bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2733: NB202: A bispecific anti-PD1/TIM-3 antibody for cancer immunotherapy
Authors: Dong Jinyu , Zhang Yu , Wang Binbin , Wang Dong , Bu Tingting , Ni Jie , Nayak Bishnu , Dong Xin 
Published: March 2024

Abstract
Despite the remarkable efficacy of PD-(L)1 therapy, a significant proportion of cancer patients fail to respond or develop resistance over time. Co-expression of T-cell immunoglobulin and mucin domain containing-3 (TIM-3) with PD-1 on primed T cells has been observed in patients exhibiting resistance to PD-1 blockade. Moreover, TIM-3 is also expressed on other immune cells, including NK and DC, and plays a negative regulatory role in these immune cells. Therefore, the dual blockade of PD-1 and TIM-3 holds potential for enhanced clinical benefits. NB202 is a bispecific anti-PD1/TIM-3 antibody that has been designed to optimize the therapeutic response of anti-PD1 therapy by maximizing TIM-3 blockade on antigen-experienced T cells, enhancing NK cell activity, and improving antigen presentation ability of antigen-presenting cells (APC). NB202 has demonstrated high affinity binding to human TIM3 and PD-1 in the low nanomolar range. Moreover, it can simultaneously bind to TIM-3 and PD-1 receptors through a trans-manner, suggesting its potent capacity to enhance the interaction between T cells and dendritic cells (DCs). In classic MLR (mixed lymphocyte reaction) and T cell stimulation assays, NB202 has exhibited superior efficacy compared to the combination of anti-PD1 mAb and anti-TIM3 monoclonal antibodies as it significantly enhances the secretion level of interferon-gamma (IFN-gamma), and particularly interleukin-2 (IL-2). Moreover, in an anti-PD1 resistant mouse model, NB202 has shown promising efficacy results.
Citation Format: Jinyu Dong, Yu Zhang, Binbin Wang, Dong Wang, Tingting Bu, Jie Ni, Bishnu Nayak, Xin Dong. NB202: A bispecific anti-PD1/TIM-3 antibody for cancer immunotherapy [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 2733.
Abstract 2745: Sequential tracking of PD-L1 expression on circulating epithelial tumor cells (CETCs) in men with primary non-metastatic prostate cancer
Authors: Schott Dorothea , Pizon Monika , Pachmann Ulrich , Pachmann Katharina , Mäurer Matthias 
Published: March 2024

Abstract
Background: Radiotherapy (RT) is an essential component of multimodality therapy in the primary or postoperative treatment of prostate cancer with curative intent by preventing local recurrence and distant metastases, indicating its impact on residual occult tumor, such as circulating tumor cells. Immunogenic changes in cancer cells induced by RT can lead to adaptive up-regulation of PD-L1 expression. As immune checkpoint inhibition plays an increasingly important role in prostate cancer, radiogenic PD-L1 upregulation may be of therapeutic importance. The aim of this study was to determine PD-L1 status on CETCs before and during RT.
Methods: Peripheral blood samples were collected from 52 primary non-metastatic prostate cancer patients. CETCs were enumerated and analyzed for PDL-L1 expression prior to (baseline), 3 and 6 weeks after the start of RT using fluorescence scanning microscopy.
Results: PD-L1 expression was detectable in CETCs and localized in the membrane and/or cytoplasm. We found a correlation between PD-L1 status in CETCs and aggressiveness of cancer disease prior to RT. The frequency of PD-L1 positive CETCs depended on the grading and Gleason score of the primary tumor. Patients with a high Gleason score and G3 tumors had significantly more PD-L1 positive CETCs compared to patients with a low Gleason Score and G1 tumors. Moreover, patients in stage I/II had significantly less PD-L1 positive CETCs compared to patients in stage III/IV (mean 54.25 vs. mean 69.65; p&lt;0.05). A higher number of PD-L1 positive CETCs were detected in patients who had radical prostatectomy before start of RT than in those who had no surgical intervention (mean 66.24 vs. mean 47.46; p&lt;0.01). Interestingly, the fraction of PD-L1 positive CETCs decreased significantly during RT only in patients with G3 tumors and a high Gleason Score.
Conclusion: Our results indicated that PD-L1 in CETCs is closely related to the aggressiveness of the primary tumor and may be a co-factor associated with the progression of prostate cancer. PD-1/PD-L1 blockade combined with RT represents a novel and promising treatment strategy that could contribute to improve the treatment efficacy of prostate cancer.
Citation Format: Dorothea Schott, Monika Pizon, Ulrich Pachmann, Katharina Pachmann, Matthias Mäurer. Sequential tracking of PD-L1 expression on circulating epithelial tumor cells (CETCs) in men with primary non-metastatic prostate 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 2745.
Abstract 2770: A novel MIRO2/MYO9B/RhoA signaling axis controls tumor cell invasion and metastasis
Authors: Boulton Dillon P. , Hughes Connor J. , Vaira Valentina , Jindal Ajita , Raza Masoom , Purdy Stephen Connor , Sant Shilpa , Ford Heide L. , Caino M. Cecilia 
Published: March 2024

