tbuckley/cabot-search huggingface dataset:
Abstract 3233: EP102: Pharmacological Inhibition of METTL3 causes tumor growth inhibition and prolongs survival in preclinical models of NSCLC, ovarian and squamous cell carcinoma
Authors: Graeme Fraser, Catherine Sorlet, Nicolas Parmentier, Elodie Brunel, Christian Coremans, Sarah Rorive, Anne-France Hartiel, Killian Oukoloff, Guillaume Dutheuil
Journal: Cancer Research (2024)

Abstract METTL3 is the RNA methyltransferase predominantly responsible for the addition of N-6-methyladenosine (m6A), the most abundant epigenetic modification to mRNA. The prevalence of m6A and the activity and expression of METTL3 have been linked to the appearance and progression of numerous hematological and solid tumor cancers. EPICS has discovered and optimized small molecule inhibitors of METTL3 (“M3i”). The aim of the current study is to evaluate the efficacy of M3i in various CDX mouse tumor models. M3i compound potency was evaluated in vitro by measuring enzymatic inhibition of METTL3/14 by scintillation proximity assay (IC50 = 2 nM). The anti-proliferative effects of M3i were measured in cell viability assays following a 72h treatment of A549 (NSCLC, IC50 = 190 nM), SKOV3 (ovarian, IC50 = 9 nM) and FaDu (hypopharyngeal squamous cell carcinoma, IC50 = 24 nM) cells. Complementary data in all three cell lines demonstrates a clear concentration-response for a target engagement biomarker (m6A; IC50 = 2-8 nM, across cell lines) as well as M3i-induced changes in biomarkers of oncogenic drivers. M3i (30 mg/kg, IP, QD) was tested in vivo in mouse models using FaDu (subcutaneous implant) in addition to A549 and SKOV3 (both orthotopic implants); all animal models were performed by LabCorp (MI, USA). Daily M3i treatment significantly prolonged survival in all three disease models consistent with efficacy on tumor growth inhibition as measured by imaging (A549, SKOV3) or direct measurement of tumor volume in the case of subcutaneous implant (FaDu). M3i has previously been shown to be effective in mouse CDX and PDX models of AML. The current results extend the application of METTL3 inhibitors to include the treatment of various types of solid tumors. The efficacy of M3i as a single-agent on tumor growth inhibition and survival advances the validation of METTL3 as a cancer target and provides additional evidence for the applicability of mRNA epigenetic mechanisms to the treatment of solid tumors. Citation Format: Graeme Fraser, Catherine Sorlet, Nicolas Parmentier, Elodie Brunel, Christian Coremans, Sarah Rorive, Anne-France Hartiel, Killian Oukoloff, Guillaume Dutheuil. EP102: Pharmacological Inhibition of METTL3 causes tumor growth inhibition and prolongs survival in preclinical models of NSCLC, ovarian and 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 3233.
Abstract 1055: ORF1p expression from LINE-1 occurs in clear cell ovarian carcinoma precursors and is detectable in patients’ plasma samples
Authors: Pamela R. de Santiago, Sho Sato, Yelena Zhuravlev, Hannah S. Rendulich, Marty S. Taylor, Connie Wu, Meaghan C. Dougher, Lauren Schwartz, David R. Walt, Kathleen H. Burns, Ronny Drapkin
Journal: Cancer Research (2024)

Abstract Long interspersed element 1 (LINE-1) retrotransposons are repetitive genomic sequences able to move across the genome by an autonomous “copy and paste” mechanism. Given the mutagenic potential of LINE-1, benign cells restrict its expression, although the molecular mechanisms involved are usually impaired in cancer. Clear cell ovarian carcinoma (CCOC) accounts for ~5-10% of ovarian cancers and is believed to arise from endometriosis. Women have a poor prognosis when it presents at an advanced stage, which emphasizes the need for a better understanding of the disease. In the present study, we found that ~85% of CCOC tumors express ORF1p, one of two proteins encoded by LINE-1. We show that CCOC cell lines retain ORF1p expression and release it into the extracellular media. By using single molecule array (Simoa) assays, we detected ORF1p in patient plasma, proposing ORF1p as a non-invasive biomarker for this disease. Finally, we found that LINE-1 retrotransposon de-repression is an early event in CCOC, as ORF1p is enhanced during the transition from typical to atypical endometriosis and that is retained in the invasive cancer. Citation Format: Pamela R. de Santiago, Sho Sato, Yelena Zhuravlev, Hannah S. Rendulich, Marty S. Taylor, Connie Wu, Meaghan C. Dougher, Lauren Schwartz, David R. Walt, Kathleen H. Burns, Ronny Drapkin. ORF1p expression from LINE-1 occurs in clear cell ovarian carcinoma precursors and is detectable in patients’ plasma samples [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 1055.
