bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2657: Preclinical model to evaluate the safety and efficacy of PODO83: A monoclonal antibody against podocalyxin that targets tumor growth and metastasis
Authors: Brassard Julyanne , Hughes Michael R. , Dean Pamela , Hernaez Diana Canals , Schwab Janella , Lau Yasmine , Roskelley Calvin D. , McNagny Kelly M. 
Published: June 2023

Abstract
Podocalyxin (PODXL) is a highly glycosylated transmembrane sialomucin normally found on the apical free surface of mesothelial, vascular endothelial, luminal mammary epithelial cells, kidney podocytes and pluripotent and hematopoietic stem cells. We were the first to show that PODXL is upregulated on human cancers and an independent predictor of poor prognosis in breast and high-grade serous ovarian carcinoma (HGSOC). We also demonstrated that PODXL expression is crucial for primary tumor growth, local invasion, and experimental metastasis to distant organs. Subsequently, these results were extended to a wide range of other tumor types. We next developed a large series of high-affinity monoclonal antibodies (mAb) to human PODXL and evaluated these for therapeutic activity against the PODXL+ metastatic breast cancer cell line, MDA-MB-231, in xenografted NOD-SCID IL2Rγ-/- (NSG) mice. One of these, PODO83, potently attenuated primary tumor growth and formation of distal metastases. The PODO83 reactive epitope maps to the juxtamembrane stalk domain (non-glycosylated region) of the PODXL core protein. As a promising therapeutic it is imperative to perform toxicity studies and determine if PODO83 adversely affects the function of PODXL on normal tissues. Accordingly, we generated a transgenic mouse strain (C57Bl/6 congenic) replacing 4 of the 8 mouse PODXL-encoding exons with the orthologous human exons (including those encoding the PODO83 epitope). These mice were healthy and we confirmed by immunohistochemistry that they exhibit appropriate PODO83 immunoreactivity in all expected tissues (podocytes, endothelia, etc). Strikingly, administration of PODO83 in vivo at high doses (4 treatments of 5 mg/kg over 14 days) resulted in no overt signs of toxicity. To now fully assess the safety and efficacy profile of the PODO83 mAb in this preclinical humanized mouse model we have developed mouse metastatic tumor cell line expressing human PODXL and will evaluate the ability of PODO83 to inhibit tumor growth and metastasis while sparing normal tissues in vivo. The results from this study will help us advance PODO83 mAb as a safe and effective approach to treating the wide variety of cancer subtypes that express PODXL.
Citation Format: Julyanne Brassard, Michael R. Hughes, Pamela Dean, Diana Canals Hernaez, Janella Schwab, Yasmine Lau, Calvin D. Roskelley, Kelly M. McNagny. Preclinical model to evaluate the safety and efficacy of PODO83: A monoclonal antibody against podocalyxin that targets tumor growth and metastasis [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 2657.
Abstract 2670: Drug combinations against Barrett's stem cells show efficacy across advanced lesions in esophageal cancer
Authors: Xian Wa , Lin Jennifer , Oraei Mona , McKeon Frank , Wang Shan , Ajani Jaffer , Crum Christopher , Bachovchin William , Khorrami Melina , Su Amber , Khorrami Melika , Song Shumei , Siegelman Jeremy , Vincent Matt , Ho Khek Yu , Yamamoto Yusuke 
Published: June 2023

Abstract
We have applied a single cell cloning technology to patient-matched endoscopic biopsies of Barrett's esophagus and co-existing lesions of low-grade dysplasia (LGD), high-grade dysplasia (HGD), and esophageal adenocarcinoma (EAC). In vitro differentiation and xenografting of these clones yields epithelia with histology corresponding to the origin of these clones, and the EAC clones yield aggressive tumors in vivo. In addition, genomic analyses of these clones reveals their phylogenetic relationships based on common and accumulating mutations. In efforts to identify drugs that would target the Barrett's stem cells for preemptive therapeutics, we performed parallel screens of small molecule libraries against Barrett's stem cells and patient-matched normal esophageal stem cells. Synthetic lethal strategies ultimately yielded drug combinations that showed low nanomolar efficacy against Barrett's stem cells that spared normal esophageal stem cells even at micromolar concentrations. The synthesis of new compositions of matter corresponding to these leads has identified powerful analogs that not only selectively eliminate stem cells of Barrett's esophagus but show similar efficacy in vitro against stem cells of LGD, HGD, and EAC. In vitro, these drug combinations show broad efficacy against Barrett's and EAC, with nanomolar elimination of 20 of 23 Barrett's cases and 6 of 7 EAC cases. In tumors derived from xenografting EAC clones, these new drug combinations show robust activity marked by tumor shrinkage and a profound loss of tumor cell clonogenicity. We foresee the potential of these synthetic lethal drug combination both as topical delivery for premetastatic lesions in the distal esophagus and perhaps as systemic applications for advanced EAC cases.
