Medicine and Health Sciences Commons^™

Retraction Note: Mir20a/106a-Wtx Axis Regulates Rhogdia/Cdc42 Signaling And Colon Cancer Progression, Gui-Fang Zhu, Yang-Wei Xu, Jian Li, Hui-Lin Niu, Wen-Xia Ma, Jia Xu, Pei-Rong Zhou, Xia Liu, Dan-Li Ye, Xiao-Rong Liu, Tao Yan, Wei-Ke Zhai, Zhi-Jun Xu, Chun Liu, Lei Wang, Hao Wang, Jia-Mao Luo, Li Liu, Xuan-Qi Li, Suiqun Guo, Hui-Ping Jiang, Peng Shen, Hui-Kuan Lin, Di-Hua Yu, Yan-Qing Ding, Qing-Ling Zhang

Faculty, Staff and Student Publications

No abstract provided.

Neuroimmune Support Of Neuronal Regeneration And Neuroplasticity Following Cerebral Ischemia In Juvenile Mice, Ricaurte A Marquez-Ortiz, Vesna Tesic, Daniel R Hernandez, Bilkis Akhter, Nibedita Aich, Porter M Boudreaux, Garrett A Clemons, Celeste Yin-Chieh Wu, Hung Wen Lin, Krista M Rodgers

Faculty, Staff and Student Publications

Ischemic damage to the brain and loss of neurons contribute to functional disabilities in many stroke survivors. Recovery of neuroplasticity is critical to restoration of function and improved quality of life. Stroke and neurological deficits occur in both adults and children, and yet it is well documented that the developing brain has remarkable plasticity which promotes increased post-ischemic functional recovery compared with adults. However, the mechanisms underlying post-stroke recovery in the young brain have not been fully explored. We observed opposing responses to experimental cerebral ischemia in juvenile and adult mice, with substantial neural regeneration and enhanced neuroplasticity detected in …

Characterization Of An Mtbp Hypomorphic Allele In A Diethylnitrosamine-Induced Liver Carcinogenesis Model, Atul Ranjan, Elizabeth A. Thoenen, Atsushi Kaida, Stephanie Wood, Terry Van Dyke, Tomoo Iwakuma

Manuscripts, Articles, Book Chapters and Other Papers

MTBP is implicated in cell cycle progression, DNA replication, and cancer metastasis. However, the function of MTBP remains enigmatic and is dependent on cellular contexts and its cellular localization. To understand the in vivo physiological role of MTBP, it is important to generate Mtbp knockout mice. However, complete deletion of the Mtbp gene in mice results in early embryonic lethality, while its heterozygous deletion shows modest biological phenotypes, including enhanced cancer metastasis. To overcome this and better characterize the in vivo physiological function of MTBP, we, for the first time, generated mice that carry an Mtbp hypomorphic allele (MtbpH …

The Philadelphia Lung Cancer Learning Community: A Multi-Health-System, Citywide Approach To Lung Cancer Screening, Julie A. Barta, Cherie P. Erkmen, Christine S. Shusted, Ronald E. Myers, Chelsea Saia, Sarah Cohen, Jocelyn Wainwright, Charnita Zeigler-Johnson, Farouk Dako, Richard Wender, Gregory C. Kane, Anil Vachani, Katharine A. Rendle

Division of Pulmonary, Allergy, and Critical Care Medicine Faculty Papers

Background

Lung cancer screening uptake for individuals at high risk is generally low across the United States, and reporting of lung cancer screening practices and outcomes is often limited to single hospitals or institutions. We describe a citywide, multicenter analysis of individuals receiving lung cancer screening integrated with geospatial analyses of neighborhood-level lung cancer risk factors. Methods

The Philadelphia Lung Cancer Learning Community consists of lung cancer screening clinicians and researchers at the 3 largest health systems in the city. This multidisciplinary, multi-institutional team identified a Philadelphia Lung Cancer Learning Community study cohort that included 11 222 Philadelphia residents who …

Immune-Active Tumor-Adjacent Tissues Are Associated With Favorable Prognosis In Stage I Lung Squamous Cell Carcinoma, Lisha Ying, Chunliu Zhang, Alexandre Reuben, Yiping Tian, Jiaoyue Jin, Canming Wang, Jing Bai, Xinyuan Liu, Jianfei Fang, Tingting Feng, Chenyang Xu, Rui Zhu, Minran Huang, Yingqi Lyu, Tingting Lu, Xiaodan Pan, Jianjun Zhang, Dan Su

