bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3537: Pharmacologic inhibition of the glycolytic pathway improves response to immune checkpoint blockade
Authors: Verma Svena , Serganova Inna , Budhu Sadna , Dong Lauren , Ko Myat , Mangarin Levi , Merghoub Taha , Wolchok Jedd , Zappasodi Roberta 
Published: June 2022

Abstract
Preferential engagement in glycolysis is a hallmark of cancer cells and contributes to the progression and metastasis of many tumor types, including melanoma and triple-negative breast cancer (TNBC). Tumor reliance on glycolysis is emerging as a mechanism of resistance to immunotherapy, due in part to lactate-mediated immunosuppression and competition for glucose between effector T cells and tumor cells within the tumor microenvironment. Elevated serum lactate dehydrogenase (LDH) levels are associated with poor outcomes in cancer patients, and we observed that serum lactate and LDH levels correlate with primary tumor burden in mice. We recently demonstrated that genetic dampening of LDH subunit A in 4T1 TNBC results in improved and long-lasting anti-tumor responses to CTLA-4 blockade in mice. Therefore, we hypothesize that combining LDH inhibitors (LDHi) with CTLA-4 blockade will be an effective strategy to combat resistance to anti-CTLA-4 therapy. Since activated T cells rely on glycolysis, we first determined that glycolytic cancers overexpress LDH (compared with immune cells) by analyzing single-cell transcripts from patient melanoma biopsies. LDHA gene expression is significantly higher in malignant cells than infiltrating CD8+ T cells, and we replicated these findings at the protein level in whole cell lysate from B16-F10 melanoma and 4T1 TNBC tumor cells and tumor-antigen specific T cells in vitro. We show that LDHi reduces tumor lactate production and glucose consumption without inhibiting anti-tumor T-cell killing in vitro. The anti-tumor effect of LDH inhibition requires adaptive immunity, as daily treatment with LDHi results in reduced tumor burden in immunocompetent but not immune-deficient mice. Finally, we show that targeting LDH in combination with CTLA-4 blockade is more effective in slowing B16-F10 growth compared with CTLA-4 blockade alone, and that this combination promotes effector T cell activation while destabilizing regulatory T cell function.
Citation Format: Svena Verma, Inna Serganova, Sadna Budhu, Lauren Dong, Myat Ko, Levi Mangarin, Taha Merghoub, Jedd Wolchok, Roberta Zappasodi. Pharmacologic inhibition of the glycolytic pathway improves response to immune checkpoint blockade [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3537.
Abstract 3545: New hybrid molecular modalities comprised of DNA-origami and interfering peptides as inhibitors of protein-protein interactions
Authors: Roman Jessica , Carter Rachel , Luchini Alessandra , Liotta Lance , Veneziano Remi , Haymond Amanda 
Published: June 2022

Abstract
Immunotherapy has shown tremendous promise in the treatment of blood cancers; however, treatment typically fails when attempted with solid tumors, such as breast cancer. However, the cases where immunotherapies have been successful in breast cancer, the results have been remarkable: full remission of stage 4 disease has been observed. This highlights the need to elucidate how the tumor microenvironment (TME) fosters a context of molecular crosstalk that is hostile to inflammatory, anti-tumor immunological responses that present a significant roadblock to consistently successful immunotherapy. Aberrant IL-33 present in the TME is believed to be one of these major factors that drives tumor progression via its ligand, ST2, and the subsequent recruitment of IL1RAcP. This activates MyD88 cascades in dysfunctional myeloid immune cells and myeloid derived suppressor cells (MDSCs), eliciting immunosuppression that promotes tumor tolerance and subsequent disease progression. To this end, preventing IL-33/ST2 signaling activation is an attractive target to possibly manipulate immune cells to recognize and mount a response against tumor cells. Our previous work has identified 4 IL1RAcP hotspot residues of interaction between it and the ST2/IL-33 complex: R157, K238, K343, and K346. Here, we designed peptides, which mimic these hotspots and the adjacent residues that interact with the ST2/IL-33 complex. Wild type peptides inhibit trimer formation in vitro as determined by immunoprecipitation and chemical crosslinking experiments. Modifications introduced to increase rigidity and stability increased affinity in vitro and showed inhibition of downstream signaling in reporter gene cell models.
