Biomedical Informatics Commons^™

Safer: Sub-Hypergraph Attention-Based Neural Network For Predicting Effective Responses To Dose Combinations, Yi-Ching Tang, Rongbin Li, Jing Tang, W Jim Zheng, Xiaoqian Jiang

Faculty, Staff and Student Publications

BACKGROUND: The potential benefits of drug combination synergy in cancer medicine are significant, yet the risks must be carefully managed due to the possibility of increased toxicity. Although artificial intelligence applications have demonstrated notable success in predicting drug combination synergy, several key challenges persist: (1) Existing models often predict average synergy values across a restricted range of testing dosages, neglecting crucial dose amounts and the mechanisms of action of the drugs involved. (2) Many graph-based models rely on static protein-protein interactions, failing to adapt to dynamic and higher-order relationships. These limitations constrain the applicability of current methods.

RESULTS: We introduce …

Tsg-6+ Cancer-Associated Fibroblasts Modulate Myeloid Cell Responses And Impair Anti-Tumor Response To Immune Checkpoint Therapy In Pancreatic Cancer, Swetha Anandhan, Shelley Herbrich, Sangeeta Goswami, Baoxiang Guan, Yulong Chen, Marc Daniel Macaluso, Sonali Jindal, Seanu Meena Natarajan, Samuel W Andrewes, Liangwen Xiong, Ashwat Nagarajan, Sreyashi Basu, Derek Ng Tang, Jielin Liu, Jimin Min, Anirban Maitra, Padmanee Sharma

Faculty, Staff and Student Publications

Resistance to immune checkpoint therapy (ICT) presents a growing clinical challenge. The tumor microenvironment (TME) and its components, namely tumor-associated macrophages (TAMs) and cancer-associated fibroblasts (CAFs), play a pivotal role in ICT resistance; however, the underlying mechanisms remain under investigation. In this study, we identify expression of TNF-Stimulated Factor 6 (TSG-6) in ICT-resistant pancreatic tumors, compared to ICT-sensitive melanoma tumors, both in mouse and human. TSG-6 is expressed by CAFs within the TME, where suppressive macrophages expressing Arg1, Mafb, and Mrc1, along with TSG-6 ligand Cd44, predominate. Furthermore, TSG-6 expressing CAFs co-localize with the CD44 expressing macrophages in the TME. …

Leukocyte Immunoglobulin-Like Receptor B1 (Lilrb1) Protects Human Multiple Myeloma Cells From Ferroptosis By Maintaining Cholesterol Homeostasis, Miao Xian, Qiang Wang, Liuling Xiao, Ling Zhong, Wei Xiong, Lingqun Ye, Pan Su, Chuanchao Zhang, Yabo Li, Robert Z Orlowski, Fenghuang Zhan, Siddhartha Ganguly, Youli Zu, Jianfei Qian, Qing Yi

Faculty, Staff and Student Publications

Multiple myeloma (MM) is a hematologic malignancy characterized by uncontrolled proliferation of plasma cells in the bone marrow. MM patients with aggressive progression have poor survival, emphasizing the urgent need for identifying new therapeutic targets. Here, we show that the leukocyte immunoglobulin-like receptor B1 (LILRB1), a transmembrane receptor conducting negative immune response, is a top-ranked gene associated with poor prognosis in MM patients. LILRB1 deficiency inhibits MM progression in vivo by enhancing the ferroptosis of MM cells. Mechanistic studies reveal that LILRB1 forms a complex with the low-density lipoprotein receptor (LDLR) and LDLR adapter protein 1 (LDLRAP1) to facilitate LDL/cholesterol …

Intratumoral Immune Triads Are Required For Immunotherapy-Mediated Elimination Of Solid Tumors, Gabriel Espinosa-Carrasco, Edison Chiu, Aurora Scrivo, Paul Zumbo, Asim Dave, Doron Betel, Sung Wook Kang, Hee-Jin Jang, Matthew D Hellmann, Bryan M Burt, Hyun-Sung Lee, Andrea Schietinger

Faculty, Staff and Students Publications

Tumor-specific CD8+ T cells are frequently dysfunctional and unable to halt tumor growth. We investigated whether tumor-specific CD4+ T cells can be enlisted to overcome CD8+ T cell dysfunction within tumors. We find that the spatial positioning and interactions of CD8+ and CD4+ T cells, but not their numbers, dictate anti-tumor responses in the context of adoptive T cell therapy as well as immune checkpoint blockade (ICB): CD4+ T cells must engage with CD8+ T cells on the same dendritic cell during the effector phase, forming a three-cell-type cluster (triad) to license CD8+ T cell cytotoxicity and cancer cell elimination. …

