Neoplasms Commons^™

An Integrative Genomics Approach For The Discovery Of Potential Clinically Actionable Diagnostic And Prognostic Biomarkers In Colorectal Cancer, Mark Fertel, Duaa Mohammad Alawad, Chindo Hicks

School of Graduate Studies Faculty Publications

Background: Despite remarkable progress in clinical management of patients and intensified screening, colorectal cancer remains the second most common cause of cancer-related death in the United States. The recent surge of next generation sequencing has enabled genomic analysis of colorectal cancer genomes. However, to date, there is little information about leveraging gene expression data and integrating it with somatic mutation information to discover potential biomarkers and therapeutic targets. Here, we integrated gene expression data with somatic mutation information to discover potential diagnostic and prognostic biomarkers and molecular drivers of colorectal cancer. Methods: We used publicly available gene expression and somatic …

Refine: A Database Of Linked Clinical Data And Genomic Biomarkers In Renal Cell Carcinoma Patients Receiving Immunotherapy-Based Treatment Regimens, Jeffrey Zhong, Albert Jang, Bashar Abuqayas, Arnab Basu, David Benjamin, Vineel Bhatlapenumarthi, Mehmet Asim Bilen, Dhvani Buch, Mark Chang, Erica Chin, Sourat Darabi, Nagendra Dhanikonda, Pooja Ghatalia, Claud Grigg, Abby Grier, Tanya Jindal, Joannah Jung, Deepak Kilari, Hamsa Kumar, Suzanna Lee, Brittany Neelands, Chinmayi Pandya, Jeff Pawalek, Jaimee Staggers, Ahmet Yildirim, Yousef Zakharia, Kevin Zarrabi, Michael Zimmerman, George Sledge, David Spetzler, Andrew Elliott, Rana Mckay, Pedro Barata

Department of Medical Oncology Faculty Papers

The REnal cancer consortium for Focused Investigation of Novel biomarkers and Expression (REFINE) consortium represents an important initiative in integrating clinical data with molecular sequencing in patients with advanced renal cell carcinoma (RCC) treated with immunotherapy-based approaches. By leveraging real-world evidence and genomic analysis, this consortium aims to explore putative predictive biomarkers with the potential to inform personalized treatment strategies. Findings from the REFINE database may further contribute to our understanding of disease courses of immunotherapy-based approaches for various molecular subtypes of RCC, associations of race and ethnicity with RCC treatment and outcomes with representation of patient populations underrepresented in …

Evaluating Algorithmic Bias On Biomarker Classification Of Breast Cancer Pathology Reports, Jordan Tschida, Mayanka Chandrashekar, Alina Peluso, Zachary Fox, Patrycja Krawczuk, Dakota Murdock, Xiao-Cheng Wu, John Gounley, Heidi A. Hanson

School of Public Health Faculty Publications

OBJECTIVES: This work evaluated algorithmic bias in biomarkers classification using electronic pathology reports from female breast cancer cases. Bias was assessed across 5 subgroups: cancer registry, race, Hispanic ethnicity, age at diagnosis, and socioeconomic status. MATERIALS AND METHODS: We utilized 594 875 electronic pathology reports from 178 121 tumors diagnosed in Kentucky, Louisiana, New Jersey, New Mexico, Seattle, and Utah to train 2 deep-learning algorithms to classify breast cancer patients using their biomarkers test results. We used balanced error rate (BER), demographic parity (DP), equalized odds (EOD), and equal opportunity (EOP) to assess bias. RESULTS: We found differences in predictive …

Single-Cell Rna Sequencing Identifies Molecular Biomarkers Predicting Late Progression To Cdk4/6 Inhibition In Patients With Hr+/Her2- Metastatic Breast Cancer, Linjie Luo, Peng Yang, Sofia Mastoraki, Xiayu Rao, Yan Wang, Nicole M Kettner, Akshara Singareeka Raghavendra, Debasish Tripathy, Senthil Damodaran, Kelly K Hunt, Jing Wang, Ziyi Li, Khandan Keyomarsi

Faculty, Staff and Student Publications

Background: Cyclin-dependent kinase 4/6 inhibitors (CDK4/6is) in combination with endocrine therapy are the standard treatment for patients with hormone receptor-positive, HER2-negative metastatic breast cancer (mBC). Despite the efficacy of CDK4/6is, intrinsic resistance occurs in approximately one-third of patients, highlighting the need for reliable predictive biomarkers.