Citation Format: Wa Xian, Jennifer Lin, Mona Oraei, Frank McKeon, Shan Wang, Jaffer Ajani, Christopher Crum, William Bachovchin, Melina Khorrami, Amber Su, Melika Khorrami, Shumei Song, Jeremy Siegelman, Matt Vincent, Khek Yu Ho, Yusuke Yamamoto. Drug combinations against Barrett's stem cells show efficacy across advanced lesions in esophageal 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 2670.
Abstract 2676: Gender-associated improvement in gemcitabine’s therapeutic outcome by Palmatine
Authors: Ybarra Meagan Marie , Yang Xiaoyu , Munoz Amanda , Villarreal Michelle , Michalek Joel , Wang Li-Ju , Chen Yidong , Yuji Ikeno , Halff Glenn , Weintraub Susan , Gosh Rita , Kumar Addanki P. 
Published: June 2023

Abstract
Despite a plethora of therapeutic strategies, improved survival is only modest for patients diagnosed with pancreatic ductal adenocarcinoma (PDAC). Additionally, between 2000 and 2018, pancreatic cancer incidence significantly increased with the greatest increase among women ages 15-35 years. We identified a protoberberine alkaloid, Palmatine (PMT), that was effective in slowing tumor growth and improving therapeutic outcome of gemcitabine (GEM) in pancreatic tumor bearing mice. Interestingly, the improved therapeutic outcome with the combination was observed in a sex-associated manner in mice. Intriguingly, PMT reduced proliferation of cells isolated from surgically resected tumor samples in 71% of female and 33% of male pancreatic cancer patients. We also observed that the correlation between PMT effects on cancer-related biological functions was associated with downregulation of STAT3 signaling. RNA-seq data from STAT3-KD pancreatic cancer cells revealed enrichment of genes associated with fatty acid metabolism. Of these, mRNA expression of ELOVL2 (Elongation of Very Long Chain Fatty Acids-Like 2) was most significantly increased suggesting a negative regulatory role for STAT3 in ELOVL2 expression. In silico analysis of the pancreatic cancer UalcanPan database shows that ELOVL2 is significantly reduced in human pancreatic tumors relative to normal pancreas and that high expression of ELOVL2 is associated with increased survival. The fatty acid elongase, ELOVL2, is involved in the production of docahexaenoic acid (DHA). Our experimental data show that PMT increased ELOVL2 expression. Taken together, these findings suggest the potential utility of PMT in therapeutic sensitization of GEM through deregulation of STAT3-mediated ELOVL2 signaling. These observations further suggest a sex-associated role for PMT in improving outcomes that may in part involve ELOVL2 function. Supported in part through VA Merit Award BX003876 and Owens Foundation pilot (APK).
Citation Format: Meagan Marie Ybarra, Xiaoyu Yang, Amanda Munoz, Michelle Villarreal, Joel Michalek, Li-Ju Wang, Yidong Chen, Ikeno Yuji, Glenn Halff, Susan Weintraub, Rita Gosh, Addanki P. Kumar. Gender-associated improvement in gemcitabine’s therapeutic outcome by Palmatine [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 2676.
