bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 5114: Development of personalized RNA-based immunotherapeutics for glioblastom
Authors: Trivedi Vrunda , Yang Changlin , Yegorov Oleg , Klippel Kelena , Fenton Graeme , von Roemeling Christina , Hoang-Minh Lan , Ogando-Rivas Elizabeth , Castillo Paul , Dyson Kyle , Moore Ginger , Mitchell Duane 
Published: April 2023

Abstract
Background: The development of successful immunotherapy targeting antigens in glioblastoma multiforme (GBM) remains a challenge owing to antigen heterogeneity and the low mutation burden in GBM. Cancer immunogenomics represents a complementary approach to the application of genomics in developing novel immunotherapies for GBM. Our goal is to develop a personalized RNA-based therapeutic vaccine that simultaneously targets a selected pool of tumor rejection antigens including all neoantigens and tumor-associated antigens (TAAs) as identified using cancer immunogenomics. We evaluated the treatment efficacy of these RNA therapeutics in combination with adoptive cellular therapy and checkpoint inhibitors.
Methods: We identified immunogenic neoantigens and TAAs that are aberrantly overexpressed in KR158-luc and GL261 murine GBM tumors using our cancer immunogenomics pipeline called the Open Reading Frame Antigen Network (O.R.A.N.). A tumor antigen-specific RNA library was created for each tumor using a novel gene enrichment strategy and validated by RNAseq. Tumor-bearing animals were treated with adoptively transferred ex vivo expanded lymphocytes and dendritic cells loaded with the tumor antigen-specific RNA as vaccines. Additionally, we treated animals with the tumor antigen-specific RNA vaccines in combination with anti-PD-1 checkpoint-blockade therapy. Tumor progression and survival outcomes were analyzed to evaluate the treatment efficacies. We determined the peripheral and tumor-infiltrating lymphocyte responses using flow cytometry, TCR sequencing, and single cell RNAseq.
Results: The tumor antigen-specific RNA vaccines were significantly effective in slowing the progression of murine GBM tumors in combination with both the adoptive cellular therapy and the checkpoint blockade therapy and improved the outcome of these therapies as compared to monotherapy alone. Additionally, we identified antigen-specific T cells targeting several of our predicted antigens and an increase in tumor-infiltrating lymphocytes and memory T cells in the treated animals.
Conclusion: Here, we developed an RNA-based immunotherapy that simultaneously targets numerous tumor-specific antigens and demonstrated its therapeutic efficacy in preclinical models of GBM.
Citation Format: Vrunda Trivedi, Changlin Yang, Oleg Yegorov, Kelena Klippel, Graeme Fenton, Christina von Roemeling, Lan Hoang-Minh, Elizabeth Ogando-Rivas, Paul Castillo, Kyle Dyson, Ginger Moore, Duane Mitchell. Development of personalized RNA-based immunotherapeutics for glioblastom. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5114.
Abstract 514: Novel potent azetidine-based inhibitors bind irreversibly to Stat3 DNA-binding domain (DBD) and are efficacious against tumor growth in mice
Authors: Chen Yue , Zhai Ning , Zhu Yinsong , Yue Peibin , Verma Nagendra , Brotherton-Pleiss Christine , Fu Wenzhen , Nakamura Kayo , Chen Weiliang , Tius Marcus , Lopez-Tapia Francisco J. , Turkson James 
Published: April 2023

Abstract
Unlike classical Signal transducer and activator of transcription (Stat) signaling, which is transient in non-transformed cells, the aberrant activation of the family member, Stat3, occurs in malignant transformation and is implicated in breast, ovarian and many other human cancers. Thus, Stat3 remains a validated and important target for the discovery of novel anticancer drugs. Despite this, the discovery and development of potent Stat3 small molecule inhibitors has proven to be a significant challenge, and no drug is available yet in the market. We have discovered novel Stat3 irreversible azetidine inhibitors with unprecedent submicromolar potency through systematic medicinal chemistry structure activity relationship (SAR). Mechanism of action of most potent azetidine inhibitors depend on whether they are salicylic acids or not, i.e., salicylic acids preferably bind irreversibly to Stat3 Cys426 site in the DNA-binding domain (DBD), and non-salicylic acids, e.g., current lead H182, bind to Stat3 Cys468 DBD site. As expected, the inhibition of Stat3 DNA-binding activity was time dependent, with IC50 in the range of 0.27-0.87 µM at one hour incubation with active Stat3. On the other hand, azetidine salicylic acids also bind to the SH2 domain, although reversibly and at much weaker affinity, as determined in fluorescent polarization (FP) assay, with IC50 of 10-16 µM at one hour incubation, while non-salicylic acids, e.g., lead H182, present no binding affinity up to 600 µM for the SH2 domain. Despite that H182 does not bind to SH2 domain, it still inhibits its phosphorylation. Though lead compound H182 presents significant mouse in vivo efficacy, mouse in vivo pharmacokinetics shows very low plasma AUC, which correlates with quite high mouse in vitro hepatocyte CLint of 138 µL/min/106 cells; however, human in vitro hepatocyte assay gives much better results and is in the middle stability range (CLint of 14.6 µL/min/106 cells). The in vivo PK in other species, e.g., rat, is being determined. H182 represents a plausible molecule for further development.