Methods: Single-cell RNA sequencing analyzed metastatic tumors from HR+/HER2- mBC patients pre-CDK4/6i treatment at baseline (BL) and/or at disease progression. BL samples were from CDK4/6i responders (median progression-free survival [mPFS] = 25.5 months), while progressors were categorized as early-progressors (EP, mPFS = 3 months) and late-progressors (LP, mPFS = 11 months). Metastatic sites included liver, …

Tissue And Imaging Biomarkers Of Response To Neoadjuvant Nivolumab Or Nivolumab Plus Ipilimumab In Patients With Resectable Hepatocellular Carcinoma, Michael Lapelusa, Shadi Chamseddine, Hop Sanderson Tran Cao, Lianchun Xiao, Elshad Hasanov, Priya Bhosale, Hesham M Amin, Yehia I Mohamed, Betul Gok Yavuz, Yara Sakr, Li Xu, Ian Hu, Sunyoung S Lee, Divya Sakamuri, Sonali Jindal, Van Nguyen, Michael A Curran, Ryan Sun, Asif Rashid, Dan Gabriel Duda, Padmanee Sharma, Aliya Qayyum, Ahmed Omar Kaseb

Faculty, Staff and Student Publications

Introduction: Perioperative immunotherapy has shown promise in some patients with early-stage hepatocellular carcinoma (HCC). This study examined tissue and imaging biomarkers associated with pathologic response in a phase II clinical trial in patients with resectable HCC.

Methods: Analysis included 18 patients with biopsy-proven resectable HCC treated with neoadjuvant nivolumab plus ipilimumab or nivolumab alone in a phase II clinical trial at MD Anderson Cancer Center (NCT03222076). Liver MRE (to measure tissue fibrosis) and biopsies (to evaluate immune activation markers) were obtained serially pretreatment and after completing neoadjuvant immunotherapy. A major pathologic response (MPR) was defined as tumor necrosis …

Transplant-Associated Tma: The Conundrum Of Diagnosis And Treatment, Ang Li, Sarah E Sartain

Faculty, Staff and Students Publications

Transplant-associated thrombotic microangiopathy (TA-TMA) after hematopoietic cell transplantation is characterized by microangiopathic hemolytic anemia (MAHA) with persistent schistocytosis, elevated markers of hemolysis, thrombocytopenia, and microvascular thrombosis leading to ischemic injuries in the kidneys and other organs. The initial evaluation of the disease requires confirmation of non-immune MAHA and careful examination of known secondary causes of TMA. Due to increased likelihood of long-term renal failure and overall mortality, a rapid diagnosis and treatment of the underlying trigger is needed. However, the diagnostic criteria proposed to define TA-TMA remain insufficient. sC5b9, the soluble form of the membrane attack complex of the terminal …

Noninvasive Multi-Cancer Detection Using Blood-Based Cell-Free Micrornas, Jason Zhang, Hallgeir Rui, Hai Hu

Department of Pharmacology, Physiology, and Cancer Biology Faculty Papers

Patients diagnosed with early-stage cancers have a substantially higher chance of survival than those with late-stage diseases. However, the option for early cancer screening is limited, with most cancer types lacking an effective screening tool. Here we report a miRNA-based blood test for multi-cancer early detection based on examination of serum microRNA microarray data from cancer patients and controls. First, a large multi-cancer training set that included 1,408 patients across 7 cancer types and 1,408 age- and gender-matched non-cancer controls was used to develop a 4-microRNA diagnostic model using 10-fold cross-validation. In three independent validation sets comprising a total of …

Keratin 17 Is A Prognostic And Predictive Biomarker In Pancreatic Ductal Adenocarcinoma, Lyanne Delgado-Coka, Lucia Roa-Peña, Sruthi Babu, Michael Horowitz, Emanuel Petricoin, Lynn Matrisian, Edik Blais, Natalia Marchenko, Felicia Allard, Ali Akalin, Wei Jiang, Md, Phd, Brent Larson, Andrew Hendifar, Vincent Picozzi, Minsig Choi, Kenneth Shroyer, Luisa Escobar-Hoyos

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

OBJECTIVES: To determine the role of keratin 17 (K17) as a predictive biomarker for response to chemotherapy by defining thresholds of K17 expression based on immunohistochemical tests that could be used to optimize therapeutic intervention for patients with pancreatic ductal adenocarcinoma (PDAC).