Abstract
Metastasis of cancer cells to vital organs remains the leading cause of cancer related deaths, emphasizing a strong need for actionable targets in advanced stage cancer. To address this, we study novel dysregulated mitochondrial signaling mechanisms that cells utilize to metastasize. Here, we focus on how outer mitochondrial membrane protein—Mitochondrial Rho GTPase 2 (MIRO2)—promotes tumor cell invasion and metastasis. Our previous work identified higher MIRO2 mRNA expression in cancer vs. normal patient samples in a multitude of cancer types, which correlated with worse patient outcomes. Furthermore, we demonstrated that MIRO2 was critical for prostate cancer cell growth and survival in vitro and in vivo. However, it remains unknown if MIRO2 only affects primary tumor growth or if this protein is important throughout tumor progression. Using siRNA mediated knockdown (KD) of MIRO2 we find MIRO2 KD ubiquitously reduces tumor cell invasion in breast, melanoma, pancreatic, and prostate cancer cells. Utilizing metastatic prostate and breast cancer models, we demonstrate that mice injected with MIRO2 shRNA cells have significantly lower metastatic burden compared to mice injected with control shRNA cells. To determine the mechanism that MIRO2 controls invasion and metastasis, we looked at which of the top protein-binding partners for MIRO2 may regulate tumor cell invasion. Of our top hits, we found that depletion of atypical myosin IXB (MYO9B) by siRNA most significantly reduced tumor cell invasion and phenocopied MIRO2 depletion. MYO9B has a well-defined role in controlling cell motility via inactivation of RhoA. Excitingly, we have found 1) MIRO2 KD results in increased active RhoA, phenocopying MYO9B KD, 2) dual ablation of MIRO2 and RhoA fully rescues tumor cell invasion, and 3) MIRO2 is required for MYO9B driven invasion. Taken together, we propose a novel signaling mechanism by which MIRO2 broadly promotes invasion and metastasis through MYO9B dependent inactivation of RhoA.
Citation Format: Dillon P. Boulton, Connor J. Hughes, Valentina Vaira, Ajita Jindal, Masoom Raza, Stephen Connor Purdy, Shilpa Sant, Heide L. Ford, M. Cecilia Caino. A novel MIRO2/MYO9B/RhoA signaling axis controls tumor cell invasion and metastasis [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 2770.
Abstract 2779: The significance of TIMP-1 and hypoxia in cancer stemness: A synergistic role in chemoresistance
Authors: Thirusenthilarasan Ilamathi , Xiao Wei , Rojiani Mumtaz V. 
Published: March 2024

Abstract
Chemotherapeutic resistance in non-small-cell lung cancer (NSCLC) poses a formidable clinical challenge. Numerous studies have highlighted the critical role of tissue inhibitor of matrix metalloproteinase-1 (TIMP-1) in tumorigenesis and, increasingly, in the development of chemoresistance. We have studied multiple aspects of the MMP-independent, tumor-promoting function of TIMP1 in human NSCLC. Our recent studies have found a pivotal role for TIMP1 in chemoresistance. In order to gain an enhanced comprehension of the mechanisms underpinning TIMP-1-mediated chemoresistance, we have sought to determine the contribution of CSCs and hypoxia. TIMP-1 plays a role in propagating stemness, although relatively unexplored in the context of CSCs within NSCLC. A second crucial factor in the development of chemoresistance in NSCLC is the interplay between intratumoral hypoxia and CSCs. As the tumor grows, metabolic demand for oxygen increases and hypoxic regions are seen in areas furthest from the blood vessels. We have shown TIMP1 levels to increase under experimentally-induced hypoxia. In the present study, we cultured NSCLC cell lines and their TIMP1 KD clones in an assay with serum-free media and found a significant decrease in spheroid size in TIMP1 KD clones. Postulating a reduction in CSC population in KD clones, we determined the NSCLC CSC markers CD133 and ALDH’s expression in the NT and KD TIMP1 clones. Flow cytometry results showed that CD133pos and ALDHhigh populations were significantly decreased in TIMP1 KD clones relative to NT clones. Moreover, KD clone of TIMP1 showed a decrease in the levels of CSC-specific Transcription factors Oct 4A and Nanog. Taken together, our findings confirm that reduction in TIMP1 expression negatively impacts CSC populations. Furthermore, we determined the mRNA levels of CD44, another CSC marker also expressed in lung cancer is upregulated under hypoxia (1% O2) in both the NT and KD clones of TIMP1. Thus, we postulate that TIMP1 enhances chemoresistance by promoting CSC propagation within a hypoxic tumor microenvironment.
Citation Format: Ilamathi Thirusenthilarasan, Wei Xiao, Mumtaz V. Rojiani. The significance of TIMP-1 and hypoxia in cancer stemness: A synergistic role in chemoresistance [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 2779.
Abstract 2796: Colibactin mutation signatures are associated with younger age of onset in colorectal cancer
Authors: Gerstberger Stefanie , Lumish Melissa , Hartner Saskia , Shah Farheen , Choi Seongmin , Luthra Anisha , Jiang Qingwen , Woo Hyung Jun , Mahmoud Ahmed , Walch Henry , Asawa Simran , Donoghue Mark , Cercek Andrea , Yaeger Rona , McPherson Andrew , Sanchez-Vega Francisco , Ganesh Karuna 
Published: March 2024

