Medicine and Health Sciences Commons^™

Evaluating The Effect Of A Taxane-Based Anti-Cancer Drug On The Adult Taste Organ Using A Mouse Model, Archana Kumari, Lucre'ce Estropia

Rowan-Virtua Research Day

Chemosensory alteration is one of the major side effects of chemotherapy that can negatively impact the quality of life of cancer patients. Decreased appetite and food aversions can consequently lead to substantial reductions in food intake and thereby malnutrition and poor patient outcomes. The chemotherapeutic agent, taxane (docetaxel), is an effective choice of treatment for breast cancer, gastric cancer, or prostate cancer. Despite its major effects as an anti-cancer medication, patients under taxane treatments have reported taste alterations. Essentially, the drug disrupts normal microtubule growth by inhibiting microtubule depolymerization. By binding to ß-tubulin, a major component of mitotic spindles, docetaxel …

Mcl-1 Inhibition Modulates Erk-Mediated Resistance In Multiple Myeloma, Omar Al-Odat, Krishne Gowda, Shantu Amin, Tulin Budak-Alpdogan, Subash Jonnalagadda, Manoj Pandey

Rowan-Virtua Research Day

Novel multiple myeloma (MM) treatments have significantly improved over the previous several decades, primarily on account of targeting bone marrow microenvironment (BMM) pathways. However, drug resistance and patient relapse remain major clinical problems. The role of BMM in the upregulation of anti-apoptotic protein Mcl-1 is well documented. The Mcl-1 protein plays a critical role in the progression and acquired drug resistance in MM. The regulation of Mcl-1, a protein characterized by a short half-life, from transcription to degradation is crucial for understanding its role in cell survival. The GSK3β and Erk play important role in the stability of Mcl-1. Also, …

The Clinical Definition And Characterization Of Field Of Cancerization In Patients With Actinic Keratoses, Stuti Prajapati, Christina Kontzias, Mallory Zaino, Steven Feldman

Rowan-Virtua Research Day

Introduction: Chronic UV radiation affects the entire area of skin exposed, leading to visible actinic keratoses (AK) and subclinical changes in the surrounding skin. AKs are hyperkeratotic lesions, with a 0.025-16% risk of transforming into squamous cell carcinoma (SCC).1 Cellular atypia around AKs is the field of cancerization (FOC). Topical AK therapies can treat the FOC, while destructive treatments address visible lesions. FDA-approved products may be approved for field sizes up to 25 cm2.1,2

Objective: To characterize the FOC and assess the correlation between the FOC and number of AKs.

Methods: 100 patients with AKs were recruited. FOC was defined …

Perioperative Ketamine Use For Post Mastectomy Pain, Alessia Cooney, Jaylyn Thompson, Naomi Watkins-Granville

Rowan-Virtua Research Day

PMPS is defined as chronic neuropathic pain following breast cancer procedures in the ipsilateral arm, chest wall, axilla or shoulder.1-3 Approximately 20 to 50% of post mastectomy patients suffer from Post Mastectomy Pain Syndrome (PMPS).1 With more than 3.8 million breast cancer survivors, due to advances in treatment, there is increased importance in findings ways to better manage the quality of life of breast cancer survivors.1,4 Ketamine induces analgesic effects through its non-competitive antagonism of NDMA receptors.5 Low doses of ketamine infusion (20–30 mg x h−1) have been shown to produce analgesia in neuropathic pain states with benefits lasting up …

Echinomycin As A Promising Therapeutic Agent Against Kshv-Related Malignancies, Jungang Chen, Zhen Lin, Jiao Song, Karlie Plaisance-Bonstaff, Jennifer James, Shengyu Mu, Steven R. Post, Lu Dai, Zhiqiang Qin

School of Medicine Faculty Publications

Kaposi’s sarcoma-associated herpesvirus (KSHV) is the etiologic agent of several human cancers, including Kaposi’s sarcoma (KS) and primary effusion lymphoma (PEL), which preferentially arise in immunocompromised patients while lack of effective therapeutic options. Oncoproteins Myc and hypoxia-inducible factor-1α (HIF1α) have been found closely related to KSHV infection, replication and oncogenesis. However, the strategies of dual targeting these two oncoproteins have never been developed and tested for treatments of KSHV-related malignancies. In the current study, we report that treatment of echinomycin dramatically regresses cell growth both in vitro-cultured KSHV + tumor cells and in vivo KS or PEL xenograft mice models, …

