Biomedical Informatics Commons^™

Mutant P53 Protects Triple-Negative Breast Adenocarcinomas From Ferroptosis In Vivo, Denada Dibra, Shunbin Xiong, Sydney M Moyer, Adel K El-Naggar, Yuan Qi, Xiaoping Su, Elisabeth K Kong, Anil Korkut, Guillermina Lozano

Faculty, Staff and Student Publications

The TP53 tumor suppressor gene is mutated early in most of the patients with triple-negative breast cancer (TNBC). The most frequent TP53 alterations are missense mutations that contribute to tumor aggressiveness. Here, we used an autochthonous somatic TNBC mouse model, in which mutant p53 can be toggled on and off genetically while leaving the tumor microenvironment intact and wild-type for p53 to identify physiological dependencies on mutant p53. In TNBCs that develop in this model, deletion of two different hotspot p53R172H and p53R245W mutants triggers ferroptosis in vivo, a cell death mechanism involving iron-dependent lipid peroxidation. Mutant p53 protects cells …

Circulating Microrna Panel For Prediction Of Recurrence And Survival In Early-Stage Lung Adenocarcinoma, Mei-Chee Tai, Leonidas E Bantis, Gargy Parhy, Taketo Kato, Ichidai Tanaka, Chi-Wan Chow, Junya Fujimoto, Carmen Behrens, Tetsunari Hase, Koji Kawaguchi, Johannes F Fahrmann, Edwin J Ostrin, Kohei Yokoi, Toyofumi F Chen-Yoshikawa, Yoshinori Hasegawa, Samir M Hanash, Ignacio I Wistuba, Ayumu Taguchi

Faculty, Staff and Student Publications

Early-stage lung adenocarcinoma (LUAD) patients remain at substantial risk for recurrence and disease-related death, highlighting the unmet need of biomarkers for the assessment and identification of those in an early stage who would likely benefit from adjuvant chemotherapy. To identify circulating miRNAs useful for predicting recurrence in early-stage LUAD, we performed miRNA microarray analysis with pools of pretreatment plasma samples from patients with stage I LUAD who developed recurrence or remained recurrence-free during the follow-up period. Subsequent validation in 85 patients with stage I LUAD resulted in the development of a circulating miRNA panel comprising miR-23a-3p, miR-320c, and miR-125b-5p and …

The Il6/Jak/Stat3 Signaling Axis Is A Therapeutic Vulnerability In Smarcb1-Deficient Bladder Cancer, Chandra Sekhar Amara, Karthik Reddy Kami Reddy, Yang Yuntao, Yuen San Chan, Danthasinghe Waduge Badrajee Piyarathna, Lacey Elizabeth Dobrolecki, David J H Shih, Zhongcheng Shi, Jun Xu, Shixia Huang, Matthew J Ellis, Andrea B Apolo, Leomar Y Ballester, Jianjun Gao, Donna E Hansel, Yair Lotan, H Courtney Hodges, Seth P Lerner, Chad J Creighton, Arun Sreekumar, W Jim Zheng, Pavlos Msaouel, Shyam M Kavuri, Nagireddy Putluri

Faculty, Staff and Student Publications

SMARCB1 loss has long been observed in many solid tumors. However, there is a need to elucidate targetable pathways driving growth and metastasis in SMARCB1-deficient tumors. Here, we demonstrate that SMARCB1 deficiency, defined as genomic SMARCB1 copy number loss associated with reduced mRNA, drives disease progression in patients with bladder cancer by engaging STAT3. SMARCB1 loss increases the chromatin accessibility of the STAT3 locus in vitro. Orthotopically implanted SMARCB1 knockout (KO) cell lines exhibit increased tumor growth and metastasis. SMARCB1-deficient tumors show an increased IL6/JAK/STAT3 signaling axis in in vivo models and patients. Furthermore, a pSTAT3 selective inhibitor, TTI-101, reduces …

Tumor- And Circulating-Free Dna Methylation Identifies Clinically Relevant Small Cell Lung Cancer Subtypes, Simon Heeke, Carl M Gay, Marcos R Estecio, Hai Tran, Benjamin B Morris, Bingnan Zhang, Ximing Tang, Maria Gabriela Raso, Pedro Rocha, Siqi Lai, Edurne Arriola, Paul Hofman, Veronique Hofman, Prasad Kopparapu, Christine M Lovly, Kyle Concannon, Luana Guimaraes De Sousa, Whitney Elisabeth Lewis, Kimie Kondo, Xin Hu, Azusa Tanimoto, Natalie I Vokes, Monique B Nilsson, Allison Stewart, Maarten Jansen, Ildikó Horváth, Mina Gaga, Vasileios Panagoulias, Yael Raviv, Danny Frumkin, Adam Wasserstrom, Aharona Shuali, Catherine A Schnabel, Yuanxin Xi, Lixia Diao, Qi Wang, Jianjun Zhang, Peter Van Loo, Jing Wang, Ignacio I Wistuba, Lauren A Byers, John V Heymach

