bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 517: 2OHOA-mediated furin inhibition: Disrupting Notch via processing, transcription, and ADAM downregulation
Authors: Rodríguez-Lorca Raquel , Beteta-Göbel Roberto , Roman Ramón , Lladó Victoria , Escribá Pablo V. , Fernández-García Paula 
Published: March 2024

Abstract
Purpose Glioblastomas (GBMs) are highly treatment-resistant and aggressive brain tumors. Herewe assessed the potential of melitherapy to treat GBM, a strategy based on regulating themembrane’s structure and organization to modify aspects of intracellular signaling. In thiscontext, we have evaluated the effects of 2-hydroxyoleic acid (2OHOA) on GBM cells, acompound currently under study in a phase IIB/III clinical trial for newly diagnosed GBMpatients. The current study aims to determine whether 2OHOA modulates the Notch pathway aspart of its antitumoral mechanism, as seen its relevance driving the pathogenesis of GBM.
Methods The effect of 2OHOA was evaluated on different components of the pathway usingseveral methods: W-blot, Q-PCR, and confocal microscopy. The relevance of HES1 in itsmechanism of action was evaluated by its overexpression and pathway activation assays byJagged1. To analyze Notch receptor processing, we performed subcellular fractionation andcolocalization studies. Furin activity was assessed by fluorescence assays measuring its substratecleavage and its binding affinity to 2OHOA was determined by surface plasmon resonance.
Results 2OHOA suppresses both the Notch3 and Notch2 signaling pathways in GBM cell linesusing a two-fold mechanism. Notch3 signaling is abolished by repressing its transcription.Instead, Notch2 pathway is hindered by blocking its first cleavage through the inactivation offurin activity by physical association. Consequently, the Notch2 receptor is retained in the Golgicomplex, preventing its trafficking to the plasma membrane to initiate the signaling cascade.Moreover, overexpression of its target gene, HES1, partially dampened the drug's antiproliferative effect showing the relevance of this pathway in the 2OHOA pharmacologicalefficacy. In addition, considering the levels of Notch intracellular domain (NICD) obtained inJagged1 assays in conjunction with 2OHOA, we evaluated the second cleavage of the Notchprocessing, being also downregulated, as ADAM10 constitutes a furin substrate.
Conclusions These findings elucidate that the antitumoral activity of 2OHOA involves theinhibition of Notch signaling, potentially driven by the direct inhibition of furin. This reveals anovel molecular target for this bioactive lipid in the therapeutic approach to treating GBM.
Citation Format: Raquel Rodríguez-Lorca, Roberto Beteta-Göbel, Ramón Roman, Victoria Lladó, Pablo V. Escribá, Paula Fernández-García. 2OHOA-mediated furin inhibition: Disrupting Notch via processing, transcription, and ADAM downregulation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 517.
Abstract 5212: Prognostic biomarkers for breast cancer: Metabolic and inflammatory pathways
Authors: McMahon Alexandra N. , Takita Cristiane , Wright Jean L. , Reis Isildinha M. , Lee Eunkyung , Yang George , Hu Jennifer J. 
Published: March 2024

