Genetic Phenomena Commons^™

The Boring Schwann Cells: Tumor Me-Tast-Asis Along Nerves, Moran Amit, Anirban Maitra

Faculty, Staff and Student Publications

Perineural spread is an ominous feature of cancer. Here, Deborde and colleagues describe for the first time the biophysical coupling driving this route of tumor spread and the role of Schwann cell activation in the mobilization of cancer cells within and along the tumor-associated nerves. See related article by Deborde et al., p. 2454 (8).

Single-Cell Transcriptomic Profiling Reveals The Tumor Heterogeneity Of Small-Cell Lung Cancer, Yanhua Tian, Qingqing Li, Zhenlin Yang, Shu Zhang, Jiachen Xu, Zhijie Wang, Hua Bai, Jianchun Duan, Bo Zheng, Wen Li, Yueli Cui, Xin Wang, Rui Wan, Kailun Fei, Jia Zhong, Shugeng Gao, Jie He, Carl M Gay, Jianjun Zhang, Jie Wang, Fuchou Tang

Faculty, Staff and Student Publications

Small-cell lung cancer (SCLC) is the most aggressive and lethal subtype of lung cancer, for which, better understandings of its biology are urgently needed. Single-cell sequencing technologies provide an opportunity to profile individual cells within the tumor microenvironment (TME) and investigate their roles in tumorigenic processes. Here, we performed high-precision single-cell transcriptomic analysis of ~5000 individual cells from primary tumors (PTs) and matched normal adjacent tissues (NATs) from 11 SCLC patients, including one patient with both PT and relapsed tumor (RT). The comparison revealed an immunosuppressive landscape of human SCLC. Malignant cells in SCLC tumors exhibited diverse states mainly related …

Biophysics Of Cancer, Alemayehu A Gorfe

Faculty, Staff and Student Publications

No abstract provided.

Family Planning, Fertility, And Career Decisions Among Female Oncologists, Anna Lee, Aleksandra Kuczmarska-Haas, Shraddha M Dalwadi, Erin F Gillespie, Michelle S Ludwig, Emma B Holliday, Fumiko Chino

Faculty, Staff and Student Publications

Importance: Female oncologists often spend their childbearing years in training and establishing careers, with many later experiencing fertility issues when starting a family. Physician fertility and family planning are rarely discussed during training. Attitudes among female oncologists regarding family planning are unknown.

Objectives: To understand barriers to family planning as well as the association of fertility treatment with career decisions and to assess experiences of pregnancy-based discrimination among female oncologists.

Design, setting, and participants: In this survey study, a novel 39-item questionnaire was distributed to US female oncologists from May 7 to June 30, 2020, via email and social media …

Svat: Secure Outsourcing Of Variant Annotation And Genotype Aggregation, Miran Kim, Su Wang, Xiaoqian Jiang, Arif Harmanci

Faculty, Staff and Student Publications

BACKGROUND: Sequencing of thousands of samples provides genetic variants with allele frequencies spanning a very large spectrum and gives invaluable insight into genetic determinants of diseases. Protecting the genetic privacy of participants is challenging as only a few rare variants can easily re-identify an individual among millions. In certain cases, there are policy barriers against sharing genetic data from indigenous populations and stigmatizing conditions.

RESULTS: We present SVAT, a method for secure outsourcing of variant annotation and aggregation, which are two basic steps in variant interpretation and detection of causal variants. SVAT uses homomorphic encryption to encrypt the data at …

Genome Interpretation Using In Silico Predictors Of Variant Impact, Panagiotis Katsonis, Kevin Wilhelm, Amanda Williams, Olivier Lichtarge

Faculty, Staff and Students Publications

Estimating the effects of variants found in disease driver genes opens the door to personalized therapeutic opportunities. Clinical associations and laboratory experiments can only characterize a tiny fraction of all the available variants, leaving the majority as variants of unknown significance (VUS). In silico methods bridge this gap by providing instant estimates on a large scale, most often based on the numerous genetic differences between species. Despite concerns that these methods may lack reliability in individual subjects, their numerous practical applications over cohorts suggest they are already helpful and have a role to play in genome interpretation when used at …