Faculty, Staff and Student Publications

Small cell lung cancer (SCLC) is an aggressive malignancy composed of distinct transcriptional subtypes, but implementing subtyping in the clinic has remained challenging, particularly due to limited tissue availability. Given the known epigenetic regulation of critical SCLC transcriptional programs, we hypothesized that subtype-specific patterns of DNA methylation could be detected in tumor or blood from SCLC patients. Using genomic-wide reduced-representation bisulfite sequencing (RRBS) in two cohorts totaling 179 SCLC patients and using machine learning approaches, we report a highly accurate DNA methylation-based classifier (SCLC-DMC) that can distinguish SCLC subtypes. We further adjust the classifier for circulating-free DNA (cfDNA) to subtype …

Androgen Drives Melanoma Invasiveness And Metastatic Spread By Inducing Tumorigenic Fucosylation, Qian Liu, Emma Adhikari, Daniel K Lester, Bin Fang, Joseph O Johnson, Yijun Tian, Andrea T Mockabee-Macias, Victoria Izumi, Kelly M Guzman, Michael G White, John M Koomen, Jennifer A Wargo, Jane L Messina, Jianfei Qi, Eric K Lau

Faculty, Staff and Student Publications

Melanoma incidence and mortality rates are historically higher for men than women. Although emerging studies have highlighted tumorigenic roles for the male sex hormone androgen and its receptor (AR) in melanoma, cellular and molecular mechanisms underlying these sex-associated discrepancies are poorly defined. Here, we delineate a previously undisclosed mechanism by which androgen-activated AR transcriptionally upregulates fucosyltransferase 4 (FUT4) expression, which drives melanoma invasiveness by interfering with adherens junctions (AJs). Global phosphoproteomic and fucoproteomic profiling, coupled with in vitro and in vivo functional validation, further reveal that AR-induced FUT4 fucosylates L1 cell adhesion molecule (L1CAM), which is required for FUT4-increased metastatic …

Serum Tumor Markers And Outcomes In Patients With Appendiceal Adenocarcinoma, Abdelrahman Yousef, Mahmoud Yousef, Mohammad A Zeineddine, Aditya More, Mohammad Fanaeian, Saikat Chowdhury, Mark Knafl, Paul Edelkamp, Ichiaki Ito, Yue Gu, Vinay Pattalachinti, Zahra Alavi Naini, Fadl A Zeineddine, Jennifer Peterson, Kristin Alfaro, Wai Chin Foo, Jeff Jin, Neal Bhutiani, Victoria Higbie, Christopher P Scally, Bryan Kee, Scott Kopetz, Drew Goldstein, Madeleine Strach, Andrew Williamson, Omer Aziz, Jorge Barriuso, Abhineet Uppal, Michael G White, Beth Helmink, Keith F Fournier, Kanwal P Raghav, Melissa W Taggart, Michael J Overman, John Paul Shen

Faculty, Staff and Student Publications

IMPORTANCE: Serum tumor markers carcinoembryonic antigen (CEA), carbohydrate antigen 19-9 (CA19-9), and cancer antigen 125 (CA125) have been useful in the management of gastrointestinal and gynecological cancers; however, there is limited information regarding their utility in patients with appendiceal adenocarcinoma.

OBJECTIVE: To assess the association of serum tumor markers (CEA, CA19-9, and CA125) with clinical outcomes and pathologic and molecular features in patients with appendiceal adenocarcinoma.

DESIGN, SETTING, AND PARTICIPANTS: This is a retrospective cohort study at a single tertiary care comprehensive cancer center. The median (IQR) follow-up time was 52 (21-101) months. Software was used to query the MD …

The Novel Phosphatase Nudt5 Is A Critical Regulator Of Triple-Negative Breast Cancer Growth, Jing Qian, Yanxia Ma, William M Tahaney, Cassandra L Moyer, Amanda Lanier, Jamal Hill, Darian Coleman, Negar Koupaei, Susan G Hilsenbeck, Michelle I Savage, Brent D G Page, Abhijit Mazumdar, Powel H Brown

