bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 412: Discovery and preclinical characterization of ISM9342A, a novel, potent, and orally bioavailable WRN inhibitor that suppresses MSI-H tumor growth
Authors: Zhao Pei , Zhu Wei , Ding Xiaoyu , Wan Jianfei , Chen Xiaojing , Zhang Man , Ding Xiao , Bavadekar Supriya , Rao Sujata , Ren Feng , Zhavoronkov Alex 
Published: March 2024

Abstract
Loss of function mutations in DNA mismatch repair genes can result in microsatellite instabilities (MSI) and high levels of MSI (MSI-H) contributes to tumorigenesis and is frequently observed in endometrial carcinoma, gastric cancer, and colorectal cancer. Although immune checkpoint inhibitors have been approved for the treatment of MSI-H tumors, there is still a large proportion of patients with MSI-H tumors who fail to respond to these therapies. Recently, two independent genome-wide loss of function screens have identified Werner syndrome helicase (WRN) as the top dependency for MSI-H cancer cell viability. WRN plays important roles in DNA repair and in the maintenance of genome integrity. Given that WRN deficiency selectively impairs the viability of MSI-H but not microsatellite stable cancer cells, WRN is a synthetic lethal target for MSI-H tumors.
ISM9342A is a novel and potent WRN inhibitor exhibiting single digit nanomolar IC50 values in both ATPase and helicase assays. ISM9342A suppressed the proliferation and increased double strand break markers in MSI-H cancer cells. Moreover, ISM9342A demonstrated promising in vivo anti-tumor efficacy in an MSI-H xenograft model along with tumor regression. ISM9342A demonstrated good drug-like properties, including excellent in vitro ADMET profiles and good in vivo exposure, including low clearance and optimal oral bioavailability across multiple preclinical species. Collectively, these findings highlight the potential of ISM9342A as a highly potent WRN inhibitor for the treatment of MSI-H tumors
Citation Format: Pei Zhao, Wei Zhu, Xiaoyu Ding, Jianfei Wan, Xiaojing Chen, Man Zhang, Xiao Ding, Supriya Bavadekar, Sujata Rao, Feng Ren, Alex Zhavoronkov. Discovery and preclinical characterization of ISM9342A, a novel, potent, and orally bioavailable WRN inhibitor that suppresses MSI-H tumor growth [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 412.
Abstract 4149: Real-time intravital trafficking of tumor infiltrating lymphocytes in breast cancer models
Authors: Ahn Soyeon , Akyildiz Kubra , Kim Hyunseok , Kim Pilhan 
Published: March 2024

Abstract
Cancer immunotherapy utilizing the immunoreactive efficiency of immune cells via adoptive cell therapy (ACT) has been a novel method of cancer treatment. In tumor microenvironment, immune cell reactivity of tumor-infiltrating lymphocytes (TILs) can facilitate cancer cell attack, which finally derives efficient suppression of tumor growth. However, the conventional evaluation for cancer immunotherapy has been generally performed by ex vivo methods, providing restricted information on lymphocyte motility and immune cell dynamics within the tumor microenvironment. In vivo data with the dynamic behavior of TILs in breast cancer can provide new insight to investigate novel targets of immune checkpoint inhibitors. In this research, longitudinal intravital imaging of motility trafficking of TILs in breast cancer animal models has been performed by utilizing intravital microscopy to unveil the immunoreactive dynamics of T cell activity in early stage. In vivo analysis of TIL motility within different breast cell lines, including 4T1 (mouse breast cancer cell), MDA-MB-231 (human triple-negative breast cancer cell), and MCF7 (human breast cancer cell), respectively, has been investigated for immune responses to cancer. We’ve monitored spatiotemporal dynamics of TIL over 11 days in breast cancer xenograft mouse model generated by tumor implantation into the dorsal skinfold imaging chamber and adoptive T cell transfer by blood circulation. In the results, the adoptive immunoreactivity of TIL has been differentiated by the timepoint of adoptive T cell transfer, distance proximity of T cells in tumors, and breast cancer types. Furthermore, anti-cancer effect coordinated with dendritic cells behaviors showed induced immune responses with accumulated dendritic cells with increased TIL count over time in breast cancer model treated with various cancer therapy such as immunotherapy, radiation therapy and anti-cancer drug (anti-PD-L1), which implied a relationship between programmed death-ligand 1 expression levels and TIL/dendritic cell motility. The result demonstrates that intravital TIL motility trafficking analysis in cancer model can be an invaluable assessment method to explain the detailed cellular/molecular mechanism of immune response to cancer involved with T lymphocytes, dendritic cells, and immune checkpoint inhibitors to accelerate the efficiency of cancer immunotherapy.