Mismatch Repair And Microsatellite Instability Testing For Immune Checkpoint Inhibitor Therapy: Guideline From The College Of American Pathologists In Collaboration With The Association For Molecular Pathology And Fight Colorectal Cancer, Angela N Bartley, Anne M Mills, Eric Konnick, Michael Overman, Christina B Ventura, Lesley Souter, Carol Colasacco, Zsofia K Stadler, Sarah Kerr, Brooke E Howitt, Heather Hampel, Sarah F Adams, Wenora Johnson, Cristina Magi-Galluzzi, Antonia R Sepulveda, Russell R Broaddus

Faculty, Staff and Student Publications

Context.—: The US Food and Drug Administration (FDA) approved immune checkpoint inhibitor therapy for patients with advanced solid tumors that have DNA mismatch repair defects or high levels of microsatellite instability; however, the FDA provided no guidance on which specific clinical assays should be used to determine mismatch repair status.

Objective.—: To develop an evidence-based guideline to identify the optimal clinical laboratory test to identify defects in DNA mismatch repair in patients with solid tumor malignancies who are being considered for immune checkpoint inhibitor therapy.

Design.—: The College of American Pathologists convened an expert panel to perform a systematic review …

First-In-Human Phase 1/1b Study To Evaluate Sitravatinib In Patients With Advanced Solid Tumors, Todd Bauer, Byong Chul Cho, Rebecca Heist, Lyudmila Bazhenova, Theresa Werner, Sanjay Goel, Dong-Wan Kim, Douglas Adkins, Richard D Carvajal, Ajjai Alva, Keith Eaton, Judy Wang, Yong Liu, Xiaohong Yan, Jamie Christensen, Saskia Neuteboom, Richard Chao, Shubham Pant

Faculty, Staff and Student Publications

Sitravatinib (MGCD516), a spectrum-selective receptor tyrosine kinase inhibitor targeting TAM (TYRO3, AXL, MERTK) and split kinase family receptors, has demonstrated preclinical anti-tumor activity and modulation of tumor microenvironment. This first-in-human phase 1/1b study included sitravatinib dose exploration and anti-tumor activity evaluation in selected patients with advanced solid tumors. Primary objectives included assessment of safety, pharmacokinetics and clinical activity of sitravatinib. Secondary objectives included identifying doses for further investigation and exploring molecular markers for patient selection. In phase 1, 32 patients received 10-200 mg, while phase 1b dose expansion comprised 161 patients (150 mg n = 99, 120 mg n = …

Targeting The Alk-Cdk9-Tyr19 Kinase Cascade Sensitizes Ovarian And Breast Tumors To Parp Inhibition Via Destabilization Of The P-Tefb Complex, Yu-Yi Chu, Mei-Kuang Chen, Yongkun Wei, Heng-Huan Lee, Weiya Xia, Ying-Nai Wang, Clinton Yam, Jennifer L Hsu, Hung-Ling Wang, Wei-Chao Chang, Hirohito Yamaguchi, Zhou Jiang, Chunxiao Liu, Ching-Fei Li, Lei Nie, Li-Chuan Chan, Yuan Gao, Shao-Chun Wang, Jinsong Liu, Shannon N Westin, Sanghoon Lee, Anil K Sood, Liuqing Yang, Gabriel N Hortobagyi, Dihua Yu, Mien-Chie Hung

Faculty, Staff and Student Publications

Poly(ADP-ribose) polymerase (PARP) inhibitors have demonstrated promising clinical activity in multiple cancers. However, resistance to PARP inhibitors remains a substantial clinical challenge. In the present study, we report that anaplastic lymphoma kinase (ALK) directly phosphorylates CDK9 at tyrosine-19 to promote homologous recombination (HR) repair and PARP inhibitor resistance. Phospho-CDK9-Tyr19 increases its kinase activity and nuclear localization to stabilize positive transcriptional elongation factor b and activate polymerase II-dependent transcription of HR-repair genes. Conversely, ALK inhibition increases ubiquitination and degradation of CDK9 by Skp2, an E3 ligase. Notably, combination of US Food and Drug Administration-approved ALK and PARP inhibitors markedly reduce tumor …

T1 Signal Intensity Ratio Of The Pancreas As An Imaging Biomarker For The Staging Of Chronic Pancreatitis, Temel Tirkes, Anil K Dasyam, Zarine K Shah, Evan L Fogel, Santhi Swaroop Vege, Liang Li, Shuang Li, Stephanie T Chang, Carlos A Farinas, Joseph R Grajo, Kareem Mawad, Naoki Takahashi, Sudhakar K Venkatesh, Ashley Wachsman, William E Fisher, Christopher E Forsmark, Phil A Hart, Stephen J Pandol, Walter G Park, Stephen K Van Den Eeden, Yunlong Yang, Mark Topazian, Dana K Andersen, Jose Serrano, Darwin L Conwell, Dhiraj Yadav, Consortium For The Study Of Chronic Pancreatitis, Diabetes, Pancreatic Cancer (Cpdpc)

Faculty, Staff and Student Publications

Purpose: Our purpose was to validate the T1 SIR (T1 score) as an imaging biomarker for the staging of CP in a large, multi-institutional, prospective study.

