bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1532: Next generation IgM antibody based multimeric platform: ePENDY (engineered pentamer body)
Authors: Kang Sungmuk , Kang Hyeonju , Koo Jihye , Kim Yoojin , Park Suho , Lee Inyoung , Yi Jiye , Lee Hong Jai , Cho Yonghyun , Hwang Hyunju , Hyun Kyunggi , Lee Chungmin , Ha Gyongsik 
Published: June 2023

Abstract
Among many candidates from the recent diverging research to develop a multivalent platform, IgM has shown potential as a pharmaceutical because of its avidity coming from natural multimeric target binding ability. IgM has a great advantage of naturally forming multimers, however, there are some unfulfilled needs to become a good pharmaceutical platform, such as limited biological activity, short half-life, safety concerns, and difficult purification steps compared to IgG. Here, we developed an antibody platform, ePENDY, by engineering IgM to improve efficacy, safety, and convenience of manufacturing process. ePENDY has a self-assembling decavalent pentameric structure and it is an improved IgM with maximized biological activity as therapeutics by using flexible linkers. In addition, ePENDY was engineered one of the effector functions of antibodies, ADCC, was greatly increased compared to IgG as well as IgM which does not have this function. More importantly, the presence or absence of effector functions can be controlled depending on the MoA (Mode of action) of the target. Serum half-life of ePENDY was significantly increased compared to natural IgM, and ePENDY showed similar PK profiles as the IgG Fc-based molecules through FcRn recycling. Unlike natural IgM, ePENDY does not bind to any IgM receptors, such as pIgR, FcμR, and Fcα/μR, thereby eliminating possible side effects. In addition, it has been confirmed that ePENDY showed a comparable expression level to that of IgG, and since the purification process can also be set up in a process like IgG, thus production of ePENDY can be facilitated. Based on these results, we are researching ePENDY which are applying various therapeutic molecules, such as antibodies, protein ligand-based active molecules and therapeutic cancer vaccines. We expect that our versatile applicable platform, safe and long acting ePENDY, can be a superior tool for the various therapeutic targets.
Citation Format: Sungmuk Kang, Hyeonju Kang, Jihye Koo, Yoojin Kim, Suho Park, Inyoung Lee, Jiye Yi, Hong Jai Lee, Yonghyun Cho, Hyunju Hwang, Kyunggi Hyun, Chungmin Lee, Gyongsik Ha. Next generation IgM antibody based multimeric platform: ePENDY (engineered pentamer body) [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 1532.
Abstract 1590: Identification and characterization of a first-generation inhibitor of claudin-1 to inhibit colon cancer progression and metastasis
Authors: Fatima Iram , Uppada Jaya Prakash , Chhonker Yashpal S. , Gowrikumar Saiprasad , Barman Susmita , Roy Sourav , Tolentino Kirsten T. , Palermo Nicholas , Natarajan Amar , Beauchamp Daniel R. , Vecchio Alex , Murry Daryl J. , Singh Amar B. , Hopkins Corey R. , Dhawan Punita 
Published: June 2023

Abstract
Colorectal cancer (CRC) is a leading cause of cancer-related deaths worldwide. Thus, developing novel and targeted therapies for inhibiting CRC progression and metastasis is urgent. Several studies, including ours, have reported a causal role for an upregulated claudin-1 expression in promoting CRC metastasis through the activation of the Src and β-catenin-signaling. In murine models of colon tumorigenesis, claudin-1 overexpression promotes oncogenic properties such as transformation and invasiveness. Conversely, the downregulation of claudin-1 inhibits colon tumorigenesis. Despite being a desirable target for cancer treatment, there are currently no known claudin-1 inhibitors with antitumor efficacy. Using a rigorous analytical design and implementing in-vitro and in-vivo testing and a brief medicinal chemistry campaign, we identified a claudin-1-specific inhibitor and named it I-6. Despite its high potency, I-6 was rapidly cleared in human liver microsomes. We, therefore, synthesized I-6 analogs and discovered a novel small molecule, PDS-0330. We determined that PDS0330 inhibits claudin-1-dependent CRC progression without exhibiting toxicity in in-vitro and in-vivo models of CRC and that it binds directly and specifically to claudin-1 with micromolar affinity. Further analyses revealed that PDS-0330 exhibits antitumor and chemosensitizer activities with favorable pharmacokinetic properties by inhibiting the association with metastatic oncogene Src. Overall, our data propose that PDS-0330 interferes with claudin-1/Src association to inhibit CRC progression and metastasis. Our findings are of direct clinical relevance and may open new therapeutic opportunities in colon cancer treatment and/or management by targeting claudin-1.