Abstract
Objective: To assess the prognostic significance of molecular biomarkers, particularly metabolic and Inflammatory pathways using samples from a prospective study of breast cancer patients undergoing adjuvant radiotherapy (RT).
Methods: We used ultra-performance liquid chromatography-mass spectrometry (UPLC-MS/MS) for measuring urine metabolites. Following normalization to osmolality, log transformation, and imputation of missing values, we used Welch’s two-sample t-test to identify biochemicals that differed significantly by progression status. We measured pre- and post-RT plasma high-sensitivity C-reactive protein (hsCRP) levels. Progression-free survival (PFS) was calculated from the date of diagnosis to the date of disease progression or last follow-up. Univariable and multivariable Cox proportional hazards regression models assessed the associations between hsCRP and PFS.
Results: In 120 breast cancer patients, carbohydrate metabolism, branch-chain amino acid (BCAA) metabolism, phosphatidylcholine metabolism, arginine metabolism, oxidative stress-related metabolites, androgenic steroids, and nucleotide metabolism had the most notable differences in patients with progression versus progression-free cases. In 488 breast cancer patients, RT significantly increased plasma hsCRP levels, and post-RT hsCRP levels were significantly higher in deceased vs. alive patients (p=0.031). In multivariable models, hsCRP had a prognostic value for all-stage and stage 0-II patients.
Conclusions: In our study of breast cancer patients receiving adjuvant RT, multiple metabolite biomarkers and post-RT plasma CRP levels were associated with a worse prognosis. BCAAs and fatty acids regulate cell metabolism by affecting mitochondrial function and inflammation signals. Thus, our findings suggest a potential role of metabolic and inflammatory pathways in breast cancer prognosis. These molecules may have potential utility as prognostic biomarkers for breast cancer patients undergoing adjuvant RT and targets for intervention.
Keywords: breast cancer, metabolomics, inflammation, prognosis
Citation Format: Alexandra N. McMahon, Cristiane Takita, Jean L. Wright, Isildinha M. Reis, Eunkyung Lee, George Yang, Jennifer J. Hu. Prognostic biomarkers for breast cancer: Metabolic and inflammatory pathways [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5212.
Abstract 5239: Discovery of AML associated therapeutic targets
Authors: Ibrahim Omar M. , Rettig Michael P. , Jayasinghe Reyka G. , Ding Li , DiPersio John F. 
Published: March 2024

Abstract
Chimeric Antigen Receptor T-cell (CART) immunotherapy has shown significant success in the treatment of hematological malignancies. However, their efficacy in AML is limited due to the disease's genetic diversity and lack of uniform antigen targets. To identify potential AML cell-surface markers, we employed a comprehensive approach that involved the utilization of 3' single-cell RNA sequencing (scRNA-seq), bulk RNA sequencing (RNA-seq), and enhanced whole exome sequencing (eWES). A total of 21 samples were analyzed, comprising 18 distinct AML patients and 3 healthy bone marrow aspirates, serving as controls. We conducted scRNAseq on 21 samples, yielding a total of 185,106 high-quality cells, which were effectively clustered into 38 unbiased groups. Notably, tumor clusters exhibited highest copy number variations and formed separate clusters from other non-tumor immune cells. To uncover key functional pathways, we conducted pathway enrichment analysis comparing tumor cells to non-tumor cells. Our findings demonstrated a significant overrepresentation of cellular processes related to Allograft rejection, IL2/STAT5 signaling, IFN-gamma response and apoptosis. To identify AML specific markers, we performed an unbiased systematic search of the scRNAseq dataset for genes with unique expression patterns in tumor cells compared to the healthy bone marrow controls. Our analysis identified differentially expressed genes, with many genes displaying relative cell and tissue specificity. Notably, among these genes, we unveiled key potential targets with cell surface specificity, including novel markers alongside previously known ones. Noteworthy candidates, such as ADGRE2, CD33, CD123, CLEC12A, and FLT3 and understudied novel markers such as CD86, CSF1R, S100 proteins and VMP1, were prominently expressed, showcasing their potential significance as targets for engineered immunotherapy. To validate and consolidate our discoveries, we conducted a cross-referencing exercise by comparing our scRNAseq data against bulk RNA data from primary human AML samples and cell lines. Bulk global proteomics, flow cytometry-based and CART generation studies are ongoing to confirm our discoveries. Our rigorous computational and experimental approach provides valuable insights into tumor-specific cell surface proteins, which hold promise as potential targets for innovative and precision immunotherapeutic interventions in the realm of AML treatment.
Citation Format: Omar M. Ibrahim, Michael P. Rettig, Reyka G. Jayasinghe, Li Ding, John F. DiPersio. Discovery of AML associated therapeutic targets [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5239.
Abstract 5265: Targeting mtDNA dynamics enhances immunogenicity and sensitizes KRAS mutant cancers to PD-1 blockade
Authors: Tanaka Kosuke , Adachi Yasuki , Yoshiya Miyuki , Owari Takuya , Yamamori-Morita Tomoko , Ohashi Akihiro , Kobayashi Susumu , Koyama Shohei , Nishikawa Hiroyoshi 
Published: March 2024