Faculty, Staff and Student Publications

The immunogenomic features of tumor-adjacent lungs (TALs) in stage I lung squamous cell carcinoma (LUSC) are not clear. Multiomics analyses of tumor tissues and paired TALs from 59 stage I LUSC patients were performed. Compared to tumors, TALs exhibited a better-preserved immune contexture indicated by upregulation of immune pathways, increased immune infiltration, and higher expression of immune effector molecules. Notably, TALs had no mutations in PTEN and KEAP1, a lower incidence of human leukocyte antigen (HLA) loss and higher expression of HLA class I genes, major histocompatibility complex (MHC) I chaperones, and interferon (IFN)-γ-associated genes. Digital spatial profiling validated the …

Advance Directives For Patients With Breast Cancer: Applying The Right Info/Right Care/Right Patient/Right Time Oncology Model, Stephanie Ossowski, Liisa Lyon, Elizabeth Linehan, Nancy P Gordon, Olga Egorova, Becky Mark, Kimberly Beringer, Thea Abbe, Aida Shirazi, Christine Weldon, Julia Trosman, Arliene Ravelo, Raymond Liu

Faculty, Staff and Student Publications

Background Advance directives (AD) are an important component of life care planning for patients undergoing treatment for cancer; however, there are few effective interventions to increase AD rates. In this quality improvement project, the authors integrated AD counseling into a novel right info/right care/right patient/right time (4R) sequence of care oncology delivery intervention for breast cancer patients in an integrated health care delivery system. Methods The authors studied two groups of patients with newly diagnosed breast cancer who attended a multidisciplinary clinic and underwent definitive surgery at a single facility. The usual care (UC) cohort (N = 139) received care …

Neurocognitive Outcomes In Adult Survivors Of Neuroblastoma: A Report From The Childhood Cancer Survivor Study, Caroline Hesko, Wei Liu, Deo K Srivastava, Tara M Brinkman, Lisa Diller, Todd M Gibson, Kevin C Oeffinger, Wendy M Leisenring, Rebecca Howell, Gregory T Armstrong, Kevin R Krull, Tara O Henderson

Faculty, Staff and Student Publications

Background: Despite survival improvements, there is a paucity of data on neurocognitive outcomes in neuroblastoma survivors. This study addresses this literature gap.

Methods: Neurocognitive impairments in survivors were compared to sibling controls from the Childhood Cancer Survivor Study (CCSS) using the CCSS Neurocognitive Questionnaire. Impaired emotional regulation, organization, task efficiency, and memory defined as scores ≥90th percentile of sibling norms. Modified Poisson regression models evaluated associations with treatment exposures, era of diagnosis, and chronic conditions. Analyses were stratified by age at diagnosis (≤1 and >1 year) as proxy for lower versus higher risk disease.

Results: Survivors (N = 837; median …

Cardiovascular Disease And Stroke In Immune Ttp-Challenges And Opportunities, Senthil Sukumar, Marshall A Mazepa, Shruti Chaturvedi

Faculty, Staff and Students Publications

Advances in the management of immune thrombotic thrombocytopenic purpura (iTTP) have dramatically improved outcomes of acute TTP episodes, and TTP is now treated as a chronic, relapsing disorder. It is now recognized that iTTP survivors are at high risk for vascular disease, with stroke and myocardial infarction occurring at younger ages than in the general population, and cardiovascular disease is the leading cause of premature death in this population. iTTP appears to have a phenotype of accelerated vascular aging with a particular predilection for cerebral circulation, and stroke is much more common than myocardial infarction. In addition to traditional cardiovascular …

Radio-Pathomic Approaches In Pediatric Neurooncology: Opportunities And Challenges, Ariana M. Familiar, Aria Mahtabfar, Anahita Fathi Kazerooni, Mahsa Kiani, Arastoo Vossough, Angela Viaene, Philip B. Storm, Adam C. Resnick, Ali Nabavizadeh

Department of Neurosurgery Faculty Papers

With medical software platforms moving to cloud environments with scalable storage and computing, the translation of predictive artificial intelligence (AI) models to aid in clinical decision-making and facilitate personalized medicine for cancer patients is becoming a reality. Medical imaging, namely radiologic and histologic images, has immense analytical potential in neuro-oncology, and models utilizing integrated radiomic and pathomic data may yield a synergistic effect and provide a new modality for precision medicine. At the same time, the ability to harness multi-modal data is met with challenges in aggregating data across medical departments and institutions, as well as significant complexity in modeling …