Abstract 7593: Photodynamic therapy improves therapeutic management of glioblastoma
Authors: Nazar Vasyliv, Karin Williams
Journal: Cancer Research (2024)

Abstract Glioblastoma (GBM) remains a formidable challenge in the realm of oncology, primarily due to the limitations of the standard of care therapies. Photodynamic therapy (PDT), which exploits the light-activated potential of 5-aminolevulinic acid (5-ALA), emerges as a promising avenue to combat GBM. In this study, primary patient-derived cell lines, Ox5 core, and G7, served as critical subjects, exposed to light excitation at wavelengths of 410 nm, 528 nm, and 810 nm, both with and without 5-ALA (protoporphyrin IX). The central objective was to rigorously assess the efficacy of PDT, either with or without 5-ALA, in reducing cell viability and curtailing clonogenic expansion. This evaluation was performed within the context of the existing standard of care for GBM, encompassing Temozolomide (TMZ) and Radiotherapy. Our results unveiled striking insights into the potential of PDT as an innovative therapeutic strategy. Notably, Ox5 cells exhibited a remarkable reduction in viability, exceeding 70%, following exposure to PDT with 410 nm light and 5-ALA at a concentration of 50μM. A similar, albeit slightly less profound, effect was observed in G7 cells, with a viability decrease of more than 53%. These outcomes, meticulously quantified through the MTT viability assay (n=4), were reinforced by statistical significance, as indicated by p-values falling below 0.05 and, lower 0.001. Furthermore, clonogenic assays employing G7 cells provided an additional layer of evidence, demonstrating a substantial inhibition of clonogenic potential following PDT treatment with 410 nm light and 5-ALA. Immunohistochemistry techniques, particularly focusing on the cleaved caspase-3 marker, in both Ox5 core and G7 cells, underscoring the mechanistic basis of the observed cell death. In stark contrast, the conventional standard of care, involving TMZ monotherapy, was tested, and the results across four biological replicates were less significant. The relative viability of Ox5 and G7 cells exhibited no statistical significance, with p-values exceeding 0.05, implying a limited impact of this regimen on cell viability. Moreover, clonogenic assays conducted under the standard of care protocol (TMZ+/-Radiotherapy) unveiled the persistence of colonies, even at higher radiation doses of 4 and 6 Gy.In summary, PDT, specifically when implemented with 410 nm light and 5-ALA, represents a breakthrough strategy that leads to substantial cell death in both Ox5 and G7 cells. This compelling alternative therapy shines a hopeful light on the horizon of GBM treatment, providing a potentially transformative approach that can augment the current standard of care. Citation Format: Nazar Vasyliv, Karin Williams. Photodynamic therapy improves therapeutic management of glioblastoma [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 7593.
