tbuckley/cabot-search huggingface dataset:
Abstract 76: Correlated multi-scale 3D optical microscopy of tumor tissues
Authors: Jingtian Zheng, Steve Seung-Young Lee
Journal: Cancer Research (2024)

Abstract Three-dimensional (3D) optical microscopy in combination with advanced tissue clearing methods permits the interrogation of intact large-sized tumor tissues. There are many optical microscopy methods (e.g. light-sheet and confocal microscopy) offering 3D tumor images at varying levels of spatial resolution (e.g. organ, tissue, cell, and molecule level). However, it is a challenge to correlatively integrate various resolution 3D images obtained by different optical microscopy of tumor tissue. In this project, we developed a correlated multi-scale 3D optical microscopy method that enables the acquisition of macroscopic to microscopic spatial information from a single tumor tissue in 3D. Firstly, we used light sheet microscopy to image a whole large-sized, cleared tumor tissue and analyzed the results to identify regions of interests (ROIs). After defining ROIs in the 3D whole tumor image, we added a UV-activatable visible dye, spiropyran, in the agarose gel surrounding the cleared tumor and exposed the sample to a UV light sheet horizontally at the height (z-axis) of the tumor where the ROIs present. The activated dye showed ‘purple’ colored lines in the agarose gel and we physically marked the gel along the visible colored lines. We further sectioned the tumor at the ROI positions using a vibratome after reversing tissue clearing process. After immunofluorescence staining and aqueous-based tissue clearing, confocal microscopy allowed the localization of various cell types in the ROIs of tumor macrosections. To validate the method for multi-scale evaluation of cancer immunotherapy, we tested it with control and DMXAA-treated mouse mammary tumor tissues. We successfully acquired the 3D images of whole tumors by capturing autofluorescence signals with a 633 nm excitation laser and its matched emission filter. Based on the autofluorescence tumor images, we defined two ROIs for each control and treated tumor and performed optical marking and physical sectioning of the tumors as described above. Next, we stained the macrosections (400 µm thick) with DAPI, CK8-DL488, CD45-DL550, and ER-TR7-DL680 to visualize cancer, immune, and stromal cells in the ROIs at cellular resolution. We quantitatively analyzed the correlated multi-scale 3D image data for assessment of the effects of DMXAA treatment on the tumor microenvironment including eradiation of cancer cells, immune infiltration, and remodeling of tumor stroma. In summary, this new microscopy method will provide comprehensive spatial information of tumor tissues and benefit a broad cancer research field such as the discovery of new tumor biomarkers and the development of effective cancer therapies. Citation Format: Jingtian Zheng, Steve Seung-Young Lee. Correlated multi-scale 3D optical microscopy of tumor tissues [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 76.
Abstract 4465: Galectin-1 regulates CD147 and downstream pathways critical for glioma progression
Authors: Maheedhara R. Guda, Andrew J. Tsung, Swapna Asuthkar, Kiran Velpula
Journal: Cancer Research (2024)