Precision Modulation Of Dysbiotic Adult Microbiomes With A Human-Milk-Derived Synbiotic Reshapes Gut Microbial Composition And Metabolites, Julie E Button, Casey M Cosetta, Abigail L Reens, Sarah L Brooker, Aislinn D Rowan-Nash, Richard C Lavin, Russell Saur, Shuning Zheng, Chloe A Autran, Martin L Lee, Adam K Sun, Amin M Alousi, Christine B Peterson, Andrew Y Koh, David J Rechtman, Robert R Jenq, Gregory J Mckenzie

Faculty, Staff and Student Publications

Manipulation of the gut microbiome using live biotherapeutic products shows promise for clinical applications but remains challenging to achieve. Here, we induced dysbiosis in 56 healthy volunteers using antibiotics to test a synbiotic comprising the infant gut microbe, Bifidobacterium longum subspecies infantis (B. infantis), and human milk oligosaccharides (HMOs). B. infantis engrafted in 76% of subjects in an HMO-dependent manner, reaching a relative abundance of up to 81%. Changes in microbiome composition and gut metabolites reflect altered recovery of engrafted subjects compared with controls. Engraftment associates with increases in lactate-consuming Veillonella, faster acetate recovery, and changes in indolelactate and p-cresol …

A Real-Time Contouring Feedback Tool For Consensus-Based Contour Training, Christopher L Nelson, Callistus Nguyen, Raymond Fang, Laurence E Court, Carlos E Cardenas, Dong Joo Rhee, Tucker J Netherton, Raymond P Mumme, Skylar Gay, Casey Gay, Barbara Marquez, Mohammad D El Basha, Yao Zhao, Mary Gronberg, Soleil Hernandez, Kelly A Nealon, Mary K Martel, Jinzhong Yang

Faculty, Staff and Student Publications

PURPOSE: Variability in contouring structures of interest for radiotherapy continues to be challenging. Although training can reduce such variability, having radiation oncologists provide feedback can be impractical. We developed a contour training tool to provide real-time feedback to trainees, thereby reducing variability in contouring.

METHODS: We developed a novel metric termed localized signed square distance (LSSD) to provide feedback to the trainee on how their contour compares with a reference contour, which is generated real-time by combining trainee contour and multiple expert radiation oncologist contours. Nine trainees performed contour training by using six randomly assigned training cases that included one …

Dosimetry Of A Novel 111indium-Labeled Anti-P-Cadherin Monoclonal Antibody (Ff-21101) In Non-Human Primates, Gregory Ravizzini, William Erwin, Louis De Palatis, Lucia Martiniova, Vivek Subbiah, Vincenzo Paolillo, Jennifer Mitchell, Asa P Mccoy, Jose Gonzalez, Osama Mawlawi

Faculty, Staff and Student Publications

P-cadherin is associated with a wide range of tumor types, making it an attractive therapeutic target. FF-21101 is a human-mouse chimeric monoclonal antibody (mAb) directed against human P-cadherin, which has been radioconjugated with indium-111 (111In) utilizing a DOTA chelator. We investigated the biodistribution of FF-21101(111In) in cynomolgus macaques and extrapolated the results to estimate internal radiation doses of 111In- and yttrium-90 (90Y)-FF-21101 for targeted radioimmunotherapy in humans. Whole-body planar and SPECT imaging were performed at 0, 2, 24, 48, 72, 96, and 120 h post-injection, using a dual-head gamma camera. Volumes of interest of identifiable source organs of radioactivity were …

Global Impact Of Somatic Structural Variation On The Cancer Proteome, Fengju Chen, Yiqun Zhang, Darshan S Chandrashekar, Sooryanarayana Varambally, Chad J Creighton

Faculty, Staff and Students Publications

Both proteome and transcriptome data can help assess the relevance of non-coding somatic mutations in cancer. Here, we combine mass spectrometry-based proteomics data with whole genome sequencing data across 1307 human tumors spanning various tissues to determine the extent somatic structural variant (SV) breakpoint patterns impact protein expression of nearby genes. We find that about 25% of the hundreds of genes with SV-associated cis-regulatory alterations at the mRNA level are similarly associated at the protein level. SVs associated with enhancer hijacking, retrotransposon translocation, altered DNA methylation, or fusion transcripts are implicated in protein over-expression. SVs combined with altered protein levels …