Abstract 22: Development and characterization of human tumor specific cytotoxic lymphocytes for preclinical drug development
Authors: Ina Rohleff, Lea Gröne, Kanstantsin Lashuk, Julia B. Schueler
Journal: Cancer Research (2024)

Abstract Heterogeneity within a tumor allows it to better adapt to changing conditions and can have therefore a negative impact on a patient’s prognosis, response to treatment and overall health. Breast cancer is a highly heterogeneous disease caused by distinct genetic mutations in mammary epithelial cells, resulting in significantly different forms of the disease and a need for highly personalized treatment schemes for patients. Hence, it is important to develop and improve (immuno)therapies for breast cancer patients. Adoptive T-cell therapy with autologous CD8+ cytotoxic T cell lymphocytes (CTL) is a promising method that has already shown promising effects in melanoma patients. Unfortunately, there is almost no information about the use in breast cancer patients. We developed an in vitro protocol to generate tumor-specific CTLs by priming on HER2+ breast cancer cell lines JIMT-1 and SKBR-3. Subsequently, these primed CTLs were tested in 2D and 3D immune cell killing assays in a life cell imaging device in combination with an endpoint viability assay. The activity was compared with unspecific CD8+T cells activated by phytohemagglutinin (PHA) or αCD2/αCD3/αCD28, HER2-peptide specific T cells and HER2-CAR T cells serving as a positive control. We investigated the feasibility to freeze CTLs for use in subsequent studies and validated the relevance of HER2 as the main druggable target in the tumor lines using an siRNA approach. The CTLs were most effective on JIMT-1 in a 3D setting, whereas the SKBR-3 CTLs displayed similar activity in 2D and in 3D. The respective CTLs were tumor line specific, as SKBR-3 CTLs did not kill efficiently the JIMT-1 cells and vice versa. The same CTLs displayed the same efficacy pattern after thawing but less pronounced. Thus, within one experimental set-up it is recommended to use either one. The Her2 knockdown in the target cells reduced the killing activity of the CTLs slightly. However, this effect was not statistically significant proving the importance of CTLs as treatment option as well as neoantigens as targets in drug development. In summary, the CTLs proved to capture the respective tumor heterogeneity showing high killing rates in both SK-BR3 and JIMT-1 being more active than HER2-peptide specific T cells. The availability of CTLs in a preclinical setting facilitates screening approaches for combinational studies. Beyond that they can serve as starting material to develop cancer vaccines and identify highly immunogenic neoantigens. Citation Format: Ina Rohleff, Lea Gröne, Kanstantsin Lashuk, Julia B. Schueler. Development and characterization of human tumor specific cytotoxic lymphocytes for preclinical drug 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 22.
Abstract 6736: Overcome the challenge for intratumoral injection of STING agonist for pancreatic cancer by systemic administration
Authors: Keyu Li, Junke Wang, Birginia Espinoza, Yirui Xiong, Nan Niu, Jianxin Wang, Noelle Jurcak, Noah Rozich, Arsen Osipov, MacKenzie Henderson, Vanessa Funes, Melissa Lyman, Alex B. Blair, Brian Herbst, Mengni He, Jialong Yuan, Diego Trafton, Chunhui Yuan, Michael Wichroski, Xubao Liu, Yuquan Wei, Lei Zheng
Journal: Cancer Research (2024)

Abstract Objective: Due to the challenge for intratumoral administration, innate agonists have not made it beyond preclinical studies for efficacy testing in most of tumor types. Pancreatic ductal adenocarcinoma (PDAC) has a T-cell excluded or deserted tumor microenvironment. Innate agonist treatments may serve as a T cell priming mechanism to sensitize PDACs to anti-PD-1 antibody (a-PD-1) treatment. Design: Using a transplant murine model with spontaneously formed liver metastasis and also the genetically engineered KPC mouse model that spontaneously develops PDAC, we compared the antitumor efficacy between intrahepatic/intratumoral and intramuscular systemic administration of BMS-986301, a next-generation STING agonist. Flow cytometry, Nanostring, and cytokine assays were used to evaluate local and systemic immune responses. Results: The study demonstrated that administration of STING agonist systemically via intramuscular injection is equivalent or potentially superior to its intratumoral injection in inducing both effector T cell response and antitumor efficacy. Compared to intratumoral administration, T cell exhaustion and immunosuppressive signals induced by systemic administration were attenuated. Nonetheless, either local or systemic treatment of STING agonist was associated with increased expression of CTLA-4 in the tumors. However, the combination of a-PD-1 and anti-CTLA-4 antibody with systemic STING agonist demonstrated the antitumor efficacy in the KPC mouse spontaneous PDAC model. Our study also demonstrated the feasibility and antitumor efficacy of systemic administration of BMS-986299, a new NLRP3 agonist. Conclusion: For the first time, our study supports the clinical development of innate agonists via systemic administration, instead of local administration, for treating PDAC. Citation Format: Keyu Li, Junke Wang, Birginia Espinoza, Yirui Xiong, Nan Niu, Jianxin Wang, Noelle Jurcak, Noah Rozich, Arsen Osipov, MacKenzie Henderson, Vanessa Funes, Melissa Lyman, Alex B. Blair, Brian Herbst, Mengni He, Jialong Yuan, Diego Trafton, Chunhui Yuan, Michael Wichroski, Xubao Liu, Yuquan Wei, Lei Zheng. Overcome the challenge for intratumoral injection of STING agonist for pancreatic cancer by systemic administration [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 6736.