METHODS: We profiled K17 expression, a hallmark of the basal molecular subtype of PDAC, by immunohistochemistry in 2 cohorts of formalin-fixed, paraffin-embedded PDACs (n = 305). We determined a K17 threshold of expression to optimize prognostic stratification according to the lowest Akaike information criterion and explored the potential relationship between K17 and chemoresistance by multivariate predictive analyses.

RESULTS: …

An Essential Gene Signature Of Breast Cancer Metastasis Reveals Targetable Pathways, Yiqun Zhang, Fengju Chen, Marija Balic, Chad J Creighton

Faculty, Staff and Students Publications

BACKGROUND: The differential gene expression profile of metastatic versus primary breast tumors represents an avenue for discovering new or underappreciated pathways underscoring processes of metastasis. However, as tumor biopsy samples are a mixture of cancer and non-cancer cells, most differentially expressed genes in metastases would represent confounders involving sample biopsy site rather than cancer cell biology.

METHODS: By paired analysis, we defined a top set of differentially expressed genes in breast cancer metastasis versus primary tumors using an RNA-sequencing dataset of 152 patients from The Breast International Group Aiming to Understand the Molecular Aberrations dataset (BIG-AURORA). To filter the genes …

Common Variation In A Long Non-Coding Rna Gene Modulates Variation Of Circulating Tgf-Β2 Levels In Metastatic Colorectal Cancer Patients (Alliance), Julia Quintanilha, Alexander Sibley, Yingmiao Liu, Donna Niedzwiecki, Susan Halabi, Layne Rogers, Bert O'Neil, Hedy Kindler, William Kelly, Alan Venook, Howard Mcleod, Mark Ratain, Andrew Nixon, Federico Innocenti, Kouros Owzar

Department of Medical Oncology Faculty Papers

BACKGROUND: Herein, we report results from a genome-wide study conducted to identify protein quantitative trait loci (pQTL) for circulating angiogenic and inflammatory protein markers in patients with metastatic colorectal cancer (mCRC). The study was conducted using genotype, protein marker, and baseline clinical and demographic data from CALGB/SWOG 80405 (Alliance), a randomized phase III study designed to assess outcomes of adding VEGF or EGFR inhibitors to systemic chemotherapy in mCRC patients. Germline DNA derived from blood was genotyped on whole-genome array platforms. The abundance of protein markers was quantified using a multiplex enzyme-linked immunosorbent assay from plasma derived from peripheral venous …

Comprehensive Peripheral Blood Immunoprofiling Reveals Five Immunotypes With Immunotherapy Response Characteristics In Patients With Cancer, Daniiar Dyikanov, Aleksandr Zaitsev, Tatiana Vasileva, Iris Wang, Arseniy Sokolov, Evgenii Bolshakov, Alena Frank, Polina Turova, Olga Golubeva, Anna Gantseva, Anna Kamysheva, Polina Shpudeiko, Ilya Krauz, Mary Abdou, Madison Chasse, Tori Conroy, Nicholas Merriam, Julia Alesse, Noel English, Boris Shpak, Anna Shchetsova, Evgenii Tikhonov, Ivan Filatov, Anastasia Radko, Anastasiia Bolshakova, Anastasia Kachalova, Nika Lugovykh, Andrey Bulahov, Anastasiia Kilina, Syimyk Asanbekov, Irina Zheleznyak, Pavel Skoptsov, Evgenia Alekseeva, Jennifer Johnson, Joseph Curry, Alban Linnenbach, Andrew South, Enjun Yang, Kirill Morozov, Anastasiya Terenteva, Lira Nigmatullina, Dmitry Fastovetz, Anatoly Bobe, Linda Balabanian, Krystle Nomie, Sheila Yong, Christopher Davitt, Alexander Ryabykh, Olga Kudryashova, Cagdas Tazearslan, Alexander Bagaev, Nathan Fowler, Adam Luginbuhl, Ravshan Ataullakhanov, Michael Goldberg