Citation Format: Soyeon Ahn, Kubra Akyildiz, Hyunseok Kim, Pilhan Kim. Real-time intravital trafficking of tumor infiltrating lymphocytes in breast cancer models [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 4149.
Abstract 416: Development of substituted oxindole derivatives as a Ku-targeted DNA-PK inhibitors for cancer therapy
Authors: Chauhan Dineshsinha , Mendoza-Munoz Pamela L. , Kushwaha Narva Deshwar , Aruri Hariprasad , Turchi John J. , Gavande Navnath S. 
Published: March 2024

Abstract
DNA double strand breaks (DSBs) are the most cytotoxic type of DNA damage. DSB repair pathway deficiency, often observed in cancer cells, results in translocations and genetic mutations that contribute to genomic instability. The generation of DNA DSBs is the primary mechanism of numerous chemo- and radio-therapeutic strategies used to treat various cancers. Modulating DSB repair pathways can have a profound impact on the clinical efficacy of DNA damaging therapies. DNA-dependent protein kinase (DNA-PK), which is composed of a DNA-PK catalytic subunit (DNA-PKcs) and Ku80-Ku70 heterodimer, acts as the molecular sensor for DSB and plays a prime role in DSB repair through non-homologous end joining (NHEJ). DNA-PK inhibitors become an attractive therapeutic target for cancer in combination with DSB-inducing radiotherapy and chemotherapy. There are at least 6-7 DNA-PK inhibitors in the preclinical and clinical stages which exhibit potential as treatment for various cancers. However, we have taken a unique and innovative approach to inhibiting DNA-PK via blocking the Ku70/80 heterodimer interaction with DNA, an essential step in DNA-PK activation and phosphorylation activity. Exploiting this unique mechanism of kinase activation, we have expanded our structure-activity relationships of pyrrolone derivatives. Modified synthetic schemes have been developed to allow a series of modifications to the X80 core structure. We have prepared furan, thiophene and pyrrole derivatives that enabled the identification of pharmacophores that impact in vitro potency and cellular off-target toxicity. Towards addressing cellular uptake and bioavailability, we identified substituted oxindole derivatives as potent Ku and DNA-PK inhibitors. These oxindole derivatives exhibited a better cellular uptake while retaining potent Ku inhibitory activity. Our data demonstrate that the cellular effects observed are a function of Ku inhibition and that this novel class of DNA-PK inhibitors can be further developed as anti-cancer therapeutics that can be used as an adjuvant to, or concomitant with radiotherapy and other cancer therapies that induce DNA damage.
Citation Format: Dineshsinha Chauhan, Pamela L. Mendoza-Munoz, Narva Deshwar Kushwaha, Hariprasad Aruri, John J. Turchi, Navnath S. Gavande. Development of substituted oxindole derivatives as a Ku-targeted DNA-PK inhibitors for cancer therapy [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 416.
