bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3209: Everolimus inhibits angiogenesis and lymphangiogenesis to affect tumor growth in TP53 mutant HNSCC
Authors: Alam Md Maksudul , Fermin Janmaris Marin , Knackstedt Mark , Noonan Mackenzie J. , Daniel Emily K. , Moore-Medlin Tara , Rong Xiaohua , Khandelwal Alok R. , Nathan Cherie-Ann O. 
Published: June 2022

Abstract
Head and neck squamous cell carcinoma (HNSCC) constitutes the eighth most common cancer globally, with the eighth highest mortality rate amongst all cancer types. TP53 is the most frequently mutated gene in HPV -negative HNSCC. HPV-negative HNSCC harboring p53 mutations have the worst clinical outcomes with 50-60% local regional and distant recurrences causing increased morbidity and mortality. TP53 mutations are associated with shorter recurrence-free and overall survival. Angiogenesis and lymphangiogenesis play a causal role in tumor recurrence and lymph node metastasis. Therefore, inhibiting tumor angiogenesis and lymphangiogenesis is important in to preventing tumor recurrence and metastasis of TP53 mutant HNSCC. Previous studies demonstrated that mTOR activates STAT3 to upregulate HIF-1α and its target proteins, VEGF-A and VEGF-C, key molecules involved in angiogenesis and lymphangiogenesis, respectively. Further, mTOR inhibitors suppress autocrine and paracrine growth stimulation of tumor and lymphatic endothelial cells by impairing the VEGF-C/VEGF-3 axis and releasing soluble VEGFR-2. Accordingly, our objective was to investigate the effect of an mTOR inhibitor, everolimus, on angiogenesis and lymphangiogenesis of HPV-negative TP53 mutant HNSCC. Everolimus treatment of HPV-negative HNSCC cell lines harboring a variety of TP53 mutations, significantly downregulated protein and mRNA levels of VEGF-A and VEGF-C. Moreover, everolimus downregulated HIF-1α protein levels suggesting a HIF-1alpha-dependent VEGF modulation. Interestingly, treatment of human microvascular and lymphatic endothelial cells (HMEC-1 and HMEC-1A, respectively) with everolimus was also associated with a significant reduction in cell proliferation, in vitro tube formation, and migration. Protein and mRNA levels of HIF-1α, VEGF-A, and VEGF-C were downregulated by everolimus treatment in both HMEC-1 and HMEC-1A cell lines. Taken together, our data suggest that everolimus prevents angiogenesis and lymphangiogenesis through the inhibition of HIF-1α, indicating a promising role for mTOR inhibitors in treating HPV-negative TP53 mutant HNSCC patients at high risk for recurrence.
Citation Format: Md Maksudul Alam, Janmaris Marin Fermin, Mark Knackstedt, Mackenzie J. Noonan, Emily K. Daniel, Tara Moore-Medlin, Xiaohua Rong, Alok R. Khandelwal, Cherie-Ann O. Nathan. Everolimus inhibits angiogenesis and lymphangiogenesis to affect tumor growth in TP53 mutant HNSCC [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3209.
Abstract 321: Inhibition of CD39 results in elevated ATP and activation of myeloid cells to promote anti-tumor immunity
Authors: Bowman Christine E. , Chen Ada , Juat Damie , Parashar Kaustubh , Clor Julie , Singh Hema , Kushwaha Ritu , Handlos Bryan , Liu Suan , Kline Janine , Zhao Xiaoning , Kwon Hyock Joo , Green David , Young Stephen W. , Fernandez-Salas Ester , Walters Matthew J. , Walker Nigel P. 
Published: June 2022

Abstract
CD39 (ENTPD1) is an ecto-nucleoside triphosphate diphosphohydrolase expressed widely in the tumor microenvironment (TME) responsible for catalyzing the conversion of ATP to AMP. Inhibition of CD39 enzymatic activity can promote anti-tumor immune responses by increasing the immunostimulatory substrate ATP and decreasing the formation of the product AMP, a precursor to immunoinhibitory adenosine. CD39 inhibition has been shown to have an anti-tumor effect by activating dendritic cells, macrophages, and NK cells in the TME to promote antigen presentation and inflammatory cytokine release.
AB598 is a novel antibody, highly specific for human and cynomolgus CD39. AB598 potently binds to CD39 expressed on human primary myeloid cells and tumor cells and potently inhibits both soluble and membrane-bound CD39 enzymatic activity.