Faculty, Staff and Student Publications

BACKGROUND: The most aggressive form of breast cancer is triple-negative breast cancer (TNBC), which lacks expression of the estrogen receptor (ER) and progesterone receptor (PR), and does not have overexpression of the human epidermal growth factor receptor 2 (HER2). Treatment options for women with TNBC tumors are limited, unlike those with ER-positive tumors that can be treated with hormone therapy, or those with HER2-positive tumors that can be treated with anti-HER2 therapy. Therefore, we have sought to identify novel targeted therapies for TNBC. In this study, we investigated the potential of a novel phosphatase, NUDT5, as a potential therapeutic target …

Identification Of New Egfr Inhibitors By Structure-Based Virtual Screening And Biological Evaluation, Shuyi Wang, Xiaotian Xu, Chuxin Pan, Qian Guo, Qinlan Li, Shanhe Wan, Zhonghuang Li, Jiajie Zhang, Xiaoyun Wu

Faculty, Staff and Student Publications

Epidermal growth factor receptor (EGFR) inhibitors have been used in clinical for the treatment of non-small-cell lung cancer for years. However, the emergence of drug resistance continues to be a major problem. To identify potential inhibitors, molecular docking-based virtual screening was conducted on ChemDiv and Enamine commercial databases using the Glide program. After multi-step VS and visual inspection, a total of 23 compounds with novel and varied structures were selected, and the predicted ADMET properties were within the satisfactory range. Further molecular dynamics simulations revealed that the reprehensive compound ZINC49691377 formed a stable complex with the allosteric pocket of EGFR …

Tumor-Specific Polycistronic Mirna Delivered By Engineered Exosomes For The Treatment Of Glioblastoma, Malcolm F Mcdonald, Anwar Hossain, Eric N Momin, Irtiza Hasan, Sanjay Singh, Satoshi Adachi, Joy Gumin, Daniel Ledbetter, Jing Yang, Lihong Long, Marc Daou, Sricharan Gopakumar, Lynette M Phillips, Brittany Parker Kerrigan, Frederick F Lang

Faculty, Staff and Student Publications

Background: Glioblastoma (GBM) has poor prognosis due to ineffective agents and poor delivery methods. MicroRNAs (miRs) have been explored as novel therapeutics for GBM, but the optimal miRs and the ideal delivery strategy remain unresolved. In this study, we sought to identify the most effective pan-subtype anti-GBM miRs and to develop an improved delivery system for these miRs.

Methods: We conducted an unbiased screen of over 600 miRs against 7 glioma stem cell (GSC) lines representing all GBM subtypes to identify a set of pan-subtype-specific anti-GBM miRs and then used available TCGA GBM patient outcomes and miR expression data to …

Development Of Resistance To Type Ii Jak2 Inhibitors In Mpn Depends On Axl Kinase And Is Targetable, Tamara Codilupi, Jakub Szybinski, Stefanie Arunasalam, Sarah Jungius, Andrew C Dunbar, Simona Stivala, Sime Brkic, Camille Albrecht, Lenka Vokalova, Julie L Yang, Katarzyna Buczak, Nilabh Ghosh, Jakob R Passweg, Alicia Rovo, Anne Angelillo-Scherrer, Dmitry Pankov, Stefan Dirnhofer, Ross L Levine, Richard Koche, Sara C Meyer

Faculty, Staff and Student Publications

PURPOSE: Myeloproliferative neoplasms (MPN) dysregulate JAK2 signaling. Because clinical JAK2 inhibitors have limited disease-modifying effects, type II JAK2 inhibitors such as CHZ868 stabilizing inactive JAK2 and reducing MPN clones, gain interest. We studied whether MPN cells escape from type ll inhibition.

EXPERIMENTAL DESIGN: MPN cells were continuously exposed to CHZ868. We used phosphoproteomic analyses and ATAC/RNA sequencing to characterize acquired resistance to type II JAK2 inhibition, and targeted candidate mediators in MPN cells and mice.

RESULTS: MPN cells showed increased IC50 and reduced apoptosis upon CHZ868 reflecting acquired resistance to JAK2 inhibition. Among >2,500 differential phospho-sites, MAPK pathway activation was …

Trps1 And Gata3 Expression In Invasive Breast Carcinoma With Apocrine Differentiation, Jing Wang, Yan Peng, Hongxia Sun, Phyu P Aung, Erika Resetkova, Clinton Yam, Aysegul A Sahin, Lei Huo, Qingqing Ding

Faculty, Staff and Student Publications

Context.—: The recently identified immunohistochemical marker TRPS1 is highly sensitive and specific for invasive breast carcinoma, especially triple-negative breast carcinoma. However, TRPS1 expression in special morphologic subtypes of breast cancer is unclear.

Objective.—: To investigate the expression of TRPS1 in invasive breast cancer with apocrine differentiation, in comparison to the expression of GATA3.