Abstract
Escherichia coli (E. coli) strains carrying the polyketide synthase (pks) island produce the genotoxin colibactin associated with pathogenesis of colorectal cancer (CRC). Colibactin binds directly to DNA, causing alkylating damage leading to double stranded DNA breaks. Colibactin mutagenesis results in mutations in hexameric A-T rich DNA motifs that can be identified by whole genome sequencing (WGS) as mutation signatures SBS28 and SBS88 (SBS-pks). Since WGS is not routinely used clinically, we developed an approach to specifically identify SBS-pks using a clinical targeted exon capture assay, MSK-IMPACT. In an institutional pan-cancer clinical cohort of 78,905 tumors we identified 15,967 samples with &gt; 20 mutations detected by MSK-IMPACT. We identified 150/1,884 samples with microsatellite stable CRC with &gt;10% mutations attributable to SBS-pks. Examining clinicopathologic and genomic features of SBS-pks+ compared to SBS-pks- CRC tumors, we found that SBS-pks+ signatures are significantly enriched in younger age of onset compared to SBS-pks- CRC patients (median age 55 vs median age 59, p= 0.0028). SBS-pks+ CRC exhibit similar driver mutations and tumor mutational burden (TMB) compared to SBS-pks- CRC but are associated with increased fraction of genome altered (FGA). To mechanistically investigate colibactin-associated damage we developed a novel long-term human colon organoid-microbe co-culture model system that takes advantage of reversal of polarity in suspension culture. WGS of human CRC organoids co-cultured for three months with pks+ and delta-pks E. coli NC101 confirmed induction of pks+ specific SBS-pks signatures, validating the model. Leveraging this model and a biobank of normal colon organoids from donors aged &lt;/&gt; 50 years, we are investigating the molecular mechanisms underlying the association of SBS-pks with younger age of onset CRC.
Citation Format: Stefanie Gerstberger, Melissa Lumish, Saskia Hartner, Farheen Shah, Seongmin Choi, Anisha Luthra, Qingwen Jiang, Hyung Jun Woo, Ahmed Mahmoud, Henry Walch, Simran Asawa, Mark Donoghue, Andrea Cercek, Rona Yaeger, Andrew McPherson, Francisco Sanchez-Vega, Karuna Ganesh. Colibactin mutation signatures are associated with younger age of onset in colorectal 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 2796.
Abstract 2816: Comparison of MB-49_luc bladder carcinoma cell clones in the orthotopic superficial bladder tumor model in C57BL/6 female mice
Authors: McArthur Mollie , Tran Melissa , Koznecki Aliccia , Ketteringham Helen , Silvio Corrine , Wenzel Shannan , Davis Cheryl , Nadaraia-Hoke Shorena , Holding Chris , Salem Logan , Caruso Victoria , Hoerner Ben , Spencer Madison , Josey Marcus , Tannu Alexa 
Published: March 2024

