Medical Specialties Commons^™

Assessing The Practicality Of Using A Single Knowledge-Based Planning Model For Multiple Linac Vendors, Raphael J Douglas, Adenike Olanrewaju, Lifei Zhang, Beth M Beadle, Laurence E Court

Faculty, Staff and Student Publications

Purpose: Knowledge-based planning (KBP) has been shown to be an effective tool in quality control for intensity-modulated radiation therapy treatment planning and generating high-quality plans. Previous studies have evaluated its ability to create consistent plans across institutions and between planners within the same institution as well as its use as teaching tool for inexperienced planners. This study evaluates whether planning quality is consistent when using a KBP model to plan across different treatment machines.

Materials and methods: This study used a RapidPlan model (Varian Medical Systems) provided by the vendor, to which we added additional planning objectives, maximum dose limits, …

Love And Fear: A Special Issue, C Sue Carter, Robert Dantzer

Faculty, Staff and Student Publications

Love and fear were forged by the same fundamental evolutionary processes that permitted life on Earth. Both love and fear are deeply interwoven with the adaptive management of stress and disease. Love and fear share common roots and both can play a role in reproduction, survival, perceived safety and wellbeing. This special issue of Comprehensive Psychoneuroendocrinology focuses specifically on the causes and consequences of love from the interactive perspectives of evolution, neurobiology and culture.

Clinical Activity Of Mitogen-Activated Protein Kinase-Targeted Therapies In Patients With Non-V600 Braf-Mutant Tumors, Matthew Dankner, Yifan Wang, Rouhi Fazelzad, Benny Johnson, Caroline A Nebhan, Ibiayi Dagogo-Jack, Nathaniel J Myall, Georg Richtig, Jillian W P Bracht, Marco Gerlinger, Eiji Shinozaki, Takayuki Yoshino, Daisuke Kotani, Jason R Fangusaro, Oliver Gautschi, Julien Mazieres, Jeffrey A Sosman, Scott Kopetz, Vivek Subbiah, Michael A Davies, Anna L Groover, Ryan J Sullivan, Keith T Flaherty, Douglas B Johnson, Andrea Benedetti, David W Cescon, Anna Spreafico, George Zogopoulos, April A N Rose

Faculty, Staff and Student Publications

Purpose: Non-V600 mutations comprise approximately 35% of all BRAF mutations in cancer. Many of these mutations have been identified as oncogenic drivers and can be classified into three classes according to molecular characteristics. Consensus treatment strategies for class 2 and 3 BRAF mutations have not yet been established.

Methods: We performed a systematic review and meta-analysis with published reports of individual patients with cancer harboring class 2 or 3 BRAF mutations from 2010 to 2021, to assess treatment outcomes with US Food and Drug Administration-approved mitogen-activated protein kinase (MAPK) pathway targeted therapy (MAPK TT) according to BRAF class, cancer type, …

Selinexor In Advanced, Metastatic Dedifferentiated Liposarcoma: A Multinational, Randomized, Double-Blind, Placebo-Controlled Trial, Mrinal M Gounder, Albiruni Abdul Razak, Neeta Somaiah, Sant Chawla, Javier Martin-Broto, Giovanni Grignani, Scott M Schuetze, Bruno Vincenzi, Andrew J Wagner, Bartosz Chmielowski, Robin L Jones, Richard F Riedel, Silvia Stacchiotti, Elizabeth T Loggers, Kristen N Ganjoo, Axel Le Cesne, Antoine Italiano, Xavier Garcia Del Muro, Melissa Burgess, Sophie Piperno-Neumann, Christopher Ryan, Mary F Mulcahy, Charles Forscher, Nicolas Penel, Scott Okuno, Anthony Elias, Lee Hartner, Tony Philip, Thierry Alcindor, Bernd Kasper, Peter Reichardt, Lore Lapeire, Jean-Yves Blay, Christine Chevreau, Claudia Maria Valverde Morales, Gary K Schwartz, James L Chen, Hari Deshpande, Elizabeth J Davis, Garth Nicholas, Stefan Gröschel, Helen Hatcher, Florence Duffaud, Antonio Casado Herráez, Roberto Diaz Beveridge, Giuseppe Badalamenti, Mikael Eriksson, Christian Meyer, Margaret Von Mehren, Brian A Van Tine, Katharina Götze, Filomena Mazzeo, Alexander Yakobson, Aviad Zick, Alexander Lee, Anna Estival Gonzalez, Andrea Napolitano, Mark A Dickson, Dayana Michel, Changting Meng, Lingling Li, Jianjun Liu, Osnat Ben-Shahar, Dane R Van Domelen, Christopher J Walker, Hua Chang, Yosef Landesman, Jatin J Shah, Sharon Shacham, Michael G Kauffman, Steven Attia

Faculty, Staff and Student Publications

Purpose: Antitumor activity in preclinical models and a phase I study of patients with dedifferentiated liposarcoma (DD-LPS) was observed with selinexor. We evaluated the clinical benefit of selinexor in patients with previously treated DD-LPS whose sarcoma progressed on approved agents.