Design.—: A total of 52 invasive breast carcinomas with apocrine differentiation, comprising 41 triple-negative breast carcinomas and 11 estrogen receptor (ER) and progesterone receptor (PR)-negative, human epidermal growth factor receptor 2 (HER2)-positive cases, along with 11 triple-negative breast carcinomas without apocrine differentiation, were evaluated for TRPS1 and …

Circulating Tumor Dna And Radiological Tumor Volume Identify Patients At Risk For Relapse With Resected, Early-Stage Non-Small-Cell Lung Cancer, H T Tran, S Heeke, S Sujit, N Vokes, J Zhang, M Aminu, V K Lam, A Vaporciyan, S G Swisher, M C B Godoy, T Cascone, B Sepesi, D L Gibbons, J Wu, J V Heymach

Faculty, Staff and Student Publications

Background: Predicting relapse and overall survival (OS) in early-stage non-small-cell lung cancer (NSCLC) patients remains challenging. Therefore, we hypothesized that detection of circulating tumor DNA (ctDNA) can identify patients with increased risk of relapse and that integrating radiological tumor volume measurement along with ctDNA detectability improves prediction of outcome.

Patients and methods: We analyzed 366 serial plasma samples from 85 patients who underwent surgical resections and assessed ctDNA using a next-generation sequencing liquid biopsy assay, and measured tumor volume using a computed tomography-based three-dimensional annotation.

Results: Our results showed that patients with detectable ctDNA at baseline or after treatment and …

Gli1-Altered Mesenchymal Tumors With Actb Or Ptch1 Fusion: A Molecular And Clinicopathologic Analysis, Darcy A Kerr, Jeffrey M Cloutier, Matthew Margolis, Douglas A Mata, Nathalie J Rodrigues Simoes, William C Faquin, Dora Dias-Santagata, Shefali Chopra, Gregory W Charville, Sintawat Wangsiricharoen, Alexander J Lazar, Wei-Lien Wang, Andrew E Rosenberg, Julie Y Tse

Faculty, Staff and Student Publications

Mesenchymal tumors with GLI1 fusions or amplifications have recently emerged as a distinctive group of neoplasms. The terms GLI1-altered mesenchymal tumor or GLI1-altered soft tissue tumor serve as a nosological category, although the exact boundaries/criteria require further elucidation. We examined 16 tumors affecting predominantly adults (median age: 40 years), without sex predilection. Several patients had tumors of longstanding duration (>10 years). The most common primary site was soft tissue (n = 9); other sites included epidural tissue (n = 1), vertebra (n = 1), tongue (n = 1), hard palate (n = 1), and liver (n = 1). Histologically, …

Crispr Screening Identifies Bet And Mtor Inhibitor Synergy In Cholangiocarcinoma Through Serine Glycine One Carbon, Yan Zhu, Dengyong Zhang, Pooja Shukla, Young-Ho Jung, Prit Benny Malgulwar, Sharmeen Chagani, Medina Colic, Sarah Benjamin, John A Copland, Lin Tan, Philip L Lorenzi, Milind Javle, Jason T Huse, Jason Roszik, Traver Hart, Lawrence N Kwong

Faculty, Staff and Student Publications

Patients with cholangiocarcinoma have poor clinical outcomes due to late diagnoses, poor prognoses, and limited treatment strategies. To identify drug combinations for this disease, we have conducted a genome-wide CRISPR screen anchored on the bromodomain and extraterminal domain (BET) PROTAC degrader ARV825, from which we identified anticancer synergy when combined with genetic ablation of members of the mTOR pathway. This combination effect was validated using multiple pharmacological BET and mTOR inhibitors, accompanied by increased levels of apoptosis and cell cycle arrest. In a xenograft model, combined BET degradation and mTOR inhibition induced tumor regression. Mechanistically, the 2 inhibitor classes converged …

Evaluation Of Potential Biomarkers For Lenvatinib Plus Pembrolizumab Among Patients With Advanced Endometrial Cancer: Results From Study 111/Keynote-146, Vicky Makker, Matthew H Taylor, Carol Aghajanian, Allen L Cohn, Marcia S Brose, Christopher Di Simone, Zhu Alexander Cao, Leah Suttner, Andrey Loboda, Razvan Cristescu, Petar Jelinic, Robert Orlowski, Lea Dutta, Junji Matsui, Corina E Dutcus, Yukinori Minoshima, Mark J Messing

Faculty, Staff and Student Publications

BACKGROUND: Lenvatinib plus pembrolizumab demonstrated clinically meaningful benefit in patients with previously treated advanced endometrial carcinoma in Study 111/KEYNOTE-146 (NCT02501096). In these exploratory analyses from this study, we evaluated the associations between clinical outcomes and gene expression signature scores and descriptively summarized response in biomarker subpopulations defined by tumor mutational burden (TMB) and DNA variants for individual genes of interest.