Citation Format: Yue Chen, Ning Zhai, Yinsong Zhu, Peibin Yue, Nagendra Verma, Christine Brotherton-Pleiss, Wenzhen Fu, Kayo Nakamura, Weiliang Chen, Marcus Tius, Francisco J. Lopez-Tapia, James Turkson. Novel potent azetidine-based inhibitors bind irreversibly to Stat3 DNA-binding domain (DBD) and are efficacious against tumor growth in mice [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 514.
Abstract 5144: Spatial T-cell atlas in more than 100 different tumor entities using BLEACH&STAIN
Authors: Huang Zhihao , Bady Elena , Müller Jan H. , Mandelkow Tim , Lurati Magalie C. , Simon Ronald , Bernreuther Christian , Jacobsen Frank , Sauter Guido , Möller Katharina , Luebke Andreas , Hinsch Andrea , Clauditz Till S. , Burandt Eike , Blessin Niclas C. 
Published: April 2023

Abstract
Background: The composition and functional state of T-cell subpopulations can highly impact patient’s outcome and response to immune checkpoint therapy. However, only little is known about the spatial interplay of most rare T-cell subpopulations.
Design: To assess the density, composition, degree of immune checkpoint expression, and spatial interplay of T-cell subpopulations in 5989 tumor samples from more than 100 tumor entities, two different types of tissue microarrays (0.6 mm and 4 mm in diameter) were stained with antibodies directed against CD3, CD4, CD8, FOXP3, T-bet, GATA3, RORyT, BCL6, FOXP3, CD56, CD45RA, CD45RO, TIM3, PD-1, CTLA-4 Granzym B, and Ki67 using our BLEACH&STAIN multiplex fluorescence immunohistochemistry approach. A deep learning-based framework comprising two different convolutional neuronal networks (U-Net and DeepLabv3+) was used for image analysis.
Results: For identification and definition of immune cell subpopulations unsupervised X-shift clustering and 2D/3D t-distributed stochastic neighbor embedding (t-SNE) using the “Rtsne” package (Rtsne (RRID:SCR_016342)) were applied and revealed 102 T-cell subpopulations at certain functional state. Within these subpopulations, the well-characterized expression profiles were visually matched with single T-cell expression profiles and documented as digital images. This process resulted in 12 main T-cell subsets that were further subclassified according to their functional state (proliferation, immune checkpoint expression) and studied according to their spatial orchestration. Interestingly, the vast majority of T-cell subsets were found in all analyzed tumor entities. However, their spatial orchestration, immune checkpoint expression profile was highly variable between different tumor entities.
Conclusion: This study provides a comprehensive overview of rare T-cells subpopulations and its spatial orchestration in more than 100 different tumor entities.
Citation Format: Zhihao Huang, Elena Bady, Jan H. Müller, Tim Mandelkow, Magalie C. Lurati, Ronald Simon, Christian Bernreuther, Frank Jacobsen, Guido Sauter, Katharina Möller, Andreas Luebke, Andrea Hinsch, Till S. Clauditz, Eike Burandt, Niclas C. Blessin. Spatial T-cell atlas in more than 100 different tumor entities using BLEACH&STAIN. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5144.