Department of Otolaryngology - Head and Neck Surgery Faculty Papers

The lack of comprehensive diagnostics and consensus analytical models for evaluating the status of a patient's immune system has hindered a wider adoption of immunoprofiling for treatment monitoring and response prediction in cancer patients. To address this unmet need, we developed an immunoprofiling platform that uses multiparameter flow cytometry to characterize immune cell heterogeneity in the peripheral blood of healthy donors and patients with advanced cancers. Using unsupervised clustering, we identified five immunotypes with unique distributions of different cell types and gene expression profiles. An independent analysis of 17,800 open-source transcriptomes with the same approach corroborated these findings. Continuous immunotype-based …

Early Screening Of Colorectal Cancer Using Feature Engineering With Artificial Intelligence-Enhanced Analysis Of Nanoscale Chromatin Modifications, Andrew Chang, Sravya Prabhala, Ali Daneshkhah, Jianan Lin, Hariharan Subramanian, Hemant Kumar Roy, Vadim Backman

Faculty, Staff and Students Publications

Colonoscopy is accurate but inefficient for colorectal cancer (CRC) prevention due to the low (~ 7 to 8%) prevalence of target lesions, advanced adenomas. We leveraged rectal mucosa to identify patients who harbor CRC field carcinogenesis by evaluating chromatin 3D architecture. Supranucleosomal disordered chromatin chains (~ 5 to 20 nm, ~1 kbp) fold into chromatin packing domains (~ 100 to 200 nm, ~ 100 to 1000 kbp). In turn, the fractal-like conformation of DNA within chromatin domains and the folding of the genome into packing domains has been shown to influence multiple facets of gene transcription, including the transcriptional plasticity …

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

Department of Medical Oncology Faculty Papers

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 …

Advances In The Clinical Application Of High-Throughput Proteomics, Miao Cui, Fei Deng, Mary L Disis, Chao Cheng, Lanjing Zhang

Faculty, Staff and Students Publications

High-throughput proteomics has become an exciting field and a potential frontier of modern medicine since the early 2000s. While significant progress has been made in the technical aspects of the field, translating proteomics to clinical applications has been challenging. This review summarizes recent advances in clinical applications of high-throughput proteomics and discusses the associated challenges, advantages, and future directions. We focus on research progress and clinical applications of high-throughput proteomics in breast cancer, bladder cancer, laryngeal squamous cell carcinoma, gastric cancer, colorectal cancer, and coronavirus disease 2019. The future application of high-throughput proteomics will face challenges such as varying protein …

Prospective Clinical And Biomarker Validation Of The American Society For Transplantation And Cellular Therapy Consensus Definition For Transplantation-Associated Thrombotic Microangiopathy, Shengling Ma, Saleh Bhar, Danielle Guffey, Rock Bum Kim, Mahrukh Jamil, Christopher I Amos, Stephanie J Lee, Sangeeta R Hingorani, Sarah E Sartain, Ang Li

Faculty, Staff and Students Publications

Transplantation-associated thrombotic microangiography (TA-TMA) is a disorder that causes severe complications after allogeneic hematopoietic cell transplantation (allo-HCT). Diagnosing TA-TMA is challenging because of the lack of standardized criteria. In this study, we aimed to evaluate the new TA-TMA consensus definition from the American Society for Transplantation and Cellular Therapy (ASTCT) panel as part of an ongoing prospective pediatric cohort study, and also to compare the impact and outcomes of using the current definition of clinical TMA (cTMA) versus the new consensus definition. We included patients age 0 to 18 years who underwent their first allo-HCT between May 2021 and January …

A Distinct Pattern Of Growth And Rac1 Signaling In Melanoma Brain Metastasis Cells, Ioana Stejerean-Todoran, Phyllis A Gimotty, Andrea Watters, Patricia Brafford, Clemens Krepler, Tetiana Godok, Haiyin Li, Zuriñe Bonilla Del Rio, Anke Zieseniss, Dörthe M Katschinski, Sinem M Sertel, Silvio O Rizzoli, Bradley Garman, Katherine L Nathanson, Xiaowei Xu, Qing Chen, Jack H Oswald, Michal Lotem, Gordon B Mills, Michael A Davies, Michael P Schön, Ivan Bogeski, Meenhard Herlyn, Adina Vultur

Faculty, Staff and Student Publications

Background: Melanoma, the deadliest of skin cancers, has a high propensity to form brain metastases that are associated with a markedly worsened prognosis. In spite of recent therapeutic advances, melanoma brain lesions remain a clinical challenge, biomarkers predicting brain dissemination are not clear and differences with other metastatic sites are poorly understood.