Loss Of Lgr5 Through Therapy-Induced Downregulation Or Gene Ablation Is Associated With Resistance And Enhanced Met-Stat3 Signaling In Colorectal Cancer Cells, Tressie A Posey, Joan Jacob, Ashlyn Parkhurst, Shraddha Subramanian, Liezl E Francisco, Zhengdong Liang, Kendra S Carmon

Faculty, Staff and Student Publications

Leucine-rich repeat-containing, G protein-coupled receptor 5 (LGR5) is highly expressed in colorectal cancer and cancer stem cells (CSCs) that play important roles in tumor initiation, progression, and metastasis. Loss of LGR5 has been shown to enhance therapy resistance. However, the molecular mechanisms that mediate this resistance remain elusive. In this study, we demonstrate conversion of LGR5+ colorectal cancer cells to an LGR5- state in response to chemotherapy, LGR5- targeted antibody-drug conjugates (ADCs), or LGR5 gene ablation led to activation of STAT3. Further investigation revealed increased STAT3 activation occurred as a result of increased mesenchymal epithelial transition (MET) factor receptor activity. …

Dimeric P53 Mutant Elicits Unique Tumor-Suppressive Activities Through An Altered Metabolic Program, Jovanka Gencel-Augusto, Xiaoping Su, Yuan Qi, Elizabeth M Whitley, Vinod Pant, Shunbin Xiong, Vrutant Shah, Jerome Lin, Encarnacion Perez, Marta L Fiorotto, Iqbal Mahmud, Abhinav K Jain, Philip L Lorenzi, Nicholas E Navin, Ellen R Richie, Guillermina Lozano

Faculty, Staff and Student Publications

Cancer-related alterations of the p53 tetramerization domain (TD) abrogate wild-type (WT) p53 function. They result in a protein that preferentially forms monomers or dimers, which are also normal p53 states under basal cellular conditions. However, their physiologic relevance is not well understood. We have established in vivo models for monomeric and dimeric p53, which model Li-Fraumeni syndrome patients with germline p53 TD alterations. p53 monomers are inactive forms of the protein. Unexpectedly, p53 dimers conferred some tumor suppression that is not mediated by canonical WT p53 activities. p53 dimers upregulate the PPAR pathway. These activities are associated with lower prevalence …

Usp36 Promotes Tumorigenesis And Drug Sensitivity Of Glioblastoma By Deubiquitinating And Stabilizing Alkbh5, Guoqiang Chang, Gloria S Xie, Li Ma, Peng Li, Linlin Li, Hope T Richard

Faculty, Staff and Student Publications

Background: ALKBH5 is aberrantly activated and exerts critical roles in facilitating the development of glioblastoma. However, the underlying activation mechanism by which ALKBH5 protein is increased in glioblastoma is not completely understood. Our study aimed to elucidate the signaling pathways involved in mediating ALKBH5 protein stability.

Methods: The contribution of deubiquitinating enzymes (DUB) to the fluctuation of ALKBH5 protein expression was globally profiled with western blot analysis. Mass spectrometry and immunoprecipitation were performed to identify the USP36 and ALKBH5 interaction. The effects of USP36 on the stability of ALKBH5 were detected with in vivo and in vitro ubiquitination assays. Cell …

Igfbp2 Expressing Midlobular Hepatocytes Preferentially Contribute To Liver Homeostasis And Regeneration, Yu-Hsuan Lin, Yonglong Wei, Qiyu Zeng, Yunguan Wang, Chase A Pagani, Lin Li, Min Zhu, Zixi Wang, Meng-Hsiung Hsieh, Natasha Corbitt, Yu Zhang, Tripti Sharma, Tao Wang, Hao Zhu

Faculty, Staff and Student Publications

Although midlobular hepatocytes in zone 2 are a recently identified cellular source for liver homeostasis and regeneration, these cells have not been exclusively fate mapped. We generated an Igfbp2-CreER knockin strain that specifically labels midlobular hepatocytes. During homeostasis over 1 year, zone 2 hepatocytes increased in abundance from occupying 21%-41% of the lobular area. After either pericentral injury with carbon tetrachloride or periportal injury with 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC), IGFBP2+ cells replenished lost hepatocytes in zones 3 and 1, respectively. IGFBP2+ cells also preferentially contributed to regeneration after 70% partial hepatectomy, as well as liver growth during pregnancy. Because IGFBP2 labeling increased …