Abstract
In preclinical research, cell inoculation via bladder wall injection is a standard for studying invasive bladder cancer into the bladder muscle wall. However, a subset of patients presents with non-muscle invasive (superficial) disease. The standard of care for these patients is excision coupled with BCG treatment via catheterization. There is a need to further establish mouse models of cell inoculation via bladder catheterization for early drug development. While the injection places cells into the bladder wall, catheterization coats the inside of the bladder by first instilling Poly-L-Lysine. After instilling Poly-L-Lysine, instillation of luciferase-tagged cell suspension occurs.
MB49-luc cell lines were generated to determine the optimal cell lines for use in analyzing treatments for superficial bladder carcinoma. MB49-luc cells display varying degrees of luciferase activity and growth in vitro. A subset of cell lines were selected for further analysis in vivo, via bioluminescent imaging, survival analysis, flow cytometry and necropsy. The data provides a preclinical reference for the selection of a cell line for analysis of new drug candidates in C57BL/6 female mice inoculated via bladder catheterization.
Citation Format: Mollie McArthur, Melissa Tran, Aliccia Koznecki, Helen Ketteringham, Corrine Silvio, Shannan Wenzel, Cheryl Davis, Shorena Nadaraia-Hoke, Chris Holding, Logan Salem, Victoria Caruso, Ben Hoerner, Madison Spencer, Marcus Josey, Alexa Tannu. Comparison of MB-49_luc bladder carcinoma cell clones in the orthotopic superficial bladder tumor model in C57BL/6 female mice [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 2816.
Abstract 2818: Investigating the role of TNIK in the pathogenesis of lung squamous cell carcinoma
Authors: Chang Jin Hee , Chowdhury Dipanwita Dutta , Council Danielle N. , Nguyen Triet , Jagtap Shreya , Chan Aaron , Khan Muhammad Ajmal , Connis Nick , Torres-Ayuso Pedro , Brognard John , Rezaee Moahmmad , Lafargue Audrey , Hann Christine , Tran Phuoc T. 
Published: March 2024

Abstract
Lung squamous cell carcinoma (LSCC) is the second most prevalent type of lung cancer with no FDA-approved targeted therapies. Platinum-based chemotherapy and immunotherapy remain the cornerstone of current treatments for advanced LSCC, and the 5-year survival rate is less than 10%. Despite abundant knowledge of the mutational landscape of LSCC, there is a paucity of effective targeted therapies. Amplification of chromosome 3q26 is the most common genomic alteration in LSCC and this leads to the overexpression of oncogenic kinases like TNIK. TNIK amplification occurs in approximately 50% of LSCC cases and is associated with tumorigenesis and therapy resistance in other cancers. Recent studies showed that TNIK maintains the survival of LSCC cells and drives LSCC progression. Furthermore, inhibiting the kinase eradicates tumor growth in TNIK-high preclinical models. These findings highlight the potential of TNIK as a therapeutic target in a subset of LSCC patients with 3q amplification. However, one major limitation of previous studies is the lack of animal models with squamous histology and patient-relevant genotypes. Therefore, we have created a novel conditional TNIK-overexpressing genetically engineered mouse model (GEMM) to better understand the roles of TNIK in tumor progression and therapy resistance in LSCC and elucidate mechanisms underlying LSCC pathogenesis. We are also producing a novel TNIK-overexpressing LSCC GEMM based on the simultaneous activation of KrasG12D and deletion of Fbxw7 (KF model). We will present validation studies such as histological and molecular profiling of our conditional TNIK GEMM and initial data on the TNIK overexpressing LSCC transgenic mouse model (KF (LSCC control) vs KF-TNIK (LSCC-TNIK)).
Citation Format: Jin Hee Chang, Dipanwita Dutta Chowdhury, Danielle N. Council, Triet Nguyen, Shreya Jagtap, Aaron Chan, Muhammad Ajmal Khan, Nick Connis, Pedro Torres-Ayuso, John Brognard, Moahmmad Rezaee, Audrey Lafargue, Christine Hann, Phuoc T. Tran. Investigating the role of TNIK in the pathogenesis of lung squamous cell carcinoma [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 2818.
Abstract 2819: Novel drug resistant CDX models for anti-cancer drugs discovery
Authors: Dai Hai-Ting , Bing Tie-Jun , An Zhi-Da , Yang Jie , Pang Tian-Yu , Gao Jia-Wei , Bo Yun-Yi , Yu Wen-Jen 
Published: March 2024