Citation Format: Jessica Roman, Rachel Carter, Alessandra Luchini, Lance Liotta, Remi Veneziano, Amanda Haymond. New hybrid molecular modalities comprised of DNA-origami and interfering peptides as inhibitors of protein-protein interactions [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3545.
Abstract 3572: Oncolytic virotherapy with the HSV-1 (VC2) vaccine strain induces anti-tumor T-cell responses in the murine 4T1 breast cancer model
Authors: Nabi Rafiq , Musarrat Farhana , Chouljenko Vladimir , Kousoulas Konstantin 
Published: June 2022

Abstract
The tumor microenvironment (TME) plays important roles in suppression of anti-tumor immune responses. Immune suppression is achieved by multiple mechanisms including interfering with antigen presentation and inhibition of effector T-cell tissue infiltration. Altering specific TME properties can reduce immune-suppression and improve anti-tumor immunity with abscopal effects. Oncolytic Virotherapy (OV) is a promising approach for cancer treatment. We evaluated the efficacy of the HSV-1 (VC2) vaccine strain for the treatment of breast cancer using the murine stage-4 (4T1) syngeneic and immunocompetent breast cancer mouse model. Following Intratumoral (IT) injection of VC2 in mice bearing implanted 4T1 tumors, treatment efficacy was evaluated by monitoring tumor weight, immune infiltration, and metastasis in the lung. Animals treated with VC2 via the IT route exhibited significantly reduced metastasis and improved intra-tumoral T-cell infiltration. Improved T-cell infiltration was not due to viral replication since improved parameters were observed during late times post VC2 treatment when no viral replication was detectable. The total area of metastasis in the lung was significantly reduced compared to control groups. VC2 treated animals via the IT route had significantly higher cytotoxic splenocytes, evident by the in-vitro killing of 4T1 cells, compared to the control group. This improved cytotoxic activity, intratumoral T-cell infiltration, and reduced metastasis in the lung suggest that IT administration of VC2 altered TME in a way that induced better antigen recognition, processing, and presentation resulting in improved anti-tumor immune responses with an abscopal effect in the lung. Further understanding of the mechanisms involved in the observed improved anti-tumor immune responses will help improve treatment efficacy and provide new approaches for the treatment of solid tumors.
Citation Format: Rafiq Nabi, Farhana Musarrat, Vladimir Chouljenko, Konstantin Kousoulas. Oncolytic virotherapy with the HSV-1 (VC2) vaccine strain induces anti-tumor T-cell responses in the murine 4T1 breast cancer model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3572.