CD39 inhibition results in increased extracellular ATP (eATP) in the TME and subsequent activation of P2X and P2Y receptors. Myeloid cells highly express both CD39 and P2X7, the P2X receptor with the weakest ligand affinity for ATP (greater than 100 μM), and most likely to be specifically activated by very high levels of eATP resulting from CD39 inhibition. Thus, the myeloid compartment has emerged as a key target associated with the therapeutic effects of CD39 inhibition. AB598 retains the ability to bind and inhibit membrane bound CD39 in the presence of high ATP (400 μM). AB598 promotes maturation of human dendritic cells in the presence of ATP, as determined by increased expression of CD83 and CD86 and decreased expression of CD14. In human macrophages treated with ATP, AB598 activates the inflammasome, resulting in the secretion of pro-inflammatory IL-18 and IL-1β. The ATP-dependent effects of AB598 support a therapeutic rationale of combining it with immunogenic therapies that induce release of ATP, such as chemotherapy and radiation, which might represent a new paradigm in the treatment of advanced solid tumors.
Citation Format: Christine E. Bowman, Ada Chen, Damie Juat, Kaustubh Parashar, Julie Clor, Hema Singh, Ritu Kushwaha, Bryan Handlos, Suan Liu, Janine Kline, Xiaoning Zhao, Hyock Joo Kwon, David Green, Stephen W. Young, Ester Fernandez-Salas, Matthew J. Walters, Nigel P. Walker. Inhibition of CD39 results in elevated ATP and activation of myeloid cells to promote anti-tumor immunity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 321.
Abstract 3228: Body mass index and ovarian cancer: Changes after diagnosis and associations with overall survival
Authors: Beeghly-Fadiel Alicia , Phillips Sharon , Bukenya George , Pradhan Pranoti , Duque Sara , Anyanwu Nneka , Son Deok-Soo , Wilson Andrew J. , Hufnagel Demetra H. , Crispens Marta A. 
Published: June 2022

Abstract
Background: While excess adiposity is positively associated with ovarian cancer risk, the relationship with patient prognosis remains to be fully elucidated, especially with regard to changes over time during survivorship.
Methods: We assembled a retrospective cohort of tumor registry confirmed ovarian, fallopian tube, and primary peritoneal cancer cases and evaluated peri- and post-diagnosis (±30 days and up to 5 years after, respectively) body mass index (BMI) from electronic medical records (EMR) from the Vanderbilt University Medical Center. Associations with overall survival (OS) were quantified by Hazards Ratios (HRs) and corresponding 95% confidence intervals (CIs) from Cox proportional hazards regression; multivariable adjustment included age, stage, grade, histologic subtype, treatment, race, and year of diagnosis.
Results: We evaluated 13,676 peri- and post-diagnosis BMI observations for 616 predominantly Caucasian (87.0%) cases; the majority had serous histology (62.5%), advanced stage (58.1% Stage III or IV), high grade (52.4% poorly or undifferentiated) disease. Compared to peri-diagnosis (median =29.0), BMI was lowest 6 months post-diagnosis (median=27.4) and then gradually increased over time among survivors. In multivariable adjusted models, each 5-unit increase in mean peri-diagnosis BMI corresponded with a nonsignificant increase (HR: 1.07, 95% CI: 0.97-1.18) while higher mean post-diagnosis BMI corresponded to a significantly decreased risk of death (HR: 0.92, 95% CI: 0.84-1.00). Adjusted models that incorporated all peri- and post-diagnosis BMI observations evaluated indicated that each 5-unit increase in BMI was associated with a 15% reduced risk of death (HR: 0.85, 95% CI: 0.77-0.94).
Conclusions: Whereas lower adiposity may be beneficial in terms of risk, higher adiposity appears to benefit ovarian cancer survival. Factors including cancer cachexia, weight loss among ill patients, and weight gain among survivors may contribute to this seemingly protective association. Additional research to disentangle the influence of BMI on ovarian cancer outcomes and inform adiposity guidance for ovarian cancer survivors is needed.
Citation Format: Alicia Beeghly-Fadiel, Sharon Phillips, George Bukenya, Pranoti Pradhan, Sara Duque, Nneka Anyanwu, Deok-Soo Son, Andrew J. Wilson, Demetra H. Hufnagel, Marta A. Crispens. Body mass index and ovarian cancer: Changes after diagnosis and associations with overall survival [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3228.
Abstract 3233: Interleukin enhancer-binding factor 2 amplification controls mRNA stability and enhances DNA damage response in metastatic melanoma
Authors: Zhang Xiaoqing , Bustos Matias A. , Gross Rebecca , Ramos Romela Irene , Takeshima Teh-Ling , Mills Gordon B. , Yu Qiang , Hoon Dave S. 