Methods: We examined a genetically diverse panel of human-derived melanoma brain metastasis (MBM) and extracranial cell lines using targeted sequencing, a Reverse Phase Protein Array, protein expression analyses, and functional studies in vitro and in vivo.

Results: Brain-specific genetic alterations were not detected; however, MBM cells in vitro …

Histopathologic And Proteogenomic Heterogeneity Reveals Features Of Clear Cell Renal Cell Carcinoma Aggressiveness, Yize Li, Tung-Shing M Lih, Saravana M Dhanasekaran, Rahul Mannan, Lijun Chen, Marcin Cieslik, Yige Wu, Rita Jiu-Hsien Lu, David J Clark, Iga Kołodziejczak, Runyu Hong, Siqi Chen, Yanyan Zhao, Seema Chugh, Wagma Caravan, Nataly Naser Al Deen, Noshad Hosseini, Chelsea J Newton, Karsten Krug, Yuanwei Xu, Kyung-Cho Cho, Yingwei Hu, Yuping Zhang, Chandan Kumar-Sinha, Weiping Ma, Anna Calinawan, Matthew A Wyczalkowski, Michael C Wendl, Yuefan Wang, Shenghao Guo, Cissy Zhang, Anne Le, Aniket Dagar, Alex Hopkins, Hanbyul Cho, Felipe Da Veiga Leprevost, Xiaojun Jing, Guo Ci Teo, Wenke Liu, Melissa A Reimers, Russell Pachynski, Alexander J Lazar, Arul M Chinnaiyan, Brian A Van Tine, Bing Zhang, Karin D Rodland, Gad Getz, D R Mani, Pei Wang, Feng Chen, Galen Hostetter, Mathangi Thiagarajan, W Marston Linehan, David Fenyö, Scott D Jewell, Gilbert S Omenn, Rohit Mehra, Maciej Wiznerowicz, Ana I Robles, Mehdi Mesri, Tara Hiltke, Eunkyung An, Henry Rodriguez, Daniel W Chan, Christopher J Ricketts, Alexey I Nesvizhskii, Hui Zhang, Li Ding, Clinical Proteomic Tumor Analysis Consortium

Faculty, Staff and Students Publications

Clear cell renal cell carcinomas (ccRCCs) represent ∼75% of RCC cases and account for most RCC-associated deaths. Inter- and intratumoral heterogeneity (ITH) results in varying prognosis and treatment outcomes. To obtain the most comprehensive profile of ccRCC, we perform integrative histopathologic, proteogenomic, and metabolomic analyses on 305 ccRCC tumor segments and 166 paired adjacent normal tissues from 213 cases. Combining histologic and molecular profiles reveals ITH in 90% of ccRCCs, with 50% demonstrating immune signature heterogeneity. High tumor grade, along with BAP1 mutation, genome instability, increased hypermethylation, and a specific protein glycosylation signature define a high-risk disease subset, where UCHL1 …

Ultrahigh Resolution Lipid Mass Spectrometry Imaging Of High-Grade Serous Ovarian Cancer Mouse Models, Xin Ma, Andro Botros, Sylvia R Yun, Eun Young Park, Olga Kim, Soojin Park, Thu-Huyen Pham, Ruihong Chen, Murugesan Palaniappan, Martin M Matzuk, Jaeyeon Kim, Facundo M Fernández

Faculty, Staff and Students Publications

No effective screening tools for ovarian cancer (OC) exist, making it one of the deadliest cancers among women. Considering that little is known about the detailed progression and metastasis mechanism of OC at a molecular level, it is crucial to gain more insights into how metabolic and signaling alterations accompany its development. Herein, we present a comprehensive study using ultra-high-resolution Fourier transform ion cyclotron resonance matrix-assisted laser desorption/ionization (MALDI) mass spectrometry imaging (MSI) to investigate the spatial distribution and alterations of lipids in ovarian tissues collected from double knockout (n = 4) and triple mutant mouse models (n …

