bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 5964: Context-dependent induction of interferon signaling by CD11b agonists supports anti-tumor immunity in mouse models and human cancer patients
Authors: Liu Xiuting , Hogg Graham , Zuo Chong , Baer John , Lander Varintra , Kang Liang , Borcherding Nicholas , Knolhoff Brett , Osterhout Robin , Galkin Anna , Bruey Jean , Carter Laura , Mpoy Cedric , Schwarz Julie , Park Haeseong , Gupta Vineet , DeNardo David 
Published: April 2023

Abstract
Chronic activation of inflammatory pathways and suppressed interferon signaling are hallmarks of myeloid cells in immunosuppressive tumors that drive poor responsiveness to conventional and immune therapies. Previous studies have identified agonistic activation of the CD11b integrin as a potential strategy to enhance anti-tumor immunity. However, the mechanisms by which CD11b-agonism reprogram tumor immunity are poorly understood, and this may impair patient selection and identification of effective treatment combinations. Here we will use a combination of in vitro systems, animal models, and samples from first in human clinical trials of the CD11b-agonist to identify the mechanism of action of this approach and identify combinations for further testing. CD11b agonism alters tumor-associated macrophage (TAM) phenotypes by simultaneously repressing NFκB/IL1-signaling and activating interferon (IFN) gene expression. Repression of NFκB/IL-1 signaling was due to rapid degradation of p65 protein by the proteosome, contributing to suppressing myeloid cells infiltration. In contrast, CD11b agonism triggers mitochondrial dysfunction to stimulate STING-induced, STAT1-mediated interferon signaling, contributing to macrophages-augmented anti-tumor T cell immunity. Tissues from phase I clinical trials shows that CD11b agonist activates STING and STAT1 signaling in TAMs in human tumors, which is in consistent with preclinical data. Furthermore, combining CD11b agonism with cytotoxic therapies, STING agonist or TLRs agonists leads to robust anti-tumor activity in PDAC models. These studies pave the way for mechanism-based therapeutic combination strategies in cancer patients.
Citation Format: Xiuting Liu, Graham Hogg, Chong Zuo, John Baer, Varintra Lander, Liang Kang, Nicholas Borcherding, Brett Knolhoff, Robin Osterhout, Anna Galkin, Jean Bruey, Laura Carter, Cedric Mpoy, Julie Schwarz, Haeseong Park, Vineet Gupta, David DeNardo. Context-dependent induction of interferon signaling by CD11b agonists supports anti-tumor immunity in mouse models and human cancer patients [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 5964.
Abstract 5968: Leukemia inhibitory factor regulates macrophage immune response in head and neck squamous cell carcinoma
Authors: Sui Yun Hua , Liu Tzu Tung , Liu Shu Chen 
Published: April 2023

Abstract
The high recurrence rate of head and neck squamous cell carcinoma (HNSCC) is associated with an immune suppressive tumor microenvironment (TME). Tumor-associated macrophage (TAM)-mediated immunosuppression is a critical feature in HNSCC TME. We provide evidence demonstrating that leukemia inhibitory factor (LIF) is involved in macrophage polarization and remodeling of the HNSCC microenvironment. By interrogating the head and neck squamous cell carcinoma RNA sequencing dataset extracted from the TCGA database, we found that the levels of LIF and M2 macrophage markers (CD163, CD206, VEGF) were enhanced in tumors compared to normal counterparts. Higher LIF expression in tumors was further correlated with worse overall survival. Immunohistochemical analysis found that macrophages with higher LIF immunoreactivities were located at the periphery of HNSCC tumors. In a macrophage-cancer cell coculture system, the presence of LIF promoted the proliferation and mobility of cancer cells and induced an M2-dominant macrophage polarization. Stimulating monocyte-derived macrophages (MDMs) with LIF increased the expression of several M2 markers (CD163, CD206, CD209, and IL10) but decreased the expression of M1 markers (iNOS, CD80, and CD86). Moreover, LIF-treated macrophages exhibited little cancer cytotoxicity compared to vehicle-treated macrophages. Treating macrophages with soluble LIF receptor (sLIFR), a LIF antagonist, partly reversed the LIF-mediated M2 polarization and enhanced cytotoxicity toward cancer cells. Results of RNA-sequencing data demonstrated that LIF suppressed antigen presentation process, type I interferon production, TNFR signaling, and molecules participating in the Hippo signaling pathway in MDMs. Mechanistic studies found that LIF might trigger M2 polarization via activating YAP1, as reflected by a reduction of p-YAP1 (S127) and an enhanced YAP1 nuclear localization in macrophages. Treating macrophages with YAP1 inhibitors (Saracatinib and Verteporfin) blocked the LIF-mediated YAP1 nuclear translocation, expression of M2 markers, and tumor-promoting effects. Our findings suggest that the presence of LIF in HNSCC promotes macrophage M2 polarization through YAP1 signaling, which assists in establishing an immune-suppressive, tumor-promoting microenvironment. The blockade of LIF-mediated effects may tailor therapeutic strategies by converting the immunosuppressive microenvironment for selected HNSCC patients.
Citation Format: Yun Hua Sui, Tzu Tung Liu, Shu Chen Liu. Leukemia inhibitory factor regulates macrophage immune response in head and neck squamous cell carcinoma [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 5968.
Abstract 6086: PALB2 germline mutations in a large cohort Middle Eastern breast-ovarian cancer patients
Authors: Bu Rong , Sira Abdul K. , Parvathareddy Sandeep , Iqbal Kaleem , Azam Saud , Qadri Zeeshan , Al-Rasheed Maha , Haqawi Wael , Diaz Mark , Victoria Ingrid G. , Al-Kuraya Khawla S. 
Published: April 2023