Abstract 2680: Combination of the Rac/Cdc42 inhibitor MBQ-167 with paclitaxel reduces metastasis in triple negative breast cancer
Authors: Cruz-Collazo Ailed M. , Grafals Nilmary , Borrero Luis D. , Dharmawardhane Suranganie 
Published: June 2023

Abstract
Metastasis represents a therapeutic challenge, especially in the case of triple negative breast cancer (TNBC), where patients often show recurrence and metastasis due to resistance to chemotherapy. The frontline therapy in TNBC is Paclitaxel, which targets actively dividing cells inducing subsequent apoptosis. Since dormant cells or metastatic cancer cells are not targeted by Paclitaxel, this strategy selects for non-dividing stem cells or more motile metastatic cells. Therefore, targeted treatment options are needed to overcome the recurrence and spreading of metastatic cells. We recently reported on MBQ-167, a Rac/Cdc42 inhibitor, which is highly effective in reducing tumor growth and metastasis in mouse models of TNBC (Cruz-Collazo et al., 2021, Molecular Cancer Therapeutics). Unpublished data show that in the MDA-MB-231 human TNBC model, MBQ-167 is as effective as Paclitaxel in reducing tumor growth and is more effective in metastasis prevention. Therefore, we hypothesize that MBQ-167 is a viable candidate for combined therapy with Paclitaxel and will reduce metastasis in TNBC. The purpose of this study is to test MBQ-167 in combination with Paclitaxel in the EGFR overexpressing MDA-MB-468 human TNBC cell line, which is highly malignant and also expresses the Rac1.B oncogenic splice variant. We found that MBQ-167 inhibits Rac, Rac1.B, and Cdc42 activation in this cell line. Next, we tested individual or combined MBQ-167 (50 mg/kg 5X a week) via oral administration and Paclitaxel (10 mg/kg 1X a week) via intraperitoneal administration in SCID mice bearing luciferase-tagged MDA-MB-468 tumors. Tumor growth and metastases were analyzed by chemiluminescence imaging followed by H&E staining of extracted lungs at necropsy. Similar to our studies with the syngeneic 4T-1/Balb/C model, in this MDA-MB-468 model, Paclitaxel increased metastasis while single agent MBQ-167 significantly reduced metastasis. MBQ-167 in combination with Paclitaxel reduced the enhanced lung metastasis in response to Paclitaxel. In conclusion, this study validates the clinical testing of MBQ-167 in combination with Paclitaxel as a potential combination therapy for TNBC.
Citation Format: Ailed M. Cruz-Collazo, Nilmary Grafals, Luis D. Borrero, Suranganie Dharmawardhane. Combination of the Rac/Cdc42 inhibitor MBQ-167 with paclitaxel reduces metastasis in triple negative breast 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 2680.
Abstract 2732: A self-replicating RNA precision medicine approach to therapeutic protein delivery of narrow therapeutic index biomolecules
Authors: Goldberg Zelanna , Maine Christian , Dailey Gabrielle P. , Domingo Christine , Picarda Gaelle , Little Hunter , Chou Annie , Sparks Jessica , Spasova Darina , Miyake-Stoner Shigeki , Rabiola Christopher A. , Crosby Erika J. , Hartman Zachary C. , Lyerly Herbert K. , Wang Nathaniel , Aliahmad Parinaz 
Published: June 2023

Abstract
Protein drug replacement using nucleic acid technologies has been a sought-after solution for in situ production of proteins with poor half-lives and challenging manufacturability. Linear mRNA approaches have failed clinically in this technological use case due to low levels of protein expression and poor durability. Self-replicating RNA (srRNA) is a new technology for expression of biotherapeutics combining the advantages of fully synthetic drug products with higher peak levels of protein expression with active expression persisting out to 49 days. RBI-2000 is a novel srRNA encapsulated in a lipid nanoparticle and encoding two distinct proteins on the same strand of RNA. The first protein is a pro-inflammatory multimeric cytokine to promote de novo immune cell generation and infiltration. The second molecule is a single chain high affinity protein antagonist of downstream mediators of the inflammasome to prevent sterile inflammation, aberrant angiogenesis, and tumor invasiveness. We selected a novel alphaviral vector which demonstrated an enhanced peak level of protein expression vs. the prototypical vector that has been used in other RNA products. These encoded proteins elicited a pharmacodynamic response that had no evidence of decay in the first 7 days following a single treatment down to doses of 0.01 mcg. Using an implanted MC38 tumor model, tumor control was obtained at the lowest, single dose tested at 0.1 mcg of RBI-2000. When tested in combination with a checkpoint inhibitor (CPI), a single dose of the CPI and a single dose of RBI-2000 at 10 mcg resulted in 80% tumor control in the mice (8/10 mice). Tumor re-challenge of the mice at a site distal to the original implantation showed 100% protection. Collectively, these data demonstrate the feasibility of novel srRNA vectors as a protein drug replacement approach including for the expression of complex, multimeric cocktails of proteins.