Citation Format: Iram Fatima, Jaya Prakash Uppada, Yashpal S. Chhonker, Saiprasad Gowrikumar, Susmita Barman, Sourav Roy, Kirsten T. Tolentino, Nicholas Palermo, Amar Natarajan, Daniel R. Beauchamp, Alex Vecchio, Daryl J. Murry, Amar B. Singh, Corey R. Hopkins, Punita Dhawan. Identification and characterization of a first-generation inhibitor of claudin-1 to inhibit colon cancer progression 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 1590.
Abstract 1659: Development of HJC0152, its analogs and protein degraders to modulate STAT3 for triple-negative breast cancer therapy
Authors: Vontz Gabrielle , Li Jun , Ma Ruixia , Xu Jimin , Zhou Mingxiang , Chen Haiying , Zhou Jia , Shen Qiang 
Published: June 2023

Abstract
Breast cancer represents the most commonly diagnosed female malignancy worldwide. Although breast cancer screening and treatments have improved significantly over the last half-century, aggressive subtypes like triple-negative breast cancer (TNBC) as well as growing chemoresistance cases continue to evade frontline therapies. STAT3, a transcription factor involved in cell proliferation, survival, and malignant transformation, plays a key role in mammary carcinogenesis, resistance, and recurrence. Both STAT3 overexpression and aberrant activation are frequently observed in primary breast tumors and their metastatic lesions. Although STAT3 is recognized as an attractive preventive and therapeutic target, there are no FDA-approved STAT3 inhibitors in clinical use. Via structure- and fragment-based drug design strategies as well as in silico molecular modeling and docking, our team previously developed a putative STAT3 inhibitor, HJC0152. This study aims to further characterize the anticancer mechanism of HJC0152 as well as optimize its potency. Our results show that HJC0152 interacts with STAT3 with a similar specificity to an experimental STAT3 inhibitor, Stattic. To further improve its potency and efficacy, we developed several HJC0152 derivatives including HJC0152-based proteolysis targeting chimera (PROTAC) degraders. Several molecules showed comparable or improved potency to HJC0152 against several breast cancer cell lines including TNBC cells. While the total STAT3 protein level reduces moderately with HJC0152 treatment, several new compounds decrease STAT3 protein level more profoundly. In particular, the newly developed HJC0152-PROTACs showed a significant late inhibition of STAT3 phosphorylation at the Tyr705 and Ser727 residues as well as a reduction in total STAT3 protein. Our data indicate that HJC0152-based analogs and protein degraders can suppress breast cancer cell proliferation, likely through targeting STAT3 signaling pathway. Future experiments will determine the molecular prolife of promising molecules as well as assess their in vivo anticancer efficacy using xenograft models. This project is supported by NIH/NCI Awards R01CA226001 and R01CA231150 to Q.S. and J.Z.
Citation Format: Gabrielle Vontz, Jun Li, Ruixia Ma, Jimin Xu, Mingxiang Zhou, Haiying Chen, Jia Zhou, Qiang Shen. Development of HJC0152, its analogs and protein degraders to modulate STAT3 for triple-negative breast cancer 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 1659.