Methods: SEAL was a phase II-III, multicenter, randomized, double-blind, placebo-controlled study. Patients age 12 years or older with advanced DD-LPS who had received two-five lines of therapy were randomly assigned (2:1) to selinexor (60 mg) or placebo twice weekly in 6-week cycles (crossover permitted). The primary end point was progression-free survival (PFS). Patients who received at least one dose of …

Regulation And Function Of Id2 In Plasmacytoid Dendritic Cells, Rachel L Babcock, Yifan Zhou, Bhakti Patel, Taylor T Chrisikos, Laura M Kahn, Allison M Dyevoich, Yusra B Medik, Stephanie S Watowich

Faculty, Staff and Student Publications

Plasmacytoid dendritic cells (pDCs) are specialized type I interferon (IFN-I) producing cells that promote anti-viral immune responses and contribute to autoimmunity. Development of pDCs requires the transcriptional regulator E2-2 and is opposed by inhibitor of DNA binding 2 (Id2). Prior work indicates Id2 is induced in pDCs upon maturation and may affect pDC IFN-I production via suppression of E2-2, suggesting an important yet uncharacterized role in this lineage. We found TLR7 agonists stimulate Id2 mRNA and protein expression in pDCs. We further show that transcriptional activation of Id2 is dependent on the E2 ubiquitin-conjugating enzyme Ubc13, but independent of IFN-I …

Probing The Structure And Function Of Polymerase Θ Helicase-Like Domain, Scott Vanson, Yuzhen Li, Richard D Wood, Sylvie Doublié

Faculty, Staff and Student Publications

DNA Polymerase θ is the key actuator of the recently identified double-strand break repair pathway, theta-mediated end joining (TMEJ). It is the only known polymerase to have a 3-domain architecture containing an independently functional family A DNA polymerase tethered by a long central region to an N-terminal helicase-like domain (HLD). Full-length polymerase θ and the isolated HLD hydrolyze ATP in the presence of DNA, but no processive DNA duplex unwinding has been observed. Based on sequence and structure conservation, the HLD is classified as a member of helicase superfamily II and, more specifically, the Ski2-like family. The specific subdomain composition …

Clinical Outcomes Of Patients With Recurrent Microsatellite-Stable Endometrial Cancer In Early-Phase Immunotherapy Clinical Trials, Jeffrey A How, Amir A Jazaeri, Siqing Fu, Jordi Rodon Ahnert, Jing Gong, Bettzy Stephen, Hanna Ferreira Dalla Pria, Priya Bhosale, Amber Johnson, Ying Yuan, Funda Meric-Bernstam, Aung Naing

Faculty, Staff and Student Publications

Recurrent microsatellite stable (MSS) endometrial cancer has poor response to conventional therapy and limited efficacy with immune checkpoint monotherapy. We conducted a retrospective study of recurrent MSS endometrial cancer patients enrolled in immunotherapy-based clinical trials at MD Anderson Cancer Center between 1 January 2010 and 31 December 2019. Patients were evaluated for radiologic response using RECIST 1.1 criteria, progression-free survival (PFS), and overall survival (OS). Thirty-five patients were treated with immune checkpoint inhibitors: 8 with monotherapy, 17 with immunotherapy (IO) in combination with another IO-only, and 10 with IO in combination with non-IO therapy. Among those treated with combination IO …

Ppp1r7 Is A Novel Translocation Partner Of Cbfb Via T(2; 16)(Q37; Q22) In Acute Myeloid Leukemia, Lulu Wang, Wei Wang, Hannah C Beird, Xueqian Cheng, Hong Fang, Guilin Tang, Gokce A Toruner, C Cameron Yin, M James You, Ghayas C Issa, Gautam Borthakur, Guang Peng, Joseph D Khoury, L Jeffrey Medeiros, Zhenya Tang

Faculty, Staff and Student Publications

In a subset of acute myeloid leukemia (AML) cases, the core binding factor beta subunit gene (CBFB) was rearranged via inv(16)(p13.1q22) or t(16;16)(p13.1;q22), in which the smooth muscle myosin heavy chain 11 gene (MYH11) was the partner (CBFB::MYH11). Rare variants of CBFB rearrangement occurring via non-classic chromosomal aberrations have been reported, such as t(1;16), t(2;16), t(3;16), t(5;16), and t(16;19), but the partners of CBFB have not been characterized. We report a case of AML with a complex karyotype, including t(2;16)(q37;q22), in which the protein phosphatase 1 regulatory subunit 7 gene (PPP1R7) at …