Abstract
Oncogene BRAF is located on chromosome 7q34, consisting of 766 amino acids and 22 exons, encoding a serine/threonine protein kinase belonging to the RAF family and plays a critical role in the MAPK signaling pathway. The mutation of BRAF was documented in nearly 8% of all human cancers including melanoma (60%), thyroid (60%), and lung adenocarcinoma (10%). The most common mutation of BRAF is V600E (Class I), which was found in more than 70% in these cancers. Despite the clinical success of approved small molecule inhibitors of BRAF V600E (vemurafenib, dabrafenib and encorafenib), this remains an area of unmet medical need because of primary or acquired drug resistance. The construction of BRAF drug-resistant cell lines plays a pivotal role in cancer research. It serves as a crucial tool for discovery of the mechanisms of drug resistance. In this study, we have developed a systematic approach for constructing drug-resistant cell lines, inducing resistance through the gradual escalation of drug concentrations. The validation of drug resistance involves morphological recordings of parent and drug-resistant cell lines, drug resistance index in vitro through IC50 measurements and in vivo through the inhibition of tumor growth (TGI) which compare to those in the parental cell line. We successfully established Vemurafenib and Dabrafenib resistant A375 cell lines (A375 Vemurafenib R, A375 Dabrafenib R) with 21 and 31.5 folds of resistance index, respectively. The in vivo drug resistance efficacy was also tested by implanting Vemurafenib resistant cells subcutaneously into NOD-SCID mice and showed that A375 Vemurafenib R exhibited robust tolerance to 50 mg/kg Vemurafenib treatment (P.O.21 days, 50mpk, TGI=17.4%), whereas the parental cells were nearly completely inhibited (P.O.21 days, 50mpk, TGI=92.3%). In addition, single-cell sequencing of A375 Vemurafenib R revealed significant gene expression differences in the MAPK and EGFR signaling pathways, aiding in the identification of new targets, and signaling pathways associated with drug resistance, thereby providing potential targets for new drug development.
Citation Format: Hai-Ting Dai, Tie-Jun Bing, Zhi-Da An, Jie Yang, Tian-Yu Pang, Jia-Wei Gao, Yun-Yi Bo, Wen-Jen Yu. Novel drug resistant CDX models for anti-cancer drugs discovery [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 2819.
Abstract 282: SFRP4+ cancer associated fibroblasts activate epithelial to mesenchymal transitions in malignant cells and dictate adverse clinical outcomes in stomach cancer
Authors: Lee Seungho , Cho Austin , Kim Hyoung-Il , Hur Hoon , Cheong Jae-Ho , Kim Tae-Min 
Published: March 2024

Abstract
Cancer-associated fibroblasts (CAFs), a pivotal component in the tumor microenvironment (TME) of gastric cancer (GC), play a crucial role in tumor progression and resistance to treatment. In this study, we performed analyses to build a comprehensive cellular landscape of fibroblasts in GC EMT using three single-cell RNA cohorts including ours (GSE183904, GSE134520 and GSE167297). We observed distinct fibroblast subtypes (CXCL14+/POSTN+, CXCL14+/APOE+, SFRP4+, and SFRP2+ fibroblasts). Among the subtypes, we observed that SFRP4+ fibroblasts sharing cellular origins with normal tissue-residing SFRP2+ myofibroblasts. Notably, SFRP4+ fibroblasts showed a regional prediction for tumor and deep tumor layers compared to normal and superficial tumor layers, respectively. To further understand the role of these fibroblasts, we employed spatial transcriptome data. Spatially resolving the cellular interactions within the TME, the adjacency of SFRP4+ CAFs to malignant cells undergoing epithelial-to-mesenchymal transition (EMT), was observed. Ligand-receptor analyses demonstrated SFRP4+CAFs regulate key genes of EMT in malignant cells (TGFBI, COL1A1, SPARC, COL3A1, COL1A2, and BGN). The regulatory roles of SFRP4+ CAFs in driving the epithelial-mesenchymal transition (EMT) of malignant cells were further validated in vitro. Clinical relevance was also demonstrated with the correlation between the abundance of SFRP4+ CAF and clinical outcomes, i.e., high SFRP4+CAF abundance was consistently associated with shorter survival of GC patients across cohorts. Thus, we present SFRP4+ CAFs as major fibroblast subtypes in GC TME. Spatial cellular architectures and in vitro evidence support that SFRP4+fibroblasts activate the EMT of malignant cells along with their association with patient prognosis. This study advances our understanding into the mechanistic roles of SFRP4+ fibroblasts in GC pathogenesis and progression, paving the way for potential targeted therapeutic strategies.
Citation Format: Seungho Lee, Austin Cho, Hyoung-Il Kim, Hoon Hur, Jae-Ho Cheong, Tae-Min Kim. SFRP4+ cancer associated fibroblasts activate epithelial to mesenchymal transitions in malignant cells and dictate adverse clinical outcomes in stomach 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 282.