METHODS: Patients with histologically confirmed metastatic endometrial carcinoma received oral lenvatinib 20 mg once daily plus intravenous pembrolizumab 200 mg every 3 weeks for 35 cycles. Archived formalin-fixed paraffin-embedded tissue was obtained from all patients. T-cell-inflamed gene expression profile (Tcell …

Induced Degradation Of Lineage-Specific Oncoproteins Drives The Therapeutic Vulnerability Of Small Cell Lung Cancer To Parp Inhibitors, Chiho Kim, Xu-Dong Wang, Zhengshuai Liu, Jianwei Hao, Shuai Wang, Peng Li, Zhenzhen Zi, Qing Ding, Seoyeon Jang, Jiwoong Kim, Yikai Luo, Kenneth E Huffman, Shreoshi Pal Choudhuri, Sofia Del Rio, Ling Cai, Han Liang, Benjamin J Drapkin, John D Minna, Yonghao Yu

Faculty, Staff and Student Publications

Although BRCA1/2 mutations are not commonly found in small cell lung cancer (SCLC), a substantial fraction of SCLC shows clinically relevant response to PARP inhibitors (PARPis). However, the underlying mechanism(s) of PARPi sensitivity in SCLC is poorly understood. We performed quantitative proteomic analyses and identified proteomic changes that signify PARPi responses in SCLC cells. We found that the vulnerability of SCLC to PARPi could be explained by the degradation of lineage-specific oncoproteins (e.g., ASCL1). PARPi-induced activation of the E3 ligase HUWE1 mediated the ubiquitin-proteasome system (UPS)-dependent ASCL1 degradation. Although PARPi induced a general DNA damage response in SCLC cells, this …

Pressing Need Of Precision Care In Her2-Positive Colorectal Cancer: The Elephant In The Room, Kanwal P S Raghav, Jonathan M Loree, Scott Kopetz

Faculty, Staff and Student Publications

Although dual HER2 inhibition has shown promising clinical activity in patients with RAS wild-type HER2-positive metastatic colorectal cancer, predictive biomarkers of response/resistance are less well characterized. Activating HER2/RTK/MAPK genomic alterations appears to blunt the clinical benefit of dual anti-HER2 therapy and may hold a potential albeit partial role in patient selection. See related article by Randon et al., p. 436.

Development Of A Rabbit Human Glioblastoma Model For Testing Of Endovascular Selective Intra-Arterial Infusion (Esia) Of Novel Stem Cell-Based Therapeutics, Peter Kan, Visish M Srinivasan, Joy Gumin, Roberto Garcia, Stephen R Chen, Jeremiah N Johnson, Dalis E Collins, Melissa M Chen, Daniel Ledbetter, Jason Huse, Zean Aaron Evan Luna, Ariadna Robledo, Viren Vasandani, Abhijit Rao, Sanjay K Singh, Elizabeth J Shpall, Juan Fueyo, Candelaria Gomez-Manzano, Frederick F Lang

Faculty, Staff and Student Publications

BACKGROUND: Endovascular selective intra-arterial (ESIA) infusion of cellular oncotherapeutics is a rapidly evolving strategy for treating glioblastoma. Evaluation of ESIA infusion requires a unique animal model. Our goal was to create a rabbit human GBM model to test IA infusions of cellular therapies and to test its usefulness by employing clinical-grade microcatheters and infusion methods to deliver mesenchymal stem cells loaded with an oncolytic adenovirus, Delta-24-RGD (MSC-D24).

METHODS: Rabbits were immunosuppressed with mycophenolate mofetil, dexamethasone, and tacrolimus. They underwent stereotactic xenoimplantation of human GBM cell lines (U87, MDA-GSC-17, and MDA-GSC-8-11) into the right frontal lobe. Tumor formation was confirmed on …

Fak Drives Resistance To Therapy In Hpv-Negative Head And Neck Cancer In A P53-Dependent Manner, Phillip M Pifer, Liangpeng Yang, Manish Kumar, Tongxin Xie, Mitchell Frederick, Andrew Hefner, Beth Beadle, David Molkentine, Jessica Molkentine, Annika Dhawan, Mohamed Abdelhakiem, Abdullah A Osman, Brian J Leibowitz, Jeffrey N Myers, Curtis R Pickering, Vlad C Sandulache, John Heymach, Heath D Skinner

Faculty, Staff and Student Publications

PURPOSE: Radiation and platinum-based chemotherapy form the backbone of therapy in human papillomavirus (HPV)-negative head and neck squamous cell carcinoma (HNSCC). We have correlated focal adhesion kinase (FAK/PTK2) expression with radioresistance and worse outcomes in these patients. However, the importance of FAK in driving radioresistance and its effects on chemoresistance in these patients remains unclear.