Methods: The prospective study population included 820 participants enrolled in the PROCEED study from nine clinical centers between June 2017 and December 2021. A radiologist at each institution used a standardized method to measure the T1 signal intensity of the pancreas and the reference organs (spleen, paraspinal muscle, liver), which was used to derive respective T1 scores. Participants were stratified according to the seven mechanistic stages of chronic pancreatitis (MSCP 0-6) based on their …

Brequinar And Dipyridamole In Combination Exhibits Synergistic Antiviral Activity Against Sars-Cov-2 In Vitro: Rationale For A Host-Acting Antiviral Treatment Strategy For Covid-19, James F Demarest, Maryline Kienle, Ruthmabel Boytz, Mary Ayres, Eun Jung Kim, J J Patten, Donghoon Chung, Varsha Gandhi, Robert A Davey, David B Sykes, Nadim Shohdy, John C Pottage, Vikram S Kumar

Faculty, Staff and Student Publications

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causative agent of coronavirus disease 2019 (COVID-19) and the associated global pandemic resulting in >400 million infections worldwide and several million deaths. The continued evolution of SARS-CoV-2 to potentially evade vaccines and monoclonal antibody (mAb)-based therapies and the limited number of authorized small-molecule antivirals necessitates the need for development of new drug treatments. There remains an unmet medical need for effective and convenient treatment options for SARS-CoV-2 infection. SARS-CoV-2 is an RNA virus that depends on host intracellular ribonucleotide pools for its replication. Dihydroorotate dehydrogenase (DHODH) is a ubiquitous host …

Handling Informative Premature Treatment Or Study Discontinuation For Assessing Between-Group Differences In A Comparative Oncology Trial, Bo Huang, Ryan Sun, Brian Claggett, Lu Tian, Ethan B Ludmir, Lee-Jen Wei

Faculty, Staff and Student Publications

This decision analytical model study examines premature treatment discontinuation in clinical trials for patients with advanced renal cell carcinoma.

A Retrospective Analysis Of Ebv-Dna Status With The Prognosis Of Lymphoma, Lihua Qiu, Junqi Si, Junnan Kang, Zehui Chen, Rexidan Nuermaimaiti, Zhengzi Qian, Lanfang Li, Shiyong Zhou, Mingjian James You, Huilai Zhang, Chen Tian

Faculty, Staff and Student Publications

Epstein-Barr virus (EBV) infection is proved to be associated with clinicopathology of lymphoma. However, little is known about the relationship between EBV-DNA status after treatment and prognosis. In this study, real-time polymerase chain reaction (PCR) was used for quantitative detection of EBV-DNA load in peripheral blood of all 26,527 patients with lymphoma, and the clinical characteristics and prognosis of 202 patients were retrospectively analysed, including 100 patients with positive EBV-DNA and 102 randomly selected patients with negative EBV-DNA. We found that the average rate of EBV-DNA positivity in lymphomas was 0.376%, and EBV-DNA-positive patients presented higher risk with elevated lactate …

Lurbinectedin, A Selective Inhibitor Of Oncogenic Transcription, In Patients With Pretreated Germline Brca1/2 Metastatic Breast Cancer: Results From A Phase Ii Basket Study, V Boni, B Pistilli, I Braña, G I Shapiro, J Trigo, V Moreno, D Castellano, C Fernández, C Kahatt, V Alfaro, M Siguero, A Zeaiter, F Longo, K Zaman, A Antón, A Paredes, G Huidobro, V Subbiah

Faculty, Staff and Student Publications

Background: Lurbinectedin, a selective inhibitor of oncogenic transcription, has shown preclinical antitumor activity against homologous recombination repair-deficient models and preliminary clinical activity in BRCA1/2 breast cancer.