The Use Of Prognostic Markers To Predict Disease Progression And Clinical Outcome In Monoclonal Gammopathy Of Undetermined Significance, Smouldering Multiple Myeloma And Multiple Myeloma., Róisín C. Mcmonagle

International Undergraduate Journal of Health Sciences

Multiple Myeloma (MM) is an incurable plasma cell malignancy with a complex and incompletely understood molecular pathogenesis. Monoclonal Gammopathy of Undetermined Significance (MGUS) and Smouldering Multiple Myeloma (SMM) precede MM, with variable risks and rates of disease progression. The continuing high relapse and death rate in MM cases has prompted research into more accurate prognostic markers to predict progression from MGUS and SMM to MM, as well as identify MM cases with aggressive disease, in order to begin early, targeted and effective therapeutic intervention. Many studies have focused on utilising current markers more effectively, including M-protein, serum-free light chain ratio, …

Biosafety And Biohazard Considerations Of Hsv-1-Based Oncolytic Viral Immunotherapy., Elizabeth Robilotti, Nathalie C Zeitouni, Marlana Orloff

Department of Medical Oncology Faculty Papers

Oncolytic viral immunotherapies are agents which can directly kill tumor cells and activate an immune response. Oncolytic viruses (OVs) range from native/unmodified viruses to genetically modified, attenuated viruses with the capacity to preferentially replicate in and kill tumors, leaving normal tissue unharmed. Talimogene laherparepvec (T-VEC) is the only OV approved for patient use in the United States; however, during the last 20 years, there have been a substantial number of clinical trials using OV immunotherapies across a broad range of cancers. Like T-VEC, many OV immunotherapies in clinical development are based on the herpes simplex virus type 1 (HSV-1), with …

The Endosomal Escape Vehicle Platform Enhances Delivery Of Oligonucleotides In Preclinical Models Of Neuromuscular Disorders, Xiang Li, Mahboubeh Kheirabadi, Patrick G Dougherty, Kimberli J Kamer, Xiulong Shen, Nelsa L Estrella, Suresh Peddigari, Anushree Pathak, Sara L Blake, Emmanuelle Sizensky, Carmen Del Genio, Arti B Gaur, Mohanraj Dhanabal, Mahasweta Girgenrath, Natarajan Sethuraman, Ziqing Qian

Faculty, Staff and Student Publications

Biological therapeutic agents are highly targeted and potent but limited in their ability to reach intracellular targets. These limitations often necessitate high therapeutic doses and can be associated with less-than-optimal therapeutic activity. One promising solution for therapeutic agent delivery is use of cell-penetrating peptides. Canonical cell-penetrating peptides, however, are limited by low efficiencies of cellular uptake and endosomal escape, minimal proteolytic stability, and toxicity. To overcome these limitations, we designed a family of proprietary cyclic cell-penetrating peptides that form the core of our endosomal escape vehicle technology capable of delivering therapeutic agent-conjugated cargo intracellularly. We demonstrated the therapeutic potential of …

Interaction Between Myelodysplasia-Related Gene Mutations And Ontogeny In Acute Myeloid Leukemia, Joseph G W Mccarter, David Nemirovsky, Christopher A Famulare, Noushin Farnoud, Abhinita S Mohanty, Zoe S Stone-Molloy, Jordan Chervin, Brian J Ball, Zachary D Epstein-Peterson, Maria E Arcila, Aaron J Stonestrom, Andrew Dunbar, Sheng F Cai, Jacob L Glass, Mark B Geyer, Raajit K Rampal, Ellin Berman, Omar I Abdel-Wahab, Eytan M Stein, Martin S Tallman, Ross L Levine, Aaron D Goldberg, Elli Papaemmanuil, Yanming Zhang, Mikhail Roshal, Andriy Derkach, Wenbin Xiao

Faculty, Staff and Student Publications

Accurate classification and risk stratification are critical for clinical decision making in patients with acute myeloid leukemia (AML). In the newly proposed World Health Organization and International Consensus classifications of hematolymphoid neoplasms, the presence of myelodysplasia-related (MR) gene mutations is included as 1 of the diagnostic criteria for AML, AML-MR, based largely on the assumption that these mutations are specific for AML with an antecedent myelodysplastic syndrome. ICC also prioritizes MR gene mutations over ontogeny (as defined in the clinical history). Furthermore, European LeukemiaNet (ELN) 2022 stratifies these MR gene mutations into the adverse-risk group. By thoroughly annotating a cohort …