Prognosticators For Patients With Pancreatic Ductal Adenocarcinoma Who Received Neoadjuvant Folfirinox Or Gemcitabine/Nab-Paclitaxel Therapy And Pancreatectomy, Yi Tat Tong, Zongshan Lai, Matthew H G Katz, Laura R Prakash, Hua Wang, Deyali Chatterjee, Michael Kim, Ching-Wei D Tzeng, Jeffrey E Lee, Naruhiko Ikoma, Asif Rashid, Robert A Wolff, Dan Zhao, Eugene J Koay, Anirban Maitra, Huamin Wang

Faculty, Staff and Student Publications

Neoadjuvant FOLFIRINOX and gemcitabine/nab-paclitaxel (GemNP) therapies are increasingly used to treat patients with pancreatic ductal adenocarcinoma (PDAC). However, limited data are available on their clinicopathologic prognosticators. We examined the clinicopathologic factors and survival of 213 PDAC patients who received FOLFIRINOX with 71 patients who received GemNP. The FOLFIRINOX group was younger (p < 0.01) and had a higher rate of radiation (p = 0.049), higher rate of borderline resectable and locally advanced disease (p < 0.001), higher rate of Group 1 response (p = 0.045) and lower ypN stage (p = 0.03) than the GemNP group. Within FOLFIRINOX group, radiation was associated with decreased lymph node metastasis (p = 0.01) and lower ypN …

Prognostic Validation Of A New Classification System For Extent Of Resection In Glioblastoma: A Report Of The Rano Resect Group, Philipp Karschnia, Jacob S Young, Antonio Dono, Levin Häni, Tommaso Sciortino, Francesco Bruno, Stephanie T Juenger, Nico Teske, Ramin A Morshed, Alexander F Haddad, Yalan Zhang, Sophia Stoecklein, Michael Weller, Michael A Vogelbaum, Juergen Beck, Nitin Tandon, Shawn Hervey-Jumper, Annette M Molinaro, Roberta Rudà, Lorenzo Bello, Oliver Schnell, Yoshua Esquenazi, Maximilian I Ruge, Stefan J Grau, Mitchel S Berger, Susan M Chang, Martin Van Den Bent, Joerg-Christian Tonn

Faculty, Staff and Student Publications

BACKGROUND: Terminology to describe extent of resection in glioblastoma is inconsistent across clinical trials. A surgical classification system was previously proposed based upon residual contrast-enhancing (CE) tumor. We aimed to (1) explore the prognostic utility of the classification system and (2) define how much removed non-CE tumor translates into a survival benefit.

METHODS: The international RANO resect group retrospectively searched previously compiled databases from 7 neuro-oncological centers in the USA and Europe for patients with newly diagnosed glioblastoma per WHO 2021 classification. Clinical and volumetric information from pre- and postoperative MRI were collected.

RESULTS: We collected 1,008 patients with newly …

Patterns Of Oncogene Coexpression At Single-Cell Resolution Influence Survival In Lymphoma, Michal Marek Hoppe, Patrick Jaynes, Fan Shuangyi, Yanfen Peng, Shruti Sridhar, Phuong Mai Hoang, Clementine Xin Liu, Sanjay De Mel, Limei Poon, Esther Hian Li Chan, Joanne Lee, Choon Kiat Ong, Tiffany Tang, Soon Thye Lim, Chandramouli Nagarajan, Nicholas F Grigoropoulos, Soo-Yong Tan, Susan Swee-Shan Hue, Sheng-Tsung Chang, Shih-Sung Chuang, Shaoying Li, Joseph D Khoury, Hyungwon Choi, Carl Harris, Alessia Bottos, Laura J Gay, Hendrik F P Runge, Ilias Moutsopoulos, Irina Mohorianu, Daniel J Hodson, Pedro Farinha, Anja Mottok, David W Scott, Jason J Pitt, Jinmiao Chen, Gayatri Kumar, Kasthuri Kannan, Wee Joo Chng, Yen Lin Chee, Siok-Bian Ng, Claudio Tripodo, Anand D Jeyasekharan