Patients and methods: This phase II basket multitumor trial (NCT02454972) evaluated lurbinectedin 3.2 mg/m2 1-h intravenous infusion every 3 weeks in a cohort of 21 patients with pretreated germline BRCA1/2 breast cancer. Patients with any hormone receptor and human epidermal growth factor receptor 2 status were enrolled. The primary efficacy endpoint was overall response rate (ORR) according to RECIST v1.1. Secondary endpoints included duration of response (DoR), progression-free survival (PFS), overall survival …

First-In-Human Study Of An Ox40 (Ivuxolimab) And 4-1bb (Utomilumab) Agonistic Antibody Combination In Patients With Advanced Solid Tumors, Omid Hamid, Alberto A Chiappori, John A Thompson, Toshihiko Doi, Siwen Hu-Lieskovan, Ferry A L M Eskens, Willeke Ros, Adi Diab, Jean-Philippe Spano, Naiyer A Rizvi, Jeffrey S Wasser, Eric Angevin, Patrick A Ott, Alison Forgie, Wenjing Yang, Cen Guo, Jeffrey Chou, Anthony B El-Khoueiry

Faculty, Staff and Student Publications

Background: Ivuxolimab (PF-04518600) and utomilumab (PF-05082566) are humanized agonistic IgG2 monoclonal antibodies against OX40 and 4-1BB, respectively. This first-in-human, multicenter, open-label, phase I, dose-escalation/dose-expansion study explored safety, tolerability, pharmacokinetics, pharmacodynamics, and antitumor activity of ivuxolimab+utomilumab in patients with advanced solid tumors.

Methods: Dose-escalation: patients with advanced bladder, gastric, or cervical cancer, melanoma, head and neck squamous cell carcinoma, or non-small cell lung cancer (NSCLC) who were unresponsive to available therapies, had no standard therapy available or declined standard therapy were enrolled into five dose cohorts: ivuxolimab (0.1-3 mg/kg every 2 weeks (Q2W)) intravenously plus utomilumab (20 or 100 mg every …

Comprehensive Multiplexed Immune Profiling Of The Ductal Carcinoma In Situ Immune Microenvironment Regarding Subsequent Ipsilateral Invasive Breast Cancer Risk, Mathilde M Almekinders, Tycho Bismeijer, Tapsi Kumar, Fei Yang, Bram Thijssen, Rianne Van Der Linden, Charlotte Van Rooijen, Shiva Vonk, Baohua Sun, Edwin R Parra Cuentas, Ignacio I Wistuba, Savitri Krishnamurthy, Lindy L Visser, Iris M Seignette, Ingrid Hofland, Joyce Sanders, Annegien Broeks, Jason K Love, Brian Menegaz, Lodewyk Wessels, Alastair M Thompson, Karin E De Visser, Erik Hooijberg, Esther Lips, Andrew Futreal, Jelle Wesseling

Faculty, Staff and Student Publications

Background: Ductal carcinoma in situ (DCIS) is treated to prevent subsequent ipsilateral invasive breast cancer (iIBC). However, many DCIS lesions will never become invasive. To prevent overtreatment, we need to distinguish harmless from potentially hazardous DCIS. We investigated whether the immune microenvironment (IME) in DCIS correlates with transition to iIBC.

Methods: Patients were derived from a Dutch population-based cohort of 10,090 women with pure DCIS with a median follow-up time of 12 years. Density, composition and proximity to the closest DCIS cell of CD20+ B-cells, CD3+CD8+ T-cells, CD3+CD8- T-cells, CD3+FOXP3+ regulatory T-cells, CD68+ cells, and CD8+Ki67+ T-cells was assessed with …

Sex-Specific Epigenetic Development In The Mouse Hypothalamic Arcuate Nucleus Pinpoints Human Genomic Regions Associated With Body Mass Index, Harry Mackay, Chathura J Gunasekara, Kit-Yi Yam, Dollada Srisai, Hari Krishna Yalamanchili, Yumei Li, Rui Chen, Cristian Coarfa, Robert A Waterland

Duncan NRI Faculty and Staff Publications

Recent genome-wide association studies corroborate classical research on developmental programming indicating that obesity is primarily a neurodevelopmental disease strongly influenced by nutrition during critical ontogenic windows. Epigenetic mechanisms regulate neurodevelopment; however, little is known about their role in establishing and maintaining the brain's energy balance circuitry. We generated neuron and glia methylomes and transcriptomes from male and female mouse hypothalamic arcuate nucleus, a key site for energy balance regulation, at time points spanning the closure of an established critical window for developmental programming of obesity risk. We find that postnatal epigenetic maturation is markedly cell type and sex specific and …