Abstract 1667: Elimusertib shows stronger antitumor activity than standard of care chemotherapy in pediatric solid tumor models
Authors: Pusch Fabian Fadi , García Heathcliff Dorado , Xu Robin , Guergen Dennis , Bei Yi , Brueckner Lotte , Roeefzaad Claudia , von Stebut Jennifer , Bardinet Victor , Gonzalez María del Rocío Chamorro , Eggert Angelika , Schulte Johannes H. , Hundsdoerfer Patrick , Seifert Georg , Haase Kerstin , Schaefer Beat , Wachtel Marco , Kühl Anja A. , Ortiz Michael , Wengner Antje M. , Scheer Monika , Henssen Anton G. 
Published: June 2023

Abstract
Elimusertib is a small molecule inhibitor of ataxia telangiectasia and Rad3-related protein (ATR) currently being tested in clinical trials. Despite the known anti-tumor activity in various cancer entities, its effect on many pediatric malignancies remains unknown. We assessed the preclinical activity of elimusertib in a cohort of over 40 cell lines and 30 patient-derived xenograft (PDX) models derived from pediatric solid tumors. Elimusertib reduced tumor growth in all PDX models, with 50% of them achieving stable disease, partial or total response, even in those derived from relapsed tumors. Moreover, elimusertib outperformed the effect of standard of care chemotherapy, particularly in alveolar rhabdomysarcoma. Molecular characterization of the models provide information on response biomarkers with diagnostic potential. In summary, elimusertib shows strong preclinical anti-tumor activity in pediatric solid tumor models, that may translate to clinically meaningful responses in patients.
Citation Format: Fabian Fadi Pusch, Heathcliff Dorado García, Robin Xu, Dennis Guergen, Yi Bei, Lotte Brueckner, Claudia Roeefzaad, Jennifer von Stebut, Victor Bardinet, María del Rocío Chamorro Gonzalez, Angelika Eggert, Johannes H. Schulte, Patrick Hundsdoerfer, Georg Seifert, Kerstin Haase, Beat Schaefer, Marco Wachtel, Anja A. Kühl, Michael Ortiz, Antje M. Wengner, Monika Scheer, Anton G. Henssen. Elimusertib shows stronger antitumor activity than standard of care chemotherapy in pediatric solid tumor models [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 1667.
Abstract 1669: In vitro and in vivo synthetic lethality: Potent tumor suppression by a novel FLT3/cKIT/CSF1R/CDK19 inhibitor
Authors: Chen Hui , Paradise Marc , Shepard Ryan , Varner Judith 
Published: June 2023

Abstract
Tumor cells are characterized by aberrant signal transduction and cell cycle control pathways that lead to unchecked cell proliferation. Unchecked tumor cell proliferation, as well as macrophage proliferation, contributes to tumor growth and spread. Inhibitors of PI3K or MEK signaling pathways can initially inhibit tumor growth until resistance due to upregulation of the alternative pathway develops. We identified a novel allosteric cKIT/FLT3/CSF1R inhibitor that induces synthetic lethality in AML, lung carcinoma, pancreatic carcinoma and other tumor cells and in proliferating macrophages in vitro and in tumors in vivo by simultaneously inhibiting the MEK-ERK and PI3K-AKT pathways and activating stress activated kinase-mediated cell cycle arrest. A series of related cKIT/FLT3/CSF1R/PDGFR allosteric inhibitors suppressed receptor tyrosine phosphorylation as well as downstream MEK-ERK and PI3K-AKT signaling and mTorc1 and cMyc gene expression pathways that control cell growth. Select cKIT/FLT3/CSF1R/PDGFR inhibitors with a unique positioning of a single side chain also inhibited CDK8/19 and stimulated phosphorylation and activation of JNK and p38. JNK activation promoted sustained ATF-2 and cJun-mediated p53 and Chk1/Chk2 activation, thereby promoting cell cycle arrest in G2/M and ultimately, apoptosis. These inhibitors potently suppressed tumor growth in vivo by halting tumor cell and macrophage proliferation in G2/M. They synergized with anti-PD-1 and anti-CTLA-4 and led to tumor eradication and immunological memory formation. These studies identify novel allosteric inhibitors with potent synthetically lethal anti-tumor activity.