Impact Of Isotype On The Mechanism Of Action Of Agonist Anti-Ox40 Antibodies In Cancer: Implications For Therapeutic Combinations, Jane E Willoughby, Lang Dou, Sabyasachi Bhattacharya, Heather Jackson, Laura Seestaller-Wehr, David Kilian, Laura Bover, Kui S Voo, Kerry L Cox, Tom Murray, Mel John, Hong Shi, Paul Bojczuk, Junping Jing, Heather Niederer, Andrew J Shepherd, Laura Hook, Stephanie Hopley, Tatyana Inzhelevskaya, Chris A Penfold, C Ian Mockridge, Vikki English, Sara J Brett, Roopa Srinivasan, Christopher Hopson, James Smothers, Axel Hoos, Elaine Paul, Stephen L Martin, Peter J Morley, Niranjan Yanamandra, Mark S Cragg

Faculty, Staff and Student Publications

BACKGROUND: OX40 has been widely studied as a target for immunotherapy with agonist antibodies taken forward into clinical trials for cancer where they are yet to show substantial efficacy. Here, we investigated potential mechanisms of action of anti-mouse (m) OX40 and anti-human (h) OX40 antibodies, including a clinically relevant monoclonal antibody (mAb) (GSK3174998) and evaluated how isotype can alter those mechanisms with the aim to develop improved antibodies for use in rational combination treatments for cancer.

METHODS: Anti-mOX40 and anti-hOX40 mAbs were evaluated in a number of in vivo models, including an OT-I adoptive transfer immunization model in hOX40 knock-in …

Hur Controls Glutaminase Rna Metabolism, Douglas Adamoski, Larissa M Dos Reis, Ana Carolina Paschoalini Mafra, Felipe Corrêa-Da-Silva, Pedro Manoel Mendes De Moraes-Vieira, Ioana Berindan-Neagoe, George A Calin, Sandra Martha Gomes Dias

Faculty, Staff and Student Publications

Glutaminase (GLS) is directly related to cell growth and tumor progression, making it a target for cancer treatment. The RNA-binding protein HuR (encoded by the ELAVL1 gene) influences mRNA stability and alternative splicing. Overexpression of ELAVL1 is common in several cancers, including breast cancer. Here we show that HuR regulates GLS mRNA alternative splicing and isoform translation/stability in breast cancer. Elevated ELAVL1 expression correlates with high levels of the glutaminase isoforms C (GAC) and kidney-type (KGA), which are associated with poor patient prognosis. Knocking down ELAVL1 reduces KGA and increases GAC levels, enhances glutamine anaplerosis into the TCA cycle, and …

Genetically Engineering Glycolysis In T Cells Increases Their Antitumor Function, Raphaëlle Toledano Zur, Orna Atar, Tilda Barliya, Shiran Hoogi, Ifat Abramovich, Eyal Gottlieb, Noga Ron-Harel, Cyrille J Cohen

Faculty, Staff and Student Publications

BACKGROUND: T cells play a central role in the antitumor response. However, they often face numerous hurdles in the tumor microenvironment, including the scarcity of available essential metabolites such as glucose and amino acids. Moreover, cancer cells can monopolize these resources to thrive and proliferate by upregulating metabolite transporters and maintaining a high metabolic rate, thereby outcompeting T cells.

METHODS: Herein, we sought to improve T-cell antitumor function in the tumor vicinity by enhancing their glycolytic capacity to better compete with tumor cells. To achieve this, we engineered human T cells to express a key glycolysis enzyme, phosphofructokinase, in conjunction …

Post-Immunotherapy Ctla-4 Ig Treatment Improves Antitumor Efficacy, Stephen Mok, Didem Ağaç Çobanoğlu, Huey Liu, James J Mancuso, James P Allison

Faculty, Staff and Student Publications

Immune checkpoint therapies (ICT) improve overall survival of patients with cancer but may cause immune-related adverse events (irAEs) such as myocarditis. Cytotoxic T lymphocyte-associated antigen 4 immunoglobulin fusion protein (CTLA-4 Ig), an inhibitor of T cell costimulation through CD28, reverses irAEs in animal models. However, concerns exist about potentially compromising antitumor response of ICT. In mouse tumor models, we administered CTLA-4 Ig 1) concomitantly with ICT or 2) after ICT completion. Concomitant treatment reduced antitumor efficacy, while post-ICT administration improved efficacy without affecting frequency and function of CD8 T cells. The improved response was independent of the ICT used, whether …

Inhibition Of Malt1 And Bcl2 Induces Synergistic Antitumor Activity In Models Of B-Cell Lymphoma, Joshua P Plotnik, Adam E Richardson, Haopeng Yang, Estela Rojas, Velitchka Bontcheva, Colleen Dowell, Sydney Parsons, Ashley Wilson, Vida Ravanmehr, Christine Will, Paul Jung, Haizhong Zhu, Sarathy Karunan Partha, Sanjay C Panchal, Raghuveer Singh Mali, Frederick J Kohlhapp, Ryan A Mcclure, Cyril Y Ramathal, Mariam D George, Manisha Jhala, Nathaniel L Elsen, Wei Qiu, Russell A Judge, Chin Pan, Anthony Mastracchio, Jared Henderson, Jonathan A Meulbroek, Michael R Green, William N Pappano