An Imaging Mass Spectrometry Investigation Into The N-Linked Glycosylation Landscape Of Pancreatic Ductal Adenocarcinoma And The Development Of Associated Tools For Enhanced Glycan Separation And Characterization, Colin Mcdowell

MUSC Theses and Dissertations

The severity of pancreatic ductal adenocarcinoma (PDAC) is largely attributed to a failure to detect the disease before metastatic spread has occurred. CA19-9, a carbohydrate biomarker, is used clinically to surveille disease progression, but due to specificity challenges is not suitable for early discovery. As CA19-9 and other prospective markers are glycan epitopes, there is great clinical interest in understanding the glycobiology of pancreatic cancer. Unfortunately, few studies have been able to link glycosylation changes directly to pancreatic tumors and instead have focused on peripheral glycan alterations in the serum of PDAC patients. To address this gap in our understanding, …

Systematically Higher Ki67 Scores On Core Biopsy Samples Compared To Corresponding Resection Specimen In Breast Cancer: A Multi-Operator And Multi-Institutional Study, Balazs Acs, Samuel C Y Leung, Kelley M Kidwell, Indu Arun, Renaldas Augulis, Sunil S Badve, Yalai Bai, Anita L Bane, John M S Bartlett, Jane Bayani, Gilbert Bigras, Annika Blank, Henk Buikema, Martin C Chang, Robin L Dietz, Andrew Dodson, Susan Fineberg, Cornelia M Focke, Dongxia Gao, Allen M Gown, Carolina Gutierrez, Johan Hartman, Zuzana Kos, Anne-Vibeke Lænkholm, Arvydas Laurinavicius, Richard M Levenson, Rustin Mahboubi-Ardakani, Mauro G Mastropasqua, Sharon Nofech-Mozes, C Kent Osborne, Frédérique M Penault-Llorca, Tammy Piper, Mary Anne Quintayo, Tilman T Rau, Stefan Reinhard, Stephanie Robertson, Roberto Salgado, Tomoharu Sugie, Bert Van Der Vegt, Giuseppe Viale, Lila A Zabaglo, Daniel F Hayes, Mitch Dowsett, Torsten O Nielsen, David L Rimm, International Ki67 In Breast Cancer Working Group Of The Breast International Group And North American Breast Cancer Group (Big-Nabcg)

Faculty, Staff and Students Publications

Ki67 has potential clinical importance in breast cancer but has yet to see broad acceptance due to inter-laboratory variability. Here we tested an open source and calibrated automated digital image analysis (DIA) platform to: (i) investigate the comparability of Ki67 measurement across corresponding core biopsy and resection specimen cases, and (ii) assess section to section differences in Ki67 scoring. Two sets of 60 previously stained slides containing 30 core-cut biopsy and 30 corresponding resection specimens from 30 estrogen receptor-positive breast cancer patients were sent to 17 participating labs for automated assessment of average Ki67 expression. The blocks were centrally cut …

Machine Learning Analyses Of Highly-Multiplexed Immunofluorescence Identifies Distinct Tumor And Stromal Cell Populations In Primary Pancreatic Tumors, Krysten Vance, Alphan Alitinok, Seth Winfree, Heather Jensen Smith, Benjamin Swanson Md, Phd, Paul M. Grandgenett, Kelsey Klute, Daniel J Crichton, Michael A. Hollingsworth

Journal Articles: Eppley Institute

BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is a formidable challenge for patients and clinicians.

OBJECTIVE: To analyze the distribution of 31 different markers in tumor and stromal portions of the tumor microenvironment (TME) and identify immune cell populations to better understand how neoplastic, non-malignant structural, and immune cells, diversify the TME and influence PDAC progression.