Cell-Type-Specific Alternative Polyadenylation Promotes Oncogenic Gene Expression In Non-Small Cell Lung Cancer Progression, Kexin Huang, Yun Zhang, Xiaorui Shi, Zhiqin Yin, Weiling Zhao, Liyu Huang, Fu Wang, Xiaobo Zhou

Faculty, Staff and Student Publications

Disrupted alternative polyadenylation (APA) is frequently involved in tumorigenesis and cancer progression by regulating the gene expression of oncogenes and tumor suppressors. However, limited knowledge of tumor-type- and cell-type-specific APA events may lead to novel APA events and their functions being overlooked. Here, we compared APA events across different cell types in non-small cell lung cancer (NSCLC) and normal tissues and identified functionally related APA events in NSCLC. We found several cell-specific 3'-UTR alterations that regulate gene expression changes showed prognostic value in NSCLC. We further investigated the function of APA-mediated 3'-UTR shortening through loss of microRNA (miRNA)-binding sites, and …

Disease Modeling And Gene Correction Of Lgmdr21 Ipscs Elucidates The Role Of Poglut1 In Skeletal Muscle Maintenance, Regeneration, And The Satellite Cell Niche, Jose L Ortiz-Vitali, Jianbo Wu, Nasa Xu, Annie W Shieh, Nima Niknejad, Megumi Takeuchi, Carmen Paradas, Chunru Lin, Hamed Jafar-Nejad, Robert S Haltiwanger, Sidney H Wang, Radbod Darabi

Faculty, Staff and Student Publications

Autosomal recessive limb-girdle muscular dystrophy 21 (LGMDR21) is caused by pathogenic variants in protein O-glucosyltransferase 1 (POGLUT1), which is responsible for O-glucosylation of specific epidermal growth factor (EGF) repeats found in ∼50 mammalian proteins, including Notch receptors. Previous data from patient biopsies indicated that impaired Notch signaling, reduction of muscle stem cells, and accelerated differentiation are probably involved in disease etiopathology. Using patient induced pluripotent stem cells (iPSCs), their corrected isotypes, and control iPSCs, gene expression profiling indicated dysregulation of POGLUT1, NOTCH, muscle development, extracellular matrix (ECM), cell adhesion, and migration as involved pathways. They also exhibited reduced in vitro …

Perceptions Of Facilitators And Barriers To Smoking Cessation Among Patients And Providers In A Cancer Center: A Single Institution Qualitative Exploratory Study, Luke M. Shenton, Udara Perera, Amy Leader, Ann C. Klassen

College of Population Health Faculty Papers

PURPOSE: Cancer patients who remain tobacco users have poorer outcomes, including increased mortality and decreased treatment tolerance; however, cessation post-diagnosis is challenging. Our formative research explored cessation-related perspectives among patients and staff at one National Cancer Institute-designated cancer center, to inform improving cessation services within oncology care.

METHODS: Using a descriptive phenomenological approach, a purposive sample of current cancer patients (n = 13) and cancer center physicians and cessation program staff (n = 9) were recruited to complete one-on-one audio-recorded in-depth qualitative interviews, to explore experiences providing or receiving cessation support, and perspectives on patients' readiness and needs regarding cessation. …

Global Proteomic Identifies Multiple Cancer-Related Signaling Pathways Altered By A Gut Pathobiont Associated With Colorectal Cancer, Ewa Pasquereau-Kotula, Giulia Nigro, Florent Dingli, Damarys Loew, Patrick Poullet, Yi Xu, Scott Kopetz, Jennifer Davis, Lucie Peduto, Catherine Robbe-Masselot, Philippe Sansonetti, Patrick Trieu-Cuot, Shaynoor Dramsi

Faculty, Staff and Student Publications

In this work, we investigated the oncogenic role of Streptococcus gallolyticus subsp. gallolyticus (SGG), a gut bacterium associated with colorectal cancer (CRC). We showed that SGG UCN34 accelerates colon tumor development in a chemically induced CRC murine model. Full proteome and phosphoproteome analysis of murine colons chronically colonized by SGG UCN34 revealed that 164 proteins and 725 phosphorylation sites were differentially regulated. Ingenuity Pathway Analysis (IPA) indicates a pro-tumoral shift specifically induced by SGG UCN34, as ~ 90% of proteins and phosphoproteins identified were associated with digestive cancer. Comprehensive analysis of the altered phosphoproteins using ROMA software revealed up-regulation of …