Abstract 4209: Unraveling the effects of the microenvironment on glioblastoma multiforme invasiveness using a xeno-free 3D hydrogel platform
Authors: Díaz Alejandra I. Ferrer , Huang John 
Published: March 2024

Abstract
Glioblastoma multiforme (GBM) is a grade IV astrocytoma and the most common type of adult brain malignancy. The overall survival of patients diagnosed with GBM is less than 5 years. Therefore, it is imperative to understand the mechanisms contributing to GBM progression, invasiveness, and survival. This study aimed to evaluate the effect of the extracellular matrix (ECM) on GBM cell invasion by performing the traditional invasion assay as well as novel  in vitro invasion assay strategies. A significant challenge with in vitro cell invasion assays is the use of animal-based ECM: the components of animal-based ECM are not characterized; the batch-to-batch variability of animal-based ECM can influence experimental findings and affect potential clinical applications; and the temperature-sensitive operation protocols make the use of animal-based ECM time-consuming and difficult for automated high-throughput assays. These challenges can be circumvented using VitroGel®, a synthetic xeno-free, bio-functional hydrogel resembling the physiological ECM with tunable biophysical and biochemical properties. In this study, we harnessed the properties of the synthetic xeno-free hydrogel system to examine how different mechanical strengths and functional ligands as well as cytokines and serum within the hydrogel matrices or in the outer well, affect GBM cell invasion. The results indicated that adjusting the mechanical strength of the ECM system affects GBM cell invasion. We further showed that the bio-functional ligands within the hydrogel matrix, such as matrix metalloproteinases, RGD peptide, and others, stimulated cell invasion. This finding exemplifies the importance of using a well-characterized ECM system given that it is difficult to evaluate how specific ECM components contribute to cell invasion using the undefined animal-based ECM. Since the composition of the hydrogel system is chemically defined, we could further control the cytokine milieu within the matrix to understand how the ECM composition affects cell migration. To demonstrate this, we added the cytokine TGF-β1 to the hydrogel and examined GBM cell invasion. Indeed, we showed that adding TGF-β1 to the synthetic VitroGel enhanced GBM cell invasion, thus illustrating that incorporating factors inside the matrix is a powerful method to evaluate chemotaxis. Altogether, this study demonstrates the potency and flexibility of using a xeno-free hydrogel for a myriad of invasion assay applications.
Citation Format: Alejandra I. Ferrer Díaz, John Huang. Unraveling the effects of the microenvironment on glioblastoma multiforme invasiveness using a xeno-free 3D hydrogel platform [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4209.
Abstract 4217: An engineered breast tumor microenvironment model, with single-cell spatial resolution, to assess spatial dynamics of tumor evolution
Authors: Helms Haylie R. , Oyama Kody A. , Davies Alexander E. , Langer Ellen M. , Bertassoni Luiz E. 
Published: March 2024

Abstract
Cellular heterogeneity is a prominent feature of the tumor microenvironment, and the organization of these cells has been linked to clinical outcomes such as disease progression and drug resistance. While retrospective analysis of patient tumors has produced a myriad of insights, samples are limited and highly complex making it challenging to validate causality. Here we present an engineered breast tumor microenvironment model, with single cell spatial resolution, to systematically identify which cell phenotypes and their spatial arrangements may be driving ductal carcinoma in situ disease progression. A microfluidic dispenser (Biopixlar, Fluicell) was optimized to enable the spatial patterning of single cells to replicate native histology. To demonstrate the high spatial precision of our method, we first replicated an annotated 2D section of a breast tumor biopsy region of interest (ROI) using MCF10A, MDA-MB-231, primary mammary fibroblasts, THP-1 derived macrophages, and primary mesenchymal stem cells. The XY coordinate of each cell was identified to create a print map matching the original biopsy. Deposited cells adhered to their intended target with an average print fidelity of 2.4 µm. Next, the stromal compartment of the ROI was altered to include phenotypes associated with tumor promoting microenvironments (i.e. cancer associated fibroblasts, M2 macrophages) and the core of the MCF10A ring filled with MDA-MB-231. Each deposited cell contained a fluorescent tag corresponding with its cell type to facilitate real time spatial tracking and annotation. The tumor microenvironments were live cell imaged for 24 hours at 5 minute intervals. MCF10A cells spread to form their junctions and create a cohesive ring, MDA-MB-231 cells proliferated and rapidly moved around within the confined space, and the cells of the stromal compartment spread to create a dense tissue like structure. The microenvironments were cultured for an additional 2-6 days, fixed, and stained for markers of proliferation, phenotype shifts, cell-cell junctions, and morphology. Unlocking the relative contributions of the specific cell types in ductal carcinoma in situ tumor microenvironment to the overall evolution of invasive breast cancer may hold the answer for many questions in early detection, treatment, and cancer avatar models.