Abstract Galectin-1 (Gal-1) is an important protein for glioma progression and glioma stem cell maintenance. Gal-1 may act through CD147, a potential Gal-1 receptor. CD147, also known as Basigin or extracellular matrix metalloproteinase inducer (EMMPRIN), is a transmembrane glycoprotein highly expressed in various cancer cells. An analysis utilizing the Gliovis database and encompassing 667 Glioblastoma Multiforme (GBM) patients segregated based on median CD147 expression levels delineated cohorts with above-median (n=339) and below-median (n=328) CD147 expression. Kaplan-Meier survival curves unveiled a significant association between heightened CD147 expression and reduced overall survival (OS) in this patient population. Experimental approaches employing immunoblotting and immunohistochemistry techniques on shGal-1 treated cell lysates and mouse brain samples exhibited decreased CD147 expression compared to respective controls. Additionally, immunocytochemical studies corroborated an augmented colocalization of Gal-1 and CD147, with a subsequent reduction in this association following shGal-1 treatment. Next, we used AC-73, a selective CD147 inhibitor, to determine the levels of CD147 and Gal-1. Treatment with 20μM AC-73 and siRNA for CD147 showed reduced CD147 levels in GSC33 and GSC20 cells while maintaining unaltered Gal-1 expression. Inhibiting CD147 did not affect Gal-1 levels, further suggesting Gal-1 acts upstream. CD147 activates matrix metalloproteinase-9 (MMP9), and CD147 knockdown reduced MMP9 levels, elucidating a Gal-1-CD147-MMP9 pathway. Overall, Gal-1 appears to act upstream of CD147 to regulate MMP9, integrins, and other factors important for glioma progression. Further elucidation of these pathways will provide insights into glioma biology and potential therapeutic targets. Citation Format: Maheedhara R. Guda, Andrew J. Tsung, Swapna Asuthkar, Kiran Velpula. Galectin-1 regulates CD147 and downstream pathways critical for glioma progression [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 4465.
Abstract 6478: Intracranial neoplasms: Disparities in access to care
Authors: Jayla Hsiung, Kamil Taneja, Lauren Ladehoff, Karan Patel, Eric Toloza
Journal: Cancer Research (2024)

Abstract Purpose: Excision of intracranial neoplasms is a life-saving procedure. However, there is not much research that has demonstrated how demographic variables interact with a patient’s access to healthcare for intracranial neoplasms. Methods: The Nationwide Inpatient Sample was queried from 2018 to 2020 to identify patients with an intracranial neoplasm. Multivariable logistic regression with patient- and hospital-level characteristics as covariates was used to identify factors associated with receiving an intracranial tumor excision. Results: From 2018 to 2020, there were 97,795 hospital encounters with a primary diagnosis of an intracranial neoplasm. Of these patients, 64.6% underwent a tumor excision procedure during their hospital visit. The average age of all patients with intracranial neoplasm was 58.90.2 years. Most intracranial neoplasm patients were male (59.0%), White (73.8%), Medicare beneficiaries (45.1%), and of the highest income quartile (26.4%). These patients commonly presented to hospitals in the West (35.0%), with a medium number of beds (36.4%), and to rural hospitals (39.1%). The most common locations of these neoplasms were the frontal (18.9%), temporal (12.0%), and parietal (7.5%) lobes. Neoplasms in more than one location in the brain occurred in 5.8% of patients. Multivariable logistic regression identified the following factors as significantly associated with a decreased odds ratio (OR) of receiving an excision surgery: identifying as Black (OR=0.63; p&amp;lt;0.001), Hispanic (OR=0.82; p=0.001), or Asian or Pacific Islander (OR=0.78; p=0.009) and being a Medicaid Beneficiary (OR=0.84; p=0.008). Presenting to a hospital in the South (OR=1.30; p&amp;lt;0.001) or in the West (OR=1.38; p&amp;lt;0.001) were associated with higher chances of having a surgical excision. Conclusion: There are very substantial differences in access to care for brain cancer patients. Race and insurance status are related to a patient’s chance of receiving tumor excision therapy. Citation Format: Jayla Hsiung, Kamil Taneja, Lauren Ladehoff, Karan Patel, Eric Toloza. Intracranial neoplasms: Disparities in access to care [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 6478.
Abstract 4976: The impact of obesity on survival in epithelial gynecological tumors
Authors: Ahmed Badran, Mahmoud Elshenawy, Waleed Fallatah, Abdullaah K. Hinkston, Saad S. Ali, Mohammed Ali Omar, Abdulaziz M. Alaklabi, Hytham M. Abdalla, Tarek Z. Arabi, Belal N. Sabbah, Hamed Alhusaini
Journal: Cancer Research (2024)