Abstract
Background: The PALB2 gene encoding protein is involved in the homologous recombination repair pathway and plays an important role in maintaining genomic integrity. PALB2 heterozygous pathological variants (PV) or likely pathogenic variants (LPV) are associated with increased risk of breast and ovarian cancer. However, the prevalence and clinicopathological association of PALB2 germline PV/LPV in Middle Eastern breast and ovarian cancers is not fully identified.
Purpose: We retrospectively screened a cohort of 918 cancer patients (791 breast cancer and 127 ovarian cancer) from Saudi Arabia using targeted capture-based next generation sequencing (NGS) method for PALB2 germline variants regardless the family history of these patients or the presence of other hereditary cancer susceptibility genes mutations. Clinicopathological criteria were also fully analyzed.
Results: Five heterozygous PVs or LPVs were identified in six cases, accounting for 0.65% (6/918) of entire cohort. Two cases (33.3%) harbored PVs and four cases (66.7%) carried LPVs. Four PVs/LPVs (80%) were frameshift along with one novel splicing LPV (c.2835-1 C&gt;A). One recurrent LPV (c.3425delT) was identified in two cases. All six affected carriers have breast cancer diagnosis with median age of 39.5 years (range 34-49 years). Only two cases (33%) have documented family history of cancer. Breast cancer phenotype was invasive ductal unilateral cancer in all cases with 66.7% of hormone receptor positive and 16% of triple negative tumors.
Conclusion: Germline PVs/LPVs in the PALB2 gene were observed in low frequency of 0.65% in Saudi breast and/or ovarian cancer. Our study confirms one recurrent LPV and one novel LPV in Saudi breast cancer patients.
Citation Format: Rong Bu, Abdul K. Sira, Sandeep Parvathareddy, Kaleem Iqbal, Saud Azam, Zeeshan Qadri, Maha Al-Rasheed, Wael Haqawi, Mark Diaz, Ingrid G. Victoria, Khawla S. Al-Kuraya. PALB2 germline mutations in a large cohort Middle Eastern breast-ovarian cancer patients [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 6086.
Abstract 6128: Deubiquitinating enzyme Inhibitor PR-619 inducesendoplasmic reticulum stress-related apoptosisin human chondrosarcoma
Authors: Kuo Kuan-Lin , Hsu Chen-Hsun , Liao Shih-Ming , Huang Kuo-Yuan 
Published: April 2023

