bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 6149: STAT3 activation promotes invasiveness and cancer stemness in lung cancer
Authors: Yeung Sai Fung , Chan Sze Man , Law Chun Ho , Chan Hoi Yin , Tsui Kwok Wing 
Published: April 2023

Abstract
Lung cancer is the leading cause of cancer-related death worldwide, featuring a high incidence and low 5-year survival rate. Nearly 40% of patients are diagnosed with metastatic disease when they are first presented to the clinic. However, drug intervention targeting established metastatic tumors remains challenging, a better understanding of therapeutically exploitable mechanisms is urgently needed. This present study aims to explore novel therapeutic intervention against metastatic lung cancer. To understand the tumor-cell-intrinsic pathway that drives metastatic progression, we generated a highly invasive subline of lung cancer cell - A549 (ATCC, USA) by serial selections for Matrigel-coated transwells. The invasive subline A549-i3 shows about 5 times higher invasion potential than the parental cell line A549-Par (p&lt;0.05, Student t-test). Colony-formation Assay and suspension growth in ultra-low attachment plates were used to measure the 2D proliferation ability and anoikis resistance, albeit with no difference. The differential efficacies between A549-Par and A549-i3 against multiple pathway inhibitors were screened using MTT assay in vitro. Notably, A549-i3 is more sensitive towards napabucasin (STAT3 inhibitor) and tipifarnib (FTase inhibitor) when compared with A549-Par, suggesting their potency in targeting cancer stemness and addicted oncogenic driver. Furthermore, napabucasin reduced the migration and invasion abilities of A549-i3 to similar extent as their parent counterpart. Overall, our preliminary data identified STAT3 as a potential therapeutic vulnerability in highly invasive cancer cells. Future work will be focused on identifying pathways responsible to sensitize highly invasive NSCLC cells toward STAT3 inhibition using multiomics approach. This project was supported by the Research Impact Fund (Ref. No.: R4015-19) from the Research Grants Council in Hong Kong.
Citation Format: Sai Fung Yeung, Sze Man Chan, Chun Ho Law, Hoi Yin Chan, Kwok Wing Tsui. STAT3 activation promotes invasiveness and cancer stemness in lung cancer. [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 6149.
Abstract 6164: NF-κB and NRF2 signaling pathways affect prognosis in HPV-associated head and neck cancer
Authors: Kothari Aditi , Schrank Travis Parke , Yarbrough Wendell Gray , Isaeva Natalia 
Published: April 2023

Abstract
Incidence of HPV associated head and neck squamous cell carcinoma (HNSCC) is on the rise, displaying a significantly favorable prognosis and overall better survival as compared to HPV negative HNSCC. Intense radiotherapy is the primary medical care leading to treatment associated morbidity in patients, thereby generating a need for de-intensification strategies. Biomarkers that can identify patients with less aggressive tumors as candidates for de-escalation therapy would revolutionize treatment. We applied an unbiased approach (weighted gene correlation network analysis (WGCNA)) that allows detection of autocorrelated gene sets on 3 independent cohorts of HPV+ HNSCC and created 22 consensus transcriptional modules by selecting genes that grouped together in WGCNA analyses from all 3 cohorts. Interestingly, only 1 module intrinsically divided HPV+ HNSCC into 2 subtypes, displaying different mutational profiles, mutational signatures, HPV gene expression patterns, HPV integration status, and patient survival. Gene set enrichment analysis revealed that this module was enriched in NF-kB genes and strongly associated with NF-κB signaling, confirming our prior findings that defined HPV+ HNSCC subtypes by presence or absence of NF-kB regulators, TRAF3 or CYLD defects and by the NF-κB activity classifier. Our studies show that NF- κB -driven intrinsic tumor characteristics contribute to increased sensitivity of NF- κB active HPV+ head and neck tumors to radiation, providing patients survival benefits. Indeed, TRAF3 or CYLD deletion activated NF-kB and dramatically increased radiation sensitivity of HPV+ head and neck cancer cells. In line with our RNA seq analysis, we found that activation of NF-κB via TRAF3/CYLD deletion significantly correlated with marked downregulation of NRF2 activity and reduced nuclear localization in in HPV+ HNSCC cells. Interestingly, TRAF3 CRISPR KO cells had lower NRF2 protein levels that were restored by MG132 treatment, indicating an involvement of KEAP1/CUL3 mediated proteasomal degradation of NRF2. In summary, our data unveils a unique relation between NF-κB pathway and radiosensitivity in HPV+ HNSCC. The distinct biological characteristics that separate patients into two subclasses associated with favorable prognosis could serve as a biomarker for personalized therapy.
Citation Format: Aditi Kothari, Travis Parke Schrank, Wendell Gray Yarbrough, Natalia Isaeva. NF-κB and NRF2 signaling pathways affect prognosis in HPV-associated head and neck cancer [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 6164.
Abstract 617: Oncogenic CXCL10 triggers CD8+ T cell exhaustion in ovarian cancer
Authors: Long Runying , Ding Tao , Siu Michelle K.L , Chan David W , He Jiangnan , Cheung Annie NY , Man Kwan , NGAN Hextan YS , Chan Karen KL 
Published: April 2023