METHODS: Whole slide imaging (WSI) and cyclic multiplexed-immunofluorescence (MxIF) was used to collect 31 different markers over the course of nine distinctive imaging series of human PDAC samples. Image registration and machine learning algorithms were developed to largely automate an imaging analysis pipeline identifying distinct cell …

Biomarkers Of Response And Resistance To Palbociclib Plus Letrozole In Patients With Er+/Her2- Breast Cancer, Mitch Dowsett, Lucy Kilburn, Mothaffar F Rimawi, C Kent Osborne, Katherine Pogue-Geile, Yuan Liu, Samuel A Jacobs, Melanie Finnigan, Shannon Puhalla, Andrew Dodson, Vera Martins, Maggie Cheang, Sophie Perry, Chris Holcombe, Nick Turner, Claire Swift, Judith M Bliss, Stephen Johnston

Faculty, Staff and Students Publications

PURPOSE: To determine (i) the relationship between candidate biomarkers of the antiproliferative (Ki67) response to letrozole and palbociclib alone and combined in ER

EXPERIMENTAL DESIGN: 307 postmenopausal women with ER+/HER2− primary breast cancer were randomly assigned to neoadjuvant treatment with letrozole for 14 weeks; letrozole for 2 weeks, then letrozole+palbociclib to 14 weeks; palbociclib for 2 weeks, then letrozole+palbociclib to 14 weeks; or letrozole+palbociclib for 14 weeks. Biopsies were taken at baseline, 2 and 14 weeks and surgery at varying times after stopping palbociclib. Immunohistochemical analyses were conducted for Ki67, c-PARP, ER, PgR, RB1, CCNE1, and CCND1.

RESULTS: Higher baselines …

Differentiating The Mechanistic Role And Chemotherapeutic Potential Of Src And Podoplanin In Oncogenic Transformation, Edward P. Retzbach

Graduate School of Biomedical Sciences Theses and Dissertations

There were an estimated 20 million new cancer cases worldwide in 2020, resulting in nearly 1000 deaths per hour [1]. Oral cancer exemplifies the difficulties of treating cancer patients. The first line for oral cancer treatment is surgery and radiation that can lead to patient disfigurement and decreased quality of life in cancer survivors [2-4]. Though there have been many developments in chemotherapy in the last 30 years, the 50% mortality rate associated with oral cancer has not changed [4, 5]. Longitudinal studies that track survival rates in oral cancer patients demonstrate a 3-fold reduction in patient deaths when patients …

Ckb Inhibits Epithelial-Mesenchymal Transition And Prostate Cancer Progression By Sequestering And Inhibiting Akt Activation, Zheng Wang, Mohit Hulsurkar, Lijuan Zhuo, Jinbang Xu, Han Yang, Samira Naderinezhad, Lin Wang, Guoliang Zhang, Nanping Ai, Linna Li, Jeffrey T Chang, Songlin Zhang, Ladan Fazli, Chad J Creighton, Fang Bai, Michael M Ittmann, Martin E Gleave, Wenliang Li

Faculty, Staff and Students Publications

Epithelial-mesenchymal transition (EMT) contributes to tumor invasion, metastasis and drug resistance. AKT activation is key in a number of cellular processes. While many positive regulators for either EMT or AKT activation have been reported, few negative regulators are established. Through kinase cDNA screen, we identified brain-type creatine kinase (CKB or BCK) as a potent suppressor for both. As a ubiquitously expressed kinase in normal tissues, CKB is significantly downregulated in several solid cancer types. Lower CKB expression is significantly associated with worse prognosis. Phenotypically, CKB overexpression suppresses, while its silencing promotes, EMT and cell migration, xenograft tumor growth and metastasis …

Novel Biomarkers Can Be Used As Targets To Combat Cancer, Harini Krishnan

Graduate School of Biomedical Sciences Theses and Dissertations

Cancer kills almost 8 million people per year worldwide. Therefore, about 13 people die from cancer every minute. Clearly, current cancer treatments are not completely effective. Moreover, many chemotherapeutic reagents are not very specific for cancer cells.

These agents attack rapidly dividing cells, including a wide array of normal cells, in addition to cancer cells, in the body. This lack of specificity can cause collateral damage and significant side effects in patients. More targeted therapies are needed to successfully combat cancer. Specific cancer biomarkers need to identified and characterized in order to develop better targeted anti-cancer drugs.