Citation Format: Zelanna Goldberg, Christian Maine, Gabrielle P. Dailey, Christine Domingo, Gaelle Picarda, Hunter Little, Annie Chou, Jessica Sparks, Darina Spasova, Shigeki Miyake-Stoner, Christopher A. Rabiola, Erika J. Crosby, Zachary C. Hartman, Herbert K. Lyerly, Nathaniel Wang, Parinaz Aliahmad. A self-replicating RNA precision medicine approach to therapeutic protein delivery of narrow therapeutic index biomolecules [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 2732.
Abstract 2733: TYMS as a novel target for AAV-based therapy
Authors: Vijayakurup Vinod , Meyer Benjamin , Nawab Akbar , Kaye Frederic J. , Guijarro Maria V. , Zajac-Kaye Maria 
Published: June 2023

Abstract
The purpose of this study is to develop a strategy for treating pancreatic neuroendocrine tumor (PanNET) through blocking Thymidylate Synthase (TYMS or TS), a DNA metabolic enzyme. Elevated TYMS levels are frequently observed in human PanNET and are associated with worse prognosis and resistance to cytotoxic agents such as 5FU. Elevated TYMS levels directly promote tumorigenesis in vitro and ectopic expression of human TS (hTS) in transgenic mice promotes adenoma development in the endocrine pancreas in vivo. Pancreatic islet tumor formation in hTS transgenic mice occurred with a long latency period, suggesting that additional somatic events are required for PanNET formation and progression. Men1 was shown to be a frequent target for somatic mutation in PanNETs (44% have MEN1 mutations). Therefore, we established a new mouse model designated hTS/Men1-/-, where hTS is overexpressed in pancreatic islet cells carrying conditional Men1 null alleles. We observed that ectopic hTS cooperates with Men1 inactivation to significantly accelerate PanNET progression and shorten survival. Since traditional TYMS inhibitors, such as 5-FU, consistently induce tumor resistance and cannot cure advanced disease, we have now tested the ability of TS-shRNA delivered using adeno-associated viral (AAV) vectors as a pharmacological safe and effective anti-tumor strategy. We packaged TS shRNA under the mouse insulin promoter (mIP) for islet-cell specific expression using capsid optimized Y to F double mutant AAV (AAV8-2M) to generate viral particles of scAAV8-2M-mIP-GFP-hTS-shRNA. We treated hTS/Men1-/- mice with intraperitoneal (IP) injection (1x1011 viral genomes/mice). Treated and control mice were analyzed for PanNET progression, TYMS expression and survival. In addition, we tested a human PanNET tumor cell line (BON) that was isogenic with or without hTS expression for tumor formation in xenograft model. We confirmed sustained reduction of TYMS levels 3 weeks after IP delivery of AA8-2M-mIP-GFP-hTS-shRNA into PanNET tissues of hTS/Men1-/- mice. In addition, AA8-2M-mIP-GFP-hTS-shRNA delivery blocked PanNET tumor progression and enhanced the survival of treated mice as compared to vector controls. We also confirmed that TYMS knock-down in BON cells by hTS-shRNA reduced xenograft tumor growth as compared to non-specific shRNA controls. In conclusion, the ability of AAV-mediated TS shRNA to block PanNET tumor progression directly demonstrates the importance of elevated TYMS in tumorigenesis and offers a novel anti-cancer strategy.
Citation Format: Vinod Vijayakurup, Benjamin Meyer, Akbar Nawab, Frederic J. Kaye, Maria V. Guijarro, Maria Zajac-Kaye. TYMS as a novel target for AAV-based therapy [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 2733.