Citation Format: Haylie R. Helms, Kody A. Oyama, Alexander E. Davies, Ellen M. Langer, Luiz E. Bertassoni. An engineered breast tumor microenvironment model, with single-cell spatial resolution, to assess spatial dynamics of tumor evolution [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 4217.
Abstract 4243: Revolutionizing cancer research, new drug screening approach with vascularized cancer organoid platform mimicking patient tumor microenvironment
Authors: Lee Mingyun , Yoon Yeo-Joon , Lee Yong-Soo , Rheey Jinguen 
Published: March 2024

Abstract
Patient-derived organoids (PDOs) are improving our understanding of cancer heterogeneity and personalized medicine. In particular, patients' intrinsic and acquired treatment resistance is being evaluated with PDOs, which has become an essential factor in developing new anticancer drugs and designing successful clinical trials. However, there are obstacles to cancer heterogeneity and patient-specific cancer therapy due to lack of understanding of tumoral diversity resulting from the tumor microenvironment (TME). Complex direct and indirect interactions between various types of TME cells and the resulting tumoral diversity are challenges that must be addressed for customized cancer therapy. Standard cancer therapy targets tumor cells without considering possible damage on the tumor microenvironment that could impair therapy response. Therefore, the construction and analysis of a platform for co-culturing cancer organoids with other cell types that make up the TME over a long period of time is necessary. We generated and performed characterization of blood vessel organoid (BVO). The BVO expressed endothelial marker CD31 and pericyte marker PDGFRβ. We attempted to co-culture with patient-derived lung cancer organoid (LCO) on Matrigel by dissociating the constructed BVO, and it was confirmed that BVO and LCO were interconnected after 10 days. This new platform was treated with Gefitinib and Poziotinib, and after 5 days of drug treatment, the IC50 value increased compared to LCO-only culture. Additionally, flow cytometry analysis confirmed that co-culturing with BVO during drug treatment resulted in a lower percentage of dead LCO cells compared to LCO-only culture. Image-based analysis also verified that co-culturing with blood vessels enhances the viability of LCOs when treated with drugs. Taken together, the co-culture of cancer organoids and BVOs present a platform that closely mimics the in vivo TME compared to the existing cancer organoid culture method. This innovative platform demonstrates higher drug resistance than existing approaches, offering a novel method for drug screening.
Citation Format: Mingyun Lee, Yeo-Joon Yoon, Yong-Soo Lee, Jinguen Rheey. Revolutionizing cancer research, new drug screening approach with vascularized cancer organoid platform mimicking patient tumor microenvironment [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 4243.
Abstract 4256: Autologous organoids and T cell co-cultures as a powerful personalized platform for immunotherapy development
Authors: Beaurivage Claudia , Sridharan BanuPriya , Mucuk Sumeyra , Nadwodny Kimberly , Poore Derek , Schepers Anna , Pourfarzad Farzin , Boj Sylvia F. 
