bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3257: Unleashing immune power: How mRNA-encoded modulators suppress tumor growth
Authors: Wang Dong , zhang zhixiang , wang peili , duan binbin , qiang xiangnan , gu qingyang 
Published: March 2024

Abstract
Subsequent to the emergence of the COVID-19 pandemic, an increased number of nucleic acid-based therapeutics have secured clinical endorsement. Unlike conventional protein-targeted therapies, nucleic acid therapeutics provide the potential for long-lasting effects and can be further categorized into oligonucleotides, single-guide RNA (sgRNA), and messenger RNA (mRNA). In this study, we aim to explore the anti-tumor properties of mRNA-encoded CD3-EpCAM Bispecific Antibody (BsAb) and mRNA-encoded IL-12 protein.
We conducted qPCR, flow cytometry, and ELISA analysis to assess the dynamic concentration of mRNA-encoded CD3-EpCAM BsAb and mRNA-encoded IL-12 protein within tumor cells post-transfection. We then accessed their effects on anti-tumor and immune activation in vitro via flow cytometry and ELISA. Furthermore, using in vivo imaging system (IVIS), we were able to determine the biodistribution of mRNA-encoded BsAb in vivo. Efficacy was evaluated in subcutaneous tumor xenograft models with mRNA content in tumors examined via qPCR. Moreover, we analyzed the activation of tumor-infiltrating immune cells post mRNA-encoded IL-12 treatment. Finally, to ascertain the preliminary safety of mRNA-encoded BsAb and mRNA-encoded IL-12 protein, we conducted serum biochemistry analysis and histopathological examination of various organs.
In this comprehensive preclinical evaluation, we found that both mRNA-encoded BsAb and mRNA-encoded IL-12 promoted the activation and cytotoxicity of human T cells, exhibiting significant inhibitory effects on tumor growth in vivo while maintaining a favorable safety profile. Our findings provide compelling evidence that mRNA therapeutics hold significant research value and exhibit promising potential for clinical applications.
Citation Format: Dong Wang, zhixiang zhang, peili wang, binbin duan, xiangnan qiang, qingyang gu. Unleashing immune power: How mRNA-encoded modulators suppress tumor growth [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 3257.
Abstract 3263: VEGFA mediates traditional EGFR-TKI resistance in non-small cell lung cancer with EGFR exon 20 insertions
Authors: Yang Yaning , Liu Chengming , Yang Guangjian , Xu Haiyan , Lei Siyu , Wang Yan 
Published: March 2024

Abstract
Background: Epidermal growth factor receptor (EGFR) exon 20 insertions (Ex20ins) accounted for 4%-12% of EGFR mutations and showed primary resistance to EGFR tyrosine kinase inhibitors (EGFR-TKIs) which is an urgent issue to be solved. In our previous studies, we found that antiangiogenetic therapy had certain advantages for patients with Ex20ins in the real-world practice. Previous research showed the tumor microenvironment has been associated with resistance to targeted therapy in sensitive mutations. However, the mechanism of resistance of EGFR-TKIs and the advantage of antiangiogenetic therapy in patients with EGFR Ex20ins were still unclear.
Methods: In this study, patients with EGFR exon 19 deletion (19del), exon 21 p.L858R (21L858R), and Ex20ins were collected to identify the efficacy of EGFR-TKIs. Stable cell lines expressing were established and used to compare signaling pathway activation. Matrigel angiogenesis assay was conducted in different cell lines. Next, we evaluated the efficacy of various treatments combined with antiangiogenetic agents or not in mouse models.
Results: We collected 23 patients with EGFR sensitive mutations and Ex20ins, respectively, and found Ex20ins presented primary resistance to TKIs and poor survival outcomes. Based on the RNA sequence of stable cell lines, it was found that Ex20ins had a higher level of VEGFA expression and enriched in MAPK pathway compared to EGFR 19del and 21L858R. Immunohistochemical studies also revealed that a higher level of VEGFA expression was observed in a cohort of NSCLC patients with Ex20ins mutation compared with 19del or L858R. Matrigel angiogenesis assay has shown consistent result that Ex20ins promoted angiogenesis in vivo. Further experiments in mouse models identified that in the group of Osimertinib, mobocertinib alone, chemotherapy alone, mobocertinib or chemotherapy combination with bevacizumab, Osimertinib achieved the worst efficacy and additional utility of antiangiogenetic agents had a more favorable efficacy.
Conclusion: Our study highlights the potential of VEGFA as a mechanism of resistance to EGFR-TKIs and induces immunosuppression microenvironment in NSCLC with Ex20ins. Furthermore, the findings suggested that antiangiogenetic therapy could be a promising therapeutic approach.
Keywords: VEGFA, targeted therapy, resistance, EGFR exon 20 insertions, non-small cell lung cancer
Citation Format: Yaning Yang, Chengming Liu, Guangjian Yang, Haiyan Xu, Siyu Lei, Yan Wang. VEGFA mediates traditional EGFR-TKI resistance in non-small cell lung cancer with EGFR exon 20 insertions [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 3263.
Abstract 3329: Development of HM-001 as a therapeutic drug for non-muscle invasive bladder cancer
Authors: Mima Shinji , Sakaki Monta , Kiya Noriaki , Kawashima Atsunari , Nonomura Norio , Kakinuma Chihaya 
Published: March 2024