Abstract 5174: PEGylated liposomal doxorubicin improves oral cancer response to radio-immunotherapy
Authors: Devkota Laxman , Bhavane Rohan , Badachhape Andrew , Veeramachaneni Ratna , Menon Renuka , Bhandari Prajwal , Cortes Sofia , Da Costa Fabio Henrique Brasil , Ghaghada Ketan , Young Simon , Sikora Andrew G. , Annapragada Ananth V. 
Published: April 2023

Abstract
Introduction: The immunosuppressive tumor microenvironment (TME) in oral cancer inhibits response to conventional treatment (surgery +/- chemoradiotherapy) and check-point inhibitor (αPD1) immunotherapy. The chemotherapeutic agent doxorubicin and its PEGylated liposomal nanoparticle formulation (PLD) have been shown to target myeloid derived suppressor cells (MDSCs) in the TME. In this preclinical work, we investigated whether PLD improves response to radio-immunotherapy in a highly aggressive and immunologically ‘cold’ oral cancer model.
Experimental Procedure: Studies were performed in the MOC2 syngeneic mouse model of oral cancer. Mice were randomized to one of seven treatment groups: αPD1, Radiation (XRT), αPD1+XRT, PLD, PLD+αPD1, PLD+XRT, PLD+αPD1+XRT. High-resolution nanoparticle contrast-enhanced computed tomography (nCECT) imaging was performed, and whole-body T2-weighted magnetic resonance imaging (MRI) used to monitor primary tumor response and development of metastases. Response evaluation criteria in solid tumors (RECIST) were used to evaluate treatment outcomes.
Results: Tumors in all non-PLD groups were treatment resistant and grew progressively, consistent with the immunologically ‘cold’ MOC2 model. In contrast, all PLD groups showed tumor regression with 25-38% complete responders (CR) and 12-88% partial responders (PR) while all animals in non-PLD groups showed progressive disease (PD). MR imaging identified a high incidence of regional and distant metastases in the non-PLD groups while the PLD groups showed decreased regional and no distant metastases (Table 1). Presence of metastases was confirmed by nCECT imaging and histopathological analysis.
Conclusion: PLD improved response to radio-immunotherapy in a highly aggressive immunologically ‘cold’ mouse model of oral cancer while simultaneously preventing disease progression and metastasis.
Citation Format: Laxman Devkota, Rohan Bhavane, Andrew Badachhape, Ratna Veeramachaneni, Renuka Menon, Prajwal Bhandari, Sofia Cortes, Fabio Henrique Brasil Da Costa, Ketan Ghaghada, Simon Young, Andrew G. Sikora, Ananth V. Annapragada. PEGylated liposomal doxorubicin improves oral cancer response to radio-immunotherapy. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5174.
Abstract 580: A novel drug suppresses pancreatic cancer growth through immunomodulation
Authors: Gaikwad Shreyas Ramchandra , Srivastava Sanjay K. 
Published: April 2023

Abstract
Drug repurposing is an effective strategy that is being used to explore new potential treatments for various diseases. In the current study, utilizing drug repurposing approach, we have identified anti-cancer activity of an anti-parasitic compound (MB). We evaluated the anti-cancer activity of MB in pancreatic ductal adenocarcinoma (PDAC). The average IC50 of MB in several human and murine PDAC cells was 4-6µM. The mode of cell death was apoptosis and which was confirmed using Annexin-V assay. Oral administration of MB suppressed tumor growth in both human and murine subcutaneous and orthotopic models at a dose of 5mg/kg. In the syngeneic orthotopic model, MB showed immune modulation wherein it increased infiltration of CD8 T-cells in the tumor microenvironment as compared to control groups. Based on this, we combined MB with anti-PD1 therapy to evaluate the combinatorial effect. Our results showed significant PDAC tumor growth suppression when a combination of MB and anti-PD1 therapy was used in an orthotopic PDAC tumor model. In conclusion, MB has a promising anti-cancer effect against PDAC tumors and we are currently exploring the molecular mechanism of action in PDAC cell lines and also evaluating if MB has any direct effect on immune cell populations.