Faculty, Staff and Student Publications

The activated B cell (ABC) subset of diffuse large B-cell lymphoma (DLBCL) is characterized by chronic B-cell receptor signaling and associated with poor outcomes when treated with standard therapy. In ABC-DLBCL, MALT1 is a core enzyme that is constitutively activated by stimulation of the B-cell receptor or gain-of-function mutations in upstream components of the signaling pathway, making it an attractive therapeutic target. We discovered a novel small-molecule inhibitor, ABBV-MALT1, that potently shuts down B-cell signaling selectively in ABC-DLBCL preclinical models leading to potent cell growth and xenograft inhibition. We also identified a rational combination partner for ABBV-MALT1 in the BCL2 …

Valine Aminoacyl-Trna Synthetase Promotes Therapy Resistance In Melanoma, Najla El-Hachem, Marine Leclercq, Miguel Susaeta Ruiz, Raphael Vanleyssem, Kateryna Shostak, Pierre-René Körner, Coralie Capron, Lorena Martin-Morales, Patrick Roncarati, Arnaud Lavergne, Arnaud Blomme, Silvia Turchetto, Eric Goffin, Palaniraja Thandapani, Ivan Tarassov, Laurent Nguyen, Bernard Pirotte, Alain Chariot, Jean-Christophe Marine, Michael Herfs, Francesca Rapino, Reuven Agami, Pierre Close

Faculty, Staff and Student Publications

Transfer RNA dynamics contribute to cancer development through regulation of codon-specific messenger RNA translation. Specific aminoacyl-tRNA synthetases can either promote or suppress tumourigenesis. Here we show that valine aminoacyl-tRNA synthetase (VARS) is a key player in the codon-biased translation reprogramming induced by resistance to targeted (MAPK) therapy in melanoma. The proteome rewiring in patient-derived MAPK therapy-resistant melanoma is biased towards the usage of valine and coincides with the upregulation of valine cognate tRNAs and of VARS expression and activity. Strikingly, VARS knockdown re-sensitizes MAPK-therapy-resistant patient-derived melanoma in vitro and in vivo. Mechanistically, VARS regulates the messenger RNA translation of valine-enriched …

Genetic Deletion Of Galectin-3 Inhibits Pancreatic Cancer Progression And Enhances The Efficacy Of Immunotherapy, Daowei Yang, Xinlei Sun, Rohan Moniruzzaman, Hua Wang, Citu Citu, Zhongming Zhao, Ignacio I Wistuba, Huamin Wang, Anirban Maitra, Yang Chen

Faculty, Staff and Student Publications

Background & aims: Pancreatic ductal adenocarcinoma (PDAC) has a desmoplastic tumor stroma and immunosuppressive microenvironment. Galectin-3 (GAL3) is enriched in PDAC, highly expressed by cancer cells and myeloid cells. However, the functional roles of GAL3 in the PDAC microenvironment remain elusive.

Methods: We generated a novel transgenic mouse model (LSL-KrasG12D/+;Trp53loxP/loxP;Pdx1-Cre;Lgals3-/- [KPPC;Lgals3-/-]) that allows the genetic depletion of GAL3 from both cancer cells and myeloid cells in spontaneous PDAC formation. Single-cell RNA-sequencing analysis was used to identify the alterations in the tumor microenvironment upon GAL3 depletion. We investigated both the cancer cell-intrinsic function and immunosuppressive function of GAL3. We also evaluated …

Epigenetic Activation Of Sox11 Is Associated With Recurrence And Progression Of Ductal Carcinoma In Situ To Invasive Breast Cancer, Warapen Treekitkarnmongkol, Vandna Shah, Kazuharu Kai, Hiroshi Katayama, Justin Wong, Farah A Ladha, Tristian Nguyen, Brian Menegaz, Wei Lu, Fei Yang, Barbara Mino, Ximing Tang, Mihai Gagea, Harsh Batra, Maria Gabriela Raso, Ignacio I Wistuba, Savitri Krishnamurthy, Sarah E Pinder, Elinor J Sawyer, Alastair M Thompson, Subrata Sen

Faculty, Staff and Student Publications

Background: Risk of recurrence and progression of ductal carcinoma in situ (DCIS) to invasive cancer remains uncertain, emphasizing the need for developing predictive biomarkers of aggressive DCIS.

Methods: Human cell lines and mouse models of disease progression were analyzed for candidate risk predictive biomarkers identified and validated in two independent DCIS cohorts.