Abstract
Mitochondrial DNA (mtDNA) can stimulate an innate immune response that potentiates the efficacy of cancer immunotherapy. However, mtDNA-targeting therapy has not been developed to enhance this innate immune system in specific cancer subtypes efficiently. Here we discover that mtDNA is enriched in KRAS mutant tumors where the DNA sensor machinery cGAS-STING signaling is primed for innate immune activation. Intriguingly, MEK inhibitor induces cytosolic mtDNA release to potently activate the cGAS-STING signaling, which in turn induces PRKN-mediated mitophagy in response to mitochondrial stress in KRAS mutant cancer cells. During the process of mitophagy, PRKN, as an E3 ubiquitin ligase, degrades BAX protein and attenuates mitochondrial pore formation, which is essential for mtDNA efflux upon MEK inhibition. Combined MEK and mitophagy inhibitors efficiently stimulate type I IFNs in both mtDNA- and STING-dependent manners, and this combination enhances the efficacy of PD-1 blockade in Kras mutant murine syngeneic tumors. In the clinic, PRKN is associated with a ‘cold tumor’ phenotype among KRAS mutant tumors. Together, targeting mtDNA dynamics by co-inhibition of MEK and mitophagy represents a promising strategy to convert ‘cold to hot tumor’ in mtDNA-enriched KRAS mutant cancers.
Citation Format: Kosuke Tanaka, Yasuki Adachi, Miyuki Yoshiya, Takuya Owari, Tomoko Yamamori-Morita, Akihiro Ohashi, Susumu Kobayashi, Shohei Koyama, Hiroyoshi Nishikawa. Targeting mtDNA dynamics enhances immunogenicity and sensitizes KRAS mutant cancers to PD-1 blockade [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5265.
Abstract 529: Investigating the synergistic effect of milciclib and PD0325901 in colorectal cancer therapy
Authors: Pei Xinyu , Nguyen Anh , Neiger Hannah , Wang Wenjia , Bautista William , Wang Lily , Cai Alvan , Gerriets Valerie A. , Cusick John K. , Shi Yihui 
Published: March 2024

Abstract
Milciclib, characterized as a potent nanomolar inhibitor of multiple cyclin-dependent kinases, has recently emerged as a promising therapeutic agent in cancer treatment, particularly with its additional role as a spliceosome modulator. Our recent studies employing RNA sequencing technology revealed a comprehensive profile of Milciclib-induced transcriptional changes in colorectal cancer cells, identifying several key regulated pathways. In light of these findings, we explored a novel therapeutic strategy: combining Milciclib with specific inhibitors targeting pathways upregulated by Milciclib treatment. This hypothesis is based on the rationale that such a combination could exert a synergistic effect. We have assessed the efficacy of this combinational therapy and found that the combination of Milciclib and PD0325901 greatly potentiates the killing of colorectal cancer cells versus either treatment alone. PD0325901 has been extensively studied for its efficacy in targeting the MEK/ERK signaling pathway, a critical pathway in many cancers, including colorectal cancer. To further characterize the underlying molecular mechanisms contributing to the observed synergistic effect, we applied quantitative proteomic analysis of 8107 proteins in human colorectal cancer cells with the treatment of different doses of Milciclib and PD0325901 administered alone, or in combination. Our results demonstrate 49 proteins were significantly decreased in a dose-dependent manner, and that many of these proteins are key players regulating pathways associated with the cell cycle, apoptosis, gene expression, metabolism, WNT signaling, and the MEK/ERK signaling pathway. The discovery of the down-regulation of these proteins and pathways after treatment provides a molecular basis to elucidate the synergistic mechanism underlying Milciclib and PD0325901 combination therapy. In conclusion, our study establishes the combinatorial use of Milciclib and PD0325901 as a potential breakthrough in the treatment of colorectal cancer, offering a promising prospect for enhancing future patient outcomes.
Citation Format: Xinyu Pei, Anh Nguyen, Hannah Neiger, Wenjia Wang, William Bautista, Lily Wang, Alvan Cai, Valerie A. Gerriets, John K. Cusick, Yihui Shi. Investigating the synergistic effect of milciclib and PD0325901 in colorectal cancer therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 529.
Abstract 5303: A novel TIGIT and 4-1BB bispecific antibody, ABL112, exhibits potent in vitro and in vivo antitumor activity through dual immune modulation
Authors: Son Wonjun , Lee Yangsoon , Park Yelim , Won Jonghwa 
Published: March 2024