Citation Format: Shreyas Ramchandra Gaikwad, Sanjay K. Srivastava. A novel drug suppresses pancreatic cancer growth through immunomodulation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 580.
Abstract 5801: Inhibition of muscarinic acetylcholine receptors in glioma stem cells blocks tumor progression
Authors: Anand Sumyuktha V. , Lee Min K. , Skorput Alexander G. , Fox Isabella B. , Young Alison L. , Christensen Brock C. , Gulledge Allan , Havrda Matthew C. 
Published: April 2023

Abstract
Primary gliomas arising within the brain are the deadliest form of brain cancer and account for 78% of all malignant brain tumors. Glioma patients have a 5 percent five-year survival rate and drug-resistant tumors often recur following surgical resection and treatment with radiation and/or chemotherapy. The cancer stem cell hypothesis suggests the presence of a subset of undifferentiated cells, namely glioma stem cells (GSCs), in the heterogenous tumor mass responsible for disease progression. Understanding mechanisms responsible for maintaining GSCs and developing strategies to deplete the GSC population could improve glioma treatment and prognosis. Some GSCs are similar to oligodendrocyte precursor cells (OPCs), which are observed in neural development and the adult brain. OPCs are prone to malignant transformation and are believed to be a cell of origin for glioma. Recent findings indicate that the well-characterized neurotransmitter acetylcholine (ACh) maintains the primitive state of normal OPCs via muscarinic ACh receptors (mAChRs) preventing maturation and cell cycle exit. We hypothesized that cholinergic signaling may also maintain the primitive state of OPC-like GSCs. We analyzed publicly available single nuclei RNASeq data of patient glioblastoma samples and observed high expression of CHRM3, encoding the M3 mAChR, in OPC-like cells of the proneural subtype of glioma. Studies in mouse OPC-like GSCs confirmed high levels of CHRM3 expression and demonstrated that ACh generated voltage changes and rapid (&lt; 1 second) increases in cytosolic calcium from internal calcium stores. Exposure to a brain permeant FDA-approved anti-muscarinic drug targeting M3mAChR suppressed proliferation, evoked calcium release, and the activation of intracellular second messengers PKC and ERK. Pharmacologic inhibition of mAChRs in established patient derived glioma grafts prevented re-initiation of tumors in subsequent host animals compared with vehicle treated tumors. These studies suggest that the cholinergic microenvironment maintains GSCs in a manner similar to normal OPCs and provides a platform for repositioning available small molecule mAChR antagonists for treatment of glioma.
Citation Format: Sumyuktha V. Anand, Min K. Lee, Alexander G. Skorput, Isabella B. Fox, Alison L. Young, Brock C. Christensen, Allan Gulledge, Matthew C. Havrda. Inhibition of muscarinic acetylcholine receptors in glioma stem cells blocks tumor progression. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5801.
Abstract 5805: Ebastine targets cancer stem cell-like properties and metastasis in triple-negative breast cancer by binding focal adhesion kinase
Authors: Seo Juyeon , Park Minsu , Ko Dongmi , Kim Seongjae , Park Soeun , Nam Kee Dal , Kang Yong Koo , Seuk So Ra , Park Jaeyoun , Jung Eunsun , Kim Yoon-Jae , Kim Ji Young , Seo Jae Hong 
Published: April 2023

Abstract
Triple-negative breast cancer (TNBC) exhibits an aggressive behavior associated with poor prognosis due to the absence of established molecular targets. Focal adhesion kinase (FAK) is a major determinant and participates in the acquisition of migration and invasion, as well as the maintenance of breast cancer stem cell (BCSC)-like traits in TNBC. We sought to investigate the effect of ebastine, a second-generation antihistamine on apoptosis, FAK activation, BCSC subpopulations and metastasis in TNBC in vitro and in vivo. TCGA dataset analysis revealed that mRNA levels of FAK were highly expressed in TNBC compared to other breast cancer subtypes. We found that ebastine binds to the tyrosine kinase domain of FAK, which blocks phosphorylation at the Y397 and Y576/577 residues and subsequent inactivation of SRC. Ebastine-induced apoptosis was associated with attenuation of JAK2/STAT3 and MEK/ERK signaling in TNBC cells. Kinetic analysis revealed a concentration-dependent impairment of cell migration in the presence of ebastine in MDA-MB-231 and 4T1 cells in vitro. Ebastine targets BCSC-like cell populations as evidenced by a sharp decline in the expression of the BCSC markers ALDH1, CD44 and CD49f and suppression of mammosphere-forming capacity. Ebastine administration led to a significant reduction in the growth ebastine of BCSC-enriched 4T1 mammospheres orthotopically injected into the mammary glands of Balb/c mice. Ebastine administration significantly impeded angiogenesis and distant metastasis while reducing MMP-2/-9 levels in circulating blood in vivo. Importantly, biochemical analysis in mice serum showed that ebastine had no effect on liver and kidney function. Our findings suggest that EBA may be an effective therapeutic repositioning candidate for the simultaneous targeting of multiple survival signaling pathways for the treatment of molecularly heterogeneous TNBC. Further investigation of ebastine as an anti-metastatic agent for the treatment of TNBC is warranted.