Elimination Of Oncogenic Kras In Genetic Mouse Models Eradicates Pancreatic Cancer By Inducing Fas-Dependent Apoptosis By Cd8+ T Cells, Krishnan K Mahadevan, Valerie S Lebleu, Elena V Ramirez, Yang Chen, Bingrui Li, Amari M Sockwell, Mihai Gagea, Hikaru Sugimoto, Lakshmi Kavitha Sthanam, Desiree Tampe, Michael Zeisberg, Haoqiang Ying, Abhinav K Jain, Ronald A Depinho, Anirban Maitra, Kathleen M Mcandrews, Raghu Kalluri

Faculty, Staff and Student Publications

Oncogenic KRASG12D (KRAS∗) is critical for the initiation and maintenance of pancreatic ductal adenocarcinoma (PDAC) and is a known repressor of tumor immunity. Conditional elimination of KRAS∗ in genetic mouse models of PDAC leads to the reactivation of FAS, CD8+ T cell-mediated apoptosis, and complete eradication of tumors. KRAS∗ elimination recruits activated CD4+ and CD8+ T cells and promotes the activation of antigen-presenting cells. Mechanistically, KRAS∗-mediated immune evasion involves the epigenetic regulation of Fas death receptor in cancer cells, via methylation of its promoter region. Furthermore, analysis of human RNA sequencing identifies that high KRAS expression in PDAC tumors shows …

Unfolding The Secrets Of Small Cell Lung Cancer Progression: Novel Approaches And Insights Through Rapid Autopsies, Zsolt Megyesfalvi, Simon Heeke, Benjamin J Drapkin, Anna Solta, Ildiko Kovacs, Kristiina Boettiger, Lilla Horvath, Busra Ernhofer, Janos Fillinger, Ferenc Renyi-Vamos, Clemens Aigner, Karin Schelch, Christian Lang, Gyorgy Marko-Varga, Carl M Gay, Lauren A Byers, Benjamin B Morris, John V Heymach, Peter Van Loo, Fred R Hirsch, Balazs Dome

Faculty, Staff and Student Publications

The understanding of small cell lung cancer (SCLC) biology has increased dramatically in recent years, but the processes that allow SCLC to progress rapidly remain poorly understood. Here, we advocate the integration of rapid autopsies and preclinical models into SCLC research as a comprehensive strategy with the potential to revolutionize current treatment paradigms.

Early Onset Horizontal Gaze Palsy And Progressive Scoliosis Due To A Noncanonical Splicing-Site Variant And A Missense Variant In The Robo3 Gene, Sheng Yi, Zailong Qin, Xunzhao Zhou, Junjie Chen, Shang Yi, Qiuli Chen, Limei Huang, Qinle Zhang, Biyan Chen, Jingsi Luo

Faculty, Staff and Student Publications

BACKGROUND: Homozygous or compound heterozygous ROBO3 gene mutations cause horizontal gaze palsy with progressive scoliosis (HGPPS). This is an autosomal recessive disorder that is characterized by congenital absence or severe restriction of horizontal gaze and progressive scoliosis. To date, almost 100 patients with HGPPS have been reported and 55 ROBO3 mutations have been identified.

METHODS: We described an HGPPS patient and performed whole-exome sequencing (WES) to identify the causative gene.

RESULTS: We identified a missense variant and a splice-site variant in the ROBO3 gene in the proband. Sanger sequencing of cDNA revealed the presence of an aberrant transcript with retention …