Targeting De Novo Lipogenesis And The Lands Cycle Induces Ferroptosis In Kras-Mutant Lung Cancer, Caterina Bartolacci, Cristina Andreani, Gonçalo Vale, Stefano Berto, Margherita Melegari, Anna Colleen Crouch, Dodge L Baluya, George Kemble, Kurt Hodges, Jacqueline Starrett, Katerina Politi, Sandra L Starnes, Daniele Lorenzini, Maria Gabriela Raso, Luisa M Solis Soto, Carmen Behrens, Humam Kadara, Boning Gao, Ignacio I Wistuba, John D Minna, Jeffrey G Mcdonald, Pier Paolo Scaglioni

Faculty, Staff and Student Publications

Mutant KRAS (KM), the most common oncogene in lung cancer (LC), regulates fatty acid (FA) metabolism. However, the role of FA in LC tumorigenesis is still not sufficiently characterized. Here, we show that KMLC has a specific lipid profile, with high triacylglycerides and phosphatidylcholines (PC). We demonstrate that FASN, the rate-limiting enzyme in FA synthesis, while being dispensable in EGFR-mutant or wild-type KRAS LC, is required for the viability of KMLC cells. Integrating lipidomic, transcriptomic and functional analyses, we demonstrate that FASN provides saturated and monounsaturated FA to the Lands cycle, the process remodeling oxidized phospholipids, such as PC. Accordingly, …

Molecular Profiles Of Serum-Derived Extracellular Vesicles In High-Grade Serous Ovarian Cancer, Li Zhao, Sara Corvigno, Shaolin Ma, Joseph Celestino, Nicole D Fleming, Richard A Hajek, Adrian Lankenau Ahumada, Nicholas B Jennings, Erika J Thompson, Hongli Tang, Shannon N Westin, Amir A Jazaeri, Jianhua Zhang, P Andrew Futreal, Anil K Sood, Sanghoon Lee

Faculty, Staff and Student Publications

Patients with high-grade serous ovarian cancer (HGSC) who have no visible residual disease (R0) after primary surgery have the best clinical outcomes, followed by patients who undergo neoadjuvant chemotherapy (NACT) and have a response enabling interval cytoreductive surgery. Clinically useful biomarkers for predicting these outcomes are still lacking. Extracellular vesicles (EVs) have been recognized as liquid biopsy-based biomarkers for early cancer detection and disease surveillance in other disease settings. In this study, we performed extensive molecular characterization of serum-derived EVs and correlated the findings with therapeutic outcomes in patients with HGSC. Using EV-DNA whole-genome sequencing and EV-RNA sequencing, we identified …

Two-Pore Channel Blockade By Phosphoinositide Kinase Inhibitors Ym201636 And Pi-103 Determined By A Histidine Residue Near Pore-Entrance, Canwei Du, Xin Guan, Jiusheng Yan

Faculty, Staff and Student Publications

Human two-pore channels (TPCs) are endolysosomal cation channels and play an important role in NAADP-evoked Ca2+ release and endomembrane dynamics. We found that YM201636, a PIKfyve inhibitor, potently inhibits PI(3,5)P2-activated human TPC2 with an IC50 of 0.16 μM. YM201636 also effectively inhibits NAADP-activated TPC2 and a constitutively-open TPC2 L690A/L694A mutant channel; whereas it exerts little effect when applied in the channel's closed state. PI-103, a YM201636 analog and an inhibitor of PI3K and mTOR, also inhibits human TPC2 with an IC50 of 0.64 μM. With mutational, virtual docking, and molecular dynamic simulation analyses, we found that YM201636 and PI-103 directly …

Tdp1-Independent Pathways In The Process And Repair Of Top1-Induced Dna Damage, Huimin Zhang, Yun Xiong, Dan Su, Chao Wang, Mrinal Srivastava, Mengfan Tang, Xu Feng, Min Huang, Zhen Chen, Junjie Chen

Faculty, Staff and Student Publications

Anticancer drugs, such as camptothecin (CPT), trap topoisomerase I (TOP1) on DNA and form TOP1 cleavage complexes (TOP1cc). Alternative repair pathways have been suggested in the repair of TOP1cc. However, how these pathways work with TDP1, a key repair enzyme that specifically hydrolyze the covalent bond between TOP1 catalytic tyrosine and the 3'-end of DNA and contribute to the repair of TOP1cc is poorly understood. Here, using unbiased whole-genome CRISPR screens and generation of co-deficient cells with TDP1 and other genes, we demonstrate that MUS81 is an important factor that mediates the generation of excess double-strand breaks (DSBs) in TDP1 …