Faculty, Staff and Student Publications

Cancers often overexpress multiple clinically relevant oncogenes, but it is not known if combinations of oncogenes in cellular subpopulations within a cancer influence clinical outcomes. Using quantitative multispectral imaging of the prognostically relevant oncogenes MYC, BCL2, and BCL6 in diffuse large B-cell lymphoma (DLBCL), we show that the percentage of cells with a unique combination MYC+BCL2+BCL6- (M+2+6-) consistently predicts survival across four independent cohorts (n = 449), an effect not observed with other combinations including M+2+6+. We show that the M+2+6- percentage can be mathematically derived from quantitative measurements of the individual oncogenes and correlates with survival in IHC (n …

Li-Fraumeni Syndrome-Associated Dimer-Forming Mutant P53 Promotes Transactivation-Independent Mitochondrial Cell Death, Joshua H Choe, Tatsuya Kawase, An Xu, Asja Guzman, Aleksandar Z Obradovic, Ana Maria Low-Calle, Bita Alaghebandan, Ananya Raghavan, Kaitlin Long, Paul M Hwang, Joshua D Schiffman, Yan Zhu, Ruiying Zhao, Dung-Fang Lee, Chen Katz, Carol Prives

Faculty, Staff and Student Publications

Cancer-relevant mutations in the oligomerization domain (OD) of the p53 tumor suppressor protein, unlike those in the DNA binding domain, have not been well elucidated. Here, we characterized the germline OD mutant p53(A347D), which occurs in cancer-prone Li-Fraumeni syndrome (LFS) patients. Unlike wild-type p53, mutant p53(A347D) cannot form tetramers and exists as a hyperstable dimeric protein. Further, p53(A347D) cannot bind or transactivate the majority of canonical p53 target genes. Isogenic cell lines harboring either p53(A347D) or no p53 yield comparable tumorigenic properties, yet p53(A347D) displays remarkable neomorphic activities. Cells bearing p53(A347D) possess a distinct transcriptional profile and undergo metabolic reprogramming. …

Osteoprogenitor-Gmp Crosstalk Underpins Solid Tumor-Induced Systemic Immunosuppression And Persists After Tumor Removal, Xiaoxin Hao, Yichao Shen, Nan Chen, Weijie Zhang, Elizabeth Valverde, Ling Wu, Hilda L Chan, Zhan Xu, Liqun Yu, Yang Gao, Igor Bado, Laura Natalee Michie, Charlotte Helena Rivas, Luis Becerra Dominguez, Sergio Aguirre, Bradley C Pingel, Yi-Hsuan Wu, Fengshuo Liu, Yunfeng Ding, David G Edwards, Jun Liu, Angela Alexander, Naoto T Ueno, Po-Ren Hsueh, Chih-Yen Tu, Liang-Chih Liu, Shu-Hsia Chen, Mien-Chie Hung, Bora Lim, Xiang H-F Zhang

Faculty, Staff and Students Publications

Remote tumors disrupt the bone marrow (BM) ecosystem (BME), eliciting overproduction of BM-derived immunosuppressive cells. However, the underlying mechanisms remain poorly understood. Herein, we characterized breast and lung cancer-induced BME shifts pre- and post-tumor removal. Remote tumors progressively lead to osteoprogenitors (OPs) expansion, hematopoietic stem cell dislocation and CD41− granulocyte-monocyte progenitor (GMP) aggregation. The tumor-entrained BME is characterized by co-localization between CD41− GMPs and OPs. OP ablation abolishes this effect and diminishes abnormal myeloid overproduction. Mechanistically, HTRA1 carried by tumor-derived small extracellular vesicles upregulates MMP-13 in OPs, which in turn induces the alterations in hematopoietic program. Importantly, these effects persist …

Using Cancer Proteomics Data To Identify Gene Candidates For Therapeutic Targeting, Diana Monsivais, Sydney E Parks, Darshan S Chandrashekar, Sooryanarayana Varambally, Chad J Creighton