Citation Format: Hui Chen, Marc Paradise, Ryan Shepard, Judith Varner. In vitro and in vivo synthetic lethality: Potent tumor suppression by a novel FLT3/cKIT/CSF1R/CDK19 inhibitor [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 1669.
Abstract 171: Prostate cancer organoids from KUCaP patient-derived xenograft(PDX) series enables us to genetic engineering human-derived cellular models
Authors: Sunada Takuro , Goto Takayuki , Sumiyoshi Takayuki , Shusuke Akamatsu , Kobayashi Takashi 
Published: June 2023

Abstract
Introduction and Objectives Cancer organoids are expected to be valuable models that recapitulate intratumor heterogeneity and the phenotypic diversity of the disease ex vivo. However, the establishment rate of prostate cancer (PCa) organoids directly from clinical specimens are still low, and we need to improve. Patient-derived xenograft model (PDX) is widely used as a human-derived in vivo model, but genetic engineering is impossible, limiting its use. We aimed to develop a method to stably grow prostate cancer organoids from PDX and evaluate the feasibility of gene engineering using PDX-derived organoids. Materials and Methods KUCaP PDX series, which were established from castration-resistant prostate cancer patient tissues, were used to establish organoids. Eight organoids from eight models of KUCaP PDX were established and maintained for at least three passages. Organoids were reinjected into immunodeficient mice to establish organoid-derived xenograft (ODX) with 100% efficacy. We compared histopathological and molecular characteristics of primary patient tumors, PDX tumors, organoids, and ODX tumors. We conducted whole exome sequencing and RNA sequencing to assess the genomic profiles across the models. Firefly luciferase was introduced into organoids to show the feasibility of genetic engineering. Results Pathological findings were similar across the models derived from the same patient. WES analysis revealed most of the mutations detected in the matched patient tumors and organoids. Hierarchical clustering of RNA sequencing showed that the primary tumors, PDX tumors, organoids, and ODX tumors derived from the same patient cluster, which indicates that even after clonal selection during the establishment of organoids, the basic molecular feature of the model is maintained (Figure). Firefly luciferase was successfully introduced in seven out of seven tested organoids and imaged the ODX tumors from these organoids in vivo. Conclusions Organoids were established with a high success rate using PDX. Firefly luciferase was successfully introduced, showed the feasibility of genetic engineering using prostate cancer organoids. Matched PDX and organoids of PCa recapitulate the basic molecular features of primary human PCa. PDX-derived organoids of PCa, which enables genetic engineering of human-derived cellular models, which could be a valuable tool to enhance PCa research.
Citation Format: Takuro Sunada, Takayuki Goto, Takayuki Sumiyoshi, Akamatsu Shusuke, Takashi Kobayashi. Prostate cancer organoids from KUCaP patient-derived xenograft(PDX) series enables us to genetic engineering human-derived cellular models [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 171.
Abstract 1712: Targeting asparagine dependency as a therapy for TP53-mutated castration-resistant prostate cancer
Authors: Yoo Young A 
Published: June 2023

Abstract
Background: The TP53 tumor suppressor is frequently altered in lethal, castration-resistant prostate cancer (CRPC). However, to date there are no effective treatments that specifically target TP53 gain-of-function (GOF) mutants. Thus, there is an urgent need to identify and target vulnerabilities that perpetuate disease progression and treatment resistance resulting from TP53 GOF mutants.
Methods: We performed RNA sequencing (RNA-seq) and liquid chromatography-mass spectrometry (LC-MS)-based metabolomics on GEM and PDX CRPC models with or without TP53 GOF mutations. Our findings were validated using genetic and pharmacologic approaches in relevant in vitro and in vivo models. We assessed the effect of L-asparaginase (ASNase) or/and glutaminase (GLS) inhibitor CB-839 in cell lines, organoids and PDX models. Tumors were characterized by histology and immunohistochemistry for relevant markers.