Integrated Dna Copy Number And Expression Profiling Identifies Igf1r As A Prognostic Biomarker In Pediatric Osteosarcoma, Aaron M Taylor, Jiayi M Sun, Alexander Yu, Horatiu Voicu, Jianhe Shen, Donald A Barkauskas, Timothy J Triche, Julie M Gastier-Foster, Tsz-Kwong Man, Ching C Lau

Center for Medical Ethics and Health Policy Staff Publications

Osteosarcoma is a primary malignant bone tumor arising from bone-forming mesenchymal cells in children and adolescents. Despite efforts to understand the biology of the disease and identify novel therapeutics, the survival of osteosarcoma patients remains dismal. We have concurrently profiled the copy number and gene expression of 226 osteosarcoma samples as part of the Strategic Partnering to Evaluate Cancer Signatures (SPECS) initiative. Our results demonstrate the heterogeneous landscape of osteosarcoma in younger populations by showing the presence of genome-wide copy number abnormalities occurring both recurrently among samples and in a high frequency. Insulin growth factor receptor 1 (IGF1R) is a …

Sox9 Directs Divergent Epigenomic States In Brain Tumor Subtypes, Debosmita Sardar, Hsiao-Chi Chen, Amanda Reyes, Srinidhi Varadharajan, Antrix Jain, Carrie Mohila, Rachel Curry, Brittney Lozzi, Kavitha Rajendran, Alexis Cervantes, Kwanha Yu, Ali Jalali, Ganesh Rao, Stephen C Mack, Benjamin Deneen

Duncan NRI Faculty and Staff Publications

Epigenetic dysregulation is a universal feature of cancer that results in altered patterns of gene expression that drive malignancy. Brain tumors exhibit subtype-specific epigenetic alterations; however, the molecular mechanisms responsible for these diverse epigenetic states remain unclear. Here, we show that the developmental transcription factor Sox9 differentially regulates epigenomic states in high-grade glioma (HGG) and ependymoma (EPN). Using our autochthonous mouse models, we found that Sox9 suppresses HGG growth and expands associated H3K27ac states, while promoting ZFTA-RELA (ZR

Limited Benefit From The Addition Of Immunotherapy To Chemotherapy In Tki-Refractory Egfr-Mutant Lung Adenocarcinoma, Lingzhi Hong, Whitney E Lewis, Monique Nilsson, Sonia Patel, Susan Varghese, Melvin J Rivera, Robyn R Du, Pingjun Chen, Haley N Kemp, Waree Rinsurongkawong, Simon Heeke, Amy R Spelman, Yasir Y Elamin, Marcelo V Negrao, Boris Sepesi, Don L Gibbons, J Jack Lee, Jia Wu, Natalie I Vokes, John V Heymach, Jianjun Zhang, Xiuning Le

Faculty, Staff and Student Publications

Background: The benefit of chemotherapy combined with immunotherapy in EGFR-mutant lung adenocarcinoma (LUAD) patients whose tumor developed resistance to EGFR tyrosine kinase inhibitors (TKIs) is not thoroughly investigated. The goal of this retrospective cohort study is to assess the clinical efficiency of immunotherapy alone or in combination with chemotherapy in a real-world setting.

Methods: This retrospective cohort study enrolled LUAD patients with EGFR sensitive mutations whose tumor had acquired resistance to EGFR TKIs and received systemic treatment with chemotherapy (chemo; n = 84), chemotherapy combined with immunotherapy (chemoIO; n = 30), chemotherapy plus bevacizumab with or without IO (withBev; n …

Neuronal Activity Induces Glucosylceramide That Is Secreted Via Exosomes For Lysosomal Degradation In Glia, Liping Wang, Guang Lin, Zhongyuan Zuo, Yarong Li, Seul Kee Byeon, Akhilesh Pandey, Hugo J Bellen

Duncan NRI Faculty and Staff Publications

Recessive variants in GBA1 cause Gaucher disease, a prevalent form of lysosome storage disease. GBA1 encodes a lysosomal enzyme that hydrolyzes glucosylceramide (GlcCer) into glucose and ceramide. Its loss causes lysosomal dysfunction and increased levels of GlcCer. We generated a null allele of the Drosophila ortholog Gba1b by inserting the Gal4 using CRISPR-Cas9. Here, we show that Gba1b is expressed in glia but not in neurons. Glial-specific knockdown recapitulates the defects found in Gba1b mutants, and these can be rescued by glial expression of human GBA1. We show that GlcCer is synthesized upon neuronal activity, and it is transported …

Kras Mutations As Essential Promoters Of Lymphangiogenesis Via Extracellular Vesicles In Pancreatic Cancer, Radu Pirlog, George A Calin