Abstract
Ovarian cancer is one of the most severe gynecologic malignancies with high mortality. Although programmed cell death 1 (PD-1) or PD-ligand 1 (PD-L1) immune checkpoint blockade (ICBs) has been used therapeutically in gynecologic cancers and has a clinically significant response in endometrial cancer, the response rate remains poor and has no different from the conventional therapies in ovarian cancer. The highly immunosuppressive microenvironment in ovarian cancer, consisting of inhibitory ligands, suppressive mediators, and cell subsets, leads to CD8+ T cell dysfunction and exhaustion and contributes to the limited efficacy of immunotherapeutic approaches. Correlative human studies have highlighted the potential importance of chemokines on the status of CD8+ T cell infiltration into tumors and on patient survival. Here, we show that CXCL10, an IFN-γ induced chemokine, derived from ovarian cancer cells, contributes to impairing CD8+ T cell antitumor immunity by regulating CD8+ T cell exhaustion in the tumor microenvironment. Clinically, we found that CXCL10 and its receptor CXCR3 had a strong positive correlation with exhausted T cell signature genes in ovarian cancer patients in TCGA and in-house cohort. Functionally, we showed that CD8+ T cell exhaustion was induced by CXCL10 activation by CRISPRa from ovarian cancer cells, whereas inhibition by CRISPRi restored CD8+ T cell antitumor immunity ex vivo and in vivo. Mechanically, ovarian cancer cells-derived CXCL10 induced the expression of CD8+ T cells exhaustion transcription factors in a CXCR3-dependent manner, driving PD-1 and TIM-3 expression on CD8+ T cells. Therapeutically, suppressing CXCL10 secretion from ovarian cancer cells enhanced the response to anti-PD-1 immunotherapy in the orthotopic mouse model. The results suggest that selectively inhibiting the oncogenic CXCL10 production may work effectively with ICBs in ovarian cancer immunotherapy. Our findings advance the understanding of the low response rate of immunotherapy in ovarian cancer and explore the potential mechanism underlying the induction of CD8+ T cell exhaustion in the tumor microenvironment.
Citation Format: Runying Long, Tao Ding, Michelle K.L Siu, David W Chan, Jiangnan He, Annie NY Cheung, Kwan Man, Hextan YS NGAN, Karen KL Chan. Oncogenic CXCL10 triggers CD8+ T cell exhaustion in ovarian cancer [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 617.
Abstract 6176: Enhancing treatment efficacy of glioblastoma cell lines by adding tumor treating fields (TTFields) to temozolomide and lomustine
Authors: Fishman Hila , Monin Roni , Dor-On Eyal , Haber Adi , Giladi Moshe , Weinberg Uri , Palti Yoram 
Published: April 2023