Results: Using transcriptomic and metabolomic analyses, we show here that TP53-mutated prostate cancer (PCa) exhibits an increased dependency on asparagine and overexpresses asparagine synthetase (ASNS, the enzyme catalyzing the synthesis of asparagine). Mechanistically, TP53 GOF mutations transcriptionally activate ASNS expression, directly as well as via ATF4, driving de novo asparagine biosynthesis to support CRPC growth. TP53-mutated CRPC cells are sensitive to asparagine restriction by knockdown of ASNS and L-asparaginase treatment to deplete the intracellular and extracellular sources of asparagine respectively. This effect was rescued by asparagine addition. Notably, pharmacological inhibition of intracellular asparagine biosynthesis using a glutaminase (GLS) inhibitor and depletion of extracellular asparagine with L-asparaginase significantly reduced asparagine production and effectively impaired CRPC growth.
Conclusions: This study highlights the significance of ASNS-mediated metabolic adaptation as a synthetic vulnerability in CRPC with TP53 GOF mutations, providing a rationale for co-targeting intracellular and extracellular asparagine production to treat these lethal prostate cancers.
Citation Format: Young A Yoo. Targeting asparagine dependency as a therapy for TP53-mutated castration-resistant prostate 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 1712.
Abstract 1720: Examining mechanistic underpinnings of chemoresistance in triple negative breast cancer
Authors: Wu Qitong , Siddharth Sumit , Verma Deepak , Parida Sheetal , Sharma Dipali 
Published: June 2023

Abstract
Background: Triple negative breast cancer (TNBC) is not only the most aggressive subtype of breast cancer, but it does also not have many targeted therapeutic options due to the lack of hormone receptor expression and enrichment of HER2. TNBCs are also more prone to the development of chemoresistance and metastatic progression, which are the main obstacles to reducing TNBC-related mortality. The objective of this study is to identify targetable key node (s) that contribute to the development of chemoresistance in TNBC.
Method: Differentially expressed genes in TNBC patients with or without relapse were analyzed to select functionally important genes in chemoresistant TNBC. TRIM29 was selected based on survival analysis. Carboplatin-resistant TNBC cells were established to explore the phenotypic and molecular differences. Various growth and migration assays were used to explore the phenotype of chemoresistant TNBC cells. The expression of TRIM29 and related pathways were assessed by immunoblotting and immunofluorescence analysis. Cells with TRIM29-knockout (KO) were developed by the CRISPR system.
Result: Chemoresistant TNBC cells overexpress TRIM29. Exhibiting the functional importance, overexpression of TRIM29 in MDAMB231 confers resistance to carboplatin. A stable knockout of TRIM29 in carboplatin-resistant cells results in an improved response to carboplatin. The breast tumor xenograft model revealed that TRIM29-KO in chemoresistant TNBC formed significantly less dense tumor in mice compared to control. Mechanistically, an enhanced expression of β-catenin was seen in chemoresistant as well as TRIM29-overexpressing cells. TRIM29-KO in carboplatin-resistant cell line results in a drastic decrease in β-catenin level. Combination treatment of carboplatin and β-catenin-inhibitor resulted in an enhanced growth inhibition in chemoresistant TNBC cells. RNA-Seq analysis revealed that there are 24 candidate genes which are overexpressed in chemoresistant TNBC cells but downregulated in TRIM29-KO chemoresistant cells, thereby demanding further investigation.
Conclusion: Our findings implicate TRIM29 enrichment as an important node in chemoresistant TNBC that may concomitantly modulate β-catenin as downstream oncogenic effectors.
Citation Format: Qitong Wu, Sumit Siddharth, Deepak Verma, Sheetal Parida, Dipali Sharma. Examining mechanistic underpinnings of chemoresistance 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 1720.