Results: RNA profiling of normal mammary and DCIS tissues (n = 48) revealed that elevated SOX11 expression correlates with MKI67, EZH2, and DCIS recurrence score. The 21T human cell line model of DCIS progression to invasive cancer and two mouse models developing mammary intraepithelial neoplasia confirmed the findings. …

Cracd Loss Induces Neuroendocrine Cell Plasticity Of Lung Adenocarcinoma, Bongjun Kim, Shengzhe Zhang, Yuanjian Huang, Kyung-Pil Ko, Youn-Sang Jung, Jinho Jang, Gengyi Zou, Jie Zhang, Sohee Jun, Kee-Beom Kim, Kwon-Sik Park, Jae-Il Park

Faculty, Staff and Student Publications

Tumor cell plasticity contributes to intratumoral heterogeneity and therapy resistance. Through cell plasticity, some lung adenocarcinoma (LUAD) cells transform into neuroendocrine (NE) tumor cells. However, the mechanisms of NE cell plasticity remain unclear. CRACD (capping protein inhibiting regulator of actin dynamics), a capping protein inhibitor, is frequently inactivated in cancers. CRACD knockout (KO) is sufficient to de-repress NE-related gene expression in the pulmonary epithelium and LUAD cells. In LUAD mouse models, Cracd KO increases intratumoral heterogeneity with NE gene expression. Single-cell transcriptomic analysis showed that Cracd KO-induced NE cell plasticity is associated with cell de-differentiation and stemness-related pathway activation. The …

A Spatiotemporal Map Of Co-Receptor Signaling Networks Underlying B Cell Activation, Katherine J Susa, Gary A Bradshaw, Robyn J Eisert, Charlotte M Schilling, Marian Kalocsay, Stephen C Blacklow, Andrew C Kruse

Faculty, Staff and Student Publications

The B cell receptor (BCR) signals together with a multi-component co-receptor complex to initiate B cell activation in response to antigen binding. Here, we take advantage of peroxidase-catalyzed proximity labeling combined with quantitative mass spectrometry to track co-receptor signaling dynamics in Raji cells from 10 s to 2 h after BCR stimulation. This approach enables tracking of 2,814 proximity-labeled proteins and 1,394 phosphosites and provides an unbiased and quantitative molecular map of proteins recruited to the vicinity of CD19, the signaling subunit of the co-receptor complex. We detail the recruitment kinetics of signaling effectors to CD19 and identify previously uncharacterized …

Sod1 Is A Synthetic-Lethal Target In Ppm1d-Mutant Leukemia Cells, Linda Zhang, Joanne I Hsu, Etienne D Braekeleer, Chun-Wei Chen, Tajhal D Patel, Alejandra G Martell, Anna G Guzman, Katharina Wohlan, Sarah M Waldvogel, Hidetaka Uryu, Ayala Tovy, Elsa Callen, Rebecca L Murdaugh, Rosemary Richard, Sandra Jansen, Lisenka Vissers, Bert B A De Vries, Andre Nussenzweig, Shixia Huang, Cristian Coarfa, Jamie Anastas, Koichi Takahashi, George Vassiliou, Margaret A Goodell

Faculty, Staff and Student Publications

The DNA damage response is critical for maintaining genome integrity and is commonly disrupted in the development of cancer. PPM1D (protein phosphatase Mg2+/Mn2+-dependent 1D) is a master negative regulator of the response; gain-of-function mutations and amplifications of PPM1D are found across several human cancers making it a relevant pharmacological target. Here, we used CRISPR/Cas9 screening to identify synthetic-lethal dependencies of PPM1D, uncovering superoxide dismutase-1 (SOD1) as a potential target for PPM1D-mutant cells. We revealed a dysregulated redox landscape characterized by elevated levels of reactive oxygen species and a compromised response to oxidative stress in PPM1D-mutant cells. Altogether, our …

Sting Agonist 8803 Reprograms The Immune Microenvironment And Increases Survival In Preclinical Models Of Glioblastoma, Hinda Najem, Spencer T Lea, Shashwat Tripathi, Lisa Hurley, Chao-Hsien Chen, Ivana William, Moloud Sooreshjani, Michelle Bowie, Genevieve Hartley, Corey Dussold, Sebastian Pacheco, Crismita Dmello, Catalina Lee-Chang, Kathleen Mccortney, Alicia Steffens, Jordain Walshon, Martina Ott, Jun Wei, Anantha Marisetty, Irina Balyasnikova, Roger Stupp, Rimas V Lukas, Jian Hu, Charles David James, Craig M Horbinski, Maciej S Lesniak, David M Ashley, Waldemar Priebe, Leonidas C Platanias, Michael A Curran, Amy B Heimberger

Faculty, Staff and Student Publications

STING agonists can reprogram the tumor microenvironment to induce immunological clearance within the central nervous system. Using multiplexed sequential immunofluorescence (SeqIF) and the Ivy Glioblastoma Atlas, STING expression was found in myeloid populations and in the perivascular space. The STING agonist 8803 increased median survival in multiple preclinical models of glioblastoma, including QPP8, an immune checkpoint blockade-resistant model, where 100% of mice were cured. Ex vivo flow cytometry profiling during the therapeutic window demonstrated increases in myeloid tumor trafficking and activation, alongside enhancement of CD8+ T cell and NK effector responses. Treatment with 8803 reprogrammed microglia to express costimulatory CD80/CD86 …