Faculty, Staff and Student Publications

Kirsten rat sarcoma virus (KRAS) gene mutations are present in more than 90% of pancreatic ductal adenocarcinomas (PDACs). KRASG12D is the most frequent alteration, promoting preneoplastic lesions and associating with a more aggressive phenotype. These tumors possess increased intratumoral lymphatic networks and frequent lymph node (LN) metastases. In this issue of the JCI, Luo, Li, et al. explored the relationship between the presence of the KRASG12D mutation and lymphangiogenesis in PDAC. The authors used in vitro and in vivo models and an elegant mechanistic approach to describe an alternative pathway for lymphangiogenesis promotion. KRASG12D induced SUMOylation of heterogenous nuclear ribonucleoprotein …

Pneumonitis After Immune Checkpoint Inhibitor Therapies In Patients With Acute Myeloid Leukemia: A Retrospective Cohort Study, Ajay Sheshadri, Alberto A Goizueta, Vickie R Shannon, David London, Guillermo Garcia-Manero, Hagop M Kantarjian, Farhad Ravandi-Kashani, Tapan M Kadia, Marina Y Konopleva, Courtney D Dinardo, Sherry Pierce, Abdulrazzak Zarifa, Aya A Albittar, Linda L Zhong, Fechukwu O Akhmedzhanov, Muhammad H Arain, Mansour Alfayez, Ahmad Alotaibi, Mehmet Altan, Aung Naing, Tito R Mendoza, Myrna C B Godoy, Girish Shroff, Sang T Kim, Saadia A Faiz, Dimitrios P Kontoyiannis, Fareed Khawaja, Kristofer Jennings, Naval G Daver

Faculty, Staff and Student Publications

Background: Immune checkpoint inhibitors (ICI), combined with hypomethylating agents, can be used to treat acute myeloid leukemia (AML), but this strategy results in a high rate of pneumonitis. The authors sought to determine risk factors for pneumonitis development and whether pneumonitis increased mortality.

Methods: The authors conducted a retrospective review of 258 AML patients who received ICI-containing regimens from 2016 to 2018. A multidisciplinary adjudication committee diagnosed pneumonia and pneumonitis by reviewing symptoms, imaging, microbiology, and response to therapies. To measure risk factors for pneumonitis and mortality, multivariate Cox proportional hazards models were constructed. Pneumonia, pneumonitis, and disease progression were …

Infiltration Of Peripheral Immune Cells Into The Olfactory Bulb In A Mouse Model Of Acute Nasal Inflammation, Hinami Asano, Sanae Hasegawa-Ishii, Ken Arae, Aki Obara, Geoffroy Laumet, Robert Dantzer, Atsuyoshi Shimada

Faculty, Staff and Student Publications

Chronic nasal inflammation induces robust olfactory bulb (OB) atrophy in mice. Here we examined initial events that occur in the OB after bilateral intranasal administration of lipopolysaccharide, focusing on the olfactory nerve fibers and meninges. We analyzed the time course of OB and meninges inflammation using histological and biochemical approaches. Within 12 h, we observed increased chemokine expression and transient infiltration of peripheral immune cells into the OB, resulting in the development of pro-inflammatory status in the OB. Meningeal immunity was activated. Resident microglia produced anti-inflammatory cytokines within 24 h. These could be the initial events that lead to OB …

The Origin Of Bladder Cancer From Mucosal Field Effects, Jolanta Bondaruk, Roman Jaksik, Ziqiao Wang, David Cogdell, Sangkyou Lee, Yujie Chen, Khanh Ngoc Dinh, Tadeusz Majewski, Li Zhang, Shaolong Cao, Feng Tian, Hui Yao, Paweł Kuś, Huiqin Chen, John N Weinstein, Neema Navai, Colin Dinney, Jianjun Gao, Dan Theodorescu, Christopher Logothetis, Charles C Guo, Wenyi Wang, David Mcconkey, Peng Wei, Marek Kimmel, Bogdan Czerniak

Faculty, Staff and Student Publications

Whole-organ mapping was used to study molecular changes in the evolution of bladder cancer from field effects. We identified more than 100 dysregulated pathways, involving immunity, differentiation, and transformation, as initiators of carcinogenesis. Dysregulation of interleukins signified the involvement of inflammation in the incipient phases of the process. An aberrant methylation/expression of multiple HOX genes signified dysregulation of the differentiation program. We identified three types of mutations based on their geographic distribution. The most common were mutations restricted to individual mucosal samples that targeted uroprogenitor cells. Two types of mutations were associated with clonal expansion and involved large areas of …

Gut Bacterial Isoamylamine Promotes Age-Related Cognitive Dysfunction By Promoting Microglial Cell Death, Yun Teng, Jingyao Mu, Fangyi Xu, Xiangcheng Zhang, Mukesh K Sriwastva, Qiaohong M Liu, Xiaohong Li, Chao Lei, Kumaran Sundaram, Xin Hu, Lifeng Zhang, Juw Won Park, Jae Yeon Hwang, Eric C Rouchka, Xiang Zhang, Jun Yan, Michael L Merchant, Huang-Ge Zhang