Faculty, Staff and Students Publications

Gene-level associations obtained from mass-spectrometry-based cancer proteomics datasets represent a resource for identifying gene candidates for functional studies. When recently surveying proteomic correlates of tumor grade across multiple cancer types, we identified specific protein kinases having a functional impact on uterine endometrial cancer cells. This previously published study provides just one template for utilizing public molecular datasets to discover potential novel therapeutic targets and approaches for cancer patients. Proteomic profiling data combined with corresponding multi-omics data on human tumors and cell lines can be analyzed in various ways to prioritize genes of interest for interrogating biology. Across hundreds of cancer …

Functional Characterization Of Age-Dependent P16 Epimutation Reveals Biological Drivers And Therapeutic Targets For Colorectal Cancer, Li Yang, Xiaomin Chen, Christy Lee, Jiejun Shi, Emily B Lawrence, Lanjing Zhang, Yumei Li, Nan Gao, Sung Yun Jung, Chad J Creighton, Jingyi Jessica Li, Ya Cui, Sumimasa Arimura, Yunping Lei, Wei Li, Lanlan Shen

Faculty, Staff and Students Publications

BACKGROUND: Methylation of the p16 promoter resulting in epigenetic gene silencing-known as p16 epimutation-is frequently found in human colorectal cancer and is also common in normal-appearing colonic mucosa of aging individuals. Thus, to improve clinical care of colorectal cancer (CRC) patients, we explored the role of age-related p16 epimutation in intestinal tumorigenesis.

METHODS: We established a mouse model that replicates two common genetic and epigenetic events observed in human CRCs: Apc mutation and p16 epimutation. We conducted long-term survival and histological analysis of tumor development and progression. Colonic epithelial cells and tumors were collected from mice and analyzed by RNA …

Comparison Of The Inhibition Of An Oct3 Transporter Inhibitor, Nilotinib, On Doxorubicin’S Effects On Cardiac And Cancer Cell Lines, Zachary G. Tan, Juliet Melnik, Aakash Belsare, James Huang, Meagan Lyons, Kimberly Dowes, Gurpreet Kaur, Lindon H. Young, Robert J. Barsotti, Qian Chen

Research Day

Introduction

Doxorubicin (DOX)-induced cardiotoxicity remains a significant barrier limiting its clinical application due to a lack of effective resolution. Targeting how DOX enters cardiac and cancer cells is a promising new strategy. Research suggests that an OCT3 transporter significantly contributes to DOX entry into the heart tissue. By contrast, it expresses much lower on breast cancer cell lines. Moreover, Nilotinib (NIB) can suppress OCT3 transporter function by 80%. Therefore, exploring the impact of NIB on the DOX’s effects on cardiac and cancer cell lines by altering DOX intracellular accumulation is intriguing.

Objective

First, we would establish a dose-response curve of …

Prolonged Length Of Stay In Illeal Conduit Compared To Neobladder Diversion In Radical Cystectomy Patients For Bladder Cancer, Ryan J. Moriarty, Young Son, Brian Thomas, Ronald Clearie, Lance Earnshaw, Dayna Devincentz, Thomas Mueller

Research Day

Background:

Radical cystectomy and urinary diversion has become the standard treatment for invasive and complicated malignancies of the bladder, urethra, and ureters. [1] Robotic-assisted radical cystectomy (RARC), introduced in the last decade, has been associated with favorable perioperative outcomes when compared to open radical cystectomy. Yet little is known about how different urinary diversion types compare in regards to length of hospital stay, readmission rates, and perioperative course. This data analysis seeks to identify the statistically significant differences in postoperative course of ileal conduit versus neobladder among patients with staged bladder cancer.

Methods:

The American College of Surgeons National Surgical …

Microparticle-Delivered Cxcl9 Prolongs Braf Inhibitor Efficacy In Melanoma, Gabriele Romano, Francesca Paradiso, Peng Li, Pooja Shukla, Lindsay N Barger, Olivia El Naggar, John P Miller, Roger J Liang, Timothy L Helms, Alexander J Lazar, Jennifer A Wargo, Francesca Taraballi, James C Costello, Lawrence N Kwong