Slow Proliferation Of Bap1-Deficient Uveal Melanoma Cells Is Associated With Reduced S6 Signaling And Resistance To Nutrient Stress, Vivian Chua, Melisa Lopez-Anton, Mizue Terai, Ryota Tanaka, Usman Baqai, Timothy J Purwin, Jelan I Haj, Francis J Waltrich, Isabella Trachtenberg, Kristine Luo, Rohith Tudi, Angela Jeon, Anna Han, Inna Chervoneva, Michael A Davies, Julio A Aguirre-Ghiso, Takami Sato, Andrew E Aplin

Faculty, Staff and Student Publications

Uveal melanoma (UM) is the deadliest form of eye cancer in adults. Inactivating mutations and/or loss of expression of the gene encoding BRCA1-associated protein 1 (BAP1) in UM tumors are associated with an increased risk of metastasis. To investigate the mechanisms underlying this risk, we explored the functional consequences of BAP1 deficiency. UM cell lines expressing mutant BAP1 grew more slowly than those expressing wild-type BAP1 in culture and in vivo. The ability of BAP1 reconstitution to restore cell proliferation in BAP1-deficient cells required its deubiquitylase activity. Proteomic analysis showed that BAP1-deficient cells had decreased phosphorylation of ribosomal S6 and …

Tmprss2 Is A Tumor Suppressor And Its Downregulation Promotes Antitumor Immunity And Immunotherapy Response In Lung Adenocarcinoma, Zhixian Liu, Qiqi Lu, Zhilan Zhang, Qiushi Feng, Xiaosheng Wang

Faculty, Staff and Student Publications

Background: TMPRSS2, a key molecule for SARS-CoV-2 invading human host cells, has an association with cancer. However, its association with lung cancer remains insufficiently unexplored.

Methods: In five bulk transcriptomics datasets, one single-cell RNA sequencing (scRNA-seq) dataset and one proteomics dataset for lung adenocarcinoma (LUAD), we explored associations between TMPRSS2 expression and immune signatures, tumor progression phenotypes, genomic features, and clinical prognosis in LUAD by the bioinformatics approach. Furthermore, we performed experimental validation of the bioinformatics findings.

Results: TMPRSS2 expression levels correlated negatively with the enrichment levels of both immune-stimulatory and immune-inhibitory signatures, while they correlated positively with the ratios …

Defining The Kras- And Erk-Dependent Transcriptome In Kras-Mutant Cancers, Jeffrey A Klomp, Jennifer E Klomp, Clint A Stalnecker, Kirsten L Bryant, A Cole Edwards, Kristina Drizyte-Miller, Priya S Hibshman, J Nathaniel Diehl, Ye S Lee, Alexis J Morales, Khalilah E Taylor, Sen Peng, Nhan L Tran, Laura E Herring, Alex W Prevatte, Natalie K Barker, Laura D Hover, Jill Hallin, Alexey Sorokin, Preeti Marie Kanikarla, Saikat Chowdhury, Oluwadara Coker, Hey Min Lee, Craig M Goodwin, Prson Gautam, Peter Olson, James G Christensen, John P Shen, Scott Kopetz, Lee M Graves, Kian-Huat Lim, Andrea Wang-Gillam, Krister Wennerberg, Adrienne D Cox, Channing J Der

Faculty, Staff and Student Publications

How the KRAS oncogene drives cancer growth remains poorly understood. Therefore, we established a systemwide portrait of KRAS- and ERK-dependent gene transcription in KRAS-mutant cancer to delineate the molecular mechanisms of growth and of inhibitor resistance. Unexpectedly, our KRAS-dependent gene signature diverges significantly from the frequently cited Hallmark KRAS signaling gene signature, is driven predominantly through the ERK mitogen-activated protein kinase (MAPK) cascade, and accurately reflects KRAS- and ERK-regulated gene transcription in KRAS-mutant cancer patients. Integration with our ERK-regulated phospho- and total proteome highlights ERK deregulation of the anaphase promoting complex/cyclosome and other components of the cell cycle machinery as …

Orthogonal Proteogenomic Analysis Identifies The Druggable Pa2g4-Myc Axis In 3q26 Aml, Matteo Marchesini, Andrea Gherli, Elisa Simoncini, Lucas Moron Dalla Tor, Anna Montanaro, Natthakan Thongon, Federica Vento, Chiara Liverani, Elisa Cerretani, Anna D'Antuono, Luca Pagliaro, Raffaella Zamponi, Chiara Spadazzi, Elena Follini, Benedetta Cambò, Mariateresa Giaimo, Angela Falco, Gabriella Sammarelli, Giannalisa Todaro, Sabrina Bonomini, Valentina Adami, Silvano Piazza, Claudia Corbo, Bruno Lorusso, Federica Mezzasoma, Costanza Anna Maria Lagrasta, Maria Paola Martelli, Roberta La Starza, Antonio Cuneo, Franco Aversa, Cristina Mecucci, Federico Quaini, Simona Colla, Giovanni Roti