EXPERIMENTAL DESIGN: We performed an in vivo shRNA screen using targetable libraries to identify novel therapeutic sensitizers for radiation and chemotherapy.

RESULTS: We identified FAK as an excellent target for both radio- and chemosensitization. Because TP53 is mutated in over 80% of HPV-negative HNSCC, we …

Proteogenomic Characterization Of Small Cell Lung Cancer Identifies Biological Insights And Subtype-Specific Therapeutic Strategies, Qian Liu, Jing Zhang, Chenchen Guo, Mengcheng Wang, Chenfei Wang, Yilv Yan, Liangdong Sun, Di Wang, Lele Zhang, Huansha Yu, Likun Hou, Chunyan Wu, Yuming Zhu, Gening Jiang, Hongwen Zhu, Yanting Zhou, Shanhua Fang, Tengfei Zhang, Liang Hu, Junqiang Li, Yansheng Liu, Hui Zhang, Bing Zhang, Li Ding, Ana I Robles, Henry Rodriguez, Daming Gao, Hongbin Ji, Hu Zhou, Peng Zhang

Faculty, Staff and Students Publications

We performed comprehensive proteogenomic characterization of small cell lung cancer (SCLC) using paired tumors and adjacent lung tissues from 112 treatment-naive patients who underwent surgical resection. Integrated multi-omics analysis illustrated cancer biology downstream of genetic aberrations and highlighted oncogenic roles of FAT1 mutation, RB1 deletion, and chromosome 5q loss. Two prognostic biomarkers, HMGB3 and CASP10, were identified. Overexpression of HMGB3 promoted SCLC cell migration via transcriptional regulation of cell junction-related genes. Immune landscape characterization revealed an association between ZFHX3 mutation and high immune infiltration and underscored a potential immunosuppressive role of elevated DNA damage response activity via inhibition of the …

Mir126-Targeted-Nanoparticles Combined With Pi3k/Akt Inhibitor As A New Strategy To Overcome Melanoma Resistance, Maria Beatrice Arasi, Gabriele De Luca, Laura Chronopoulou, Francesca Pedini, Eleonora Petrucci, Michela Flego, Annarita Stringaro, Marisa Colone, Luca Pasquini, Massimo Spada, Valentina Lulli, Maria Chiara Perrotta, George Adrian Calin, Cleofe Palocci, Mauro Biffoni, Federica Felicetti, Nadia Felli

Faculty, Staff and Student Publications

Metastatic melanoma poses significant challenges as a highly lethal disease. Despite the success of molecular targeting using BRAFV600E inhibitors (BRAFis) and immunotherapy, the emergence of early recurrence remains an issue and there is the need for novel therapeutic approaches. This study aimed at creating a targeted delivery system for the oncosuppressor microRNA 126 (miR126) and testing its effectiveness in combination with a phosphatidylinositol 3-kinase (PI3K)/ protein kinase B (AKT) inhibitor for treating metastatic melanoma resistant to BRAFis. To achieve this, we synthesized chitosan nanoparticles containing a chemically modified miR126 sequence. These nanoparticles were further functionalized with an antibody specific to …

Clic1-Mediated Autophagy Confers Resistance To Ddp In Gastric Cancer, Zhen-Liang Nong, Kun Zhao, Ye Wang, Zhu Yu, Cong-Jun Wang, Jun-Qiang Chen

Faculty, Staff and Student Publications

Gastric cancer has been a constant concern to researchers as one of the most common malignant tumors worldwide. The treatment options for gastric cancer include surgery, chemotherapy and traditional Chinese medicine. Chemotherapy is an effective treatment for patients with advanced gastric cancer. Cisplatin (DDP) has been approved as a critical chemotherapy drug to treat various kinds of solid tumors. Although DDP is an effective chemotherapeutic agent, many patients develop drug resistance during treatment, which has become a severe problem in clinical chemotherapy. This study aims to investigate the mechanism of DDP resistance in gastric cancer. The results show that intracellular …

Exploratory Pilot Study To Characterize The Immune Landscapes Of Malignant Pleural Effusions And Their Corresponding Primary Tumors From Patients With Breast Carcinoma And Lung Adenocarcinoma, Caddie Laberiano-Fernandez, Qiong Gan, Sophia Mei Wang, Auriole Tamegnon, Ignacio Wistuba, Esther Yoon, Sinchita Roy-Chowdhuri, Edwin Roger Parra

Faculty, Staff and Student Publications

Introduction: Malignant pleural effusion (MPE) is a frequent complication of advanced malignancies. In this pilot study, we characterized the immune landscapes of MPEs, compared them to their primary tumor (PT) samples from breast carcinoma (BC) and lung adenocarcinoma (LADC), and tested the utility of multiplexed image technology in cytological samples.