Proteogenomic Insights Suggest Druggable Pathways In Endometrial Carcinoma, Yongchao Dou, Lizabeth Katsnelson, Marina A Gritsenko, Yingwei Hu, Boris Reva, Runyu Hong, Yi-Ting Wang, Iga Kolodziejczak, Rita Jui-Hsien Lu, Chia-Feng Tsai, Wen Bu, Wenke Liu, Xiaofang Guo, Eunkyung An, Rebecca C Arend, Jasmin Bavarva, Lijun Chen, Rosalie K Chu, Andrzej Czekański, Teresa Davoli, Elizabeth G Demicco, Deborah Delair, Kelly Devereaux, Saravana M Dhanasekaran, Peter Dottino, Bailee Dover, Thomas L Fillmore, Mckenzie Foxall, Catherine E Hermann, Tara Hiltke, Galen Hostetter, Marcin Jędryka, Scott D Jewell, Isabelle Johnson, Andrea G Kahn, Amy T Ku, Chandan Kumar-Sinha, Paweł Kurzawa, Alexander J Lazar, Rossana Lazcano, Jonathan T Lei, Yi Li, Yuxing Liao, Tung-Shing M Lih, Tai-Tu Lin, John A Martignetti, Ramya P Masand, Rafał Matkowski, Wilson Mckerrow, Mehdi Mesri, Matthew E Monroe, Jamie Moon, Ronald J Moore, Michael D Nestor, Chelsea Newton, Tatiana Omelchenko, Gilbert S Omenn, Samuel H Payne, Vladislav A Petyuk, Ana I Robles, Henry Rodriguez, Kelly V Ruggles, Dmitry Rykunov, Sara R Savage, Athena A Schepmoes, Tujin Shi, Zhiao Shi, Jimin Tan, Mason Taylor, Mathangi Thiagarajan, Joshua M Wang, Karl K Weitz, Bo Wen, C M Williams, Yige Wu, Matthew A Wyczalkowski, Xinpei Yi, Xu Zhang, Rui Zhao, David Mutch, Arul M Chinnaiyan, Richard D Smith, Alexey I Nesvizhskii, Pei Wang, Maciej Wiznerowicz, Li Ding, D R Mani, Hui Zhang, Matthew L Anderson, Karin D Rodland, Bing Zhang, Tao Liu, David Fenyö

Faculty, Staff and Students Publications

We characterized a prospective endometrial carcinoma (EC) cohort containing 138 tumors and 20 enriched normal tissues using 10 different omics platforms. Targeted quantitation of two peptides can predict antigen processing and presentation machinery activity, and may inform patient selection for immunotherapy. Association analysis between MYC activity and metformin treatment in both patients and cell lines suggests a potential role for metformin treatment in non-diabetic patients with elevated MYC activity. PIK3R1 in-frame indels are associated with elevated AKT phosphorylation and increased sensitivity to AKT inhibitors. CTNNB1 hotspot mutations are concentrated near phosphorylation sites mediating pS45-induced degradation of β-catenin, which may render …

Treatment Of Older Adults With Flt3-Mutated Aml: Emerging Paradigms And The Role Of Frontline Flt3 Inhibitors, Nicholas J Short, Daniel Nguyen, Farhad Ravandi

Faculty, Staff and Student Publications

FLT3 is the most frequently mutated gene in acute myeloid leukemia (AML), with FLT3 internal tandem duplication (ITD) mutations being associated with a more aggressive clinical course. While two large, randomized clinical trials have shown a survival benefit with the frontline use of an oral FLT3 inhibitor (midostaurin or quizartinib) in patients with FLT3-mutated AML, the role of FLT3 inhibitors in older adults with newly diagnosed FLT3-mutated AML remains unclear. A definitive improvement in survival has not been observed in intensively treated patients over 60 years of age receiving frontline FLT3 inhibitors. Furthermore, many patients with FLT3-mutated AML are unsuitable …

Integrative Multi-Omic Cancer Profiling Reveals Dna Methylation Patterns Associated With Therapeutic Vulnerability And Cell-Of-Origin, Wen-Wei Liang, Rita Jui-Hsien Lu, Reyka G Jayasinghe, Steven M Foltz, Eduard Porta-Pardo, Yifat Geffen, Michael C Wendl, Rossana Lazcano, Iga Kolodziejczak, Yizhe Song, Akshay Govindan, Elizabeth G Demicco, Xiang Li, Yize Li, Sunantha Sethuraman, Samuel H Payne, David Fenyö, Henry Rodriguez, Maciej Wiznerowicz, Hui Shen, D R Mani, Karin D Rodland, Alexander J Lazar, Ana I Robles, Li Ding, Clinical Proteomic Tumor Analysis Consortium

Faculty, Staff and Student Publications

DNA methylation plays a critical role in establishing and maintaining cellular identity. However, it is frequently dysregulated during tumor development and is closely intertwined with other genetic alterations. Here, we leveraged multi-omic profiling of 687 tumors and matched non-involved adjacent tissues from the kidney, brain, pancreas, lung, head and neck, and endometrium to identify aberrant methylation associated with RNA and protein abundance changes and build a Pan-Cancer catalog. We uncovered lineage-specific epigenetic drivers including hypomethylated FGFR2 in endometrial cancer. We showed that hypermethylated STAT5A is associated with pervasive regulon downregulation and immune cell depletion, suggesting that epigenetic regulation of STAT5A …

