restore the invasive and EMT phenotype. Based on our current findings, CD44 may be crucial for maintaining an anchorage-independent and invasive phenotype of HNSCC but plays a minor role in carcinoma cell migration.
Citation Format: Ali Khammanivong, Raj Gopalakrishnan, Erin B. Dickerson. CD44/SMURF1 signaling maintains cancer stem cell-like invasive cells in head and neck squamous cell carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2886. doi:10.1158/1538-7445.AM2017-2886
Abstract 290: A novel function of HGF in the activation of Chk1 phosphorylation in colon cancer cells
Authors: Song Na , Che Xiaofang , Qu Xiujuan , Xu Lu , Hou Kezuo , Liu Yunpeng 
Published: July 2017

Abstract
ATR/Chk1 pathway plays an essential role in modulation of DNA damage response (DDR) and homologous recombination (HR). Particularly, Chk1 phosphorylation is involved in cancer prognosis and therapeutic resistance. Although some receptor tyrosine kinases (RTKs) participate in the regulation of Chk1 phosphorylation, the effect of hepatocyte growth factor (HGF) on Chk1 phosphorylation is unknown. In the present study, Western blotting and subcellular fractionation were performed to identify the expression and the location of Chk1 phosphorylation in the presence of HGF. With small interfering RNA transfections, co-immunoprecipitations were performed to detect the interaction between TopBP1 and ATR complex. Our results demonstrated that HGF moderately activated Chk1 phosphorylation in colon cancer cells via upregulation of TopBP1, RAD51, and complex formation of TopBP1 and ATR. Furthermore, AKT activation promoted by HGF served as an important intermediator linking HGF/MET signaling and Chk1 phosphorylation. Depletion of AKT activity attenuated expression of basal line p-Chk1 and induced Chk1 activation due to HGF stimulation. Meantime, activation of AKT directly regulated expression of TopBP1 and RAD51. Suppression of AKT restored HGF-induced upregulation of TopBP1, RAD51, and enhancement of TopBP1/ATR complex as well. Our studies showed that HGF was implicated in regulating Chk1 phosphorylation and further demonstrated that AKT activity was responsible for HGF-induced Chk1 phosphorylation, which might potentially result in management of prognosis and therapeutic sensitivity in cancer therapy.
Note: This abstract was not presented at the meeting.
Citation Format: Na Song, Xiaofang Che, Xiujuan Qu, Lu Xu, Kezuo Hou, Yunpeng Liu. A novel function of HGF in the activation of Chk1 phosphorylation in colon cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 290. doi:10.1158/1538-7445.AM2017-290
Abstract 2940: TH17: mediators of metastatic growth acceleration after surgery
Authors: Sud Vikas , Tohme Samer , Windt Dirk J. van der , Huang Hai , Tsung Allan 
Published: July 2017

Abstract
Surgery is known to accelerate the growth and progression of metastases in patients undergoing oncological resections with 50-60% patients having recurrent metastasis after resection making it a major reason for treatment failure. This impedes the efficacy of adjuvant chemotherapy and overall prognosis of the patient. Studies have proved that inflammatory cascade initiated by surgery that increases metastatic growth and progression is mediated through a specific mechanism of neutrophil cell death called Neutrophil Extracellular Traps (NETs). We investigated the mechanism of how NET formation after surgical stress increases metastatic growth by influencing a pro-tumor microenvironment in order to specifically identify targets for perioperative therapy to keep metastases dormant and improve the effect of chemotherapy and overall prognosis. 12 week old male C57BL/6J mice (WT) and mice in which NET formation was inhibited, ie, WT mice injected with DNAse and global homozygous knockout of peptidyl arginine deaminase 4 (PAD4), an essential nuclear protein for NET formation, underwent splenic injection of 100,000 cells of the murine colorectal cancer cell line, MC-38, followed with either 70% hepatic ischemia-reperfusion (IR) for 60 minutes after 7 days or no IR. Livers were harvested at multiple time points and assessed for changes in both innate and adaptive immune cell populations by flow cytometry. On gross examination, the livers of the NET deficient mice had fewer tumors as compared to the WT mice. Mice, which underwent IR after tumor cell injection in both groups showed an increase in nodules formation versus those with just tumor cell injection, however were still more in WT than NET deficient mice. Flow cytometry revealed a decrease in both TH17 (0.36% of T cells in no IR mice vs 0.0036% in IR mice) and CD8 cells (71% of T cells in no IR mice vs 34.8% in IR mice) in mice subjected to IR versus those with only tumor injection. We found that increased tumors after surgical stress, which were mediated by NET formation, were caused due to a decrease in anti-tumor activity of CD8 cells regulated via TH17 cells. If controlled in the perioperative period, it may reduce acceleration in metastatic foci and improve the overall prognosis. We are further investigating the mechanism of NETs influencing the tumor immune environment.
Citation Format: Vikas Sud, Samer Tohme, Dirk J. van der Windt, Hai Huang, Allan Tsung. TH17: mediators of metastatic growth acceleration after surgery [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2940. doi:10.1158/1538-7445.AM2017-2940
Abstract 2956: Chemical library screen identifies compounds that target S100A8/S100A9 complex and MDSC accumulation
Authors: Lee Eunmi , Ouzounova Maria , Piranlioglu Raziye , Andaloussi Abdeljabar El , Arbag Sena , Zhou Gang , Korkaya Hasan 
Published: July 2017