Pin-Pointing The Key Hubs In The Ifn-Γ Pathway Responding To Sars-Cov-2 Infection, Ayelen Toro, Sofia Lage-Vickers, Juan Bizzotto, Felipe Vilicich, Agustina Sabater, Gaston Pascual, Sabrina Ledesma-Bazan, Pablo Sanchis, Maria Sol Ruiz, Ana Paula Arevalo, Jorge L Porfido, Mercedes Abbate, Rocio Seniuk, Estefania Labanca, Nicolas Anselmino, Nora M Navone, Daniel F Alonso, Elba Vazquez, Martina Crispo, Javier Cotignola, Geraldine Gueron

Faculty, Staff and Student Publications

Interferon gamma (IFN-γ) may be potential adjuvant immunotherapy for COVID-19 patients. In this work, we assessed gene expression profiles associated with the IFN-γ pathway in response to SARS-CoV-2 infection. Employing a case-control study from SARS-CoV-2-positive and -negative patients, we identified IFN-γ-associated pathways to be enriched in positive patients. Bioinformatics analyses showed upregulation of MAP2K6, CBL, RUNX3, STAT1, and JAK2 in COVID-19-positive vs. -negative patients. A positive correlation was observed between STAT1/JAK2, which varied alongside the patient's viral load. Expression of MX1, MX2, ISG15, and OAS1 (four well-known IFN-stimulated genes (ISGs)) …

Impad1 And Syt11 Work In An Epistatic Pathway That Regulates Emt-Mediated Vesicular Trafficking To Drive Lung Cancer Invasion And Metastasis, Rakhee Bajaj, B Leticia Rodriguez, William K Russell, Amanda N Warner, Lixia Diao, Jing Wang, Maria G Raso, Wei Lu, Khaja Khan, Luisa S Solis, Harsh Batra, Ximing Tang, Jared F Fradette, Samrat T Kundu, Don L Gibbons

Faculty, Staff and Student Publications

Lung cancer is a highly aggressive and metastatic disease responsible for approximately 25% of all cancer-related deaths in the United States. Using high-throughput in vitro and in vivo screens, we have previously established Impad1 as a driver of lung cancer invasion and metastasis. Here we elucidate that Impad1 is a direct target of the epithelial microRNAs (miRNAs) miR-200 and miR∼96 and is de-repressed during epithelial-to-mesenchymal transition (EMT); thus, we establish a mode of regulation of the protein. Impad1 modulates Golgi apparatus morphology and vesicular trafficking through its interaction with a trafficking protein, Syt11. These changes in Golgi apparatus dynamics alter …

Temporal Lobe White Matter Asymmetry And Language Laterality In Epilepsy Patients, Nikolaos Soldatos, Huy Pham, Walid D Fakhouri, Binh Ngo, Panagiotis Lampropoulos, Tiffany Tran, Robin Weltman

Faculty, Staff and Student Publications

(1) Background: Several studies showed a sustained temperature of 47 °C or 50 °C for one minute resulted in vascular stasis and bone resorption with only limited bone regrowth over a 3–4-week healing period. The purpose of the present study was to evaluate the temperature changes (ΔΤ) that occur during the preparation of dental implant osteotomies using MIS® straight drills versus Densah® burs in a clockwise (cutting) drilling protocol. (2) Methods: Two hundred forty (240) osteotomies of two different systems’ drills were prepared at 6 mm depth at 800, 1000, and 1200 revolutions per minute (RPM), in fresh, unembalmed tibiae, …

Insular Cortical Circuits As An Executive Gateway To Decipher Threat Or Extinction Memory Via Distinct Subcortical Pathways, Qi Wang, Jia-Jie Zhu, Lizhao Wang, Yan-Peng Kan, Yan-Mei Liu, Yan-Jiao Wu, Xue Gu, Xin Yi, Ze-Jie Lin, Qin Wang, Jian-Fei Lu, Qin Jiang, Ying Li, Ming-Gang Liu, Nan-Jie Xu, Michael X Zhu, Lu-Yang Wang, Siyu Zhang, Wei-Guang Li, Tian-Le Xu