Materials and methods: We evaluated the immune contexture of 6 BC and 5 LADC MPEs and their PTs using 3 multiplex immunofluorescence panels. We explored the associations between sample characteristics and pleural effusion-free survival.

Results: No MPE samples had positive programmed death-ligand 1 expression in malignant cells, although 3 of …

Circulating Tumor Dna (Ctdna) As A Biomarker Of Response To Therapy In Advanced Hepatocellular Carcinoma Treated With Nivolumab, Yehia I Mohamed, Sunyoung S Lee, Tarik Demir, Shadi Chamseddine, Zishuo Ian Hu, Lianchun Xiao, Khaled Elsayes, Jeffrey S Morris, Robert A Wolff, Rikita Hiatia, Aliya Qayyum, Asif Rashid, Dan G Duda, James C Yao, Michael Lapelusa, Eugene J Koay, Armeen Mahvash, Ahmed Al Azzam, Ecaterina E Dumbrava, Manal Hassan, Hesham M Amin, Ahmed Omar Kaseb

Faculty, Staff and Student Publications

Background: Circulating tumor DNA (ctDNA) is a promising non-invasive marker for detection, diagnosis, treatment selection, and prognosis of hepatocellular carcinoma (HCC).

Objective: This study aimed to examine the utility of ctDNA as a prognostic and predictive tool in HCC patients treated with nivolumab.

Methods: We analyzed pre-treatment ctDNA from 44 HCC patients using comprehensive genomic testing on a commercially available platform. We utilized log rank test and univariate Cox models to correlate overall survival (OS) and progression-free survival (PFS) with ctDNA expressions.

Results: Of 44 patients, 77.3% were men with median age of 67 years. All but 3 patients had …

Egfr, Hla-G, Cd70, C-Met, And Ny-Eso1 As Potential Biomarkers In High Grade Epithelial Ovarian Carcinoma, Duc Vo, Yan Liu, Anil K Sood, Katy Rezvani, Amir A Jazaeri, Jinsong Liu

Faculty, Staff and Student Publications

High grade epithelial ovarian carcinoma is an aggressive tumor. Treatment includes platinum therapy, however it recurs in most patients due to therapy resistance. In this project, we study the immunohistochemical (IHC) expression of five potential biomarkers/prognostic markers in high grade epithelial ovarian carcinoma: EGFR, HLA-G, CD70, c-MET, and NY-ESO1. A cohort of 274 patients is used. We compare the IHC expression with age, stage, ascites status, family history of cancer, disease free survival (DFS) and overall survival (OS). EGFR expression is significantly correlated with family history and worse OS. HLA-G is associated with worse OS. To confirm the results of …

Single-Cell Rna Sequencing Analysis Identifies Acute Changes In The Tumor Microenvironment Induced By Interferon Α Gene Therapy In A Murine Bladder Cancer Model, Alexis R Steinmetz, Morgan Pierce, Alberto Martini, Come Tholomier, Ganiraju Manyam, Yan Chen, Akshay Sood, Jonathan J Duplisea, Burles A Johnson, Bogdan A Czerniak, Byron H Lee, Chinnaswamy Jagannath, Seppo Yla-Herttuala, Nigel R Parker, David J Mcconkey, Colin P Dinney, Sharada Mokkapati

Faculty, Staff and Student Publications

Introduction: Nadofaragene firadenovec (Ad-IFNα/Syn3) is now approved for BCG-unresponsive bladder cancer (BLCA). IFNα is a pleiotropic cytokine that causes direct tumor cell killing via TRAIL-mediated apoptosis, angiogenesis inhibition, and activation of the innate and adaptive immune system. We established an immunocompetent murine BLCA model to study the effects of murine adenoviral IFNα (muAd-Ifnα) gene therapy on cancer cells and the tumor microenvironment using a novel murine equivalent of Nadofaragene firadenovec (muAd-Ifnα).