Abstract Background: The impact of obesity on the survival of patients with epithelial gynecological tumors is not yet clear. We aim to elucidate the impact of body mass index (BMI) on epithelial gynecological tumors in a large tertiary center at Saudi Arabia. Methods: We retrospectively reviewed the medical files of all patients with pathologically confirmed epithelial gynecological tumors at our center. Then, we assessed the difference in overall survival (OS) according to primary tumor location, BMI, stage at presentation, and performance status (PS) at presentation using log-rank tests. Results: 400 patients were included in the analysis. The mean age at diagnosis was 56.1±13 years. 242 (60.5%) patients were diagnosed with uterine carcinomas, 137 (34.3%) with ovarian carcinomas, and 21 (5.3%) with cervical carcinomas. 278 (69.5%) patients were obese at presentation, 74 (18.5%) were overweight, 43 (10.8%) were within normal range, and 7 (1.8%) were underweight. The PS at presentation was 0, 1, 2, 3, and 4 in 351 (87.8%), 17 (4.3%), 10 (2.5%), 16 (4%), and 6 (1.5%) patients, respectively. Cervical cancer was associated with long OS, while ovarian cancers demonstrated poor prognosis (p=0.0159). There was no difference in OS between different BMI groups (p=0.072). Patients with stage 4 cancers had significantly shorter OS (p&amp;lt;0.0001). Patients with PS 4 at presentation was associated with the worst prognosis (p&amp;lt;0.0001). Interpretation: Shorter OS was associated with ovarian carcinomas, advanced staging, and poor PS at presentation. BMI classification had no impact on OS. Further studies are needed to confirm our findings. Citation Format: Ahmed Badran, Mahmoud Elshenawy, Waleed Fallatah, Abdullaah K. Hinkston, Saad S. Ali, Mohammed Ali Omar, Abdulaziz M. Alaklabi, Hytham M. Abdalla, Tarek Z. Arabi, Belal N. Sabbah, Hamed Alhusaini. The impact of obesity on survival in epithelial gynecological tumors [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 4976.
Abstract 3610: Utilizing fructose metabolism to fuel anti-tumor immunity
Authors: Tanya Schild, Rachel Chirayil, Lyric Haughton, Patrick Wallisch, Marjan Berishaj, David A. Scheinberg, Kayvan R. Keshari
Journal: Cancer Research (2024)

Abstract Consumption of fructose in the form of high fructose corn syrup is elevated in the western diet, but it is not fully understood how fructose metabolism influences anti-tumor immunity. Fructose is canonically metabolized in the intestine and the liver and can shunt into glycolysis. In certain tumor types, fructose metabolism becomes deregulated, allowing tumor cells to metabolize fructose to power their biosynthetic processes. Similarly, reprogramming immune cells to be able to efficiently metabolize fructose may help us power immunotherapy to work in difficult to treat cancers, especially in individuals who have high fructose in their blood or in the tumor microenvironment (TME). Imparting effector T cells with the ability to use fructose for fuel can overcome one of the major metabolic limitations of the TME: limited nutrient supply. As T cells become activated, they alter their metabolism to support growth and proliferation. Activated CD8+ T cells upregulate their glycolysis which results in increased biosynthetic processes, such as synthesis of macromolecules and effector cytokines. However, tumor cells also consume substantial amounts of glucose, resulting in a glucose-depleted microenvironment, which could be one of the major barriers to immunotherapy working in solid tumors. Therefore, we engineered T cells to overexpress a fructose transporter, GLUT5, which is normally not expressed in the immune compartment at high levels. We hypothesized that increased fructose uptake by CD8+ T cells will ameliorate exhaustion caused by the glucose-low tumor microenvironment. Indeed, we determined that GLUT5 T cells are more efficient in killing in low glucose supplemented with fructose. We also observed that GLUT5 expression restores T cell glycolytic capacity under fructose to that of unexhausted T cells under glucose replete conditions. Similarly, GLUT5-expressing T cells proliferate faster in vitro and exhibit an improved ability to control B16 tumor growth in vivo. Additionally, combining GLUT5 cell infusion with checkpoint inhibition resulted in durable tumor control and prolonged mouse survival. Further, engineered CD19-targeted CAR T cells with expression of GLUT5 were more metabolically active and cytotoxic in low glucose conditions, mimicking the TME. In conclusion, GLUT5 expression in effector CD8+ and CAR T cells may allow immunotherapy to function in solid tumors under low glucose conditions. Citation Format: Tanya Schild, Rachel Chirayil, Lyric Haughton, Patrick Wallisch, Marjan Berishaj, David A. Scheinberg, Kayvan R. Keshari. Utilizing fructose metabolism to fuel anti-tumor immunity [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 3610.
Abstract 1515: Tertiary lymphoid structures restrain cancer evolution by supporting stem-like CD8+ T cells for sustained anti-tumor immunity
Authors: Pengxiang Wang, Chi Zhou, Zhiting Wei, Yue Wang, Yuli Gao, Fangliangzi Meng, Jian Zhou, Jia Fan, Qi Liu, Yunfan Sun
Journal: Cancer Research (2024)