Faculty, Staff and Student Publications

The intestinal microbiome releases a plethora of small molecules. Here, we show that the Ruminococcaceae metabolite isoamylamine (IAA) is enriched in aged mice and elderly people, whereas Ruminococcaceae phages, belonging to the Myoviridae family, are reduced. Young mice orally administered IAA show cognitive decline, whereas Myoviridae phage administration reduces IAA levels. Mechanistically, IAA promotes apoptosis of microglial cells by recruiting the transcriptional regulator p53 to the S100A8 promoter region. Specifically, IAA recognizes and binds the S100A8 promoter region to facilitate the unwinding of its self-complementary hairpin structure, thereby subsequently enabling p53 to access the S100A8 promoter and enhance S100A8 expression. …

Treatment-Free Remission After Ceasing Venetoclax-Based Therapy In Patients With Acute Myeloid Leukemia, Chong Chyn Chua, Danielle Hammond, Andrew Kent, Ing Soo Tiong, Marina Y Konopleva, Daniel A Pollyea, Courtney D Dinardo, Andrew H Wei

Faculty, Staff and Student Publications

The clinical benefit of adding venetoclax (VEN) to hypomethylating agents or low-dose cytarabine in older and/or unfit patients with newly diagnosed acute myeloid leukemia (AML) has been confirmed in phase 3 studies. With the increased uptake of VEN-based therapies for patients with AML, a pertinent question is whether treatment can be safely ceased among patients who have achieved sustained remission. We hypothesized that a proportion of patients opting to cease therapy may benefit from a treatment-free remission (TFR) period without indefinite treatment. We report the retrospective outcomes of 29 patients in remission for a minimum of 12 months on VEN-based …

High-Sensitivity Next-Generation Sequencing Mrd Assessment In All Identifies Patients At Very Low Risk Of Relapse, Nicholas J Short, Hagop Kantarjian, Farhad Ravandi, Marina Konopleva, Nitin Jain, Rashmi Kanagal-Shamanna, Keyur P Patel, Walid Macaron, Tapan M Kadia, Sa Wang, Jeffrey L Jorgensen, Joseph D Khoury, Musa Yilmaz, Partow Kebriaei, Koichi Takahashi, Guillermo Garcia-Manero, Naval Daver, Sean M Post, Xuelin Huang, Steven M Kornblau, Sara Pelletier, Wilmer Flores, Jairo Matthews, Rebecca Garris, Elias Jabbour

Faculty, Staff and Student Publications

Measurable residual disease (MRD) is highly prognostic for relapse and overall survival (OS) in acute lymphoblastic leukemia (ALL), although many patients with apparent "MRD negativity" by standard assays still relapse. We evaluated the clinical impact of a highly sensitive next-generation sequencing (NGS) MRD assay in 74 adults with ALL undergoing frontline therapy. Among remission samples that were MRD negative by multiparameter flow cytometry (MFC), 46% were MRD+ by the NGS assay. After 1 cycle of induction chemotherapy, MRD negativity by MFC at a sensitivity of 1 × 10-4 and NGS at a sensitivity of 1 × 10-6 was achieved in …

Metabolic Requirement For Got2 In Pancreatic Cancer Depends On Environmental Context, Samuel A Kerk, Lin Lin, Amy L Myers, Damien J Sutton, Anthony Andren, Peter Sajjakulnukit, Li Zhang, Yaqing Zhang, Jennifer A Jiménez, Barbara S Nelson, Brandon Chen, Anthony Robinson, Galloway Thurston, Samantha B Kemp, Nina G Steele, Megan T Hoffman, Hui-Ju Wen, Daniel Long, Sarah E Ackenhusen, Johanna Ramos, Xiaohua Gao, Zeribe C Nwosu, Stefanie Galban, Christopher J Halbrook, David B Lombard, David R Piwnica-Worms, Haoqiang Ying, Marina Pasca Di Magliano, Howard C Crawford, Yatrik M Shah, Costas A Lyssiotis

Faculty, Staff and Student Publications

Mitochondrial glutamate-oxaloacetate transaminase 2 (GOT2) is part of the malate-aspartate shuttle, a mechanism by which cells transfer reducing equivalents from the cytosol to the mitochondria. GOT2 is a key component of mutant KRAS (KRAS*)-mediated rewiring of glutamine metabolism in pancreatic ductal adenocarcinoma (PDA). Here, we demonstrate that the loss of GOT2 disturbs redox homeostasis and halts proliferation of PDA cells in vitro. GOT2 knockdown (KD) in PDA cell lines in vitro induced NADH accumulation, decreased Asp and α-ketoglutarate (αKG) production, stalled glycolysis, disrupted the TCA cycle, and impaired proliferation. Oxidizing NADH through chemical or genetic means resolved the redox imbalance …