Abstract 358: Restoring necroptosis in colorectal cancer cells to overcome chemotherapeutic resistance
Authors: Ermine Kaylee , Chen Dongshi , Wang Peng , Yu Jian , Zhang Lin 
Published: June 2022

Abstract
Colorectal cancer (CRC) is a leading cause of cancer related deaths in the United States. CRC patients are often treated with chemotherapeutic drugs, such as 5-fluorouracil (5-FU), and resistance to chemotherapy is a major clinical problem. It is well-established that 5-FU induces apoptosis in cancer cells, but apoptosis inhibition does not block the anticancer effect of 5-FU, suggesting a role of non-apoptotic cell death. Necroptosis is a regulated form of necrosis controlled by Receptor-Interacting Protein kinase 1 (RIP1), RIP3, and Mixed Lineage Kinase domain-Like (MLKL). TCGA RNA-Seq data reveal that RIP1 and RIP3 are frequently downregulated in CRC, with RIP3 downregulation correlating with worse clinical outcomes. We found that loss of RIP3 expression in CRC cells is associated with decreased 5-FU sensitivity. RIP3 silencing in CRC was shown to be caused by promoter hypermethylation. However, the exact functional role of RIP3 in response to anticancer therapies remains unclear. Our studies reveal that RIP3-expressing CRC cells were able to undergo both apoptosis and necroptosis in response to 5-FU treatment, which was abrogated upon knock-out or inhibition of RIP3. Restoration of RIP3 in RIP3-silenced CRC cells by transfection enhanced 5-FU sensitivity, along with restored necroptosis and enhanced apoptosis. Furthermore, we have shown that RIP3 expression can be restored in RIP3-silenced CRC cells by the DNA methyltransferase 1 inhibitor 5-aza-2’-deoxycytidine (5-aza-dC), which also enhances 5-FU sensitivity. This effect of 5-aza-dC is partially dependent on RIP3 and suppressed by a RIP3 inhibitor. Together, our results suggest RIP3 plays a critical role in response to 5-FU and other chemotherapeutic agents, and that restoring RIP3 expression can be used to potentiate chemotherapy. These results provide novel insight into the functional role of RIP3 in CRC chemotherapy, which could be explored for developing improved and personalized CRC treatments based on RIP3 status.
Citation Format: Kaylee Ermine, Dongshi Chen, Peng Wang, Jian Yu, Lin Zhang. Restoring necroptosis in colorectal cancer cells to overcome chemotherapeutic resistance [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 358.
Abstract 3606: Lenalidomide switch control of CAR T-cell phenotype and function via degradable membrane-bound IL-7
Authors: Kann Michael C. , Tepper Alexander , Silva Harrison J. , Lane Isabel C. , Bouffard Amanda A. , Larson Rebecca C. , Ebert Benjamin L. , Maus Marcela V. , Jan Max 
Published: June 2022

Abstract
CAR T cells have had marked success in the treatment of hematologic malignancies such as B-cell acute lymphoblastic leukemia and multiple myeloma. However, some patients fail to have sustained responses, in large part to due limited persistence of their CAR T cells. Previous attempts to prolong CAR T cell survival have attempted to combine CAR T cell therapy and cytokine therapy (IL-2, IL-15) to increase persistence, but this combination of T cell activation and high levels of systemic cytokines can lead to toxicities. To enhance CAR T cell persistence and while mitigating potential cytokine toxicities, we present a bicistronic CAR T engineered to express a membrane-bound drug-degradable IL-7 (mbdIL7) on its surface in addition to a 2nd generation anti-CD19 CAR.
The mbdIL7 is composed of an IL-7 molecule anchored to the cell by a CD80 hinge/transmembrane domain and followed by a cytoplasmic super-degron tag and drives JAK/STAT5 signal transduction. Both mbdIL7 abundance and STAT5 phosphorylation can be efficiently suppressed with lenalidomide, an FDA approved drug, at sub-therapeutic doses. The mbdIL7 can supplant the requirement of exogenous cytokines during manufacturing and leads to a more central memory-biased T cell phenotype. mbdIL7 CAR T cell proliferation remains antigen-dependent. These novel mbdIL7 CAR T cells have similar in vitro effects to traditional CAR T against models of leukemia and lymphoma, but have distinct transcriptional profiles associated with lower levels of exhaustion. In an orthotopic xenograft lymphoma model, mbdIL7 CAR T cells demonstrate markedly enhanced anti-tumor activity compared to traditional anti-CD19 CAR T cells. In addition, mbdIL7 CAR T cells have increased expansion/persistence in the blood, bone marrow, and spleen. The inclusion of a membrane-bound degradable IL-7 into the backbone of a traditional anti-CD19 CAR allows for spatial and temporal control of a pro-persistence cytokine leading to a more effective CAR T treatment. This presents a potential controllable CAR T for patients that are currently not responding conventional FDA-approved products.