Faculty, Staff and Student Publications

Threat and extinction memories are crucial for organisms' survival in changing environments. These memories are believed to be encoded by separate ensembles of neurons in the brain, but their whereabouts remain elusive. Using an auditory fear-conditioning and extinction paradigm in male mice, here we discovered that two distinct projection neuron subpopulations in physical proximity within the insular cortex (IC), targeting the central amygdala (CeA) and nucleus accumbens (NAc), respectively, to encode fear and extinction memories. Reciprocal intracortical inhibition of these two IC subpopulations gates the emergence of either fear or extinction memory. Using rabies-virus-assisted tracing, we found IC-NAc projection neurons …

Amino Acids, Microbiota-Related Metabolites, And The Risk Of Incident Diabetes Among Normoglycemic Chinese Adults: Findings From The 4c Study, Shuangyuan Wang, Mian Li, Hong Lin, Guixia Wang, Yu Xu, Xinjie Zhao, Chunyan Hu, Yi Zhang, Ruizhi Zheng, Ruying Hu, Lixin Shi, Rui Du, Qing Su, Jiqiu Wang, Yuhong Chen, Xuefeng Yu, Li Yan, Tiange Wang, Zhiyun Zhao, Ruixin Liu, Xiaolin Wang, Qi Li, Guijun Qin, Qin Wan, Gang Chen, Min Xu, Meng Dai, Di Zhang, Xulei Tang, Zhengnan Gao, Feixia Shen, Zuojie Luo, Yingfen Qin, Li Chen, Yanan Huo, Qiang Li, Zhen Ye, Yinfei Zhang, Chao Liu, Youmin Wang, Shengli Wu, Tao Yang, Huacong Deng, Jiajun Zhao, Shenghan Lai, Yiming Mu, Lulu Chen, Donghui Li, Guowang Xu, Guang Ning, Weiqing Wang, Yufang Bi, Jieli Lu

Faculty, Staff and Student Publications

Although previous studies suggest that amino acids (AAs) and microbiota-related metabolites (MRMs) are associated with type 2 diabetes mellitus (T2DM), the results remain unclear among normoglycemic populations. We test 28 serum AAs and 22 MRMs in 3,414 subjects with incident diabetes and matched normoglycemic controls from the China Cardiometabolic Disease and Cancer Cohort (4C) Study. In fully adjusted logistic regression models, per SD increment of branched-chain AAs, aromatic AAs, asparagine, alanine, glutamic acid, homoserine, 2-aminoadipic acid, histidine, methionine, and proline are positively associated with incident T2DM. In the MRM panel, serum carnitines, N-acetyltryptophan, and uric acid are positively associated with …

Intensity-Modulated Radiation Therapy Reduces Patient-Reported Chronic Toxicity Compared With Conventional Pelvic Radiation Therapy: Updated Results Of A Phase Iii Trial, Anamaria R Yeung, Snehal Deshmukh, Ann H Klopp, Karen M Gil, Lari Wenzel, Shannon N Westin, Andre A Konski, David K Gaffney, William Small, J Spencer Thompson, Desiree E Doncals, Guilherme H C Cantuaria, David P D'Souza, Amy Chang, Vijayananda Kundapur, Dasarahally S Mohan, Michael L Haas, Yong Bae Kim, Catherine L Ferguson, Stephanie L Pugh, Lisa A Kachnic, Deborah W Bruner

Faculty, Staff and Student Publications

Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned coprimary or secondary analyses are not yet available.

Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported.

The purpose of this update was to determine differences in patient-reported chronic toxicity and disease outcomes with intensity-modulated radiation therapy (IMRT) compared with conventional pelvic radiation. Patients with cervical and endometrial cancers who received postoperative pelvic radiation …

Mri-Based Digital Models Forecast Patient-Specific Treatment Responses To Neoadjuvant Chemotherapy In Triple-Negative Breast Cancer, Chengyue Wu, Angela M Jarrett, Zijian Zhou, Nabil Elshafeey, Beatriz E Adrada, Rosalind P Candelaria, Rania M M Mohamed, Medine Boge, Lei Huo, Jason B White, Debu Tripathy, Vicente Valero, Jennifer K Litton, Clinton Yam, Jong Bum Son, Jingfei Ma, Gaiane M Rauch, Thomas E Yankeelov