Faculty, Staff and Student Publications

The overexpression of the ecotropic viral integration site-1 gene (EVI1/MECOM) marks the most lethal acute myeloid leukemia (AML) subgroup carrying chromosome 3q26 abnormalities. By taking advantage of the intersectionality of high-throughput cell-based and gene expression screens selective and pan-histone deacetylase inhibitors (HDACis) emerge as potent repressors of EVI1. To understand the mechanism driving on-target anti-leukemia activity of this compound class, here we dissect the expression dynamics of the bone marrow leukemia cells of patients treated with HDACi and reconstitute the EVI1 chromatin-associated co-transcriptional complex merging on the role of proliferation-associated 2G4 (PA2G4) protein. PA2G4 overexpression rescues AML cells from the …

Klrg1 Cell Depletion As A Novel Therapeutic Strategy In Patients With Mature T-Cell Lymphoma Subtypes, Bimarzhan Assatova, Robert Willim, Christopher Trevisani, Garrett Haskett, Khyati Maulik Kariya, Kusha Chopra, Sung Rye Park, Michael Yevgeniy Tolstorukov, Sean M Mccabe, Jessica Duffy, Abner Louissaint, Jani Huuhtanen, Dipabarna Bhattacharya, Satu Mustjoki, Min Jung Koh, Foster Powers, Elizabeth A Morgan, Lei Yang, Brandy Pinckney, Matthew J Cotton, Andrew Crabbe, Jessica Beth Ziemba, Ian Brain, Tayla B Heavican-Foral, Javeed Iqbal, Ronald Nemec, Anna Baird Rider, Josie Germain Ford, Min Ji Koh, Nora Scanlan, David J Feith, Thomas P Loughran, Won Seog Kim, Jaehyuk Choi, Juliette Roels, Lena Boehme, Tom Putteman, Tom Taghon, Jeffrey A Barnes, P Connor Johnson, Eric D Jacobsen, Steven A Greenberg, David M Weinstock, Salvia Jain

Faculty, Staff and Student Publications

Purpose: Develop a novel therapeutic strategy for patients with subtypes of mature T-cell and NK-cell neoplasms.

Experimental design: Primary specimens, cell lines, patient-derived xenograft models, commercially available, and proprietary anti-KLRG1 antibodies were used for screening, target, and functional validation.

Results: Here we demonstrate that surface KLRG1 is highly expressed on tumor cells in subsets of patients with extranodal NK/T-cell lymphoma (ENKTCL), T-prolymphocytic leukemia (T-PLL), and gamma/delta T-cell lymphoma (G/D TCL). The majority of the CD8+/CD57+ or CD3-/CD56+ leukemic cells derived from patients with T- and NK-large granular lymphocytic leukemia (T-LGLL and NK-LGLL), respectively, expressed surface KLRG1. The humanized afucosylated anti-KLRG1 …

Irx4204 Induces Senescence And Cell Death In Her2-Positive Breast Cancer And Synergizes With Anti-Her2 Therapy, Cassandra L Moyer, Amanda Lanier, Jing Qian, Darian Coleman, Jamal Hill, Vidyasagar Vuligonda, Martin E Sanders, Abhijit Mazumdar, Powel H Brown

Faculty, Staff and Student Publications

PURPOSE: Rexinoids, agonists of nuclear retinoid X receptor (RXR), have been used for the treatment of cancers and are well tolerated in both animals and humans. However, the usefulness of rexinoids in treatment of breast cancer remains unknown. This study examines the efficacy of IRX4204, a highly specific rexinoid, in breast cancer cell lines and preclinical models to identify a biomarker for response and potential mechanism of action.

EXPERIMENTAL DESIGN: IRX4204 effects on breast cancer cell growth and viability were determined using cell lines, syngeneic mouse models, and primary patient-derived xenograft (PDX) tumors. In vitro assays of cell cycle, apoptosis, …

Evaluations Of An Early Change In Tumor Pathophysiology In Response To Radiotherapy With Oxygen Enhanced Electron Paramagnetic Resonance Imaging (Oe Epri), Tianzhe Li, Grace A Murley, Xiaofei Liang, Renee L Chin, Jorge De La Cerda, F William Schuler, Mark D Pagel

Faculty, Staff and Student Publications

Purpose: Electron Paramagnetic Resonance Imaging (EPRI) can image the partial pressure of oxygen (pO2) within in vivo tumor models. We sought to develop Oxygen Enhanced (OE) EPRI that measures tumor pO2 with breathing gases of 21% O2 (pO221%) and 100% O2 (pO2100%), and the differences in pO2 between breathing gases (ΔpO2). We applied OE EPRI to study the early change in tumor pathophysiology in response to radiotherapy in two tumor models of pancreatic cancer.

