bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 232: The abscopal effect: modelling and predicting the effect of radiation therapy on non-irradiated tumour when combined with immune checkpoint blockers
Authors: Brightman Frances , Ortega Fernando , Orrell David , Chassagnole Christophe 
Published: July 2021

Abstract
We have developed preclinical and clinical ‘Virtual Tumour' (‘VT') models that can predict how a tumour will respond to drug exposure. This agent-based method is particularly suitable for modelling not only tumour cells, but also those involved in the immune response, and interactions between cells (1-3). The purpose of the study was to extend the VT platform to be able to model simultaneously i) the response of a tumour treated with radiation only or in combination with immune-checkpoint blockers, ii) the tumour response in areas where radiation has not been performed in the absence/presence of an immune-checkpoint blocker. Building on previous work, in which the VT platform was extended by the addition of a module that captures the synergistic of PD(L)-1 blockade with conventional anticancer therapies, we have further expanded the model to integrate the immune-checkpoint blocker module with other immune species activated by irradiation of the target tumour - in particular circulating CD8+ T cells - in order to be able to mimic the systemic abscopal effect. Ultimately, this expansion enables us to simulate the effect of tumour growth control on out-of-field tumour lesions when delivered in combination with an immune-checkpoint blocker. Through preclinical case studies derived from the literature (4) we demonstrate that the extended VT can be applied to simulate the efficacy of diverse radiation regimens in combination with immune-checkpoint blockers, and correctly describe the combination treatment effect on the progression of irradiated and non-irradiated tumours. Furthermore, we demonstrate that the model can be applied to optimize the timing of the combination in order to maximize the systemic efficacy of the treatment. Our enhanced VT capability represents a key step towards a strategic tool for optimizing dosing and scheduling of immune-checkpoint block and radiation combinations. [1] Brightman, FA et al., Abstract 680. Cancer Res 75, 4866-66 (2015). [2] Ortega, F et al., Abstract 4866. Cancer Res 79, (13 Suppl) (2019). [3] Orrell, DA et al., Abstract 4918. Cancer Res 71, (8 Suppl) (2011). [4] Dovedi, S et al., Clin Cancer Res 23(18); 5514-26 (2017).
Citation Format: Frances Brightman, Fernando Ortega, David Orrell, Christophe Chassagnole. The abscopal effect: modelling and predicting the effect of radiation therapy on non-irradiated tumour when combined with immune checkpoint blockers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 232.
Abstract 2321: Comprehensive metabolic profiling of high MYC medulloblastoma revealed key differences between in vitro and in vivo in glucose and glutamine usage
Authors: Pham Khoa Dang , Poore Bradley , Hanaford Allison , Maxwell Micah J. , Sweeney Heather , Parthasarathy Akhila , Alt Jesse , Rais Rana , Slusher Barbara S. , Eberhart Charles G. , Raabe Eric H. 
Published: July 2021

Abstract
Medulloblastoma is the most common malignant brain tumor of children. Genomic amplification of MYC is a hallmark of a subset of poor-prognosis medulloblastoma. In other cancers, high-level expression of MYC increase glutamine transport and fuels the TCA cycle, supporting cell growth and proliferation. However, the metabolism of high MYC amplified medulloblastoma subgroup remains underexplored. We performed comprehensive metabolic studies of xenografts of human MYC-amplified medulloblastoma tumors. We found that glucose was the main carbon source for TCA cycle. We also found that glutaminase ii pathway was the main pathway utilizing glutamine. In orthotopic xenografts, glutathione was the most abundant upregulated metabolite in tumor compared to normal brain. Glutamine derived glutathione was synthesized through glutamine transaminase K (GTK) enzyme in vivo, and it was significantly inhibited by glutamine analog 6-diazo-5-oxo-l-norleucine (DON). We engineered a DON prodrug with higher lipophilicity (JHU395) and found that JHU395 suppressed medulloblastoma growth in vitro and induced apoptosis. A single dose of JHU395 induced apoptosis in orthotopic D425 MED tumors but not in normal cerebellum or cortex. Twice weekly 15mg/kg dosing of JHU395 significantly extended the survival of the mice with D425 MED orthotopic xenografts (p&lt;0.001 by log-rank test comparing treated vs vehicle control). Glutamine antagonists exploit MYC-amplified medulloblastoma's reliance on glutamine metabolism and may have therapeutic applications in human patients.
Citation Format: Khoa Dang Pham, Bradley Poore, Allison Hanaford, Micah J. Maxwell, Heather Sweeney, Akhila Parthasarathy, Jesse Alt, Rana Rais, Barbara S. Slusher, Charles G. Eberhart, Eric H. Raabe. Comprehensive metabolic profiling of high MYC medulloblastoma revealed key differences between in vitro and in vivo in glucose and glutamine usage [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2321.
Abstract 2325: Hypoxia-mediated ATF4 induction promotes survival in detached conditions in metastatic murine mammary cancer cells
Authors: Kiesel Violet A. , Hursting Stephen D. , Teegarden Dorothy 
Published: July 2021