Published: March 2024

Abstract
Recent advances in cancer immunotherapy have had a positive impact on the life expectancy of patients for an extensive range of clinical indications. With new treatment strategies and druggable targets being identified at an increasing pace, the number of patients eligible for cancer immunotherapy is expected to expand steadily. However, promising therapeutic developments face hurdles in translating preclinical findings into therapy since conventional 2D cancer models hold low clinical predictive value. We developed an innovative alternative, building on the discovery that adult stem cells proliferate and organize into three-dimensional organotypic structures when they are embedded into extracellular matrix. Patient-derived organoids are generated from normal and malignant tissues and stored as high-quality biobanks that yield highly reproducible results. HUB Organoids® recapitulate complex characteristics of the parental tissue, including molecular heterogeneity, as well as morphological and functional traits. Since cancer progression and response to immunotherapy are governed by immune cell interactions in the tumor microenvironment, we developed an assay in which colorectal (CRC) and non-small cell lung cancer (NSCLC) tumor organoids are co-cultured with paired tumor infiltrating lymphocytes (TIL) that are simultaneously expanded as a source of tumor reactive cells. Paired resources allow for the screening of immune-modulatory therapies under physiologic conditions, not depending on peptide-pulsing and alloreactivity. We quantify tumor organoid killing and TILs reactivity by combining imaging-based analysis of apoptotic cells with flow cytometry to measure cytokine release by cytotoxic TILs. Here, we show that our system is robust and reproducible with an establishment rate of 75%, allowing for expansion of TILs that preserve T cell receptor repertoires. First line expansion of both PDO and TIL components can be used to effectively build coculture models and probe the tumor and immune components, respectively. Our system offers a powerful tool for the development and validation of cancer immunotherapy and can help to stratify cancer patients for susceptibility to various types of immunotherapies. We certify that the research use of each of the HBS marked above was conducted according to the expectations of each institution.
Citation Format: Claudia Beaurivage, BanuPriya Sridharan, Sumeyra Mucuk, Kimberly Nadwodny, Derek Poore, Anna Schepers, Farzin Pourfarzad, Sylvia F. Boj. Autologous organoids and T cell co-cultures as a powerful personalized platform for immunotherapy development [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 4256.
Abstract 4299: A lineage-specific role of oncogenic protein kinase Cι in lung adenocarcinoma
Authors: Nguyen Duy T. , Yin Ning , Weems Capella R. , Jamieson Lee , Meneses Kayleah , Liu Yi , Murray Nicole R. , Fields Alan P. 
Published: March 2024

Abstract
Lung adenocarcinoma (LUAD), the most prevalent subtype of lung cancer, can arise from two different cell populations: alveolar type 2 (AT2) cells and bronchiolar club cells. By utilizing genomic data from the cancer genome atlas program, human LUAD cell lines, and the well-characterized LSL-KrasG12D/Trp53-/- (KP) mouse model, we demonstrated that tumors arising from club cells are much more aggressive and follow a different trajectory of tumorigenesis when compared to those arising from AT2 cells. Intriguingly, our data strongly suggest that expression and signaling activity of protein kinase C iota (PKCι) can profoundly affect the cell of origin and oncogenic signaling pathways employed by resultant tumors. Specifically, KP-mediated transformation of club cells appears to be dependent on PKCι-ELF3-NOTCH3 and PKCι-YAP1 signaling axes, while AT2 cell malignancy is dependent on the PKCι-independent WNT signaling. In addition, club-cell-origin tumors exhibit an enrichment of cancer stem cells and increased infiltration of immunosuppressive myeloid cells in comparison to AT2-cell-origin tumors. This results in accelerated progression and increased likelihood of metastasis by LUAD tumors that originate from club cells. Taken together, our results indicate that PKCι expression and signaling activity can profoundly influence the cells of origin, tumor trajectories, and therapeutic vulnerabilities of LUAD tumors.
Citation Format: Duy T. Nguyen, Ning Yin, Capella R. Weems, Lee Jamieson, Kayleah Meneses, Yi Liu, Nicole R. Murray, Alan P. Fields. A lineage-specific role of oncogenic protein kinase Cι in lung adenocarcinoma [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 4299.