Abstract Currently, our understanding of the mechanism underlying the immune response on extending the survival of patients with aggressive tumors remains limited. In this study, we generated multi-regional genomic and transcriptional data coupled with digital pathology from 28 long-term survivors (LTSs) and 34 stage-matched short-term survivors, with intrahepatic cholangiocarcinoma (iCCA). Our investigation unveiled that mature tertiary lymphoid structures (TLSs) within the tumors of LTSs exerted significant immune pressure on the tumor, leading to the restriction in generating clonal mutations and increased subclonal diversity. Employing single-cell profiling, we identified significant enrichment of IgM+ naïve B cells and TCF7+ stem-like CD8+ T cells in TLS-positive tumors. Spatial profiling further highlighted that TCF7+ stem-like CD8+ T cells preferentially localized in TLS, facilitating reduced vulnerability to unfavorable environmental factors. Functionally, TCF7+ stem-like CD8+ T cells displayed strong capacity to differentiate into effector subsets while maintaining a diverse T-cell receptor repertoire. Mechanistically, we identified that naïve B cells promote activation and differentiation of stem-like CD8+ T cells within the TLS niche through IgM-FcμR axis, which primed these T cells for enhanced anti-tumor immunity. In summary, our findings underscore that TLS plays a pivotal role in orchestrating enduring and effective anti-tumor immunity, which yield strong immune stress on cancer evolution and ultimately contributing to better prognosis of patients. Citation Format: Pengxiang Wang, Chi Zhou, Zhiting Wei, Yue Wang, Yuli Gao, Fangliangzi Meng, Jian Zhou, Jia Fan, Qi Liu, Yunfan Sun. Tertiary lymphoid structures restrain cancer evolution by supporting stem-like CD8+ T cells for sustained anti-tumor immunity [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 1515.
Abstract 7309: Edible mushroom derived antioxidant, vialinin A, prevents melanoma growth and invasion
Authors: Alexandria Vo, Amber Zafar
Journal: Cancer Research (2024)

Abstract Melanoma is the second leading invasive cancer with a greater capacity to invade and metastasize. Increased oxidative stress has been shown to be involved in melanoma growth and spread. Several antioxidants, vitamins, and other phytochemicals have been shown to prevent melanoma cancer growth. However, the chemopreventive efficacy of vialinin-A, an edible mushroom-derived p-terphenyl antioxidant, on cancer growth and invasion is unknown. We, therefore, hypothesized that with its potent anti-oxidative and anti-inflammatory actions, vialinin-A could prevent melanoma cell growth and invasion. B16-F10 melanoma cells were treated without or with various concentrations of vialinin-A. The cell viability was determined by MTT assay and apoptosis by annexin-V staining. Our results suggest that vialinin-A prevents melanoma cell growth in a dose-dependent manner. Vialinin-A also prevents the invasion and migration of melanoma cells. Further, vialinin-A prevents the generation of reactive oxygen species and promotes apoptosis of B16-F10 cells. In addition, vialinin-A increases the activation of caspase-3 and cleavage of PARP protein. Vialinin-A also regulated the expression of various anti-apoptotic, pro-apoptotic, and inflammatory markers in melanoma cells. In conclusion, our results suggest that vialinin-A, through regulating oxidative stress-modulated apoptotic pathways, could prevent melanoma cell growth and invasion and has potential chemopreventive properties. Citation Format: Alexandria Vo, Amber Zafar. Edible mushroom derived antioxidant, vialinin A, prevents melanoma growth and invasion [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 7309.
Abstract 241: Patient-derived organoids as a reliable screening platform for assessing ADC efficacy and specificity
Authors: Daniele Mori, Vineeta Adegbenro, Francisco Morales, René Overmeer, Sabina Lukovac, Sylvia Boj, Merel Derksen
Journal: Cancer Research (2024)