Abstract
It is reported that PR-619 is a deubiquitination enzyme inhibitor that can exert anti-tumor effects on a variety of malignancies. We conducted this study to explore the antitumor effects of PR-619 on chondrosarcoma in vitro and in vivo by using two different classes of human chondrosarcoma cell lines SW-11353 and JJ012. To determine these effects, we measured cell viability (MTT), apoptosis (detection of Annexin V-FITC labeling using flow cytometry) and western blot to evaluate molecules associated with apoptosis and cell stress. In addition, we used a nude mouse xenograft mouse model to determine the effect of PR-619 on tumor growth. As our data revealed, in addition to inducing BAD and activating Capase-7, Caspase-8, and PARP, PR-619 also has a dose-effect that induces cytotoxicity, proliferation restriction, and apoptosis in these human chondrosarcoma cells. PR-619 has also been found to activate endoplasmic reticulum pressure-related molecules (caspase-4 and CHOP) and other stress responses (activation of JNK and c-Jun). We conclusively demonstrated the ability of PR-619 to inhibit tumor growth while achieving minimal general toxicity in a developed xenograft mouse model of chondrosarcoma. Therefore, we conclude that PR-619 exacts an antitumor effect in conjunction with cellular and endoplasmic reticulum pressure in human chondrosarcoma. These findings suggest that PR-619 may provide a novel therapeutic strategy for chondrosarcoma.
Citation Format: Kuan-Lin Kuo, Chen-Hsun Hsu, Shih-Ming Liao, Kuo-Yuan Huang. Deubiquitinating enzyme Inhibitor PR-619 inducesendoplasmic reticulum stress-related apoptosisin human chondrosarcoma [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 6128.
Abstract 6225: SERPINB3 promotes the aggressive basal-like/squamous subtype and correlates with poor prognosis in pancreatic ductal adenocarcinoma through metabolic reprogramming
Authors: Ohara Yuuki , Tang Wei , Huaitian Liu , Yang Shouhui , He Peijun , Cawley Helen , Valenzuela Paloma , Zhang Lin , Gaedcke Jochen , Ghadimi B. Michael , Gaida Matthias M. , Bergmann Frank , Alexander H. Richard , Hanna Nader , Ambs Stefan , Hussain S. Perwez 
Published: April 2023

Abstract
In this study, we aimed to find genes with a key function in the development of molecular subtypes in pancreatic ductal adenocarcinoma (PDAC). Through transcriptome analysis, we discovered that the endogenous serine/cysteine proteinase inhibitor SERPINB3 (squamous cell carcinoma antigen 1, SCCA1) was distinctively upregulated in the basal-like/squamous subtype, known as an aggressive subtype, and this upregulation associated with decreased patient survival in both a test (N=123) and a validation cohort (N=84). In additional investigations of the tumor metabolome and transcriptome using PDAC patient tumors and cell lines, SERPINB3 and the basal-like/squamous subtype showed a robust relationship with upregulated levels of amino acids (e.g., hydroxyproline) whereas SERPINB3 promoted a gene signature indicative of the basal-like/squamous subtype. Additional mechanistic studies revealed that SERPINB3 and hydroxyproline promoted the migration/invasion of PDAC cells. Moreover, SERPINB3 also promoted metastasis in an orthotopic mouse model of PDAC through stromal factors that increased tumor microvessel density. To conclude, inhibiting SERPINB3 function may attenuate disease progression of the basal-like/squamous subtype in PDAC through changes to the tumor stroma and tumor metabolism.
Citation Format: Yuuki Ohara, Wei Tang, Liu Huaitian, Shouhui Yang, Peijun He, Helen Cawley, Paloma Valenzuela, Lin Zhang, Jochen Gaedcke, B. Michael Ghadimi, Matthias M. Gaida, Frank Bergmann, H. Richard Alexander, Nader Hanna, Stefan Ambs, S. Perwez Hussain. SERPINB3 promotes the aggressive basal-like/squamous subtype and correlates with poor prognosis in pancreatic ductal adenocarcinoma through metabolic reprogramming [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 6225.
Abstract 6236: Stellettin B induces apoptosis and autophagy in human bladder cancer RT112 cells
Authors: Chen Mei-Chuan , Chang Chun-Han 
Published: April 2023