Procedures: We developed a protocol that intraperitoneally administered OX071, a trityl radical contrast agent, and then acquired anatomical MR images to localize the tumor. Subsequently, we …

The Kat Module Of The Saga Complex Maintains The Oncogenic Gene Expression Program In Mycn- Amplified Neuroblastoma, Clare F Malone, Nathaniel W Mabe, Alexandra B Forman, Gabriela Alexe, Kathleen L Engel, Ying-Jiun C Chen, Melinda Soeung, Silvi Salhotra, Allen Basanthakumar, Bin Liu, Sharon Y R Dent, Kimberly Stegmaier

Faculty, Staff and Student Publications

Pediatric cancers are frequently driven by genomic alterations that result in aberrant transcription factor activity. Here, we used functional genomic screens to identify multiple genes within the transcriptional coactivator Spt-Ada-Gcn5-acetyltransferase (SAGA) complex as selective dependencies for MYCN-amplified neuroblastoma, a disease of dysregulated development driven by an aberrant oncogenic transcriptional program. We characterized the DNA recruitment sites of the SAGA complex in neuroblastoma and the consequences of loss of SAGA complex lysine acetyltransferase (KAT) activity on histone acetylation and gene expression. We demonstrate that loss of SAGA complex KAT activity is associated with reduced MYCN binding on chromatin, suppression of …

Selective Refueling Of Car T Cells Using Ada1 And Cd26 Boosts Antitumor Immunity, Yue Hu, Abhijit Sarkar, Kevin Song, Sara Michael, Magnus Hook, Ruoning Wang, Andras Heczey, Xiaotong Song

Faculty, Staff and Student Publications

Chimeric antigen receptor (CAR) T cell therapy is hindered in solid tumor treatment due to the immunosuppressive tumor microenvironment and suboptimal T cell persistence. Current strategies do not address nutrient competition in the microenvironment. Hence, we present a metabolic refueling approach using inosine as an alternative fuel. CAR T cells were engineered to express membrane-bound CD26 and cytoplasmic adenosine deaminase 1 (ADA1), converting adenosine to inosine. Autocrine secretion of ADA1 upon CD3/CD26 stimulation activates CAR T cells, improving migration and resistance to transforming growth factor β1 suppression. Fusion of ADA1 with anti-CD3 scFv further boosts inosine production and minimizes tumor …

Developing A Membrane-Proximal Cd33-Targeting Car T Cell, Ruby Freeman, Sanam Shahid, Abdul G Khan, Serena C Mathew, Sydney Souness, Erin R Burns, Jasmine S Um, Kento Tanaka, Winson Cai, Sarah Yoo, Andrew Dunbar, Young Park, Devin Mcavoy, Kinga K Hosszu, Ross L Levine, Jaap Jan Boelens, Ivo C Lorenz, Renier J Brentjens, Anthony F Daniyan

Faculty, Staff and Student Publications

BACKGROUND: CD33 is a tractable target in acute myeloid leukemia (AML) for chimeric antigen receptor (CAR) T cell therapy, but clinical success is lacking.

METHODS: We developed 3P14HLh28Z, a novel CD33-directed CD28/CD3Z-based CAR T cell derived from a high-affinity binder obtained through membrane-proximal fragment immunization in humanized mice.

RESULTS: We found that immunization exclusively with the membrane-proximal domain of CD33 is necessary for identification of membrane-proximal binders in humanized mice. Compared with clinically validated lintuzumab-based CAR T cells targeting distal CD33 epitopes, 3P14HLh28Z showed enhanced in vitro functionality as well as superior tumor control and increased overall survival in both …

Unraveling Etc Complex I Function In Ferroptosis Reveals A Potential Ferroptosis-Inducing Therapeutic Strategy For Lkb1-Deficient Cancers, Chao Mao, Guang Lei, Amber Horbath, Min Wang, Zhengze Lu, Yuelong Yan, Xiaoguang Liu, Lavanya Kondiparthi, Xiong Chen, Jun Cheng, Qidong Li, Zhihao Xu, Li Zhuang, Bingliang Fang, Joseph R Marszalek, Masha V Poyurovsky, Kellen Olszewski, Boyi Gan

Faculty, Staff and Student Publications

The role of the mitochondrial electron transport chain (ETC) in regulating ferroptosis is not fully elucidated. Here, we reveal that pharmacological inhibition of the ETC complex I reduces ubiquinol levels while decreasing ATP levels and activating AMP-activated protein kinase (AMPK), the two effects known for their roles in promoting and suppressing ferroptosis, respectively. Consequently, the impact of complex I inhibitors on ferroptosis induced by glutathione peroxidase 4 (GPX4) inhibition is limited. The pharmacological inhibition of complex I in LKB1-AMPK-inactivated cells, or genetic ablation of complex I (which does not trigger apparent AMPK activation), abrogates the AMPK-mediated ferroptosis-suppressive effect and sensitizes …