Krasg12d Inhibition Reprograms The Tumor Microenvironment Of Early And Advanced Pancreatic Cancer To Promote Fas-Mediated Killing By Cd8+ T Cells, Krishnan K Mahadevan, Kathleen M Mcandrews, Valerie S Lebleu, Sujuan Yang, Hengyu Lyu, Bingrui Li, Amari M Sockwell, Michelle L Kirtley, Sami J Morse, Barbara A Moreno Diaz, Michael P Kim, Ningping Feng, Anastasia M Lopez, Paola A Guerrero, Francesca Paradiso, Hikaru Sugimoto, Kent A Arian, Haoqiang Ying, Yasaman Barekatain, Lakshmi Kavitha Sthanam, Patience J Kelly, Anirban Maitra, Timothy P Heffernan, Raghu Kalluri

Faculty, Staff and Student Publications

The KRASG12D mutation is present in nearly half of pancreatic adenocarcinomas (PDAC). We investigated the effects of inhibiting the KRASG12D mutant protein with MRTX1133, a non-covalent small molecule inhibitor of KRASG12D, on early and advanced PDAC and its influence on the tumor microenvironment. Employing 16 different models of KRASG12D-driven PDAC, we demonstrate that MRTX1133 reverses early PDAC growth, increases intratumoral CD8+ effector T cells, decreases myeloid infiltration, and reprograms cancer associated fibroblasts. MRTX1133 leads to regression of both established PanINs and advanced PDAC. Regression of advanced PDAC requires CD8+ T cells and immune checkpoint blockade (ICB) synergizes with MRTX1133 …

Elimination Of Oncogenic Kras In Genetic Mouse Models Eradicates Pancreatic Cancer By Inducing Fas-Dependent Apoptosis By Cd8+ T Cells, Krishnan K Mahadevan, Valerie S Lebleu, Elena V Ramirez, Yang Chen, Bingrui Li, Amari M Sockwell, Mihai Gagea, Hikaru Sugimoto, Lakshmi Kavitha Sthanam, Desiree Tampe, Michael Zeisberg, Haoqiang Ying, Abhinav K Jain, Ronald A Depinho, Anirban Maitra, Kathleen M Mcandrews, Raghu Kalluri

Faculty, Staff and Student Publications

Oncogenic KrasG12D (Kras*) is critical for the initiation and maintenance of pancreatic ductal adenocarcinoma (PDAC), and a known repressor of tumor immunity. Conditional elimination of Kras* in genetic mouse models of PDAC leads to reactivation of Fas, CD8+ T cell mediated apoptosis, and complete eradication of tumors. Kras* elimination recruits activated CD4+ and CD8+ T cells and promotes the activation of antigen presenting cells. Mechanistically, Kras* mediated immune evasion involves epigenetic regulation of the Fas death receptor in cancer cells, via methylation of its promoter region. Further, analysis of human RNA sequencing identifies that high KRAS expressing PDAC tumors show …

Stereotactic Ablative Radiotherapy With Or Without Immunotherapy For Early-Stage Or Isolated Lung Parenchymal Recurrent Node-Negative Non-Small-Cell Lung Cancer: An Open-Label, Randomised, Phase 2 Trial, Joe Y Chang, Steven H Lin, Wenli Dong, Zhongxing Liao, Saumil J Gandhi, Carl M Gay, Jianjun Zhang, Stephen G Chun, Yasir Y Elamin, Frank V Fossella, George Blumenschein, Tina Cascone, Xiuning Le, Jenny V Pozadzides, Anne Tsao, Vivek Verma, James W Welsh, Aileen B Chen, Mehmet Altan, Reza J Mehran, Ara A Vaporciyan, Stephen G Swisher, Peter A Balter, Junya Fujimoto, Ignacio I Wistuba, Lei Feng, J Jack Lee, John V Heymach

Faculty, Staff and Student Publications

BACKGROUND: Stereotactic ablative radiotherapy (SABR) is the standard treatment for medically inoperable early-stage non-small-cell lung cancer (NSCLC), but regional or distant relapses, or both, are common. Immunotherapy reduces recurrence and improves survival in people with stage III NSCLC after chemoradiotherapy, but its utility in stage I and II cases is unclear. We therefore conducted a randomised phase 2 trial of SABR alone compared with SABR with immunotherapy (I-SABR) for people with early-stage NSCLC.

METHODS: We did an open-label, randomised, phase 2 trial comparing SABR to I-SABR, conducted at three different hospitals in TX, USA. People aged 18 years or older …