Abstract Antibody-drug conjugates (ADCs) are a new class of pharmaceutical drugs designed to deliver cytotoxic agents to cells expressing specific antigens selectively. Based on Paul Ehrlich’s “magic bullet” concept, ADCs are designed to target cancer cells, minimizing systemic toxicity typical of conventional chemotherapy. ADCs structurally consist of a particular monoclonal antibody linked to a cytotoxic agent. Patient-derived Organoids (PDOs) provide a new tool for studying cancer biology and patient stratification. PDOs are adult stem cell-based culture systems maintaining the patient-specific genetic and phenotypic characteristics, including surface marker expression. HUB Organoids has generated a large biobank of PDOs characterized on the genomic and transcriptomic level. The work presented here shows the suitability of the organoid platform for performing ADC screening. Organoids were selected based on their target-antigen (TA) expression, assessed by flow cytometry and RPKM. Organoid killing was assessed with a viability readout (CellTiter Glo) after six days of treatment. Results of viability screening show a correlation between TA-targeting ADC-induced organoid killing and TA expression in the organoids. These results reveal that PDOs hold value for the preclinical development of ADCs and for evaluating their tumor specificity. Moreover, PDOs have the potential to predict patient specific response to ADCs. Citation Format: Daniele Mori, Vineeta Adegbenro, Francisco Morales, René Overmeer, Sabina Lukovac, Sylvia Boj, Merel Derksen. Patient-derived organoids as a reliable screening platform for assessing ADC efficacy and specificity [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 241.
Abstract 4660: Characterization of a nicotinamide-based kinase inhibitor HSN748 for inhibition of RET-driven tumors
Authors: Ujjwol Khatri, Neetu Dayal, Tao Shen, Xueqing Hu, Herman Sintim, Jie Wu
Journal: Cancer Research (2024)

Abstract Rearranged during transfection (RET) is a protein tyrosine kinase that is aberrantly activated by gene fusions or mutations in many types of human cancer including thyroid cancer and non-small cell lung cancer (NSCLC). Selpercatinib (LOXO-292) and pralsetinib (BLU-667) are FDA approved RET-selective tyrosine kinase inhibitors (TKIs) being used to treat RET-altered cancer. However, these tumors develop selpercatinib/pralsetinib-resistance via acquisition of RET(G810C/R/S) mutations located at the solvent front of the ATP binding pocket. The overall goal of our research is to discover next-generation of RET kinase inhibitors to inhibit selpercatinib/pralsetinib-resistant RET solvent-front mutants. In this study, we characterized one of the nicotinamide-based RET kinase inhibitor, HSN748, in vitro and in vivo. HSN748 was able to inhibit selpercatinib/pralsetinib-resistant RET(G810C/R) solvent-front mutations. In BaF3/KIF5B-RET(G810C) tumor xenograft experiment, HSN748 treatment resulted in tumor regression. In immune competent transgenic mice, KIF5B-RET-induced lung tumors regressed after HSN748 treatment by oral gavage for one month (10-15 mg/kg, QD) without affecting body weight. These results identify HSN748 as an orally available RET inhibitor capable of inhibiting KIF5B-RET and its solvent-front mutant-driven tumors. Citation Format: Ujjwol Khatri, Neetu Dayal, Tao Shen, Xueqing Hu, Herman Sintim, Jie Wu. Characterization of a nicotinamide-based kinase inhibitor HSN748 for inhibition of RET-driven tumors [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 4660.