tbuckley/cabot-search huggingface dataset:
Abstract 7237: Rapid-onset squamous cell carcinoma and spontaneous regression following papillomavirus infection
Authors: Andrea Bilger, Ella T. Ward-Shaw, Denis L. Lee, Renee E. King, Shwu-Yuan Wu, Michael A. Newton, Cheng-Ming Chiang, Darya Buehler, Kristina Matkowskyj, John P. Sundberg, Rong Hu, Paul F. Lambert
Journal: Cancer Research (2025)

Abstract Squamous cell carcinoma (SCC) development in mammals is thought to require months or years from the time that initial changes occur. We show that SCCs induced by the mouse papillomavirus MmuPV1, which are generally diagnosed 4-6 months post infection, can be found as soon as 2 weeks post infection. SCCs developed within 2 weeks in immune-competent, adult FVB (FVB/NTac) mice at sites prone to human papillomavirus (HPV)-induced tumors and cancers in human patients: the base of the tongue, the anus, and the skin. The anterior tongue, less susceptible than the base of the tongue to HPV-induced cancer in humans, was resistant to rapid-onset cancer. The presence of invasive cancer in histological tissue sections was verified by multiple pathologists. These diagnoses were corroborated by the results of a classic test of malignancy: skin tumors obtained two weeks post infection grew ectopically as subcutaneous grafts in immune-deficient hosts. Preventative treatment with a novel BRD4 inhibitor dramatically reduced the frequency of ear skin SCCs present 2 weeks post infection and significantly reduced overall disease severity. Like many human papillomaviruses, MmuPV1 lacks an E5 gene. Expression of HPV16 E5 driven by the Keratin 14 promoter in FVB mice (FVB/NTac-Tg(KRT14-HPV16E5*)33Plam/Plam) significantly increased the frequency of rapid-onset invasive cancers caused by MmuPV1 at the base of the tongue and in the anus. In an E5-transgenic mouse with a persistent MmuPV1-induced ear skin lesion, we detected a lymph node metastasis at 38 weeks - further demonstrating a cancer phenotype. Cancers and less severe dysplasia induced by infection at the base of the tongue or the anus spontaneously regressed within 4 to 8 weeks of infection; however, ear lesions persisted. When CD4+ and CD8+ T cells were depleted, lesions at the base of the tongue and anus also persisted, indicating that spontaneous regression involves a T cell-mediated immune response. These results indicate that papillomavirus infection alone is sufficient to induce rapid onset of invasive cancer, and that persistence of disease depends on the tissue-specific immune microenvironment. Citation Format: Andrea Bilger, Ella T. Ward-Shaw, Denis L. Lee, Renee E. King, Shwu-Yuan Wu, Michael A. Newton, Cheng-Ming Chiang, Darya Buehler, Kristina Matkowskyj, John P. Sundberg, Rong Hu, Paul F. Lambert. Rapid-onset squamous cell carcinoma and spontaneous regression following papillomavirus infection [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 7237.
Abstract 2734: Exploring epigenetic control of immunogenicity in small cell lung cancer through multi-omics analyses
Authors: Sana Parveen, Ramesh Adhinaveni, Meijun Du, Neshatul Haque, Tianxiang Liu, Kun Fang, Raul Urrutia, Victor X. Jin, Hui-Zi Chen
Journal: Cancer Research (2025)