Abstract
Bladder cancer is one of the most prevalent cancers worldwide. Although most of the patients have good prognosis and good life expectancy with standard treatments, recurrence rate and five-year survival rate have not been significantly improved in patients with bladder cancer, demonstrating there is an urgent need for development of a novel therapeutic strategy for the treatment of bladder cancer. Stellettin B (SP-2), a triterpene isolated from marine sponge Jaspis stellifera , suppresses cell viability in bladder cancer RT112 cells without severe toxicity toward normal uroepithelial SV-HUC-1 cells. Our results showed that SP-2 induces accumulation of cells at subG1 phase in parallel with increase of early apoptotic cells via annexin V/PI staining and activation of cell apoptotic death proteins. Moreover, non-cytotoxic concentrations of SP-2 induces LC3-II formation and p62 downregulation to activate autophagy in RT112 cells, suggesting autophagy may play a role in SP-2 -induced cell death. Inhibition of autophagy by pharmacological inhibitors (3-MA and chloroquine) or ATG5 knockout protects stellettin B-induced apoptosis and cell viability suppression, indicating SP-2 induces autophagy to promotes cell death. Taken together, stellettin B may be a promising therapeutic agent for bladder cancer treatment.
Citation Format: Mei-Chuan Chen, Chun-Han Chang. Stellettin B induces apoptosis and autophagy in human bladder cancer RT112 cells [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 6236.
Abstract 6720: Using proteasome inhibition to hyperactivate the integrated stress response in aggressive pediatric brain tumors
Authors: Novak Orlandi Valencia , Findlay Tyler , Rubens Jeffrey , Eberhart Charles , Raabe Eric H. 
Published: April 2023

Abstract
H3K27-altered diffuse midline glioma (DMG) and atypical teratoid/rhabdoid tumor (AT/RT) are aggressive pediatric brain tumors with dismal outcomes. DMG and AT/RT have increased baseline activation of the integrated stress response (ISR), an evolutionarily conserved system that enables cells to tolerate various forms of stress. This activation is manifested by elevated levels of ATF4 and NRF2 in DMG and AT/RT, respectively. Transient or low-level expression of these transcription factors protect cells from stress, while sustained, high-level activation leads to cell death. Ixazomib is an orally bioavailable proteasome inhibitor that causes endoplasmic reticulum stress, which is a major upstream activator of the ISR. We hypothesized that the high baseline level of ATF4 in DMG and NRF2 in AT/RT would make these tumors susceptible to ISR activators such as ixazomib. After determining the IC50 of ixazomib, DMG and AT/RT cell lines (JHH-DIPG1, JHH-DIPG16A, and CHLA06) were treated with increasing concentrations of the drug. Cleaved caspase 3 immunofluorescence showed a significant increase of apoptosis in all cell lines (JHH-DIPG16A and CHLA06 p&lt;0.0001, JHH-DIPG1 p=0.0008 by ANOVA). Additionally, western blots for cleaved PARP and phospho-Rb expression detected induction of apoptosis and suppression of cell proliferation in JHH-DIPG1 treated with ixazomib. We are currently testing ixazomib in combination with idarubicin, a brain-penetrant anthracycline, and gemcitabine, a brain-penetrant nucleoside analog. Synergy testing in CHLA06 showed an overall zero-interaction-potency (ZIP) synergy score of 23.464 with inhibitory concentrations of ixazomib and idarubicin in the low nanomolar range (scores of 10 or above indicate synergy). Similarly, ixazomib and gemcitabine synergized to suppress CHLA06 growth and induce apoptosis (67% Annexin V+ cells in combination compared to 14 and 24% Annexin V+ with single agent treatment). In the future, we will determine if ixazomib selectively kills DMG and AT/RT while sparing normal cells in iPSC brain organoids. We will also test ixazomib singly and in combination with traditional chemotherapy in orthotopic xenografts of AT/RT. These results suggest that ixazomib, especially in combination with idarubicin, gemcitabine or other ISR activators, has the potential to serve as an effective therapy for aggressive pediatric brain tumors.
Citation Format: Orlandi Valencia Novak, Tyler Findlay, Jeffrey Rubens, Charles Eberhart, Eric H. Raabe. Using proteasome inhibition to hyperactivate the integrated stress response in aggressive pediatric brain tumors [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 6720.
Abstract 6725: Targeting urea cycle dysfunction to prevent and treat osteosarcoma
Authors: Offenbacher Rachel , Ciero Paul , Loeb David 
Published: April 2023