Abstract
We previously demonstrated that MDSC subsets accumulated in primary tumor and distant organs regulate tumor plasticity. The mouse transcriptome analysis of in vitro co-cultures and samples from syngeneic mouse model revealed that granulocytic subset of myeloid-derived suppressor cells (gMDSCs) from metastatic 4T1 tumor bearing mice regulate several hundred genes in tumor cells upon co-culture. The top genes are S100A8, S100A9, MMP8, FPR1, CCL3, and TGFβ2 which also predicted poor survival in human solid tumors including breast cancer. Therefore, we called these 6 genes as “metastatic gene signature”. It has been reported that S100A8/S100A9 heterotetramer, called calprotectin, play a key role in inflammation-associated cancer progression. To investigate the role of calprotectin (S100A8/A9) in tumor-mediated immunosuppression and metastasis, we first utilized Tasquinimod, a small molecule targeting S100A9 only. However, Tasquinimod treatment of 4T1 tumor-bearing mice had a moderate anti-tumor activity which may be due to a limited activity on granulocytic MDSC accumulation. In addition, we determined that there was a significant upregulation of S100A8 in MDSCs from Tasquinimod treated mice. This data suggested that inhibiting only S100A9 leads to activation of S100A8 and thus may be ineffective targeting of MDSCs. We therefore run a computational screen of the NCI chemical library against the crystal structure of calprotectin (S100A8/S100A9) and identified 40 lead compounds. We then performed in vitro screening assay to identify compounds that inhibit MDSC induction. We identified 3 compounds that significantly suppressed gMDSC differentiation. We are currently performing in vivo studies with these 3 candidate drugs in our murine breast cancer model and will present our findings at the AACR meeting. We believe that this study will provide a novel drug targeting S100A8/S100A9 heterotetramer, a key molecule in MDSC induction and its regulatory functions during tumor progression.
Citation Format: Eunmi Lee, Maria Ouzounova, Raziye Piranlioglu, Abdeljabar El Andaloussi, Sena Arbag, Gang Zhou, Hasan Korkaya. Chemical library screen identifies compounds that target S100A8/S100A9 complex and MDSC accumulation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2956. doi:10.1158/1538-7445.AM2017-2956
Abstract 2960: Adipocytes sequester and metabolize daunorubicin
Authors: Sheng Xia , Parmentier Jean-Hugues , Tucci Jonathan , Pei Hua , Cortez-Toledo Omar , Dieli-Conwright Christina , Oberley Matthew , Neely Michael , Orgel Etan , Louie Stan , Mittelman Steven D. 
Published: July 2017

Abstract
Obesity is associated with poorer outcome from many cancers, including childhood acute lymphoblastic leukemia (ALL). We have previously shown that adipocytes protect ALL cells from the anthracycline, daunorubicin (DNR). We therefore investigated whether adipocytes sequester and/or metabolize DNR in the ALL microenvironment. Using fluorescence and LC/MS measures, we demonstrated that adipocytes absorb DNR, reducing the intracellular DNR concentration in co-cultured BV173 ALL cells (after 48 hours, median fluorescent intensity of ALL cultured with adipocytes was 1.7±1.0 vs. 5.0±1.7 of those cultured alone, p&lt;0.01). Mouse adipocytes convert DNR to the less active metabolite, daunorubicinol (DNR-ol); over 48 hours, media DNR decreased to 0.1±0.2 (vs. 24.8±8.76 ng/mL in control wells). At the same time, DNR-ol increased to 15.0±1.9 (vs. 0.7±0.6 in control wells; both p&lt;0.05). Similar conversion of DNR to DNR-ol was observed in both mouse adipose explants and human adipose tissue biopsy samples ex vivo. qPCR confirmed human subcutaneous adipose tissue expresses several enzymes capable of metabolizing DNR, including AKR1A1, 1B1, 1C1, 1C2, 1C3, 7A2, and CBR1 and 3 (expression ranged between 20 and 195% β-actin). Using immunohistochemistry, we confirmed expression of AKR1C1, 1C2, and 1C3 in bone marrow adipocytes of children during the first month of treatment for ALL. Finally, two hours after an intravenous dose of DNR in mice, we found that the DNR-ol to DNR ratio was higher in subcutaneous (0.60±0.26) and omental (0.55±0.21) adipose than in white blood cells (0.16±0.11), bone marrow (undetectable DNR-ol), and spleen (undetectable DNR-ol). Together, these data demonstrate that adipocytes sequester and inactivate DNR, likely due to their expression of AKR and CBR enzymes. These findings uncover a novel and important mechanism which could promote local anthracycline resistance by cancer cells in microenvironment rich in adipocytes, such as bone marrow, omentum, and breast.
Citation Format: Xia Sheng, Jean-Hugues Parmentier, Jonathan Tucci, Hua Pei, Omar Cortez-Toledo, Christina Dieli-Conwright, Matthew Oberley, Michael Neely, Etan Orgel, Stan Louie, Steven D. Mittelman. Adipocytes sequester and metabolize daunorubicin [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2960. doi:10.1158/1538-7445.AM2017-2960