Published: June 2022

Abstract
Background: 1q21.3 amplification is frequently observed in metastatic melanoma. Interleukin enhancer-binding factor 2 (ILF2) is in the 1q21.3 amplified region. The functional role of ILF2 as well as its contribution in promoting an aggressive phenotype in cutaneous metastatic melanoma is unknown.
Methods: In silico analyses were performed using the TCGA SKCM dataset with clinical annotations. The results were validated in three melanoma cohort microarray datasets from the GEO database. Melanoma tissues mRNA levels were assessed by RNA in situ hybridization and protein levels were analyzed by immunohistochemistry. Four stable metastatic melanoma cell lines were established for in vitro ILF2 functional characterization.
Results: Our results showed that the ILF2 copy number variation (CNV) is positively correlated with ILF2 mRNA expression (r=0.68, p&lt;0.0001). Additionally, ILF2 mRNA expression significantly increased with melanoma progression (p&lt;0.0001) and is significantly associated with poor overall survival in metastatic melanoma patients (p=0.026). In vitro, ILF2 overexpression (ILF2-OV) enhances cellular proliferation, whereas ILF2 knockdown decreases cellular proliferation by blocking the cell cycle. Mechanistically, we demonstrated the interaction between ILF2 and the splicing factor U2AF2. Reinforcing their functions as a complex, the U2AF2 knockdown reverses the cellular proliferation effects mediated by ILF2-OV. The levels of U2AF2 mRNA and protein levels increased during melanoma progression. Stage IIIB-C melanoma patients with high ILF2-U2AF2 expression showed significantly shorter overall survival (p=0.024). Functional assays showed that enhanced ILF2/U2AF2 expression promotes a more efficient DNA-damage repair by increasing RAD50 and ATM mRNA expression. Paradoxically, metastatic melanoma cell lines with ILF2-OV were more sensitive to ATM inhibitors.
Conclusion: Our study uncovered that the ILF2 and U2AF2 complex may have biological implications in controlling the mRNA stability of RAD50 and ATM in metastatic melanoma. Clinically, ILF2 amplification is associated with melanoma progression, triggers a functional downstream pathway in metastatic melanoma that promotes DNA damage repair, and increases the sensitivity to ATM inhibitors.
Citation Format: Xiaoqing Zhang, Matias A. Bustos, Rebecca Gross, Romela Irene Ramos, Teh-Ling Takeshima, Gordon B. Mills, Qiang Yu, Dave S. Hoon. Interleukin enhancer-binding factor 2 amplification controls mRNA stability and enhances DNA damage response in metastatic melanoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3233.
Abstract 3261: LNG-451, a potent inhibitor of EGFR exon 20 insertion mutations with high CNS exposure
Authors: Pearson Paul G. , Pandey Anjali , Roth Bruce , Saxton Tracy , Estes Daniel J. , Trivedi Ravi , Agrawal Himanshu , Hallur Gurulingappa , Ahmad Ishtiyaque , Jenkins Helen , Murray Brion W. 
Published: June 2022

Abstract
Exon 20 insertion mutations (Ex20ins) are the 3rd most common type of EGFR oncogenic mutation in lung cancer patients and are often associated with brain metastases. While several small molecules have been approved (mobocertinib) or are in clinical development (e.g. CLN-081, BDTX-189) none have demonstrated meaningful CNS activity and they can be associated with treatment-limiting adverse events, including wild-type (WT) EGFR-mediated toxicities. LNG-451 is a potent covalent inhibitor of EGFR Ex20ins (IC50 7 - 78 nM) and other EGFR oncogenic mutations (e.g L858R IC50 = 3 nM, exon 19 deletion IC50 = 24 nM) while being selective against WT EGFR (IC50 = 1630 nM). LNG-451 causes tumor regression in both cell line-derived and patient-derived EGFR Ex20ins-dependent xenograft tumor models. In a rat CNS PK model, a single oral dose of 30 mg/kg LNG-451 achieved high exposures in plasma (AUC0 - 8h = 9771 ng•h/mL) and brain (AUC0 - 8h = 10,041 ng•h/g). In a rat steady-state CNS PK model, unbound partition coefficient for LNG-451 was determined to be Kpu,u = 0.66. To evaluate the potential for LNG-451 to treat metastatic brain disease driven by EGFR mutations, an intracranial PC9-luc xenograft mouse model harboring an EGFR exon 19 deletion mutation was used (LNG-451 cellular EGFR Del19 IC50 = 10.6 nM). LNG-451 had dose-dependent exposures in the plasma and brain with both high mean brain exposure (e.g 1074 ng/g with 25 mg/kg LNG-451) and high mean brain to plasma ratios (e.g. 0.451 for 25 mg/kg LNG-451). LNG-451 treatments were well-tolerated and produced significant anti-tumor activities with 99.5% (2.5 mg/kg LNG-451) and 99.9% (25 mg/kg LNG-451) reductions in total bioluminescence signal (BLI) and regression of tumor BLI (2.5 mg/kg LNG-451 28.8% regression; 25 mg/kg LNG-451, 80.3% regression). An ex vivo imaging analysis of the brain and spinal cords from all animals at the end of the study showed a dose-dependent decrease in the bioluminescent signal in both brain and spinal cords from mice treated with LNG-451 relative to the vehicle control animals. Taken together, LNG-451 is a CNS-penetrant, wild-type EGFR-sparing, EGFR Ex20ins inhibitor that is expected to provide strong anti-tumor efficacy for patients with advanced/metastatic solid cancers harboring oncogenic EGFR exon 20 insertions with reduced WT EGFR driven toxicities.