Abstract
Background: Tumor Treating Fields (TTFields) are electric fields that disrupt cellular processes critical for cancer cell viability and tumor progression, ultimately leading to cell death. Concurrent maintenance temozolomide (TMZ) with TTFields was approved by the FDA in 2014 for treatment of patients with newly diagnosed glioblastoma (ndGBM). Recently, the addition of lomustine (CCNU) to TMZ demonstrated clinical benefit in ndGBM patients. The aim of the current study was to examine in GBM cells the effect of TTFields concurrent with TMZ and CCNU.
Methods: Human GBM cell lines (U-87 MG, LN229, U118, and LN18) with various MGMT expression levels were treated with TTFields (intensity of 0.83 V/cm RMS; frequency of 200 kHz) using the inovitro system. Effectiveness of TTFields concomitant with TMZ and/or CCNU was tested by measuring cell count and colony formation. Levels of DNA repair proteins in control and TTFields-treated cells were measured using Western blot.
Results: The cell lines displayed different sensitivity to TMZ, in accordance with their MGMT expression level, but showed a comparable response to TTFields. TTFields concomitant with TMZ displayed an additive effect on cell numbers, irrespective of MGMT expression levels. The effect of TTFields concomitant with CCNU was additive in cell lines expressing MGMT, whereas it trended toward synergy in cell lines not expressing MGMT. Application of TTFields to the cells downregulated expression of proteins from the Fanconi Anemia-BRCA pathway for DNA repair. TTFields concurrent with both TMZ and CCNU provided higher efficacy relative to TMZ plus CCNU or TTFields apart.
Conclusions: Efficacy of TMZ and CCNU may be enhanced by TTFields, with synergism seen for the latter case in cells with limited MGMT expression. The BRCAness state induced by TTFields rationalizes these outcomes, as DNA damage induced by CCNU requires the BRCA pathway for repair, especially in the absence of MGMT. The results suggest a potential benefit for concomitant TTFields with the TMZ/CCNU combination in ndGBM.
Citation Format: Hila Fishman, Roni Monin, Eyal Dor-On, Adi Haber, Moshe Giladi, Uri Weinberg, Yoram Palti. Enhancing treatment efficacy of glioblastoma cell lines by adding tumor treating fields (TTFields) to temozolomide and lomustine [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 6176.
Abstract 618: CRISPR screening identifies the deubiquitylase ATXN3 as a PD-L1 positive regulator for tumor immune evasion
Authors: Wang Shengnan , Lyer Radhika , Fang Deyu 
Published: April 2023

Abstract
Regulation of tumoral PD-L1 expression is critical to advance our knowledge in understating the tumor evasion of immunosurveillance and for improvement of antitumor immunotherapy. While several E3 ubiquitin ligases and ubiquitin-specific peptidases regulate PD-L1 protein stability, the deubiquitinases involved in PD-L1 transcription for cancer cell immune evasion have not been identified. Herein, we developed a CRISPR-based screening platform and identified ATXN3 as a top positive regulator for PD-L1 transcription. Analysis of TCGA database revealed a statistically significant positive correlation between ATXN3 and CD274 expression in more than 80% human cancers, indicating that ATXN3 is a positive regulator for PD-L1 transcription in broad spectra of human cancers. ATXN3 promotes PD-L1 transcription induced by multiple tumor microenvironmental (TME) factors including inflammatory cytokine IFN-γ and hypoxia through protecting their downstream transcription factors IRF1, STAT3 and HIF-2α. In addition, ATXN3 functions as a deubiquitinase of PD-L1 transcription factors YAP-1 and JunB, indicating ATNX3 promotes PD-L1 expression through multiple pathways. Targeted deletion of ATXN3 in cancer cells resulted in reduced PD-L1 expression and consequently enhanced antitumor immunity in mice, which are partially revised by reconstitution of PD-L1 expression. Further, tumoral ATXN3 suppression improves the preclinical efficacy of checkpoint blockade antitumor immunotherapy and partially dependent on CD8+ T cells. Importantly, ATXN3 expression is increased in human lung adenocarcinoma and melanoma and its levels are positively corelated with PD-L1 as well as its transcription factor IRF1 and HIF-2α. Collectively, our study identifies a previously unknown deubiquitinase ATXN3 as a positive regulator for PD-L1 transcription and provides a rationale for ATXN3 targeting in sensitizing checkpoint blockade antitumor immunotherapy.
Citation Format: Shengnan Wang, Radhika Lyer, Deyu Fang. CRISPR screening identifies the deubiquitylase ATXN3 as a PD-L1 positive regulator for tumor immune evasion [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 618.
Abstract 6184: Pre-clinical study of SYX3759, a novel PARG inhibitor for the treatment of homologous recombination deficient malignancies
Authors: Tang Xuzhen , Cui Yaqi , Zhang Lanqiao , Jin Huihui , Xu Zeqiong , He Hu , Ge Chongxun , Liu Song , Yu Xiaochun , Shi Song 
Published: April 2023