Methods: Tumors were induced by instilling MB49 cells into the bladders of mice; luciferase imaging confirmed tumor development. Mice were treated with adenovirus control (Ad-Ctrl; empty vector), or muAd-Ifnα …

Analysis Of B7-H4 Expression Across Salivary Gland Carcinomas Reveals Adenoid Cystic Carcinoma-Specific Prognostic Relevance, Juliana Mota Siqueira, Yoshitsugu Mitani, Camilla Oliveira Hoff, Flavia Bonini, Luana Guimaraes De Sousa, Mario L Marques-Piubelli, Anurag Purushothaman, Mutsumi Mitani, Hui Dai, Shiaw-Yih Lin, Michael T Spiotto, Ehab Y Hanna, Daniel J Mcgrail, Adel K El-Naggar, Renata Ferrarotto

Faculty, Staff and Student Publications

B7-H4 (VTCN1), a member of the B7 family, is overexpressed in several types of cancer. Here we investigated the pattern of expression of B7-H4 in salivary gland carcinomas (SGC) and assessed its potential as a prognostic marker and therapeutic target. Immunohistochemistry (IHC) analyses were performed in a cohort of 340 patient tumors, composed of 124 adenoid cystic carcinomas (ACC), 107 salivary duct carcinomas (SDC), 64 acinic cell carcinomas, 36 mucoepidermoid carcinomas (MEC), 9 secretory carcinomas (SC), as well as 20 normal salivary glands (controls). B7-H4 expression was scored and categorized into negative (< 5% expression of any intensity), low (5%-70% expression of any intensity or >70% with weak intensity), or high ( …

Multiplex Spatial Analysis Reveals Increased Cd137 Expression And M-Mdsc Neighboring Tumor Cells In Refractory Classical Hodgkin Lymphoma, José L Solórzano, Victoria Menéndez, Edwin Parra, Luisa Solis, Ruth Salazar, Mónica García-Cosío, Fina Climent, Sara Fernández, Eva Díaz, Alejandro Francisco-Cruz, Joseph Khoury, Mei Jiang, Auriole Tamegnon, Carlos Montalbán, Ignacio Melero, Ignacio Wistuba, Carlos De Andrea, Juan F García

Faculty, Staff and Student Publications

The Hodgkin and Reed - Sternberg (HRS) cells in classical Hodgkin Lymphoma (cHL) actively modify the immune tumor microenvironment (TME) attracting immunosuppressive cells and expressing inhibitory molecules. A high frequency of myeloid cells in the TME is correlated with an unfavorable prognosis, but more specific and rare cell populations lack precise markers. Myeloid-derived suppressor cells (MDSCs) have been identified in the peripheral blood of cHL patients, where they appear to be correlated with disease aggressiveness. TNFRSF9 (CD137) is a T cell co-stimulator expressed by monocytic and dendritic cells. Its expression has also been described in HRS cells, where it is …

From Mitochondria To Tumor Suppression: Acat1’S Crucial Role In Gastric Cancer, Wei He, Yanfang Li, Song-Bai Liu, Ying Chang, Shiyuan Han, Xingyu Han, Zixin Ma, Hesham M Amin, Yao-Hua Song, Jin Zhou

Faculty, Staff and Student Publications

Acetyl CoA acetyltransferase 1 (ACAT1), a mitochondrial enzyme, is mainly involved in the formation and decomposition of ketones, isoleucine, and fatty acids. Previous clinical studies showed that mutations in the ACAT1 gene lead to ketoacidosis, Notably the role of ACAT1 in human cancer' pathogenesis varies depending on cancer type, and its specific role in gastric cancer remains largely unknown. In the current study, we found that the expression of ACAT1 in primary late-stage gastric cancer tumor tissues was significantly lower than in early-stage tumors. This observation was further confirmed in high-grade gastric cancer cell line MKN45. The expression of CD44 …

Siglec15, Negatively Correlated With Pd-L1 In Hcc, Could Induce Cd8+ T Cell Apoptosis To Promote Immune Evasion, Zheng Chen, Mincheng Yu, Bo Zhang, Lei Jin, Qiang Yu, Shuang Liu, Binghai Zhou, Jiuliang Yan, Wentao Zhang, Xiaoqiang Li, Yongfeng Xu, Yongsheng Xiao, Jian Zhou, Jia Fan, Mien-Chie Hung, Qinghai Ye, Hui Li, Lei Guo

Faculty, Staff and Student Publications

Functional roles of SIGLEC15 in hepatocellular carcinoma (HCC) were not clear, which was recently found to be an immune inhibitor with similar structure of inhibitory B7 family members. SIGLEC15 expression in HCC was explored in public databases and further examined by PCR analysis. SIGLEC15 and PD-L1 expression patterns were examined in HCC samples through immunohistochemistry. SIGLEC15 expression was knocked-down or over-expressed in HCC cell lines, and CCK8 tests were used to examine cell proliferative ability in vitro. Influences of SIGLEC15 expression on tumor growth were examined in immune deficient and immunocompetent mice respectively. Co-culture system of HCC cell lines and …