Tumor cells can …

Molecular Characterization Of Glioblastoma Cancer Stem Cells, Jo Meagan Garner

Theses and Dissertations (ETD)

Malignant gliomas are locally aggressive, highly vascular tumors that have an overall survival time less than 14 months, and current therapies provide little improvement in the disease course and outcome. While glioblastoma multiforme (GBM) patients present uniform histological phenotypes, the molecular determinants of the disease vary considerably between individual cases resulting in complicated prognosis. The heterogeneity, aggressiveness and rapid tumor relapse of GBM is believed to be sustained by cancer stem-like cell populations that are able to initiate and maintain tumors. Although CSCs represent only a small fraction of cells within a tumor, their high tumor-initiating capacity and therapeutic resistance …

Analysis Of The Regulation And Function Of Cip2a To Identify Candidate Biomarkers For Prostate Cancer, Diana Savoly

Graduate School of Biomedical Sciences Theses and Dissertations

Protein Phosphatase 2A (PP2A) is a tumor suppressor involved in the regulation of several signaling pathways and the cell cycle. PP2A becomes inactivated by several inhibitors, including Cancerous Inhibitor of PP2A (CIP2A). CIP2A has been identified as an oncogene, which is over-expressed in cancers and inhibits PP2A through direct interaction. CIP2A is recognized as a biomarker for cancer; however, it is not cancer-specific. Therefore, we identified and examined the use of CIP2A-regulated proteins as potential biomarkers in prostate cancer to better diagnose prostate cancer in patients. Currently, Prostate Specific Antigen (PSA) is widely used to detect prostate cancer; however, it …

Scanning In Situ Spectroscopy Pplatform For Imaging Surgical Breast Tissue Specimens, Venkataramanan Krishnaswamy, Ashley M. Laughney, Wendy A. Wells, Keith D. Paulsen, Brian W. Pogue

Dartmouth Scholarship

A non-contact localized spectroscopic imaging platform has been developed and optimized to scan 1 x 1 cm² square regions of surgically resected breast tissue specimens with ~150-micron resolution. A color corrected, image-space telecentric scanning design maintained a consistent sampling geometry and uniform spot size across the entire imaging field. Theoretical modeling in ZEMAX allowed estimation of the spot size, which is equal at both the center and extreme positions of the field with ~5% variation across the designed waveband, indicating excellent color correction. The spot sizes at the center and an extreme field position were also measured experimentally using the …

Renal Thrombotic Microangiopathy In Mice With Combined Deletion Of Endocytic Recycling Regulators Ehd3 And Ehd4., Manju George, Mark A. Rainey, Mayumi Naramura, Kirk W. Foster, Melissa S. Holzapfel, Laura L. Willoughby, Guoguang Ying, Rasna M. Goswami, Channabasavaiah B. Gurumurthy, Vimla Band, Simon C. Satchell, Hamid Band

Journal Articles: Eppley Institute

Eps15 Homology Domain-containing 3 (EHD3), a member of the EHD protein family that regulates endocytic recycling, is the first protein reported to be specifically expressed in the glomerular endothelium in the kidney; therefore we generated Ehd3(-/-) mice and assessed renal development and pathology. Ehd3(-/-) animals showed no overt defects, and exhibited no proteinuria or glomerular pathology. However, as the expression of EHD4, a related family member, was elevated in the glomerular endothelium of Ehd3(-/-) mice and suggested functional compensation, we generated and analyzed Ehd3(-/-); Ehd4(-/-) mice. These mice were smaller, possessed smaller and paler kidneys, were proteinuric and died between …

Let-7 Expression Defines Two Differentiation Stages Of Cancer, Scott Shell, Sun-Mi Park, Amir Reza Radjabi, Robert Schickel, Emily Kistner, David Jewell

Dartmouth Scholarship

The early phases of carcinogenesis resemble embryonic development, often involving the reexpression of embryonic mesenchymal genes. The NCI60 panel of human tumor cell lines can genetically be subdivided into two superclusters (SCs) that correspond to CD95 Type I and II cells. SC1 cells are characterized by a mesenchymal and SC2 cells by an epithelial gene signature, suggesting that SC1 cells represent less differentiated, advanced stages of cancer. miRNAs are small 20- to 22-nucleotide-long noncoding RNAs that inhibit gene expression at the posttranscriptional level. By performing miRNA expression analysis on 10 Type I and 10 Type II cells, we have determined …