Abstract
Although PARP inhibitors (PARPi) are very successful on the treatment of BRCA-mutant cancer, the tumor spectrum targeted by PARPi is quite narrow. Interestingly, Poly(ADP-ribose) Glycohydrolase (aka PARG), the major dePARylation enzyme, has emerged as a promising therapeutic target for cancer treatment. Here, we have developed a cell membrane permeable PARG inhibitor with subnanomolar IC50. SYX3759 directly binds to the catalytic domain of PARG and induces significant accumulation of PARylation at DNA lesions, where it traps numerous DNA repair factors, such as XRCC1. Compared to PARPi, such as Olaparib, SYX3759 shows selective and potent cytotoxicity on a broader spectrum of homologous recombination deficient (HRD) tumors both in vitro and in vivo. Moreover, SYX3759 is well tolerated at the highest dose tested without obvious adverse effect on hematopoiesis. Collectively, SYX3759 is a potent PARG inhibitor both in vitro and in vivo warranting future clinical trials for the treatment of HRD cancers and beyond.
Citation Format: Xuzhen Tang, Yaqi Cui, Lanqiao Zhang, Huihui Jin, Zeqiong Xu, Hu He, Chongxun Ge, Song Liu, Xiaochun Yu, Song Shi. Pre-clinical study of SYX3759, a novel PARG inhibitor for the treatment of homologous recombination deficient malignancies. [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 6184.
Abstract 6191: Temozolomide-associated DNA damage processes related to glioblastoma-immune interactions
Authors: Choe Elizabeth Y. , White Forest M. 
Published: April 2023

Abstract
How do cancer cells convert an external perturbation into an interaction with the immune system? The processes associated with antigen presentation remain largely unknown, especially in cancer cells responding to treatment. These intracellular changes may be critical in cancers where immunotherapies need significant optimization, such as glioblastoma. Glioblastoma is also a particularly relevant cancer to characterize the cellular response to perturbations, since all patients currently receive temozolomide, an alkylating agent, regardless of their prognosis.
We used mass spectrometry methods to quantify temozolomide-associated changes to the repertoire of peptides presented on MHC class I molecules in vitro over time, as well as the associated changes that occur in DNA damage signaling and protein synthesis. We treated U87-MG cells with temozolomide and directly profiled the peptide-MHC repertoire, ATM/ATR kinase substrate phosphorylation, and newly-synthesized proteins via isotopically labeled and non-canonical amino acid-tagged proteins after 24, 48, and 72 hours.
These proteomics approaches identified several MHC-peptides, including phosphorylated peptides, whose presentation changes over time after treatment with temozolomide. We also found that the temporal dynamics of the DNA damage response mirrored that of immunopeptidome remodeling. Additionally, temozolomide alters translation at these time points, with newly-synthesized proteins reflecting internal cell stress processes.
These findings suggest potential treatment-associated antigens against which to design vaccines as well as particular signaling nodes that could be modulated with combination therapies to improve presentation of these peptides.
Citation Format: Elizabeth Y. Choe, Forest M. White. Temozolomide-associated DNA damage processes related to glioblastoma-immune interactions [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 6191.
Abstract 6192: MSI2 regulates DNA damage response signaling and tumor progression in murine NSCLC
Authors: Bychkov Igor , Deneka Alexander , Topchu Iuliia , Pangeni Rajendra P. , Lengner Christopher , Izumchenko Evgeny , Patel Jyoti , Karanicolas John , Makhov Petr , Boumber Yanis 
Published: April 2023