Abstract 2501: High mutation burden and ultraviolet light signature in conjunctival squamous cell carcinoma
Authors: Bita Esmaeli, Frederico O. Gleber-Netto, Oded Sagiv, Curtis R. Pickering, Neil Gross, Jing Ning, Melisachew M. Yeshi, Jonas Mitku, Michael T. Tetzlaff, Priyadharsini Nagarajan
Journal: Cancer Research (2024)

Abstract Purpose: Conjunctival squamous cell carcinoma (conjSCC) is endemic in sub-Saharan Africa and is a major cause of ocular morbidity and mortality. This study aims to evaluate Tumor Mutation Burden (TMB), genomic signature, and histologic characteristics of conjunctival squamous cell carcinoma (conjSCC) in two cohorts of patients; one from the USA and one from Ethiopia. Methods: Whole exome sequencing data, PD-L1 expression, histologic features, and human papillomavirus (HPV) status were analyzed in conj SCC tumors of 25 patients treated at an Ethiopian (ETH) cancer center and 29 patients treated at a US cancer center. Genomic alterations in conjSCC were compared with SCCs from other anatomic sites using data from The Cancer Genome Atlas (TCGA). Results: TMB was found to be relatively high in conjunctival SCC (3.01/Mb, log10), was comparable to TMB values associated with cutaneous SCC, and was higher than most other SCC types available in the TCGA database. ETH samples had higher tumor mutational burden compared to the US cohort (3.34 vs 2.73). Solar elastosis was seen in a higher percentage of tumors from Ethiopia compared with the US cohort (78% vs. 10%). HPV status was similar between the cohorts (ETH: 21%, MDA: 28%). PD-L1 positivity defined as &amp;gt; 1% of tumor cells was seen in 33 of 53 tumors (62%). Mutations associated with ultraviolet light (UV) signature were the most frequently encountered signatures in both cohorts (SBS7b: 74% and SBS7a: 72%). UV signatures were more prevalent in the ETH cohort compared with the US cohort. Conclusions: Conjunctival SCC is associated with a high TMB providing the opportunity for immune checkpoint inhibitor therapy for patients with locally advanced and/or metastatic conjunctival SCC. Clinical trials are needed to assess the efficacy of immune checkpoint inhibitors in patients with conjunctival SCC, particularly in sub-Saharan Africa where this cancer is more frequently seen, and is associated with significant morbidity and mortality. Citation Format: Bita Esmaeli, Frederico O. Gleber-Netto, Oded Sagiv, Curtis R. Pickering, Neil Gross, Jing Ning, Melisachew M. Yeshi, Jonas Mitku, Michael T. Tetzlaff, Priyadharsini Nagarajan. High mutation burden and ultraviolet light signature in conjunctival 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 2501.
Abstract 2818: Investigating the role of TNIK in the pathogenesis of lung squamous cell carcinoma
Authors: 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
Journal: Cancer Research (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 2816: Comparison of MB-49_luc bladder carcinoma cell clones in the orthotopic superficial bladder tumor model in C57BL/6 female mice
Authors: 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
Journal: Cancer Research (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.