Abstract
Introduction: Osteosarcoma (OS) is the most common primary malignant bone tumor in adolescents and young adults. Intensive multimodal treatment cures almost 75% of patients who present with localized disease; however, only 25% of patients who present with metastases become long term survivors, and those who suffer a metastatic relapse are almost never cured. Polyamine metabolism and signaling play important roles in multiple cancers but have not previously been studied in osteosarcoma. D, L-alpha-difluoromethylornithine (DFMO) is an irreversible inhibitor of ornithine decarboxylase (ODC), the initial, rate-limiting enzyme within the polyamine biosynthetic pathway, and has been studied in a number of different cancers as either a therapeutic or a chemopreventive agent. We investigated the role of polyamines in OS proliferation and metastasis and whether blocking the polyamine synthetic pathway with DFMO had therapeutic potential in the treatment of OS.
Methods: We evaluated proliferation, apoptosis, clonogenic growth and the ability to grow under nonadherent conditions in vitro using established OS lines. To investigate the effect of DFMO on tumor growth in vivo, we implanted fragments of patient derived xenograft into the tibias of NOD/SCID/IL-2Rγ null mice. Upon confirmation of tumor growth, mice were randomized to either receive drinking water or drinking water supplemented with 2% DFMO. A third cohort of mice received water supplemented with 2% DFMO only after hindlimb amputation.
Results: DFMO has a profound effect on the proliferation of OS cell lines in vitro. Utilizing caspase assays, we determined that DFMO does not induce apoptosis, but is cytostatic and inhibits proliferation. We found that DFMO prevents the clonogenic growth of 3 different OS cell lines in soft agar and prevents spheroid formation under non-adherent conditions. Interestingly, once established, spheroidss were not disrupted by the addition of DFMO. In vivo, administration of 2% DFMO after hindlimb amputation decreased local recurrence and limited metastasis (p=0.02).
Conclusion: DFMO inhibits proliferation and clonogenic growth in vitro, and decreases distant metastasis in vivo. Since pediatric dosing and safety data are already established, our findings are readily translatable to clinical trials.
Citation Format: Rachel Offenbacher, Paul Ciero, David Loeb. Targeting urea cycle dysfunction to prevent and treat osteosarcoma. [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 6725.
Abstract 6757: Identification of predictive factors for early relapse in patients with unresectable stage III NSCLC receiving consolidation durvalumab after concurrent chemoradiation
Authors: Yeo Chang Dong , Kang Hye Seon , Kim In Kyoung , Lee Sang Haak , Kim Jin Woo 
Published: April 2023

Abstract
Background: Patients with locally advanced, unresectable, non-small cell lung cancer (NSCLC) receiving definitive concurrent chemoradiation (CCRT) benefit from durvalumab consolidation therapy. However, predictive factors for early relapse during durvalumab maintenance were not identified.
Patients and Methods: The present study used the lung cancer cohort of the Catholic Medical Centers at the Catholic University of Korea from 2018 to 2021. In all, 51 NSCLC patients that were treated with durvalumab consolidation therapy after definitive CCRT. Early relapse was considered if it occurred within 6 months of starting initial durvalumab therapy.
Results: During study period, 15 (29.4%) relapsed among 51 included patients. Median time from initial therapy of durvalumab to progression was 107.73 ± 47.69 days in early relapse group. In mutivariate analysis, younger age (HR 0.713, 95% CI 0.572-0.888, P=0.003), higher pack years (HR 1.311, 95% CI 1.109-1.549, P=0.001), non-COPD (HR 0.030, 95% CI 0.001-0.677, P=0.027), anemia (HR 23.30, 95% CI 2.030-267.48, P=0.011) and stage IIIC (vs. stage IIIA) (HR 17.890, 95% CI 1.997-160.243, P=0.010) were independent predictive factors for early relapse during durvalumab consolidation therapy.
Conclusion: Younger age, higher pack years, non-COPD, anemia and stage IIIC were independent predictive factors for early relapse during durvalumab consolidation therapy in patients with unresectable stage III NSCLC after definitive CCRT. Careful patient selection and clinical attention are needed for high-risk individuals.
Citation Format: Chang Dong Yeo, Hye Seon Kang, In Kyoung Kim, Sang Haak Lee, Jin Woo Kim. Identification of predictive factors for early relapse in patients with unresectable stage III NSCLC receiving consolidation durvalumab after concurrent chemoradiation. [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 6757.