Immunophenotypic And Molecular Features Of Acute Myeloid Leukemia With Plasmacytoid Dendritic Cell Differentiation Are Distinct From Blastic Plasmacytoid Dendritic Cell Neoplasm, Wei Wang, Jie Xu, Joseph D Khoury, Naveen Pemmaraju, Hong Fang, Roberto N Miranda, C Cameron Yin, Siba El Hussein, Fuli Jia, Zhenya Tang, Shimin Hu, Marina Konopleva, L Jeffrey Medeiros, Sa A Wang

Faculty, Staff and Student Publications

Acute myeloid leukemia (AML) with ≥2% plasmacytoid dendritic cells (pDC) has been recently described as AML with pDC differentiation (pDC-AML) characterized by pDC expansion with frequent RUNX1 mutations. In this study, we investigated a cohort of 53 pDC-AML cases representing about 3% of all AML cases. We characterized their immunophenotype and genetic profiles and compared these findings with blastic plasmacytoid dendritic cell neoplasm (BPDCN). pDC-differentiation/expansion was preferentially observed in AML with an immature myeloid or myelomonocytic immunophenotype, where myeloblasts were frequently positive for CD34 (98%), CD117 (94%), HLA-DR (100%) and TdT (79%), with increased CD123 (89%) expression. The median number …

Multi-Modal Molecular Programs Regulate Melanoma Cell State, Miles C Andrews, Junna Oba, Chang-Jiun Wu, Haifeng Zhu, Tatiana Karpinets, Caitlin A Creasy, Marie-Andrée Forget, Xiaoxing Yu, Xingzhi Song, Xizeng Mao, A Gordon Robertson, Gabriele Romano, Peng Li, Elizabeth M Burton, Yiling Lu, Robert Szczepaniak Sloane, Khalida M Wani, Kunal Rai, Alexander J Lazar, Lauren E Haydu, Matias A Bustos, Jianjun Shen, Yueping Chen, Margaret B Morgan, Jennifer A Wargo, Lawrence N Kwong, Cara L Haymaker, Elizabeth A Grimm, Patrick Hwu, Dave S B Hoon, Jianhua Zhang, Jeffrey E Gershenwald, Michael A Davies, P Andrew Futreal, Chantale Bernatchez, Scott E Woodman

Faculty, Staff and Student Publications

Melanoma cells display distinct intrinsic phenotypic states. Here, we seek to characterize the molecular regulation of these states using multi-omic analyses of whole exome, transcriptome, microRNA, long non-coding RNA and DNA methylation data together with reverse-phase protein array data on a panel of 68 highly annotated early passage melanoma cell lines. We demonstrate that clearly defined cancer cell intrinsic transcriptomic programs are maintained in melanoma cells ex vivo and remain highly conserved within melanoma tumors, are associated with distinct immune features within tumors, and differentially correlate with checkpoint inhibitor and adoptive T cell therapy efficacy. Through integrative analyses we demonstrate …

Tp53 Copy Number And Protein Expression Inform Mutation Status Across Risk Categories In Acute Myeloid Leukemia, Mehrnoosh Tashakori, Tapan Kadia, Sanam Loghavi, Naval Daver, Rashmi Kanagal-Shamanna, Sherry Pierce, Dawen Sui, Peng Wei, Farnoosh Khodakarami, Zhenya Tang, Mark Routbort, Carol A Bivins, Elias J Jabbour, L Jeffrey Medeiros, Kapil Bhalla, Hagop M Kantarjian, Farhad Ravandi, Joseph D Khoury

Faculty, Staff and Student Publications

Mutant TP53 is an adverse risk factor in acute myeloid leukemia (AML), but large-scale integrated genomic-proteomic analyses of TP53 alterations in patients with AML remain limited. We analyzed TP53 mutational status, copy number (CN), and protein expression data in AML (N = 528) and provide a compilation of mutation sites and types across disease subgroups among treated and untreated patients. Our analysis shows differential hotspots in subsets of AML and uncovers novel pathogenic variants involving TP53 splice sites. In addition, we identified TP53 CN loss in 70.2% of TP53-mutated AML cases, which have more deleterious TP53 mutations, as well as …