Abstract
T cell immunoreceptor with Ig and ITIM domains (TIGIT) is an immune checkpoint molecule responsible for delivering inhibitory signals that suppress immune activation. Due to its inhibitory role in the immune response, TIGIT has emerged as a potential therapeutic target for various malignancies, with several clinical trials exploring the use of anti-TIGIT blocking antibodies with anti-PD-(L)1 therapies. Recent reports have indicated elevated expression of 4-1BB within intra-tumoral Tregs. Therefore, we hypothesized that a dual targeting approach involving both TIGIT and 4-1BB could effectively enhance intra-tumoral immunity.
ABL112, a First-in-Class bispecific antibody targeting TIGIT and 4-1BB, demonstrated the induction of T cell activation by blocking the TIGIT signaling and TIGIT dependent 4-1BB clustering. By having intact Fc, ABL112 bound to FcγRI and its crosslinking with 4-1BB also induced 4-1BB activation. ABL112 selectively depleted Treg cells but not other T cells in vitro, potentially through antibody-dependent cell-mediated cytotoxicity.
ABL112 demonstrated superior efficacy in tumor regression compared to anti-TIGIT monoclonal antibody across various mouse tumor models. Additionally, combining ABL112 with pembrolizumab significantly inhibited tumor growth better than combining anti-TIGIT monoclonal antibody with pembrolizumab. According to immune cell depletion assay, ABL112-mediated tumor suppressive activity was predominantly driven by CD8+ T cells, with a partial tumor reduction by CD4+ T cell or NK cell depletion. Mice with complete remission (CR) were further protected from the tumor re-challenge after 3 months of cessation of ABL112 treatment, and the proportion of tumor-specific memory T cells in the blood increased, suggesting long-term immunological memory has been established. In conclusion, ABL112 exhibited potent in vitro and in vivo anti-tumor activity through multiple mode of action including TIGIT inhibition and 4-1BB activation. These results strongly suggest that ABL112 is an innovative and promising therapeutic option with the combination of anti-PD-(L)1 therapies for cancer patients.
Citation Format: Wonjun Son, Yangsoon Lee, Yelim Park, Jonghwa Won. A novel TIGIT and 4-1BB bispecific antibody, ABL112, exhibits potent in vitro and in vivo antitumor activity through dual immune modulation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5303.
Abstract 5321: Chronic use of tobacco products promotes breast cancer progression through α7 nAChR/STING pathway activation
Authors: Mugisha Samson , Baba Shahnawaz , Labhsetwar Shreyas , Klemke Richard , Desgrosellier Jay 
Published: March 2024

Abstract
Tobacco-use is associated with an increased risk of developing aggressive breast cancer, however the cause remains unclear. While there is a dose-dependent decrease of patients’ overall survival due to tobacco-use, the risk persists even after cessation. Here we show that chronic treatment with of breast cancer cells with low-dose nicotine significantly increases tumorsphere formation, self-renewal and tumor growth, while the acute treatment has little effect. Interestingly, these outcomes were noted even weeks after nicotine treatment was stopped. Mechanistically, this was attributed to α7 nAChR, previously described as an essential regulator of inflammation. In fact, α7 nAChR knock-out prevented activation of the STING antiviral pathway by reducing the nicotine-induced mRNA expression of STING, CCL5, CXCL10 and STAT3. Overall, these findings highlight long-term impact of nicotine on cancer progression through α7 nAChR/STING pathway. This may inform new biomarkers for diagnosis and potential new treatment strategies to combat tobacco-related breast cancers.
Citation Format: Samson Mugisha, Shahnawaz Baba, Shreyas Labhsetwar, Richard Klemke, Jay Desgrosellier. Chronic use of tobacco products promotes breast cancer progression through α7 nAChR/STING pathway activation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5321.
Abstract 5322: Discovery of CRD1601, a potent and selective HPK1 inhibitor with robust in vivo anti-cancer activity
Authors: Banerjee Monali , Shrivastava Ritesh , Pryde David , Middya Sandip , Debnath Sabyasachi , Middya Anindita , Yadav Dharmendra , Rawat Nidhi , Ghosh Rajib , Padaliya Manisha , Basu Sourav , Surya Arjun 
Published: March 2024