Citation Format: Juyeon Seo, Minsu Park, Dongmi Ko, Seongjae Kim, Soeun Park, Kee Dal Nam, Yong Koo Kang, So Ra Seuk, Jaeyoun Park, Eunsun Jung, Yoon-Jae Kim, Ji Young Kim, Jae Hong Seo. Ebastine targets cancer stem cell-like properties and metastasis in triple-negative breast cancer by binding focal adhesion kinase. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5805.
Abstract 5807: mTOR regulates stem cells of glioblastoma by altering the self-renewal and proliferation
Authors: Gellerson Olivia , Bree Julie , Das Mohan , Kleinman George , Gandhi Chirag , Jhanwar-Uniyal Meena 
Published: April 2023

Abstract
The mechanistic target of rapamycin (mTOR: aka mammalian target of rapamycin), a serine/threonine kinase, functions by forming two multiprotein complexes termed mTORC1 and mTORC2. Glioblastoma (GBM) is a malignant and lethal brain tumor that remains incurable partly due to the existence of untreatable cancer stem cells (CSC). The pathogenesis of GBM is largely due to the loss of the tumor suppressor gene PTEN, which is implicated in the aberrant activation of the mTOR pathway. The major cause of tumor recurrence, growth, and invasion is the presence of a unique population of CSC. Resistance to conventional therapies appears to be caused by both extensive genetic abnormalities and dysregulation of the transcription landscape. Consequently, CSCs have emerged as targets of interest in new treatment paradigms. Evidence suggests that inhibition of the mTOR pathway can also be applied to target CSCs. In this study, we explored the role of the mTOR pathway in the regulation of stem cells of GBM. GBM stem cells were treated with various inhibitors of canonical PI3K/AKT/mTOR pathways such as rapamycin (mTORC1 inhibitor), PP242 (ATP binding mTORC1/2 inhibitor), LY294002 (PI3K inhibitor), and MAPK inhibitor, U0126. We previously demonstrated the presence of CSC in the peritumor area of GBM. A significant number of GBM tumors expressed stem cell marker nestin and activated mTOR (pmTORSer2448), with most tumor cells co-expressing both markers. The expression of stem cell marker NANOG was suppressed following rapamycin treatment, while U0126 induced translocation of NANOG from the nucleus to the cytoplasm. The neurospheres were disrupted following rapamycin and LY294002 treatments. Rapamycin or PP242 treatments given with differentiating agent All-trans-retinoic acid reduced stem cell proliferation. Treatment with novel small molecule dual inhibitors of mTORC1/2 demonstrated that Torin1 and Torin2 suppressed the proliferation of GBM CSC, while XL388 was less effective. Torin1 and XL388 delay the process of self-renewal as compared to controls, whereas Torin2 halted the self-renewal of GBM CSC. Additionally, Torin2 was able to eradicate tumor cells. Torin2 effectively targeted CSCs of GBM by halting self-renewal and inhibiting cell proliferation, underscoring the use of Torin2 in the treatment of GBM.
Citation Format: Olivia Gellerson, Julie Bree, Mohan Das, George Kleinman, Chirag Gandhi, Meena Jhanwar-Uniyal. mTOR regulates stem cells of glioblastoma by altering the self-renewal and proliferation. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5807.