Dissecting The Treatment-Naive Ecosystem Of Human Melanoma Brain Metastasis, Jana Biermann, Johannes C Melms, Amit Dipak Amin, Yiping Wang, Lindsay A Caprio, Alcida Karz, Somnath Tagore, Irving Barrera, Miguel A Ibarra-Arellano, Massimo Andreatta, Benjamin T Fullerton, Kristjan H Gretarsson, Varun Sahu, Vaibhav S Mangipudy, Trang T T Nguyen, Ajay Nair, Meri Rogava, Patricia Ho, Peter D Koch, Matei Banu, Nelson Humala, Aayushi Mahajan, Zachary H Walsh, Shivem B Shah, Daniel H Vaccaro, Blake Caldwell, Michael Mu, Florian Wünnemann, Margot Chazotte, Simon Berhe, Adrienne M Luoma, Joseph Driver, Matthew Ingham, Shaheer A Khan, Suthee Rapisuwon, Craig L Slingluff, Thomas Eigentler, Martin Röcken, Richard Carvajal, Michael B Atkins, Michael A Davies, Albert Agustinus, Samuel F Bakhoum, Elham Azizi, Markus Siegelin, Chao Lu, Santiago J Carmona, Hanina Hibshoosh, Antoni Ribas, Peter Canoll, Jeffrey N Bruce, Wenya Linda Bi, Praveen Agrawal, Denis Schapiro, Eva Hernando, Evan Z Macosko, Fei Chen, Gary K Schwartz, Benjamin Izar

Faculty, Staff and Student Publications

Melanoma brain metastasis (MBM) frequently occurs in patients with advanced melanoma; yet, our understanding of the underlying salient biology is rudimentary. Here, we performed single-cell/nucleus RNA-seq in 22 treatment-naive MBMs and 10 extracranial melanoma metastases (ECMs) and matched spatial single-cell transcriptomics and T cell receptor (TCR)-seq. Cancer cells from MBM were more chromosomally unstable, adopted a neuronal-like cell state, and enriched for spatially variably expressed metabolic pathways. Key observations were validated in independent patient cohorts, patient-derived MBM/ECM xenograft models, RNA/ATAC-seq, proteomics, and multiplexed imaging. Integrated spatial analyses revealed distinct geography of putative cancer immune evasion and evidence for more abundant …

Long-Term Follow-Up For The Development Of Subsequent Malignancies In Patients Treated With Genetically Modified Iecs, David H M Steffin, Ibrahim N Muhsen, Laquisa C Hill, Carlos A Ramos, Nabil Ahmed, Meenakshi Hegde, Tao Wang, Mengfen Wu, Stephen Gottschalk, Sarah B Whittle, Premal D Lulla, Maksim Mamonkin, Bilal Omer, Rayne H Rouce, Andras Heczey, Leonid S Metelitsa, Bambi J Grilley, Catherine Robertson, Virginia Torrano, Natalia Lapteva, Adrian P Gee, Cliona M Rooney, Malcolm K Brenner, Helen E Heslop

Faculty, Staff and Students Publications

Subsequent malignancies are well-documented complications in long-term follow-up of cancer patients. Recently, genetically modified immune effector (IE) cells have shown benefit in hematologic malignancies and are being evaluated in clinical trials for solid tumors. Although the short-term complications of IE cells are well described, there is limited literature summarizing long-term follow-up, including subsequent malignancies. We retrospectively reviewed data from 340 patients treated across 27 investigator-initiated pediatric and adult clinical trials at our center. All patients received IE cells genetically modified with γ-retroviral vectors to treat relapsed and/or refractory hematologic or solid malignancies. In a cumulative 1027 years of long-term follow-up, …

Vitamin E Enhances Cancer Immunotherapy By Reinvigorating Dendritic Cells Via Targeting Checkpoint Shp1, Xiangliang Yuan, Yimin Duan, Yi Xiao, Kai Sun, Yutao Qi, Yuan Zhang, Zamal Ahmed, Davide Moiani, Jun Yao, Hongzhong Li, Lin Zhang, Arseniy E Yuzhalin, Ping Li, Chenyu Zhang, Akosua Badu-Nkansah, Yohei Saito, Xianghua Liu, Wen-Ling Kuo, Haoqiang Ying, Shao-Cong Sun, Jenny C Chang, John A Tainer, Dihua Yu

Faculty, Staff and Student Publications

Despite the popular use of dietary supplements during conventional cancer treatments, their impacts on the efficacies of prevalent immunotherapies, including immune-checkpoint therapy (ICT), are unknown. Surprisingly, our analyses of electronic health records revealed that ICT-treated patients with cancer who took vitamin E (VitE) had significantly improved survival. In mouse models, VitE increased ICT antitumor efficacy, which depended on dendritic cells (DC). VitE entered DCs via the SCARB1 receptor and restored tumor-associated DC functionality by directly binding to and inhibiting protein tyrosine phosphatase SHP1, a DC-intrinsic checkpoint. SHP1 inhibition, genetically or by VitE treatment, enhanced tumor antigen cross-presentation by DCs and …