Citation Format: Paul G. Pearson, Anjali Pandey, Bruce Roth, Tracy Saxton, Daniel J. Estes, Ravi Trivedi, Himanshu Agrawal, Gurulingappa Hallur, Ishtiyaque Ahmad, Helen Jenkins, Brion W. Murray. LNG-451, a potent inhibitor of EGFR exon 20 insertion mutations with high CNS exposure [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3261.
Abstract 3289: PD-1 peptide/IL-12 combination gene therapy for the treatment of melanoma
Authors: Heller Loree , Shi Guilan , Synowiec Jody , Heller Richard 
Published: June 2022

Abstract
Immune checkpoint inhibitors (ICIs) such as PD-1 targeting antibodies nivolumab and pembrolizumab are FDA approved as therapies for many cancers. These ICIs inhibit PD-1 ligand binding, removing interference with T cell function, allowing T cell proliferation, and restoring the anti-tumor activity. Potential factors predicting checkpoint blockade success include PD-L1 expression, the presence of tumor infiltrating lymphocytes, microsatellite instability, and tumor mutational burden. ICIs are most effective clinically in combination therapies. Here, we devised a simple ICI gene therapy as a possible alternative to traditional and expensive monoclonal antibodies. We designed plasmids encoding the mouse sequences homologous to the nivolumab and pembrolizumab binding regions, which overlap the PD-1 ligand binding site. We hypothesized that, when produced intratumorally, each PD-1 peptide should bind PD-L1 and block T cell binding. Since B16F10 mouse melanoma cells and tumors express PD-L1, we tested this theory in this model. We directly demonstrated peptide-PD-L1 binding histologically on B16F10 mouse melanoma tumors. Systemic expression of the encoded peptides did not induce changes in general demeanor, discomfort or weight changes in mice, implying that intratumor expression would also be non-toxic. We then tested these peptide plasmids therapeutically. Intratumor electroporation delivery of the peptide plasmids to palpable B16F10 mouse melanoma tumors significantly increased tumor doubling time and induced approximately 10% long-term tumor regression. Delivery of a plasmid encoding IL-12 induced long-term tumor regression in approximately 40% of mice as well as a reduction myeloid-derived suppressor cells and T regulatory cells and an increase infiltration of CD8+ T cells, creating an inflamed tumor microenvironment. This modulation of the tumor microenvironment suggested the potentiation of a combination therapy. This combination synergistically increased long-term regression to 80-100%, depending on the peptide plasmid delivered, over either PD-1 peptide or IL-12 gene therapy alone. These results demonstrated that the delivery of immune regulators with differing activities may be a promising and potentially inexpensive alternative to monoclonal antibody therapies.
Citation Format: Loree Heller, Guilan Shi, Jody Synowiec, Richard Heller. PD-1 peptide/IL-12 combination gene therapy for the treatment of melanoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3289.
Abstract 329: Understanding the role of GPR30 in the estrogen non-genomic signaling in inflammatory breast cancer
Authors: Soto Xavier S. Bittman , Lopez Adrian J. Rivera , Peterson Esther A. 