Abstract
Lung cancer is one of the most frequently diagnosed cancers and is the leading cause of cancer-related death worldwide, accounting for &gt;2.2 million of new cancer diagnoses and 1.8 million cancer-related deaths in 2020. Non-small cell lung cancer (NSCLC) is the most common type of lung cancer, including adenocarcinomas and squamous cell carcinomas. Many lung adenocarcinomas have activating driver mutations in KRAS (~32% tumors), often co-occurring with mutations inactivating the TP53 tumor suppressor. Expression of the RNA-binding protein Musashi-2 (MSI2) MSI2 regulates target mRNA translation, and its expression is progressively elevated along with tumor stage in lung cancers. We previously showed that MSI2 actively promotes lung cancer growth, invasion, and metastasis, in part through promoting expression and activity of the TGFβR1/SMAD3 and EGFR signaling cascades. We now find that genetic MSI2 deficiency in a murine lung tumor model, Krasmut/Trp53KO/Msi2KO (KPM2) decreases both the total tumor number and tumor burden in comparison to control Krasmut/Trp53KO (KP) mice. Using a panel of KPM2 and KP cell lines we established from tumors from these mice, we found KPM2 cell lines demonstrate a significant decrease in proliferation compared to KP cell lines. Interestingly, reverse phase protein array (RPPA) comparison analysis of KPM2 and KP cell lines showed that MSI2 strongly and positively regulates expression of Ataxia-Telangiectasia Mutated (ATM) protein, with lower levels observed in KPM2 cells. The ATM serine/threonine protein kinase is a key transducer of DDR signaling in cases of double-strand breaks; ATM activation causes G1/S cell cycle arrest, contributes to efficiency of DNA repair, and triggers apoptosis in cases of repair failure. Notably, KPM2 cells showed significantly higher levels of γH2AX, suggesting inefficient DDR. Finally, untreated or cisplatin-treated KPM2 cells demonstrated G2/M arrest and had increased level of apoptosis as demonstrated by increase in caspase 3 cleavage, consistent with ATM loss and compensatory activation of Ataxia-telangiectasia and Rad3-related protein (ATR). Taken together, our data suggests that one of the consequences of MSI2 upregulation in NSCLC includes maintenance of an efficient DDR. Targeting MSI2 and its downstream signaling would be of therapeutic interest.
Citation Format: Igor Bychkov, Alexander Deneka, Iuliia Topchu, Rajendra P. Pangeni, Christopher Lengner, Evgeny Izumchenko, Jyoti Patel, John Karanicolas, Petr Makhov, Yanis Boumber. MSI2 regulates DNA damage response signaling and tumor progression in murine NSCLC [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 6192.
Abstract 6202: 6-Phosphofructo-2-kinase in regulating DNA damage and repair in EGFR-driven lung cancer
Authors: Lypova Nadiia , Lanceta Lilibeth , Dougherty Susan , Chesney Jason , Imbert-Fernandez Yoannis 
Published: April 2023

Abstract
Activating mutations of epidermal growth factor receptor (mutEGFR) are established drivers of lung tumor development, aggressiveness, and resistance to targeted therapies. While targeting mutEGFR with small-molecule tyrosine kinase inhibitors (EGFR-TKIs) dramatically improved progression-free survival in patients with non-small cell lung cancers (NSCLCs), intrinsic or acquired resistance to TKI therapy limits the duration of an effective response to TKIs. Alteration in DNA damage response (DDR) plays a vital role in genomic stability and cancer progression and helps cells to escape apoptosis, limiting the efficacy of targeted therapies.
Interestingly, lung cancer cells exposed to EGFR-TKIs demonstrate attenuated glycolytic flux - one of the major providers of precursors for de novo nucleotide synthesis. A key regulator of glycolysis is the enzyme 6-phosphofructo-2-kinase (PFKFB3). PFKFB3 synthesizes fructose 2,6-bisphosphate (F2,6BP), which is a potent allosteric activator of the glycolytic rate-limiting enzyme, 6-phosphofructo-1-kinase (PFK1). Accordingly, F2,6BP controls flux throughout the entire glycolytic pathway.
In preliminary studies, we provide evidence that PFKFB3 plays multiple roles in regulating the efficacy of DDR in lung cancer cells exposed to EGFR-TKIs. We show that PFKFB3 is required for EGFR-driven glucose metabolism, which provides a list of intermediates utilized in nucleotide synthesis. PFKFB3 regulates the expression of ribonucleotide reductase small subunit M2 (RRM2) of the ribonucleotide reductase (RNR), which is important for de novo onsite synthesis of deoxynucleotide triphosphate (dNTP) during DNA replication and repair. Moreover, a PFKFB3 inhibitor, PFK-158, increases oxidative stress in mutEGFR lung cancer cell lines and, as a result, promotes DNA damage. Importantly, we found that PFKFB3 plays an important role in the chromatin binding of scaffold proteins regulating the assembly of DNA repair complex.
Our studies suggest that PFKFB3 plays an important role in DDR and provide a clear rationale to propose the use of PFKFB3 inhibitors in combination with EGFR inhibitors to increase the efficiency and/or overcome resistance to EGFR-TKIs.
Citation Format: Nadiia Lypova, Lilibeth Lanceta, Susan Dougherty, Jason Chesney, Yoannis Imbert-Fernandez. 6-Phosphofructo-2-kinase in regulating DNA damage and repair in EGFR-driven lung cancer [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 6202.