Faculty, Staff and Student Publications

Triple-negative breast cancer (TNBC) is persistently refractory to therapy, and methods to improve targeting and evaluation of responses to therapy in this disease are needed. Here, we integrate quantitative MRI data with biologically based mathematical modeling to accurately predict the response of TNBC to neoadjuvant systemic therapy (NAST) on an individual basis. Specifically, 56 patients with TNBC enrolled in the ARTEMIS trial (NCT02276443) underwent standard-of-care doxorubicin/cyclophosphamide (A/C) and then paclitaxel for NAST, where dynamic contrast-enhanced MRI and diffusion-weighted MRI were acquired before treatment and after two and four cycles of A/C. A biologically based model was established to …

Serologic Versus Molecular Testing For Screening For Hepatitis C Virus Infection In Patients With Hematologic Malignancies, Harrys A Torres, Georgios Angelidakis, Ying Jiang, Minas Economides, Khalis Mustafayev, Marcel Yibirin, Robert Orlowski, Richard Champlin, Srdan Verstovsek, Issam Raad

Faculty, Staff and Student Publications

Testing for antibody against hepatitis C virus (anti-HCV) is a low-cost diagnostic method worldwide; however, an optimal screening test for HCV in patients with cancer has not been established. We sought to identify an appropriate screening test for HCV infection in patients with hematologic malignancies and/or hematopoietic cell transplants (HCT). Patients in our center were simultaneously screened using serological (anti-HCV) and molecular (HCV RNA) assays (February 2019-November 2019). In total, 214 patients were enrolled in this study. Three patients (1.4%) were positive for anti-HCV, and 2 (0.9%) were positive for HCV RNA. The overall percentage agreement was 99.5% (95% CI: …

Targeting Ras Mutant Colorectal Cancer With Dual Inhibition Of Mek And Cdk4/6, Alexey V Sorokin, Preeti Kanikarla Marie, Lea Bitner, Muddassir Syed, Melanie Woods, Ganiraju Manyam, Lawrence N Kwong, Benny Johnson, Van K Morris, Philip Jones, David G Menter, Michael S Lee, Scott Kopetz

Faculty, Staff and Student Publications

UNLABELLED: KRAS and NRAS mutations occur in 45% of colorectal cancers, with combined MAPK pathway and CDK4/6 inhibition identified as a potential therapeutic strategy. In the current study, this combinatorial treatment approach was evaluated in a co-clinical trial in patient-derived xenografts (PDX), and safety was established in a clinical trial of binimetinib and palbociclib in patients with metastatic colorectal cancer with RAS mutations. Across 18 PDX models undergoing dual inhibition of MEK and CDK4/6, 60% of tumors regressed, meeting the co-clinical trial primary endpoint. Prolonged duration of response occurred predominantly in TP53 wild-type models. Clinical evaluation of binimetinib and palbociclib …

Inhibition Of Uba6 By Inosine Augments Tumour Immunogenicity And Responses, Lei Zhang, Li Jiang, Liang Yu, Qin Li, Xiangjun Tian, Jingquan He, Ling Zeng, Yuqin Yang, Chaoran Wang, Yuhan Wei, Xiaoyue Jiang, Jing Li, Xiaolu Ge, Qisheng Gu, Jikun Li, Di Wu, Anthony J Sadler, Di Yu, Dakang Xu, Yue Gao, Xiangliang Yuan, Baokun He

Faculty, Staff and Student Publications

Anti-cancer immunity and response to immune therapy is influenced by the metabolic states of the tumours. Immune checkpoint blockade therapy (ICB) is known to involve metabolic adaptation, however, the mechanism is not fully known. Here we show, by metabolic profiling of plasma samples from melanoma-bearing mice undergoing anti-PD1 and anti-CTLA4 combination therapy, that higher levels of purine metabolites, including inosine, mark ICB sensitivity. Metabolic profiles of ICB-treated human cancers confirm the association between inosine levels and ICB sensitivity. In mouse models, inosine supplementation sensitizes tumours to ICB, even if they are intrinsically ICB resistant, by enhancing T cell-mediated cytotoxicity and …

Clinical Activity Of Checkpoint Inhibitors In Angiosarcoma: A Retrospective Cohort Study, Vinod Ravi, Aparna Subramaniam, Jing Zheng, Behrang Amini, Van A Trinh, Jocelyn Joseph, Robert G Mennel, Andrew J Bishop, Erich M Sturgis, Ryan P Goepfert, Sudha Yalamanchili, Gilberto Botello, Bettzy Stephen, Sarina A Piha-Paul, Anisha B Patel, Alexander J Lazar, Anthony P Conley, Robert S Benjamin, Shreyaskumar R Patel, Phillip A Futreal, Neeta Somaiah, Aung Naing

Faculty, Staff and Student Publications

Background: Systemic treatments for angiosarcoma remains an area of unmet clinical need. The authors conducted this retrospective study to assess the clinical activity of checkpoint inhibitors in patients with angiosarcoma. The primary objective was to assess the objective response rate, and the secondary objective was to assess the progression-free and overall survival durations and disease control rate.