Faculty, Staff and Student Publications

Patients with BRAF-mutant melanoma show substantial responses to combined BRAF and MEK inhibition, but most relapse within 2 years. A major reservoir for drug resistance is minimal residual disease (MRD), comprised of drug-tolerant tumor cells laying in a dormant state. Towards exploiting potential therapeutic vulnerabilities of MRD, we established a genetically engineered mouse model of BrafV600E-driven melanoma MRD wherein genetic BrafV600E extinction leads to strong but incomplete tumor regression. Transcriptional time-course analysis after BrafV600E extinction revealed that after an initial surge of immune activation, tumors later became immunologically "cold" after MRD establishment. Computational analysis identified candidate T-cell recruiting chemokines as …

Impact Of Clonal Plasma Cells In Autografts On Outcomes In High-Risk Multiple Myeloma Patients, Oren Pasvolsky, Denái R Milton, Mikael Rauf, Sassine Ghanem, Adeel Masood, Ali H Mohamedi, Mark R Tanner, Qaiser Bashir, Samer Srour, Neeraj Saini, Paul Lin, Jeremy Ramdial, Yago Nieto, Guilin Tang, Hans C Lee, Krina K Patel, Partow Kebriaei, Sheeba K Thomas, Donna M Weber, Robert Z Orlowski, Katy Rezvani, Richard Champlin, Elizabeth J Shpall, Pei Lin, Muzaffar H Qazilbash

Faculty, Staff and Student Publications

Most patients with multiple myeloma (MM) undergoing autologous hematopoietic stem cell transplantation (autoHCT) eventually relapse, perhaps due to the presence of clonal plasma cells (CPC) in the autograft. We conducted a retrospective analysis to evaluate the impact of CPC in the autograft on the outcomes of high-risk chromosomal abnormalities (HRMM) patients undergoing autoHCT between 2008 and 2018. Patients were divided into CPC+ or CPC- in the autograft by next-generation flow cytometry (NGF). There were 75 CPC + autografts (18%) and 341 CPC- (82%). The CPC + group was less likely to achieve MRD-negative complete remission post-transplant (11% vs. 42%; p < 0.001). Median progression free survival (PFS) and overall survival (OS) were (12.8 vs. 32.1 months) and (36.4 vs. 81.2 months) in the CPC + and CPC- groups, respectively (both p < 0.001). Also in the subset of patients with MRD-negative ≥VGPR prior to autoHCT, those with CPC + autografts had inferior PFS (HR 4.21, p = 0.006) and OS (HR 7.04, p = 0.002) compared to CPC-. In multivariable analysis, the degree of CPC positivity in the autograft was independently predictive of worse PFS (HR 1.50, p = 0.001) and OS (HR 1.37, p = 0.001). In conclusion, both the presence and degree of CPC in the autograft were highly predictive of inferior PFS and OS.

Clinical Outcomes Of Immunotherapy Continued Beyond Radiographic Disease Progression In Older Adult Patients With Advanced Non-Small Cell Lung Cancer, Eric K Singhi, Frank Mott, Michelle Worst, Cheuk Hong Leung, J Jack Lee, Brett Carter, Carolyn J Presley, John V Heymach, Mehmet Altan

Faculty, Staff and Student Publications

Immunotherapy is an effective and generally well-tolerated treatment strategy for older adult patients (aged ≥70 years) with advanced non-small cell lung cancer (NSCLC). Unfortunately, most patients who receive immunotherapy eventually exhibit disease progression during treatment. The present study reports on a subset of older adult patients with advanced NSCLC who could effectively continue immunotherapy beyond radiographic disease progression due to perceived clinical benefit. Local consolidative radiotherapy may be used in select older adult patients to prolong the duration of immunotherapy they receive, with a particular consideration of their preexisting co-morbidities, performance status and tolerance of potential toxicities associated with combined …

Meditation-Type Exercise For The Management Of Chemotherapy Related Cognitive Impairment In Breast Cancer Patients, Christine Cain

Evidence-Based Practice Project Reports

Chemotherapy-related cognitive impairment (CRCI), or “chemobrain”, is one of the most troublesome side effects of chemotherapy (Dijkshoorn et al., 2020). Ongoing CRCI may negatively affect relationships, confidence, sleep, fatigue, anxiety, and the ability to return to work activities leading to a decreased quality of life (Johns et al., 2016; Gokal et al., 2018). The purpose of this evidence-based practice (EBP) project was to assess the efficiency of a meditation-type exercise intervention, chair yoga, on decreasing perceived cognitive impairment (PCI) in breast cancer patients. The PICOT question for this project was: In breast cancer patients with chemotherapy related cognitive impairment (P), …