Abstract
Regions of hypoxia are common in solid tumors and drive changes in gene expression that increase risk of cancer metastasis. Tumor cells must respond to the stress of hypoxia by activating genes to modify cell metabolism and antioxidant response to improve survival. The goal of the current studies was to determine the effect of hypoxia on cell metabolism and markers of oxidative stress in non-metastatic M-Wnt compared to metastatic metM-Wntlung murine mammary cancer cell lines. We show that hypoxia increased expression of genes involved in antioxidant response in metastatic compared to non-metastatic cells, including glutamate cysteine ligase catalytic and modifier subunits and malic enzyme 1. Further, hypoxia induces a greater suppression of glutamine to glutamate conversion in metastatic cells (15% in metastatic cells compared to 9% in non-metastatic cells). Interestingly, hypoxia increased the mRNA level of the transaminase glutamic pyruvic transaminase 2 (Gpt2, 7.7-fold) only in metM-Wntlung cells. The change in Gpt2 expression was accompanied by transcriptional (4.2-fold) and translational (6.5-fold) induction of the integrated stress response effector protein activating transcription factor 4 (ATF4), which mediated survival of hypoxic metastatic cells in detached conditions, as shown by genetic ATF4 depletion. These data indicate that more aggressive, metastatic cancer cells rely on metabolic reprogramming and induction of antioxidant defense, including activation of ATF4, in hypoxia for survival in detached conditions.
Citation Format: Violet A. Kiesel, Stephen D. Hursting, Dorothy Teegarden. Hypoxia-mediated ATF4 induction promotes survival in detached conditions in metastatic murine mammary cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2325.
Abstract 2331: Metabolic evasion of mCRPC immunotherapy by ACOD1 production of itaconate
Authors: Schofield James H. , Hawk Mark A. , Rahmy Sharif , Sheldon Ryan D. , Leimbach Casey , Sun Seunghoon , Lu Xin , Jones Russell G. , Schafer Zachary T. 
Published: July 2021

Abstract
The use of immune checkpoint blockade (ICB) therapies in the form of αPD-1 & αCTLA-4 monoclonal antibodies (mAb) have made great strides in the battle against melanoma, lung, and breast cancers. However, these strategies are not universally effective. Roadblocks occur as certain cancers cannot be targeted by these therapies or may develop resistance to ICB. How resistance to ICB therapy arises represents a crucial barrier to more effective use of these therapies. Recent studies have demonstrated that the metabolic milieu of the tumor microenvironment (TME) plays a role in regulating the anti-tumor immune response. However, the specific mechanisms by which cancer cell secreted metabolites in the TME impact the responsiveness of cancer cells to ICB remain poorly understood. In order to better understand the factors that influence the effectiveness of ICB, we utilized a mouse model (Smad4-/-/Pten-/-/Trp53-/-) of male castration resistant prostate cancer (mCRPC) that is responsive to αCTLA-4 and αPD-1 ICB. Using serial culture and injection of residual tumor cells that survive ICB, we generated cell lines that had developed resistance to ICB. Unbiased metabolomic screening of these cell lines revealed a stark increase in the production of the anti-inflammatory metabolite itaconate in the resistant cell lines. This observation was supported by the increased abundance of the enzyme responsible for itaconate production, aconitate decarboxylase 1 (ACOD1) among the resistant lines. Reduction of this enzyme through shRNA compromises the viability of ICB resistant cells but not sensitive cells. Interestingly, conditioned media from the resistant cell lines restricts the in vitro activation of naïve CD8+ T cells. Furthermore, the reduction of ACOD1 among the resistant population results in increased activation of CD8+ T cells when treated with conditioned media from these resistant cells. These observations also extend to other, more established cell lines like the Lewis lung carcinoma (LLC). Taken together, these results indicate that cancerous epithelial cell production of itaconate, through the activity of ACOD1, may represent a mechanism that antagonizes T cell activation and thus promotes ICB evasion.
Citation Format: James H. Schofield, Mark A. Hawk, Sharif Rahmy, Ryan D. Sheldon, Casey Leimbach, Seunghoon Sun, Xin Lu, Russell G. Jones, Zachary T. Schafer. Metabolic evasion of mCRPC immunotherapy by ACOD1 production of itaconate [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2331.
Abstract 2339: Halting head & neck squamous cell carcinoma progression by broadly targeting glutamine metabolic pathways
Authors: Allevato Michael , Yokoyama Yumi , Wild Robert , Gutkind Silvio 
Published: July 2021