Citation Format: Michael C. Kann, Alexander Tepper, Harrison J. Silva, Isabel C. Lane, Amanda A. Bouffard, Rebecca C. Larson, Benjamin L. Ebert, Marcela V. Maus, Max Jan. Lenalidomide switch control of CAR T-cell phenotype and function via degradable membrane-bound IL-7 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3606.
Abstract 362: MYCN-amplified neuroblastoma is addicted to iron and vulnerable to ferroptosis
Authors: Floros Konstantinos V. , Johnson-Berro Mia O. , Kurupi Richard , Fairchild Carter K. , Dalton Krista , Hu Bin , Puchalapalli Madhavi , Dozmorov Mikhail G. , Koblinski Jennifer E. , Olzmann James A. , Cowart Lauren A. , Faber Anthony C. 
Published: June 2022

Abstract
MYCN is amplified in 20% to 25% of neuroblastoma, and MYCN-amplified neuroblastoma contributes to a large percent of pediatric cancer-related deaths. Therapy improvements for this subtype of cancer are a high priority. Ferroptosis is an iron-dependent, oxidative form of cell death that is counteracted mainly by the production of Glutathione Peroxidase 4 (GPX4), a phospholipid hydroperoxidase that is produced through the glutathione pathway. The identification of cancers that may benefit from ferroptosis inducers are just emerging. Here we uncover a MYCN-dependent therapeutic vulnerability in neuroblastoma. Namely, amplified MYCN rewires the cell through expression of key receptors, ultimately enhancing iron influx through increased expression of the iron import transferrin receptor 1 (TFR1). Accumulating iron causes reactive oxygen species (ROS) production, and MYCN-amplified neuroblastomas show enhanced reliance on the system Xc- cystine/glutamate antiporter for ROS detoxification through increased transcription of this receptor. By performing metabolomics, we demonstrate that the transsulfuration pathway is also activated by MYCN. The increased activation of both pathways leads to cysteine accumulation that results in inhibition of lipid peroxidation. Utilizing drugs that target the main components of the glutathione and transsulfuration pathway we sensitize the MYCN neuroblastomas to ferroptotic cell death. These data provide novel insights into how MYCN alters the transcriptome in neuroblastoma to confer growth and survival advantages and simultaneously sheds light on the mechanism of action of ferroptosis inducers with potential application in other types of cancer.
Citation Format: Konstantinos V. Floros, Mia O. Johnson-Berro, Richard Kurupi, Carter K. Fairchild, Krista Dalton, Bin Hu, Madhavi Puchalapalli, Mikhail G. Dozmorov, Jennifer E. Koblinski, James A. Olzmann, Lauren A. Cowart, Anthony C. Faber. MYCN-amplified neuroblastoma is addicted to iron and vulnerable to ferroptosis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 362.
Abstract 3622: DNA damage drives DNA methylation and 3D chromatin organization alterations in glioblastoma
Authors: Modrek Aram S. , Do Catherine , Zhang Zeyan , Deng Yingwen , Karp Jerome , Ezhilarasan Ravesanker , Cova Giulia , Snuderl Matija , Tsirigos Aristotelis , Skok Jane , Sulman Erik P. 