Methods: Patient data were obtained using The University of Texas MD Anderson Cancer Center Tumor Registry database. The final study population was refined to only include patients who had undergone pembrolizumab monotherapy. The objective response rate was evaluated using RECIST/irRECIST version 1.1. Progression-free …

Bet Inhibition Induces Vulnerability To Mcl1 Targeting Through Upregulation Of Fatty Acid Synthesis Pathway In Breast Cancer, Gonghong Yan, Augustin Luna, Heping Wang, Behnaz Bozorgui, Xubin Li, Maga Sanchez, Zeynep Dereli, Nermin Kahraman, Goknur Kara, Xiaohua Chen, Caishang Zheng, Daniel Mcgrail, Nidhi Sahni, Yiling Lu, Ozgun Babur, Murat Cokol, Bora Lim, Bulent Ozpolat, Chris Sander, Gordon B Mills, Anil Korkut

Faculty, Staff and Student Publications

Therapeutic options for treatment of basal-like breast cancers remain limited. Here, we demonstrate that bromodomain and extra-terminal (BET) inhibition induces an adaptive response leading to MCL1 protein-driven evasion of apoptosis in breast cancer cells. Consequently, co-targeting MCL1 and BET is highly synergistic in breast cancer models. The mechanism of adaptive response to BET inhibition involves the upregulation of lipid synthesis enzymes including the rate-limiting stearoyl-coenzyme A (CoA) desaturase. Changes in lipid synthesis pathway are associated with increases in cell motility and membrane fluidity as well as re-localization and activation of HER2/EGFR. In turn, the HER2/EGFR signaling results in the accumulation …

Openkbp-Opt: An International And Reproducible Evaluation Of 76 Knowledge-Based Planning Pipelines, Aaron Babier, Rafid Mahmood, Binghao Zhang, Victor G L Alves, Ana Maria Barragán-Montero, Joel Beaudry, Carlos E Cardenas, Yankui Chang, Zijie Chen, Jaehee Chun, Kelly Diaz, Harold David Eraso, Erik Faustmann, Sibaji Gaj, Skylar Gay, Mary Gronberg, Bingqi Guo, Junjun He, Gerd Heilemann, Sanchit Hira, Yuliang Huang, Fuxin Ji, Dashan Jiang, Jean Carlo Jimenez Giraldo, Hoyeon Lee, Jun Lian, Shuolin Liu, Keng-Chi Liu, José Marrugo, Kentaro Miki, Kunio Nakamura, Tucker Netherton, Dan Nguyen, Hamidreza Nourzadeh, Alexander F I Osman, Zhao Peng, José Darío Quinto Muñoz, Christian Ramsl, Dong Joo Rhee, Juan David Rodriguez, Hongming Shan, Jeffrey V Siebers, Mumtaz H Soomro, Kay Sun, Andrés Usuga Hoyos, Carlos Valderrama, Rob Verbeek, Enpei Wang, Siri Willems, Qi Wu, Xuanang Xu, Sen Yang, Lulin Yuan, Simeng Zhu, Lukas Zimmermann, Kevin L Moore, Thomas G Purdie, Andrea L Mcniven, Timothy C Y Chan

Faculty, Staff and Student Publications

Objective.To establish an open framework for developing plan optimization models for knowledge-based planning (KBP).

Approach.Our framework includes radiotherapy treatment data (i.e. reference plans) for 100 patients with head-and-neck cancer who were treated with intensity-modulated radiotherapy. That data also includes high-quality dose predictions from 19 KBP models that were developed by different research groups using out-of-sample data during the OpenKBP Grand Challenge. The dose predictions were input to four fluence-based dose mimicking models to form 76 unique KBP pipelines that generated 7600 plans (76 pipelines × 100 patients). The predictions and KBP-generated plans were compared to the reference …