Abstract
Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cancer worldwide, resulting in over 14,600 deaths each year in the United States alone. HNSCC is associated with human papillomavirus (HPV) infection, and tobacco use and abusive alcohol intake. Recent revolutionary immunotherapy approaches have changed the landscape of treatment options in HNSCC. However, less than 20% of HNSCC patients respond to FDA-approved anti-PD1 immune checkpoint blockade (ICB) (pembrolizumab and nivolumab), often not leading to durable responses. This highlights the unmet need to identify novel therapeutic options and biomarkers predicting more favorable response to maximize the efficacy of immune-oncology (IO) strategies for HNSCC treatment. Glutamine is a conditionally essential amino acid for rapidly proliferating cancer cells making glutamine pathway inhibition an attractive approach for anti-cancer therapy. Treatment with the glutamine antagonist (DRP-104), which irreversibly inhibits all known enzymes involved in glutamine metabolism within the tumor, resulted in metabolically halted cell growth in vitro in a large panel of cell lines (n=8) representing the spectra of HPV- and HPV+ HNSCC, with an IC50 of 0.2-25uM, Interestingly, HNSCC cells bearing genetic alterations in PIK3CA/PTEN were significantly more sensitive to glutamine antagonism in comparison to unaltered HNSCC cells. The dependence of glutamine in HNSCC growth and the increased sensitivity of PIK3CA/PTEN aberrant cells was also observed in orosphere assays and 6 distinct HNSCC tumor xenografts in NOD SCID mice. We next investigated the efficacy of glutamine suppression in the context of an intact immune system, taking advantage of new syngeneic HNSCC model system, 4MOSC and MOC1. Specifically, we recently developed orthotopic syngeneic mouse models, 4MOSC, reflecting human tobacco-related HNSCC genomic alterations and mutational landscape (Wang et al., Nature Comm 2019), while MOC1 is a DMBA-induced mouse HNSCC cell line grown in the subcutaneous flank of mice (Judd et al. Cancer Res 2011). Monotherapy administration of DRP- 104 (1.4mg/kg) was potent as a monotherapy in all three syngeneic HNSCC models. We also observed a trend of increased sensitivity when DRP-104 was combined with anti-PD-1 therapy. Our data suggest that broad glutamine antagonism using DRP-104 has therapeutic potential in HNSCC by both dismantling cancer metabolism and enhancing the anti-tumor immune response of immune checkpoint blockade. Clinical trials of DRP-104 are currently ongoing.
Citation Format: Michael Allevato, Yumi Yokoyama, Robert Wild, Silvio Gutkind. Halting head & neck squamous cell carcinoma progression by broadly targeting glutamine metabolic pathways [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2339.
Abstract 234: Risk of sepsis among patients with prostate cancer: A network-based modeling approach
Authors: Jazayeri Ali , Jafari Niusha , Yang Christopher C. , Nikita Nikita , Yao Grace Lu 
Published: July 2021