Abstract
Background: Haematopoietic Progenitor Kinase (HPK-1, MAP4K1) is a member of the STE20 family of serine/threonine kinases, expressed predominantly in hematopoietic cells. HPK-1 functions as a negative regulator of T-cell and B-cell receptor activation by triggering proteasomal degradation and disrupting signalosome complexes downstream of TCR and BCR. HPK1 inhibition is a novel IO strategy that could combine with existing chemotherapies and immunotherapies.
Methods: Curadev used a pharmacophore based approach to discover novel small molecule HPK-1 inhibitors using in vitro enzymatic and phenotypic cellular screens using primary cells. CRD1601, the clinical candidate was selected based on its ability to enhance human T-cell proliferation through the induction of IL2 and IFNγ. Syngeneic tumor models were used to assess anti-tumor activity of selected compounds as a monotherapy or combination therapy.
Results: CRD1601 is a potent HPK1 inhibitor with a single digit nanomolar IC50 value in enzymatic assay and potent cellular activity in the SLP76 assay. A single dose of CRD1601 in mice treated with an anti-CD3 antibody caused systemic enhancement of pro-inflammatory cytokines such as IL2, IFN gamma and reduced pSLP76 levels in the spleen. Further, CRD1601 reversed the immunosuppressive effect of PGE2 and NECA. CRD1601 demonstrated significant single agent activity in murine tumor models while also synergizing with chemotherapy and immunotherapy.
Conclusions: Inhibition of HPK-1 is a promising therapeutic modality that could augment the effects of existing anti-cancer treatments including immunotherapy. CRD1601 is a potent and selective HPK-1 inhibitor with favorable drug like properties that has been selected from a rich portfolio of active compounds and shows promising in vivo activity in tumor models.
Citation Format: Monali Banerjee, Ritesh Shrivastava, David Pryde, Sandip Middya, Sabyasachi Debnath, Anindita Middya, Dharmendra Yadav, Nidhi Rawat, Rajib Ghosh, Manisha Padaliya, Sourav Basu, Arjun Surya. Discovery of CRD1601, a potent and selective HPK1 inhibitor with robust in vivo anti-cancer activity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5322.
Abstract 5345: Development and validation of humanized HLA mouse model platforms for preclinical evaluation of novel peptide vaccines
Authors: Niu Zhenlan , Yu Xuan , Shen Zhiyuan , Guo Jing , Lin Qingcong , Xu Hui 
Published: March 2024

Abstract
The human leukocyte antigen (HLA) class I major histocompatibility complex (MHC) plays an integral role in immune surveillance by presenting intracellular antigen peptides on the cell surface, enabling recognition by cytotoxic T cells and subsequent elimination. Harnessing this intrinsic process for cancer immunotherapy is a promising therapeutic strategy; thus, developing preclinical models to evaluate the efficacy of novel peptide vaccines in vivo and ex vivo is critical. Previously, we developed a humanized MHC I mouse model (B-HLA-A2.1 mice), in which we successfully demonstrated efficacy of peptide vaccines as assessed by splenocyte IFN-γ production measured via ELISpot. Here, we provide evidence that B-HLA-A2.1 mice can also mount immune responses to NY-ESO-1 and WT1-Db126 peptides using the same assay. Additionally, immunization with WT1-Db126 at 7, 14, and 21 days prior to tumor inoculation with WT1-expressing MC38 colon cancer cells significantly reduced tumor volume. Additionally, we have generated two new humanized HLA models: B-HLA-A11.1 mice and B-HLA-A24.2 mice. Flow cytometric data demonstrate successful expression of the human HLAs on the cell surface of splenocytes isolated from both strains. Compared to wild-type C57BL/6 mice, analysis of leukocyte and lymphocyte subpopulations in the humanized mice indicates that the CD4/CD8 ratio is altered in favor of CD4+ T cells in both strains, similar to what was observed in B-HLA-A2.1 humanized mice. Despite these observed alterations, B-HLA-A24.2 mice were able to mount an immune response to peptide SART2 93-101, which was measured by splenocyte IFN-γ production. In summary, our data indicate that humanized HLA-A mice provide a powerful preclinical model for in vivo/ex vivo evaluation of novel peptide vaccines.
Citation Format: Zhenlan Niu, Xuan Yu, Zhiyuan Shen, Jing Guo, Qingcong Lin, Hui Xu. Development and validation of humanized HLA mouse model platforms for preclinical evaluation of novel peptide vaccines [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5345.