Brg1/Brm Inhibitor Targets Aml Stem Cells And Exerts Superior Preclinical Efficacy Combined With Bet Or Menin Inhibitor, Warren Fiskus, Jessica Piel, Mike Collins, Murphy Hentemann, Branko Cuglievan, Christopher P Mill, Christine E Birdwell, Kaberi Das, John A Davis, Hanxi Hou, Antrix Jain, Anna Malovannaya, Tapan M Kadia, Naval Daver, Koji Sasaki, Koichi Takahashi, Danielle Hammond, Patrick K Reville, Jian Wang, Sanam Loghavi, Rwik Sen, Xinjia Ruan, Xiaoping Su, Lauren B Flores, Courtney D Dinardo, Kapil N Bhalla

Faculty, Staff and Student Publications

BRG1 (SMARCA4) and BRM (SMARCA2) are the mutually exclusive core ATPases of the chromatin remodeling BAF (BRG1/BRM-associated factor) complexes. They enable transcription factors/cofactors to access enhancers/promoter and modulate gene expressions responsible for cell growth and differentiation of acute myeloid leukemia (AML) stem/progenitor cells. In AML with MLL1 rearrangement (MLL1r) or mutant NPM1 (mtNPM1), although menin inhibitor (MI) treatment induces clinical remissions, most patients either fail to respond or relapse, some harboring menin mutations. FHD-286 is an orally bioavailable, selective inhibitor of BRG1/BRM under clinical development in AML. Present studies show that FHD-286 induces differentiation and lethality in AML cells with …

Ataxia-Telangiectasia Mutated Loss-Of-Function Displays Variant And Tissue-Specific Differences Across Tumor Types, Patrick G Pilié, Virginia Giuliani, Wei-Lien Wang, Daniel J Mcgrail, Christopher A Bristow, Natalie Y L Ngoi, Keith Kyewalabye, Khalida M Wani, Hung Le, Erick Campbell, Nora S Sanchez, Dong Yang, Jinesh S Gheeya, Rohit Vivek Goswamy, Vijaykumar Holla, Kenna Rael Shaw, Funda Meric-Bernstam, Chiu-Yi Liu, Xiaoyan Ma, Ningping Feng, Annette A Machado, Jennifer P Bardenhagen, Christopher P Vellano, Joseph R Marszalek, Eeson Rajendra, Desiree Piscitello, Timothy I Johnson, Maria Likhatcheva, Elias Elinati, Jayesh Majithiya, Joana Neves, Vera Grinkevich, Marco Ranzani, Marina Roy Luzarraga, Marie Boursier, Lucy Armstrong, Lerin Geo, Giorgia Lillo, Wai Yiu Tse, Alexander J Lazar, Scott E Kopetz, Mary K Geck Do, Sarah Lively, Michael G Johnson, Helen M R Robinson, Graeme C M Smith, Christopher L Carroll, M Emilia Di Francesco, Philip Jones, Timothy P Heffernan, Timothy A Yap

Faculty, Staff and Student Publications

PURPOSE: Mutations in the ATM gene are common in multiple cancers, but clinical studies of therapies targeting ATM-aberrant cancers have yielded mixed results. Refinement of ATM loss of function (LOF) as a predictive biomarker of response is urgently needed.

EXPERIMENTAL DESIGN: We present the first disclosure and preclinical development of a novel, selective ATR inhibitor, ART0380, and test its antitumor activity in multiple preclinical cancer models. To refine ATM LOF as a predictive biomarker, we performed a comprehensive pan-cancer analysis of ATM variants in patient tumors and then assessed the ATM variant-to-protein relationship. Finally, we assessed a novel ATM LOF …

Targeting Ccl2/Ccr2 Signaling Overcomes Mek Inhibitor Resistance In Acute Myeloid Leukemia, Rucha V Modak, Katia G De Oliveira Rebola, John Mcclatchy, Mona Mohammadhosseini, Alisa Damnernsawad, Stephen E Kurtz, Christopher A Eide, Guanming Wu, Ted Laderas, Tamilla Nechiporuk, Marina A Gritsenko, Joshua R Hansen, Chelsea Hutchinson, Sara J C Gosline, Paul Piehowski, Daniel Bottomly, Nicholas Short, Karin Rodland, Shannon K Mcweeney, Jeffrey W Tyner, Anupriya Agarwal

Faculty, Staff and Student Publications

Purpose: Emerging evidence underscores the critical role of extrinsic factors within the microenvironment in protecting leukemia cells from therapeutic interventions, driving disease progression, and promoting drug resistance in acute myeloid leukemia (AML). This finding emphasizes the need for the identification of targeted therapies that inhibit intrinsic and extrinsic signaling to overcome drug resistance in AML.

Experimental design: We performed a comprehensive analysis utilizing a cohort of ∼300 AML patient samples. This analysis encompassed the evaluation of secreted cytokines/growth factors, gene expression, and ex vivo drug sensitivity to small molecules. Our investigation pinpointed a notable association between elevated levels of CCL2 …