Abstract
Background: Prostate cancer (PCa) is the most common cancer among men, and sepsis is a leading cause of death in PCa, yet their association has not been quantified. This study aims to quantify the association between sepsis severity (identified as sepsis, severe sepsis, and septic shock) and prostate complications among PCa subgroups.
Methods: We used the SEER-Medicare data to identify patients diagnosed with PCa in 2010 -2015. PCa patients were classified as: localized or regional (L/R) stage and distant (D) stage and further stratified as survivors and non-survivors. Patients with no history of PCa composed the control group. Our network-based modeling approach used sepsis and prostate complications (identified using ICD codes) as network nodes. The association between complication pairs, represented as edges, were weighted by the probability of complication pairs occurring concurrently. The network densities for each subgroup were computed at different thresholds based on the weights of the edges.
Results: We identified 27,166 patients with PCa and 22,223 as controls. Increase in threshold was associated with highest decline in network density among controls followed by L/R survivors (Table). Additionally, prostate and sepsis complications co-occur more frequently among stage D than stage L/R patients. Also, stage D patients experience prostate complications with more severe sepsis conditions (severe sepsis and septic shock) than other subpopulations. The variances and medians of edges' weights among all subgroups were statistically different (p&lt;0.001).
Conclusions: This is the first population-based study using network-based modeling to quantify the association between varying degrees of sepsis severity and prostate complications among PCa subgroups. The differentiating complication pairs identified among subgroups can be used as features in machine-learning algorithms to predict the severity of patient outcomes and to improve patient prognosis.
Table: Network densities of sepsis and PCa complication pairs at different weight thresholds for each PCa subgroupsNetwork densities at various threshold weightsQuantiles of Weights in Network (Median (Q1,Q3))Threshold Levels0.0000.0100.0200.0300.040Control0.1930.0050.0030.0010.0010.005 (0.002, 0.016)Stage L\R survivors0.2410.0290.0110.0070.0050.007 (0.003, 0.021)Stage L\R non-survivors0.1580.0380.0140.0070.0040.012 (0.005, 0.029)Stage D survivors0.0840.0270.0060.0020.0010.013 (0.006, 0.032)Stage D non-survivors0.1300.0360.0170.0090.0040.012 (0.005, 0.029)
Citation Format: Ali Jazayeri, Niusha Jafari, Christopher C. Yang, Nikita Nikita, Grace Lu Yao. Risk of sepsis among patients with prostate cancer: A network-based modeling approach [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 234.
Abstract 2341: Metabolomic analysis reveals unique biochemical signatures associated with microbial dysbiosis, inflammation and energy metabolism in breast tissues of obese and nonobese black and white breast cancer patients
Authors: Starlard-Davenport Athena , Smith Alana , Tolley Elizabeth , Lu Lu 
Published: July 2021

Abstract
Black women are more likely to be diagnosed with late-stage breast cancer than white women and have the lowest probability of cause-specific survival. Obesity is associated with increased breast cancer risk and deaths in black women. Insulin-resistant obesity features chronic systemic and local inflammation of fat, which has been linked to breast cancer outcomes. The breast also consists of a mucosal immune system that provides a complex mechanical barrier and an inherent defense against pathogens. Growing evidence shows that an imbalance in the microbiome due to inflammation may give rise to cancer development. However, there is a lack of data on the role of the microbiome in breast tumors from black women. Using a global metabolomics approach, we investigated normal (n= 24) and breast cancer (n=27) tissue from black and white women to identify microbial metabolites and metabolomic signatures that differ by breast tumor subtype and obesity status. Principal component analysis and hierarchical clustering of the global metabolite profiling data revealed separation between the metabolic signatures of normal and breast tumor tissue. Random forest analysis also revealed a unique biochemical signature in normal versus breast tumors by obesity status and breast tumor subtype, including triple negative breast tumors. Our data show that obesity associates with a unique set of metabolic pathways that facilitate the handling of inflammation, protein catabolism and tissue remodeling, and energy metabolism, which may be regulated by microbial processing in breast tumor tissue.
Citation Format: Athena Starlard-Davenport, Alana Smith, Elizabeth Tolley, Lu Lu. Metabolomic analysis reveals unique biochemical signatures associated with microbial dysbiosis, inflammation and energy metabolism in breast tissues of obese and nonobese black and white breast cancer patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2341.
Abstract 2353: Metabolic reprogramming by SLC1A5 downregulation in pancreatic cancer cells
Authors: Sharma Raj Kumar , Krishnamachary Balalji , Sivakumar Ishwarya , Mironchik Yelena , Bharti Santosh Kumar , Bhujwalla Zaver M. 
Published: July 2021