Abstract 2863: Interferon-gamma induces NOS2 and COX2 in ER- breast cancer that drives increase metastatic potential
Authors: Cheng Yuk Sing Robert , Ridnour Lisa , Walke Abigail , Kedei Noemi , Wink Adelaide , Edmonston Elijah , Butcher Donna , Dorsey Tiffany , Heinz William , Bryant Richard , Kinders Robert , Lipkowitz Stanley , Wong Stephen , Pore Milind , Hewitt Stephen , McVicar Daniel , Anderson Stephen , Chang Jenny , Ambs Stefan , Lockett Stephen , Wink David 
Published: June 2023

Abstract
NOS2 and COX2 expression is significantly correlated with poor prognosis in ER- breast cancer. Multiple pro-oncogenic pathways involving metastasis, proliferation, angiogenesis, immunosuppression, and chemoresistance are stimulated in a synergistic manner by NOS2 and COX2, resulting in much more aggressive cancers. In this study, our single-cell RNAseq data demonstrated that certain combinations of cytokines, IFNg with TNFA or IL1B, drove NOS2 and COX2 expressions in vitro in the MDA-MB-231 cell line after 48 hours. Analysis of t-SNE plots indicates that the clustering patterns of NOS2 and COX2 are also related to cytokine expression. Moreover, according to our spatial proteomic analysis, CD8 that are associated with IFNg are more likely to have a positive response, indicating a dichotomy in the requirement for IFNg. To better understand this mystery, the spatial distribution of NOS2 and COX2 with CD8 cells in 21 ER- breast tumors was evaluated. In the presence of tumor-excluded CD8, high expression and clustering of NOS2-positive cells were seen near the tumor-stromal interface, showing that NOS2-positive cells were excluded from the tumor. Within the tumor nest, strong expression and population clustering of COX2 reached into the immune desert. In contrast, tumor-penetrant CD8 cells were few and poorly expressed. Metastasis and chemoresistance were among the leading causes of death in this cohort, and it was shown in vitro that IFNg/IL1B or TNFA increased tumor cell migration, suggesting that the interface of tumor with stromal restricted lymphoid aggregates provides the unique spatial environment to increase NOS2 expression and increase metastatic potential. The spatial study of the TME (tumor microenvironment) provides vital insight into how NOS2 and restricted CD8 lead to a higher probability of poor survival.
Citation Format: Yuk Sing Robert Cheng, Lisa Ridnour, Abigail Walke, Noemi Kedei, Adelaide Wink, Elijah Edmonston, Donna Butcher, Tiffany Dorsey, William Heinz, Richard Bryant, Robert Kinders, Stanley Lipkowitz, Stephen Wong, Milind Pore, Stephen Hewitt, Daniel McVicar, Stephen Anderson, Jenny Chang, Stefan Ambs, Stephen Lockett, David Wink. Interferon-gamma induces NOS2 and COX2 in ER- breast cancer that drives increase metastatic potential [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 2863.
Abstract 2864: Selective suppression of melanoma lacking IFN-γ pathway by JAK inhibition depends on T cells and host TNF signaling
Authors: Shen Hongxing , Huang Fengyuan , Zhang Xiangmin , Ojo Oluwagbemiga A. , Li Yuebin , Trummell Hoa Quang , Anderson Joshua C. , Fiveash John , Bredel Markus , Yang Eddy , Willey Christopher , Chong Zechen , Bonner James , Shi Lewis Z. 
Published: June 2023

Abstract
Therapeutic resistance to immune checkpoint blockers (ICBs) is a pressing issue, limiting ICB efficacy to a small proportion of cancer patients. Concerted efforts from our group and others have identified that loss of IFN-γ signaling genes in melanoma is a major mechanism of resistance to ICBs. However, strategies of overcoming this resistance have been largely elusive. Moreover, given the indispensable role of T cells in governing ICBs, little is known about how tumor-intrinsic loss of IFN-γ signaling impacts tumor-infiltrating T cells (TILs). In this study, we report that melanomas with defective IFN-γ signaling (IFNγR1KO) have reduced infiltration and function of TILs. Intriguingly, IFNγR1KO melanoma cells harbor a network of constitutively active protein tyrosine kinases (PTKs) centered on JAK1/2, essential downstream components of the IFN-γ signaling. Additional mechanistic studies reveal that JAK1/2 activation is mediated by augmentation of the mTOR pathway. Importantly, targeting active JAK1/2 with FDA-approved Ruxolitinib (Ruxo) selectively suppresses growth of IFNγR1KO but not scrambled control melanoma, in a T cell and host TNF-dependent manner. Together, our results highlight an important role of tumor-intrinsic IFN-γ signaling in shaping TILs and manifest a therapeutic target that can be leveraged to bypass ICB resistance of melanomas defective of IFN-γ signaling.
Citation Format: Hongxing Shen, Fengyuan Huang, Xiangmin Zhang, Oluwagbemiga A. Ojo, Yuebin Li, Hoa Quang Trummell, Joshua C. Anderson, John Fiveash, Markus Bredel, Eddy Yang, Christopher Willey, Zechen Chong, James Bonner, Lewis Z. Shi. Selective suppression of melanoma lacking IFN-γ pathway by JAK inhibition depends on T cells and host TNF signaling [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 2864.