Spatial Transcriptomics Depict Ligand-Receptor Cross-Talk Heterogeneity At The Tumor-Stroma Interface In Long-Term Ovarian Cancer Survivors, Sammy Ferri-Borgogno, Ying Zhu, Jianting Sheng, Jared K Burks, Javier A Gomez, Kwong Kwok Wong, Stephen T C Wong, Samuel C Mok

Faculty, Staff and Student Publications

Advanced high-grade serous ovarian cancer (HGSC) is an aggressive disease that accounts for 70% of all ovarian cancer deaths. Nevertheless, 15% of patients diagnosed with advanced HGSC survive more than 10 years. The elucidation of predictive markers of these long-term survivors (LTS) could help identify therapeutic targets for the disease, and thus improve patient survival rates. To investigate the stromal heterogeneity of the tumor microenvironment (TME) in ovarian cancer, we used spatial transcriptomics to generate spatially resolved transcript profiles in treatment-naïve advanced HGSC from LTS and short-term survivors (STS) and determined the association between cancer-associated fibroblasts (CAF) heterogeneity and survival …

Cancer Stem Cell Assay-Guided Chemotherapy Improves Survival Of Patients With Recurrent Glioblastoma In A Randomized Trial, Tulika Ranjan, Soma Sengupta, Michael J. Glantz, Richard M. Green, Alexander Yu, Dawit Aregawi, Rekha Chaudhary, Ricky Chen, Mario Zuccarello, Christine Lu-Emerson, Hugh D. Moulding, Neil Belman, Jon Glass, Aaron Mammoser, Mark Anderson, Jagan Valluri, Nicholas Marko, Jason Schroeder, Steven Jubelirer, Frances Chow, Pier Paolo Claudio, Anthony M. Alberico, Seth T. Lirette, Krista L. Denning, Candace M. Howard

Department of Neurosurgery Faculty Papers

Therapy-resistant cancer stem cells (CSCs) contribute to the poor clinical outcomes of patients with recurrent glioblastoma (rGBM) who fail standard of care (SOC) therapy. ChemoID is a clinically validated assay for identifying CSC-targeted cytotoxic therapies in solid tumors.

In a randomized clinical trial (NCT03632135), the ChemoID assay, a personalized approach for selecting the most effective treatment from FDA-approved chemotherapies, improves the survival of patients with rGBM (2016 WHO classification) over physician-chosen chemotherapy. In the ChemoID assay-guided group, median survival is 12.5 months (95% confidence interval [CI], 10.2-14.7) compared with 9 months (95% CI, 4.2-13.8) in the physician-choice group (p = …

A Geospatial Approach To Identify Patterns Of Antibiotic Susceptibility At A Neighborhood Level In Wisconsin, United States, Laurel Legenza, Kyle Mcnair, Song Gao, James P Lacy, Brooke J Olson, Thomas R Fritsche, Lucas T Schulz, Samantha Lamuro, Frances Spray-Larson, Tahmeena Siddiqui, Warren E Rose

Faculty, Staff and Student Publications

The global threat of antimicrobial resistance (AMR) varies regionally. This study explores whether geospatial analysis and data visualization methods detect both clinically and statistically significant variations in antibiotic susceptibility rates at a neighborhood level. This observational multicenter geospatial study collected 10 years of patient-level antibiotic susceptibility data and patient addresses from three regionally distinct Wisconsin health systems (UW Health, Fort HealthCare, Marshfield Clinic Health System [MCHS]). We included the initial Escherichia coli isolate per patient per year per sample source with a patient address in Wisconsin (N = 100,176). Isolates from U.S. Census Block Groups with less than 30 isolates …

Results Of Salvage Therapy With Mini-Hyper-Cvd And Inotuzumab Ozogamicin With Or Without Blinatumomab In Pre-B Acute Lymphoblastic Leukemia, Hagop Kantarjian, Fadi G Haddad, Nitin Jain, Koji Sasaki, Nicholas J Short, Sanam Loghavi, Rashmi Kanagal-Shamanna, Jeffrey Jorgensen, Issa Khouri, Partow Kebriaei, Yesid Alvarado, Tapan Kadia, Shilpa Paul, Guillermo Garcia-Manero, Bouthaina Dabaja, Musa Yilmaz, Jovitta Jacob, Rebecca Garris, Susan O'Brien, Farhad Ravandi, Elias Jabbour

Faculty, Staff and Student Publications

Background: Historically, adults with relapsed-refractory acute lymphoblastic leukemia (ALL) experienced poor outcomes with intensive chemotherapy. This mature analysis explores the benefit of the addition of sequential blinatumomab to low-intensity mini-Hyper-CVD chemotherapy with inotuzumab ozogamicin in this setting.