Published: June 2022

Abstract
Inflammatory Breast Cancer (IBC) is rare and the most aggressive subtype of all breast cancers, reporting rapid progression, poor prognosis, and a unique clinical diagnosis (blockage of lymph vessels by tumor emboli). Approximately, 40% of IBC cases are classified as triple-negative breast cancer (TNBC), meaning they test negative for hormone receptors (estrogen and progesterone) and the amplification of the epidermal growth factor receptor 2 (HER2), which leads to no effective targeted therapies availability. However, 17β-estrogen (E2) has been found to enhance the migration and invasion phenotypes of TN-IBC cells and it has been associated with the presence of a membrane G-protein coupled estrogen receptor (GPR30) and a novel cytoplasmic estrogen receptor (ERα36 isoform) that can undergo an estrogen non-genomic (rapid) cell’s response. Recent studies have also reported a crosstalk between these estrogen non-genomic receptors and the epidermal growth factor receptor (EGFR) signaling pathway in the presence of E2, inducing phosphorylation of the extracellular signal-regulated kinase (ERK1/2) and promoting oncogenic phenotypes (migration & invasion) in TN-IBC cells. However, the exact role of GPR30 and ERα36 in the non-genomic signaling pathway remains elusive in TN-IBC. We hypothesis that GPR30 and ERα36 are necessary to undergo de estrogen non-genomic signaling and promote oncogenic phenotypes in TN-IBC SUM149 cells after E2 treatment.
Methods: We have measured migratory activity and tumor emboli formation of SUM149 cells (by wound-healing and 3D-cell proliferation assay), and phosphorylation levels of ERK1/2 and AKT kinases (by western-blot) after treatments in time-points with E2 alone and in combination with G15 (GPR30 antagonist drug). We are also working to identify protein partners of GPR30 (by Ip and Mass-spec) after E2 treatment, including physical interaction with ERα36, in TN-IBC and other types of breast cancers.
Results: G15 treatment in Sum149 cells significantly reduced E2-induced ERK1/2 phosphorylation, indicating that GPR30 is necessary for the estrogen non-genomic signaling pathway and has direct involvement with the EGFR signaling cascade. Data acquired from these experiments will contribute to a better understanding of TN-IBC’s molecular structure and create new opportunities to develop novel targeted therapies.
Citation Format: Xavier S. Bittman Soto, Adrian J. Rivera Lopez, Esther A. Peterson. Understanding the role of GPR30 in the estrogen non-genomic signaling in inflammatory breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 329.
Abstract 3292: Double targeting oncolytic herpes simplex virus type 1 (oHSV-1) exhibits effective antitumor activity against EpCAM-expressing cancer cells
Authors: Baek Hyunjung , Joo Hyun-Yoo , Park Eun-Ran , Ahn Chun-Seob , Lee Sujung , Kim Hyeri , Han Mihee , Kim Bora , Kwon Heechung 
Published: June 2022

Abstract
Oncolytic virotherapy is a new modality of immunotherapy using spontaneously occurring or genetically engineered viruses to selectively replicate in and kill cancer cells, no harming normal cells. Currently, various oncolytic herpes simplex virus (oHSVs) with enhanced tumor targeting, antitumor efficacy, and safety have been explored in many different models, and on a range of tumor targets. It has been a difficult task to completely retarget HSV to cancer-specific antigens at the plasma membrane of selected tumors, while maintaining the fully lytic potential of HSV. This approach achieved by a deep knowledge of virus natural receptor recognition, binding, and entry mechanisms. Two strategies have been employed including the incorporation of single-chain antibodies (scFv) into gD, gC or gH and the use of soluble adapter molecules that are capable of binding to both HSV and the specific receptor on the target cell. In the previous study, we first reported that HSV could retarget to gastric carcinoma cells by HVEM-CEA adapter molecule. Although we have been shown reasonable efficiency of retargeted cell transduction in vitro and in vivo, it required purification of the adapter protein and continuous addition to the virus prior to infection. To overcome the limitations of adapter molecules, we developed a self-retargeting system by incorporation of adapter expression cassette into the HSV genome that enables the sustained secretion of adapter protein while the viral replication in infected tumor cells. Furthermore, to strengthen the retargeting modality, we constructed a novel, double targeted oHSV, carries no deletion/attenuation, consisting of self-retargeting adapter and modified gH to EpCAM. Our results show that the initial infection and subsequent viral spread depend on cellular EpCAM expression. When injected intravenously (i.v.), they caused no harm to tumor-free mice up to the maximum tested dosage (2 x 108 PFU). When a single intratumoral dose of double targeting oHSV (2 x 106 infectious units) were administered in a xenograft model they rendered 80% of mice tumor-free. Our findings suggest that the double retargeting platform of HSV carrying self-retargeting adapter and modified gH may be potent in cancer-specific cell killing and thus useful for the treatment of EpCAM expressing various cancers.
Citation Format: Hyunjung Baek, Hyun-Yoo Joo, Eun-Ran Park, Chun-Seob Ahn, Sujung Lee, Hyeri Kim, Mihee Han, Bora Kim, Heechung Kwon. Double targeting oncolytic herpes simplex virus type 1 (oHSV-1) exhibits effective antitumor activity against EpCAM-expressing cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3292.