Abstract
HM-001 is a drug containing sodium chlorite as the active ingredient that is being developed as a drug for non-muscle invasive bladder cancer (NMIBC), and is currently undergoing physician-led clinical trials. It has been discovered that sodium chlorite generates radicals in an acidic environment, and phosphatidylserine on the surface of tumor cells acts as a Lewis acid to generate radicals. HM-001, like other anticancer drugs and BCG, is intended to be injected into the bladder, retained, and then excreted. GLP studies using the same administration method has been completed, and no toxic changes have been observed in human trial doses. The efficacy of HM-001 against NMIBC was evaluated using an orthotopic transplantation model of UM-UC-3, a bladder cancer cell line. In the model, cells were transplanted into the bladder of SCID mouse after epithelial removal with trypsin, 600, 800, 1,600, and 3,200 ppm of HM-001 were administered once a week, and the weight of the excised bladder was calculated. After 4 weeks, the tumor weight was calculated and the tumor weight suppression rate in the control group was evaluated. As a result, the medicinal efficacy was confirmed at concentrations of 800ppm or higher. On the other hand, the UM-UC-3 model is a commonly used model, but it mimics CIS (carcinoma in situ) and can only partially mimic NMIBC. That is, other models are needed to evaluate efficacy for low- and high-grade NMIBC other than CIS. Therefore, we established high-grade and low-grade PDX and evaluated the effectiveness of HM-001 against low- and high-grade PDX through ex vivo testing. First, patient-derived tissue was transplanted into SCID mice, allowed to grow, and then removed. After extraction, they were cut into 2 mm3 pieces, exposed to HM-001 at 800, 1600, and 3200 ppm for 2 hours, and then transplanted into SCID mice. As a result of comparing the tumor size after transplantation with the control group, a dose-dependent tumor regression effect was confirmed in high-grade and low-grade PDX. NMIBC is divided into low-, medium-, and high-risk categories, with different treatment methods and drugs used for each. In particular, low-grade forms are restricted to low- and intermediate-risk groups. The results of this study show that HM-001 is effective not only for high-risk (including CIS) NMIBC but also for low- and intermediate-risk (low-grade) NMIBC.
Citation Format: Shinji Mima, Monta Sakaki, Noriaki Kiya, Atsunari Kawashima, Norio Nonomura, Chihaya Kakinuma. Development of HM-001 as a therapeutic drug for non-muscle invasive bladder cancer [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 3329.
Abstract 3330: BPP, a dual functional inhibitor, targets MLL-rearranged acute myeloid leukemia: Unraveling mechanisms and expanding therapeutic horizons
Authors: Chen Tai-Lin , Su Tsann-Long , Lee Te-Chang 
Published: March 2024

Abstract
Refractory/recurrent acute myeloid leukemia (AML) poses a formidable clinical challenge, with MLL translocations implicated in approximately 10% of AML cases and a staggering 75% in infant leukemia, bearing an unfavorable prognosis. Our investigation focuses on BPP, a dual-functional inhibitor capable of inducing DNA cross-linking and suppressing angiogenesis. In a diverse panel of solid tumor and leukemic cells, BPP exhibited exceptional sensitivity against MLL-rearranged AML cell types. In MOLM13 and MV4-11 xenograft models, BPP showcased outstanding tumor suppression, with some tumors even achieving complete remission. In-house acute toxicity testing, BPP treated group showed excellent safety margin in both blood chemistry and pathological examination. Remarkably, BPP demonstrated significant cytotoxicity not only in FLT3-WT AML but also in FLT3-ITD AML. Delving into the mechanism, BPP was found to induce FLT3-ITD and MLL degradation by triggering DNA damage and ER stress. Comet assays revealed a dose-dependent accumulation of DNA fragments in MLL cells upon BPP exposure.The involvement of the KMT2A gene in chromosomal translocation in THP1 cells was highlighted, with BPP treatment resulting in a significant increase in Heat-shock protein. Notably, the combination of ganetespib, an FDA-approved HSP90 inhibitor, with BPP exhibited synergistic effects in both in vitro and in vivo models, inducing synthetic lethality and inhibiting HR repair. Furthermore, BPP not only reduced leukemic stem cells in colony formation assays but also demonstrated sensitivity in relapsed/refractory (R/R) and multiple drug-resistant patient samples. These findings collectively position BPP as a promising candidate for the treatment of MLL-rearranged AML, offering multifaceted therapeutic potential.
Citation Format: Tai-Lin Chen, Tsann-Long Su, Te-Chang Lee. BPP, a dual functional inhibitor, targets MLL-rearranged acute myeloid leukemia: Unraveling mechanisms and expanding therapeutic horizons [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 3330.
Abstract 3334: Combined treatment with PG3 and Nelfinavir induced synergistic apoptosis though sustained activation of integrated stress response
Authors: Tian Xiaobing , El-Deiry Wafik S. 
Published: March 2024