Abstract
Introduction: Pancreatic cancers exhibit limited response to chemo- and radiation therapy. Identifying novel targets for pancreatic cancer treatment is important for new treatment strategies. Because pancreatic cancer cells are ‘glutamine avid' [1], targeting glutamine metabolic pathways can provide novel options for treatment. The glutamine transporter, SLC1A5, is being actively investigated as a pharmacological target in cancer [2]. Here we have engineered human pancreatic cells expressing shRNA to downregulate the glutamine transporter SLC1A5. We performed high-resolution 1H magnetic resonance spectroscopy (MRS) to understand the metabolic reprograming that occurs with SLC1A5 downregulation in these two cell lines.
Method: Panc1 and Pa04C pancreatic cancer cell lines were genetically engineered to express shRNA against SLC1A5 using lentiviral transduction. Downregulation of SLC1A5 was verified with qRTPCR and immunoblotting. Control cells expressing an empty vector (EV) were also engineered. Dual phase extraction was performed as previously described [3]. High-resolution 1H MRS was performed on the aqueous phase extracts and recorded on a 750 MHz spectrometer. All data acquisition, processing and quantification was performed with TOPSPIN 3.5 software. Spectra were obtained from Panc1EV (n=4), Pa04CEV (n=4), Panc1_SLC1A5_shRNA (n=4) and Pa04C_SLC1A5_shRNA (n=4) cells.
Results and Discussion: SLC1A5 downregulation significantly decreased the glutamine/glutamate ratio in Pa04C_SLC1A5_shRNA cells but not in Panc1_SLC1A5_shRNA cells. Instead, in Panc1_SLC1A5_shRNA cells, a significant decrease of the amino acids leucine, isoleucine, valine, tyrosine, histidine, and phenylalanine was observed. Lactate and fumarate also significantly decreased in Panc1_SLC1A5_shRNA cells. Other than the significant decrease of glutamine/glutamate in the Pa04C_SLC1A5_shRNA cells, no other significant metabolic differences were observed in these cells. Our data expand the understanding of the diverse metabolic reprogramming that occurs following SLC1A5 downregulation in two human pancreatic cancer cell lines that may lead to the development of additional metabolic targets.
Supported by NIH R01CA193365 and R35CA209960.1. Son J et al., Nature. 2013; 2. Bhutia YD et al., Biochim Biophys Acta. 2016; 3. Winnard PT Jr. et al., J Cachexia Sarcopenia Muscle. 2020.
Citation Format: Raj Kumar Sharma, Balalji Krishnamachary, Ishwarya Sivakumar, Yelena Mironchik, Santosh Kumar Bharti, Zaver M. Bhujwalla. Metabolic reprogramming by SLC1A5 downregulation in pancreatic cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2353.
Abstract 2361: The functional roles of miRNA-193a-3p in colorectal cancer
Authors: Hiraide Sakura , Takahashi Masanobu , Yoshida Yuya , Komine Keigo , Ishioka Chikashi 
Published: July 2021

Abstract
Background: Patients with BRAF-mutated colorectal cancer (CRC) have a poor prognosis despite recent therapeutic advances such as combination therapy with BRAF, MEK, and EGFR inhibitors.
Aim: Our aim was to clarify the functions of the microRNAs (miRNAs) involved in oncogenesis and sensitivity to BRAF inhibitors and MEK inhibitors in BRAF-mutated CRC.
Methods and Results: To identify miRNAs that sensitize a BRAF inhibitor dabrafenib (DAB) and a MEK inhibitor trametinib (TRA), we screened 240 miRNAs in BRAF-mutated CRC cell line RKO. Among the screened miRNAs, we tried to elucidate the novel functional roles of miR-193a-3p in CRC cell lines. We found that miR-193a-3p overexpression inhibited cell proliferation in CRC cell lines. The protein array analysis revealed that protein phosphorylation levels were altered by miR-193a-3p overexpression in various pathways such as cell-cycle-related pathways and PI3K-AKT pathways. The enhanced cytotoxicity by miR-193a-3p in addition to DAB and TRA was validated in multiple BRAF-mutated cell lines. Furthermore, the enhanced cytotoxicity by miR-193a-3p in addition to DAB and TRA was shown to be through inhibiting reactivation of MAPK signaling. This enhanced cytotoxicity by miR-193a-3p was even observed under treatment of DAB, TRA, and an anti-EGFR antibody.
Conclusions: Our study shows that miR-193a-3p regulates multiple proteins involved in oncogenesis, and proposes that the combination therapy of miR-193a-3p and BRAF/MEK inhibitors could be a promising treatment strategy in BRAF-mutated CRC.
Citation Format: Sakura Hiraide, Masanobu Takahashi, Yuya Yoshida, Keigo Komine, Chikashi Ishioka. The functional roles of miRNA-193a-3p in colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2361.