Abstract Background: Small Cell Lung Cancer (SCLC) is an aggressive neuroendocrine malignancy characterized by epigenetic dysregulation. EZH2, a key component of the Polycomb Repressive Complex 2 (PRC2), is overexpressed in SCLC and correlates with poor prognosis. Recent studies show that EZH2 inhibition enhances SCLC cell immunogenicity, though the underlying mechanisms remain unclear. Aim: This study investigates how EZH2 function alters the epigenetic landscape in SCLC using an integrated multi-omics approach. In SCLC cell lines treated with EZH1/2 dual inhibitor valemetostat, we examine changes in chromatin accessibility (ATAC-seq), three-dimensional chromatin organization (micro-C profile), and gene expression (RNA-seq). Key Findings: Gene set enrichment analysis of RNA-seq data revealed upregulation of genes involved in antigen processing, presentation, and inflammatory response pathways following EZH1/2 dual inhibition in SCLC cell line H146. ATAC-seq analysis showed increased chromatin accessibility of genes with increased expression, primarily in distal regulatory regions. Crucially, we addressed the limitation of ATAC-seq in providing only one-dimensional accessibility information by performing Micro-C profiling. This approach confirmed that EZH1/2 dual inhibition led to the formation of neo-loops between accessible promoters and their enhancers. Specifically, we observed gained loops leading to increased HLA-B and HLA-C expression with valemetostat treatment. Validating these findings at the transcriptional and protein levels, qRT-PCR and flow cytometry analyses confirmed increased surface expression of pan-HLA molecules following valemetostat treatment. Functional inhibition of EZH1/2 was confirmed by Western blot analyses showing decreased H3K27me3 levels. These results collectively demonstrate that EZH1/2 controls gene expression in SCLC by establishing long-range interactions between promoter and enhancer elements through modulation of chromatin accessibility, ultimately impacting the expression of key immunogenic factors. Conclusion: Our integrative multi-omics approach reveals a comprehensive model of EZH1/2 contribution to SCLC pathogenesis, highlighting its role in chromatin reorganization and gene expression regulation. Future work will focus on identifying additional therapeutically relevant genes within the EZH1/2-regulated network for potential intervention strategies. Citation Format: Sana Parveen, Ramesh Adhinaveni, Meijun Du, Neshatul Haque, Tianxiang Liu, Kun Fang, Raul Urrutia, Victor X. Jin, Hui-Zi Chen. Exploring epigenetic control of immunogenicity in small cell lung cancer through multi-omics analyses [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 2734.
Abstract 6668: MNK2-dependent activation of <i>de novo</i> lipid synthesis drives breast cancer brain metastasis
Authors: Jessie Ling Ai Wong, Giselle Sek Suan Nah, Fatin Nasha Binte Sulaimi, Kian Leong Lee, Kassoum Nacro, Kaustubh Bhinge, Amanda E.D. Van Swearingen, Carey K. Anders, Sin Tiong Ong
Journal: Cancer Research (2025)

Patients with triple-negative breast cancer (TNBC) have poor prognosis, attributed to a ten-fold increased risk of developing brain metastases (compared to patients with other breast cancer subtypes), as well as the limited availability of effective therapies for breast cancer brain metastasis (BCBM). Recent work has revealed that SREBP1, a master transcription factor regulating de novo lipid synthesis, is required for BCBM survival in the lipid-depleted brain microenvironment. Given that previous studies have highlighted a link between MAPK interacting protein kinases (MNK) and lipid biosynthetic pathways, we investigated whether MNKs are essential for lipid biosynthesis in BCBM. We found that MNK2 and SREBP1 are upregulated in BCBM compared to paired primary cancers (n= 5 pairs, p&amp;lt;0.05). This upregulation is also observed in neurotropic 231-Br relative to its parental MDA-MB-231 TNBC cell line. Using a novel brain-penetrant MNK1/2 inhibitor, ETC-501, we show that MNK activity is required for growth of 231-Br cells in lipid-depleted conditions, as well as de novo lipid synthesis. Using a combination of immunofluorescence- and immunoblot-based assays, we find that ETC-501 prevents the nuclear translocation of SREBP1 and causes an accumulation of the precursor form of SREBP1 in the endoplasmic reticulum, preventing its processing into the mature form required for nuclear localization, and lipogenic gene activation. Importantly, we find that both genetic &amp; pharmacological inactivation of MNK prevents the establishment of BCBM in vivo. In rescue experiments, we find that expression of mature SREBP1c restores lipid droplet levels in ETC-501-treated cells. Our study reveals a critical role for MNK2 in regulating SREBP1 and lipid synthesis, providing new insights into TNBC BCBM. Inhibitors of MNK kinases, such as ETC-501, may offer potential in managing TNBC patients at high-risk for BCBM. Citation Format: Jessie Ling Ai Wong, Giselle Sek Suan Nah, Fatin Nasha Binte Sulaimi, Kian Leong Lee, Kassoum Nacro, Kaustubh Bhinge, Amanda E.D. Van Swearingen, Carey K. Anders, Sin Tiong Ong. MNK2-dependent activation of de novo lipid synthesis drives breast cancer brain metastasis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 6668.
Abstract 2195: Development of a faster potency assay for evaluation of immune cell-mediated cytotoxicity in vitro
Authors: Danielle Califano, Ben Streeter, Sierra Barnes, Denise Sullivan, Daniel Millard, Stacie Chvatal
Journal: Cancer Research (2025)