Abstract
Integrated stress response (ISR) activation has been linked to many human diseases, including cancer and neurological diseases. The ISR controls protein synthesis and proteostasis. ISR main effector ATF4 transcriptional factor regulates the balance between survival and cell death. Under acute ISR, ATF4 promotes cell adaptation and survival. Sustained ISR leads to ATF4-mediated apoptosis. In many cancers, mutations or overexpression of oncogenes, results in enhanced cell proliferation and increased protein synthesis, which activate the ISR. Therefore, protein translation is reduced to maintain proteostasis. In other words, many cancers are primed by the ISR. Therefore, additional push by small molecule ISR-inducers will disrupt the balance and force cancer cells to enter apoptosis. Nelfinavir activates ATF4 through inhibition of eIF2α specific phosphatases CReP and GADD34. PG3 upregulates ATF4 through the HRI/eIF2α/ATF4 pathway. We hypothesize that combined treatment of PG3 and Nelfinavir will sustain upregulation of ATF4, and lead to ATF4-mediated cell apoptosis. Cell viability assays indicated that the combined treatment potently and synergistically inhibited cell viability in colorectal cancer cell lines HT29, SW480 and HCT116 p53−/−, osteosarcoma cell line U2OS and breast cancer cell lines MCF7 and T47D. The combined treatment sustained the induction of ATF4 and enhanced the expression of its proapoptotic target genes, CHOP and PUMA, and cell apoptosis. We confirmed that the enhanced induction of ATF4, CHOP and PUMA is through the ISR because ISRIB (ISR inhibitor) blocked the combined treatment-induced upregulation of ATF4, CHOP and PUMA.
Citation Format: Xiaobing Tian, Wafik S. El-Deiry. Combined treatment with PG3 and Nelfinavir induced synergistic apoptosis though sustained activation of integrated stress response [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 3334.
Abstract 3438: Associations between estimated endotoxin exposure and circulating immunological markers among male farmers
Authors: Ezennia Somayina C. , Beane-Freeman Laura E. , Chang Vicky C. , Xie Shuai , Andreotti Gabriella , Friesen Melissa C. , Hofmann Jonathan N. 
Published: March 2024

Abstract
Occupational exposure to endotoxin has been associated with reduced lung cancer risk. Farmers who perform certain tasks (e.g., raising hogs) can be highly exposed to endotoxin. The mechanisms through which endotoxin could confer a lower risk of lung cancer, while likely to be immune mediated, are not clear. To address this gap, we evaluated associations between estimated endotoxin exposure and circulating immunologic markers among male farmers in the Biomarkers of Exposure and Effect in Agriculture (BEEA) study. Our investigation included 122 non-smoking farmers from Iowa, oversampling those raising hogs (n=61). We evaluated 58 serologic markers, including some linked to lung cancer, that were measured using multiplex bead-based assays. Based on an algorithm linking personal air measurements in BEEA and published data to reported farming tasks, we estimated cumulative endotoxin exposure in the last 30 days and 12 months before sample collection. We used multivariable linear regression to estimate geometric mean ratios of immune markers across exposure quartiles, overall and by season of sample collection. Higher endotoxin exposure in the last 30 days was associated with increased levels of FGF-2, MIP-3A/CCL20, and sIL-4R (Ptrend ≤ 0.02), and with decreased levels of MDC/CCL22 (Ptrend = 0.02). In analyses stratified by season, the positive associations with FGF-2 and MIP-3A/CCL20 were most apparent in the winter (Ptrend = 0.002 and 0.03, respectively); we also observed an inverse association with sCD27 levels in the summer (Ptrend = 0.03). Similar patterns were observed for endotoxin exposure in the last 12 months. This study is the first to use novel algorithm-based endotoxin exposure estimates to evaluate associations with intermediate lung cancer-related markers. Several markers were associated with endotoxin levels in an exposure-response manner. Our findings suggest possible biological mechanisms through which endotoxin may reduce risk of lung cancer.
Table 1. Associations between estimated endotoxin exposure in the last 30 days and selected serum im
Citation Format: Somayina C. Ezennia, Laura E. Beane-Freeman, Vicky C. Chang, Shuai Xie, Gabriella Andreotti, Melissa C. Friesen, Jonathan N. Hofmann. Associations between estimated endotoxin exposure and circulating immunological markers among male farmers [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 3438.
Abstract 3470: Evaluation of the association between sickle cell disease and breast cancer using the All of Us Research Program dataset
Authors: Jubilee Ivan T. , Evans Lauren K. , Lemieux KiTani Parker 
Published: March 2024