Methods: Mini-Hyper-CVD (cyclophosphamide and dexamethasone at 50% dose reduction, no anthracycline, methotrexate at 75% dose reduction, cytarabine at 83% dose reduction) was combined with inotuzumab during the first 4 courses. From Patient #68 and onwards, inotuzumab was given in reduced and fractionated doses, and blinatumomab was added sequentially for 4 courses. Maintenance therapy with prednisone, vincristine, 6-mercaptopurine and methotrexate was given for 12 …

Examining Ndufab1 Expression In Head And Neck Squamous Cell Carcinoma, Addison Stevens

Poster Presentations

Honors research poster.

Introduction: Head and neck squamous cell carcinoma (HNSCC) is approximately 4% of all cancers and 2% of all cancer associated mortality in the United States. In 2023, there will be an estimated 67,000 new cases of HNSCC, along with 15,400 deaths, in the United States. HNSCC locations include the oral cavity, oropharynx, nasopharynx, hypopharynx, and larynx. Major risk factors for HNSCC include tobacco use, alcohol use, and human papilloma virus (HPV). Epidermal growth factor receptor (EGFR) is currently the only approved molecular targeted therapy for HNSCC. Therefore, new therapeutics and biomarkers for HNSCC are warranted. Mitochondria are …

Application Of Informatics Tools To Facilitate The Practice Of Precision Medicine With Genomic Testing And Clinical Data, Michael Sayer

Pharmaceutical Sciences (PhD) Dissertations

The practice of precision medicine considers a variety of sources of information to optimize patient care. Factors such as patient demographics, clinical history, and lab test values have well understood effects on treatment outcomes and influence decision making. However, effective inclusion of biomolecular data such as protein expression and DNA sequencing data within the practice of precision medicine needs continued study. Informatics tools offer solutions to allow these complex data sources to be effectively embraced. Utilization of informatics tools to visualize data pertaining to the gene selection practices of pharmacogenomic (PGx) tests effectively communicated large amounts of information into concise …

Combination Therapy With Trastuzumab And Niraparib: Quantifying Early Proliferative Alterations In Her2+ Breast Cancer Models, Ameer Mansur, Patrick N. Song, Yun Lu, Andrew C. Burns, Luke Sligh, Eddy S. Yang, Anna G. Sorace

Markey Cancer Center Faculty Publications

HER2–targeted treatments have improved survival rates in HER2+ breast cancer patients, yet poor responsiveness remains a major clinical obstacle. Recently, HER2+ breast cancer cells, both resistant and responsive to HER2–targeted therapies, have demonstrated sensitivity to poly–(ADP– ribose) polymerase (PARP) inhibition, independent of DNA repair deficiencies. This study seeks to describe biological factors that precede cell viability changes in response to the combination of trastuzumab and PARP inhibition. Treatment response was evaluated in HER2+ and HER2– breast cancer cells. Further, we evaluated the utility of 3′–Deoxy–3′–[18F]–fluorothymidine positron emission tomography ([18F]FLT–PET) imaging for early response assessment in a HER2+ patient derived xenograft …

Outcomes Of Da R-Epoch Versus R-Chop In Treating Patients Diagnosed With Double-Expressor Lymphoma, Phat Duong, Ishmael Jaiyesimi

Posters

Double-expressor lymphoma (DEL) is a subtype of Diffuse Large B-cell lymphoma (DLBCL) that is associated with poor prognosis. The standard treatment for DLBCL is rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP). It is hypothesized that the aggressive nature of DEL deserves a more intense regimen such as dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin plus rituximab (DA-R-EPOCH). A comparison of outcomes between those two treatments is needed to guide clinical decisions.