Abstract Assessment of the efficacy of CAR T cell therapy relies on robust in vitro potency assays that evaluate the interaction between CAR T cells and cancer cells. Traditional methods require extended incubation periods of target cells of over 24 hours, limiting throughput and efficiency in assay development. In this study, we aimed to significantly reduce assay time by utilizing an impedance-based system to monitor the cytotoxic activity of CAR T cells against SKOV3 cancer cells. By comparing the standard protocol with an expedited approach that allows for a shorter resting period of target cells, we aim to establish a more efficient framework for potency testing that maintains accuracy, while facilitating faster advancements in CAR T cell therapies. In addition to shortening the overall assay time, adding CAR T cells at an earlier timepoint also ensures that the true Effector to Target (E:T) ratios are maintained by reducing the time for target cell doubling. Here, we describe an in vitro potency assay that shortens the assay time course from 72+ hours to 24 hours for immune cell-mediated cytotoxicity. SKOV3 target cells were seeded at 10k cells per well into a 96-well microplate with embedded electrodes in the substrate that detect the attachment and proliferation of target cells. HER-2 CAR T cells were added at either 4 or 24 hours post SKOV3 cell seeding at multiple E:T ratios (1:10, 1:5, 1:2, 1:1, and 5:1). The killing kinetics among each group were directly compared by calculating the Kill Time 50 (KT50), or the time required for 50% of the target cells to be killed. The KT50 for target cells treated at 4 hours was 91.6 ± 3.7 (1:10), 47.8 ± 22.7 (1:5), 19.8 ± 1.8 (1:2), 16.6 ± 0.9 (1:1), and 9.1 ± 0.7 (5:1) hours, while the KT50 for target cells treated at 24 hours was 150.0 ± 3.6 (1:10), 115.6 ± 7.1 (1:5), 83.8 ± 4.5 (1:2), 48.7 ± 2.5 (1:1), and 29.2 ± 0.8 (5:1) hours. As expected, the well groups treated with CAR T cells at 4 hours demonstrated faster KT50 times due to less SKOV3 cell proliferation and, therefore, more accurate E:T ratios. At 24 hours post CAR T addition, a dose response curve was generated and the EC50 was determined to be an E:T ratio of 1:2.4 for target cells treated 4 hours post seeding and E:T ratio of 1:1 for target cells treated 24 hours post seeding. Overall, the data described illustrates a label-free, in vitro workflow to assess potency of CAR T cells in a quicker, more efficient manner using the Maestro Z impedance assay. Citation Format: Danielle Califano, Ben Streeter, Sierra Barnes, Denise Sullivan, Daniel Millard, Stacie Chvatal. Development of a faster potency assay for evaluation of immune cell-mediated cytotoxicity in vitro [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 2195.
Abstract 6849: RIT1M90I is a driver of lung adenocarcinoma tumorigenesis and resistance to targeted therapy
Authors: Ashley DiMarco, Mirunalini Ravichandran, Jeffery Lau, Anthony Lima, Eva Lin, Julie Weng, Luca Gerosa, Pablo Saenz-Lopez Larracho, Thomas Hunsaker, Yang Xiao, Monika Mis, Charles Havnar, Kai Barck, Klara Totpal, Oded Foreman, Mark Merchant, Nicole Sodir, Danilo maddalo
Journal: Cancer Research (2025)

Abstract RIT1 is a RAS-family GTPase that is mutated in 2.4% and amplified in up to 14% of lung adenocarcinoma patients. Yet, the oncogenic potential of RIT1 in the lungs is not completely understood. Many patients with RIT1 alterations are considered ‘oncogene-negative’, hence they are not eligible for any targeted therapy in the clinic. The role of RIT1 in cancer has been historically understudied due to the lack of in vitro and in vivo models harboring RIT1 alterations. In this study, we generated the first murine model of RIT1M90I-mutant lung cancer. We found that RIT1M90I was tumorigenic in the lungs and the tumors displayed histopathological features similar to lung adenocarcinoma. We leveraged this new model to assess both ex vivo and in vivo sensitivity of RIT1 tumors to the SHP2 inhibitor, migoprotafib, in combination with other targeted therapies. Finally, we showed that RIT1M90I can also drive resistance to the KRASG12C inhibitor, divarasib, and that the combination with migoprotafib can revert this phenotype. Our data shows that RIT1M90I is a bona fide oncogenic driver of NSCLC and mediator of targeted therapy resistance as a co-occurring mutation. Taken together, our study suggests that RIT1-altered cancer patients may benefit from combination treatment with SHP2 inhibitor in the primary and resistance setting. Citation Format: Ashley DiMarco, Mirunalini Ravichandran, Jeffery Lau, Anthony Lima, Eva Lin, Julie Weng, Luca Gerosa, Pablo Saenz-Lopez Larracho, Thomas Hunsaker, Yang Xiao, Monika Mis, Charles Havnar, Kai Barck, Klara Totpal, Oded Foreman, Mark Merchant, Nicole Sodir, Danilo maddalo. RIT1M90I is a driver of lung adenocarcinoma tumorigenesis and resistance to targeted therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 6849.
Abstract 6669: Vagal perturbation of the gut-brain axis deters cancer-associated cachexia
Authors: Aliesha D. Garrett, Xiling Shen, Ayelet Erez, Naama Darzi
Journal: Cancer Research (2025)