Abstract
Background: The All of Us Research Program (AoURP) dataset was used to evaluate pharmacological treatment modalities in patients with both breast cancer (BC) and sickle cell disease (SCD). This study aims to identify treatment strategies for sickle cell patients with BC that may inform improved treatment options for patients living with either or both conditions, as there is an imminent need in this patient population.
Methods: We investigated the relationship between SCD and BC using the AoURP dataset. Criteria were female patients with a confirmed diagnosis of concomitant SCD and BC were selected. Hematologic, antineoplastics, and immunomodulating agents prescribed to patients were identified. Analysis was conducted in a Jupyter Notebook environment by way of R. Using FDA-approved and off-label indications, medication use patterns were used to reverse-engineer patient information and identify trends between SCD and BC.
Results: Nine female patients had concomitant diagnoses of SCD and BC, which aligned with the inclusion criteria. African Americans were significantly represented in this cohort, making up sixty-seven of patients. Twenty-two percent of patients did not indicate race, while eleven percent of patients identified as Caucasian. All patients included in the study were prescribed anemic therapy. Eleven percent of patients were prescribed an FDA-approved medication for SCD. Seventy-eight percent of patients were prescribed hormone-targeted BC medications. Thirty-three percent of patients were prescribed the immunotherapy regimen, Dinutuximab with adjunctive interferon-alpha. Eleven percent of patients were prescribed cytotoxic therapy.
Conclusion: Further investigation is warranted for dinutuximab use in BC treatment, specifically the triple negative subtype, as currently no targeted therapeutic options exist, and prognosis is poor. The data suggests dinutuximab with adjunctive interferon-alpha may be promising for triple-negative BC patients with SCD.
Citation Format: Ivan T. Jubilee, Lauren K. Evans, KiTani Parker Lemieux. Evaluation of the association between sickle cell disease and breast cancer using the All of Us Research Program dataset [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 3470.
Abstract 3515: SynAI: An AI-driven cancer drug synergism prediction platform
Authors: Yan Kuan , Jia Runjun , Guo Sheng 
Published: March 2024

Abstract
Introduction: The SynAI solution is an adaptive AI-driven in silico drug synergism screening solution aiming to discover the potential therapeutic value of compounds at an early development stage. Given one of both compound inputs in SMILE sequences, SynAI can predict the potential Bliss score of compounds in any given cell line without the need for compound synthesis or structural analysis.The evaluation version of SynAI is accessible at https://synai.crownbio.com
Methods: The AI core of SynAI was constructed using the MLP (multi-layer perceptron) network under the PyTorch machine learning framework. The AI core of SynAI was trained against NCI-Almanac and DrugCombDB datasets. In total, these datasets consist of over 12 million in vitro synergism tests across 150 cancer cell lines of different origins. On average, each cell line is tested against over 6000 two-compound combinations of FDA-approved cancer drugs. One MLP network was trained for each cell line. Essentially, these networks predict the Bliss score for any combination of SMILE-based feature sets known as molecular fingerprints. The networks were trained against the NCI Almanac set and verified against NCI and DrugCombDB using n-fold cross-validation to avoid model overfitting. During the training, a hyperparameter tuning (HT) study was performed for SynAI and other popular algorithms; allowing an objective comparison of SynAI performances.
Results: Compared to existing synergism prediction platforms, SynAI yields similar performance in all categories (cf. Table 1) but provides more flexibility for data input using SMILE sequences directly. In addition, the AI core of SynAI can be constantly updated with new inputs from different cell lines and drug combinations. Table 1. Pearson cross correlation (PCC) between measured and predicted Bliss scores of NCI test set
Conclusions: Its adaptive and dynamic nature allows SynAI to learn from new data feeds from future studies and has significant potential in reducing the time and cost of synergism screening.
PCC Score Cell Lines Algorithm MCF7 OVCAR-8 SK-MEL-5 SynAI 0.68 ± 0.02 0.56 ± 0.07 0.86 ± 0.02 RF 0.64 ± 0.02 0.55 ± 0.03 0.89 ± 0.02 GBX 0.66 ± 0.02 0.48 ± 0.05 0.88 ± 0.02 RNN 0.54 ± 0.12 0.43 ± 0.06 0.83 ± 0.08
Citation Format: Kuan Yan, Runjun Jia, Sheng Guo. SynAI: An AI-driven cancer drug synergism prediction platform [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 3515.