Published: June 2022

Abstract
In glioblastoma, treatment with radiation and chemotherapy leads to DNA-damage and most DNA breaks are faithfully repaired, but the impact on the epigenome has not been thoroughly investigated. Since epigenetic alterations in DNA-methylation can impact the binding of factors involved in chromatin folding, such as CTCF as well as transcription factors that bind regulatory elements, the downstream impact on gene regulation could lead to the emergence of treatment resistance. Here, using radiation, we show there are significant and wide-spread alterations in DNA-methylation after treating multiple glioblastoma cultures. However, it is difficult to study these alterations because breaks are introduced at different sites in each cell, resulting in irreproducible DNA methylation alterations between replicates and cell lines. To circumvent this issue, we have developed a “multi-cut” CRISPR-Cas9 DNA break system that targets 142 or 483 pre-defined loci. We find that induction of mapped genome-wide cuts reproduces a similar level of toxicity as standard doses of radiation and we characterize the kinetics of overall cellular resolution of DNA damage using immunofluorescence markers and COMET assays. In order to assess repair efficiency (i.e., deletions, translocations, complete repair), we have designed a custom panel of DNA probes that flank the 142 or 483 sites to allow for high coverage sequencing of each cut site. To understand how DNA damage may lead to local epigenetic alterations and 3D chromatin organization changes, we performed HiC (genome-wide chromosome conformation capture), before and after cut induction, and subject cultures to further downstream analysis. Our findings show significant mega-base scale alterations in chromatin contacts centered around cut sites. To understand how these alterations may contribute to treatment resistance after DNA damage, we show these alternating chromatin contacts result in new promoter and enhancer interactions, which may drive gene-expression alterations after DNA damage at nearby loci. These results provide a mechanistic view of the interplay between DNA damage, DNA methylation and genome re-organization in glioblastoma. Importantly, these studies shed light on how these alterations evolve and their effect on local gene expression and ensuing treatment resistance.
Citation Format: Aram S. Modrek, Catherine Do, Zeyan Zhang, Yingwen Deng, Jerome Karp, Ravesanker Ezhilarasan, Giulia Cova, Matija Snuderl, Aristotelis Tsirigos, Jane Skok, Erik P. Sulman. DNA damage drives DNA methylation and 3D chromatin organization alterations in glioblastoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3622.
Abstract 3658: Ototoxicity of chemotherapy and radiation agents used in pediatric cancer treatment
Authors: Moore Brittney T. , Tsien Fern , Sheets Gabrielle , Umrigar Ayesha , Doss Jordan , Norman Michael , Stark Matthew , Prasad Pinki , Musso Amanda , Hicks Chindo , Otohinoyi David , Zabaleta Jovanny , Li Li 
Published: June 2022

Abstract
Many highly effective therapies used to treat cancer have been associated with irreversible development of detrimental neurological sequelae following the survival of childhood and adolescent cancer. While cancer treatment-induced late effects vary due to patient-related risk factors, cancer survivors who received chemotherapy or radiation may develop conductive or sensorineural hearing loss (SNHL). The purpose of this project is to determine which neuroinflammation-associated genes and biological pathways are affected by pediatric cancer treatments, and which treatment protocols are associated with increased ototoxicity. We hypothesize that cancer treatment causes abnormal gene expression of neuroinflammation and deafness-associated genes. The hypothesis will be tested with two specific aims. Aim I is to perform a retrospective review of diagnostic audiograms from pediatric cancer survivors enrolled in the Treatment After Cancer and Late Effects Center at Children’s Hospital New Orleans, Louisiana (CHNOLA). Aim II is to perform Nanostring neuroinflammation gene expression analysis followed by Ingenuity Pathway Analysis (IPA) of brain autopsy specimens from deceased pediatric patients who have previously undergone cancer treatment (Pathology Department, CHNOLA). Preliminary results revealed abnormal upregulation or downregulation of key genes, some of which are related to hearing loss and cochlear neuron degeneration when compared to age-matched controls (e.g., GJA1 and CASP3). The present study may provide information regarding which cancer treatment agents are ototoxic and reveal the candidate risk genes and pathways that contribute to auditory late effects. The long term goal of this project is to identify the needs of cancer survivors who are affected by treatment-induced hearing loss and provide them and their families with access to educational materials, medical resources, and social support to increase their health-related quality of life.
Citation Format: Brittney T. Moore, Fern Tsien, Gabrielle Sheets, Ayesha Umrigar, Jordan Doss, Michael Norman, Matthew Stark, Pinki Prasad, Amanda Musso, Chindo Hicks, David Otohinoyi, Jovanny Zabaleta, Li Li. Ototoxicity of chemotherapy and radiation agents used in pediatric cancer treatment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3658.