Abstract Cancer-associated cachexia (CAC) is a wasting syndrome present in 80% of advanced cancer patients. CAC decreases the quality of life, causes higher mortality, and causes resistance to treatments with increased toxicity. CAC is currently incurable and directly responsible for up to 30% of all cancer deaths. We find that cancer-induced systemic inflammation disrupts vagal tone via infiltration of innate immune cells into the brain, involving the vagal dorsal motor nucleus of the hindbrain. This disruption leads to CCL2-driven vagal hyperactivation and elevated acetylcholine output to the liver, resulting in the downregulation of hepatocyte nuclear factor 4 alpha (HNF4α), a key regulator of liver metabolism. We further demonstrate that a right cervical vagotomy in mice with lung or pancreatic cancer disrupts the abnormal CNS-liver vagal crosstalk, restoring liver metabolism and feeding behavior, thereby alleviating cachexia symptoms independent of tumor burden. Importantly, electrical, chemical, or surgical disruption of the right vagus nerve, including via a custom wireless implantable device, restores liver metabolism, alleviates CAC manifestations, and synergizes with chemotherapy, significantly improving the overall well-being and survival rates of mice with lung or pancreatic cancer. Our findings have substantial translational potential for CAC treatment, mainly as non-invasive vagal interventions are already FDA-approved for other therapeutic applications. Citation Format: Aliesha D. Garrett, Xiling Shen, Ayelet Erez, Naama Darzi. Vagal perturbation of the gut-brain axis deters cancer-associated cachexia [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 6669.
Abstract 7247: Leveraging advanced mass spectrometry for enhanced immunopeptidomics in human and murine cells
Authors: Richard C. Jones, Michael J. Ford, Daneil A. Bochar, Michael R. Pisano
Journal: Cancer Research (2025)

Abstract Immunopeptidomics is the study of peptides presented by Class I and Class II Major Histocompatibility Complexes (MHC). Presented peptides originate from a complex intracellular processing pipeline, culminating in the presentation of proteolytically derived fragments on the cell surface bound to MHC molecules. Advances in our understanding of the immune system have spurred significant interest in identifying these peptides and characterizing the immunopeptidome. Recent advances in mass spectrometry have significantly increased sensitivity, enabling unprecedented depth of immunopeptidome coverage and facilitating assays with reduced starting material requirements. To build on recent advancements, we utilized the Orbitrap Astral mass spectrometer, a cutting-edge technology offering superior sensitivity and resolution, to profile immunopeptidomes from human and murine cell lines. Comparative analyses with traditional immunopeptidomics workflows highlighted the Orbitrap Astral's remarkable ability to enhance peptide identification, particularly for low-abundance peptides that were previously challenging to detect. This advancement enabled a deeper and more comprehensive characterization of the immunopeptidome, unveiling valuable insights into antigen presentation. The integration of the Orbitrap Astral represents a major advancement in the field of immunopeptidomics, facilitating unprecedented sensitivity in the profiling of antigen presentation. These findings have important implications for cancer research, particularly in the development of targeted immunotherapies and the broader understanding of immune responses in oncology. Citation Format: Richard C. Jones, Michael J. Ford, Daneil A. Bochar, Michael R. Pisano. Leveraging advanced mass spectrometry for enhanced immunopeptidomics in human and murine cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 7247.
Abstract 6174: Macrophage-based immunotherapy of platinum-resistant ovarian cancer
Authors: Jan Brancewicz, Maciej Bialasek, Bartłomiej Taciak, Ilona Marszalek, Konrad Gabrusiewicz, Tomasz Rygiel, Magdalena Krol
Journal: Cancer Research (2025)

Abstract Platinum-resistant ovarian cancer remains one of the greatest challenges in oncology, with limited treatment options and poor survival outcomes. To address this unmet need we develop MDC-735, a novel allogeneic, off-the-shelf macrophage-based therapy. MDC-735 leverages the breakthrough TRAIN (TRAnsfer of Iron-binding proteiN) mechanism, discovered by our team, to enable macrophages to deliver drug-loaded ferritin complexes directly to tumor cells. This approach bypasses drug resistance, penetrates hypoxic tumor regions, and overcomes challenges faced by conventional therapies. In preclinical studies, MDC-735 demonstrated remarkable efficacy in multiple solid tumor models, including platinum-resistant ovarian cancer, showing significant tumor shrinkage, long-term animal survival and immune activation. This unique therapy employs allogeneic macrophages loaded with a tubulin polymerization inhibitor, achieving targeted delivery while minimizing systemic toxicity. The ability of MDC-735 to alter the tumor microenvironment and induce immune resistance to recurrence highlights its potential as a game-changing therapy. This innovative therapy promises to transform the landscape of platinum-resistant ovarian cancer treatment, providing a scalable and effective solution for a disease with limited options. Citation Format: Jan Brancewicz, Maciej Bialasek, Bartłomiej Taciak, Ilona Marszalek, Konrad Gabrusiewicz, Tomasz Rygiel, Magdalena Krol. Macrophage-based immunotherapy of platinum-resistant ovarian cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 6174.
Abstract 7086: Serological assays for early detection of HPV-associated oropharyngeal cancer
Authors: Mingyue Wang, Jermaine Brown, John C. Smith, Leonid Dzantiev, Anu Mathew, Martin Stengelin, George Sigal, Padhma Yuvaraj, Karen S. Anderson, Jacob Wohlstadter
Journal: Cancer Research (2025)

Abstract Research Use Only (RUO) sample-sparing MULTI-ARRAY serology immunoassays have been developed for human antibodies to several HPV-16 early antigens. These assays are intended to support research of oropharyngeal cancer (OPC) linked to the human papillomavirus (HPV).The HPV virus can infect the mouth and throat and cause cancers of the oropharynx, i.e. the back of the throat, including the base of the tongue and tonsils. HPV-related cancer incidence is increasing dramatically among men and is unlikely to decrease in the foreseeable future, despite vaccination efforts. As a result, this may become one of the most common cancers in middle-aged men in the United States by 2045. The HPV16 genome consists of six early genes (E1, E2, E4, E5, E6, and E7) and two late genes (L1 and L2) that constitute the viral capsid. Antibodies to early HPV-16 antigens are commonly present in those with OPC but are detected in only approximately 1% of the general population. These antibodies are present many years before cancer develops; thus, they are ideal biomarkers for early detection of OPC.Immunoassays for antibodies against HPV-16 early antigens E1, E2, E6, and E7 were developed in a high-throughput multiplexed format using electrochemiluminescence (ECL) detection, and MULTI-ARRAY 10-spot 96-well plates. Each well has an array presenting recombinant antigens manufactured by Meso Scale Diagnostics, LLC. The assay uses 25 uL of 2, 500x diluted serum or plasma. The assay format is simple: diluted sample is incubated in the well with the antigen array followed by a wash and detection of bound anti-HPV antibodies using an anti-human IgG antibody labeled with the SULFO-TAG ECL label. Assay performance was evaluated with approximately 200 commercially sourced samples from apparently healthy individuals and 14 samples from individuals known to be positive for at least one HPV-16 early antigen using an established reference method (Programmable Protein (RAPID) ELISA, Anderson 2015). There was excellent agreement between the two methods.This high-throughput MULTI-ARRAY assay may be useful in research applications requiring screening of a large number of samples for HPV-16 antibodies.For Research Use Only. Not for use in diagnostic procedures. Citation Format: Mingyue Wang, Jermaine Brown, John C. Smith, Leonid Dzantiev, Anu Mathew, Martin Stengelin, George Sigal, Padhma Yuvaraj, Karen S. Anderson, Jacob Wohlstadter. Serological assays for early detection of HPV-associated oropharyngeal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 7086.