Medical Specialties Commons^™

Muscle-Specific Errγ Activation Mitigates Muscle Atrophy After Acl Injury, Aiping Lu, Katie J Sikes, Ping Guo, Matthieu Huard, Shelbi Green, Kelly Santangelo, Jacob Singer, Ashley Groesbeck, Scott Tashman, Vihang A Narkar, Johnny Huard

Faculty, Staff and Student Publications

Anterior cruciate ligament (ACL) injury adversely affects skeletal muscle, leading to muscle atrophy and weakness, significantly impacting clinical outcomes. This study aimed to determine if estrogen-related receptor gamma (ERRγ) overexpression in skeletal muscle could mitigate muscle atrophy after ACL injury. An animal model with selective overexpression of ERRγ in skeletal muscle (ERR-gamma transgenic mice, TG) and WT control mice were used for this study. All the mice received a mechanical ACL rupture and were euthanized at 4- and 8-week post-injury. Muscle histology, atrophy, and function were evaluated and compared between the TG and WT mice. Muscle-specific ERRγ activation in TG …

New Onset Diabetes Predicts Clinical Outcomes In Patients With Pancreatic Adenocarcinoma, Chirayu Mohindroo, Paul S Dy, Suraj P Hande, Christopher R D'Adamo, Arun Mavanur, Asha Thomas, Florencia Mcallister, Ana De Jesus-Acosta

Faculty, Staff and Student Publications

Background: One percent of pancreatic adenocarcinoma (PDAC) patients are diagnosed with new onset diabetes (NOD) over the age of 50 years within 3 years. Therefore, NOD is a major factor for early diagnosis of PDAC. Research has focused on understanding the differences between NOD and type 2 diabetes, particularly in relation to PDAC. However, conflicting data exists regarding their impact on survival outcomes in PDAC patients. We performed this multi-center study to assess the prevalence and influence of NOD on clinical outcomes in patients with PDAC within a community-based hospital system.

Methods: We conducted a retrospective cohort study of 138 …

Is The Pendulum Slowly Starting To Swing Back?, Michael S Ewer, Jay Herson

Faculty, Staff and Student Publications

No abstract provided.

Impact Of Measurable Residual Disease Clearance Kinetics In Patients With Aml Undergoing Intensive Chemotherapy, Wei-Ying Jen, Koji Sasaki, Farhad Ravandi, Tapan M Kadia, Sa A Wang, Wei Wang, Sanam Loghavi, Naval G Daver, Courtney D Dinardo, Ghayas C Issa, Hussein A Abbas, Cedric Nasnas, Alex Bataller, Samuel Urrutia, Omer S Karrar, Sherry Pierce, Hagop M Kantarjian, Nicholas J Short

Faculty, Staff and Student Publications

The prognostic impact of measurable residual disease (MRD) in acute myeloid leukemia (AML) is unequivocal; however, the optimal time point for achieving undetectable MRD is unclear. We retrospectively studied patients with newly diagnosed (ND) AML who achieved remission with frontline intensive chemotherapy and had MRD assessed by flow cytometry after induction (time point 1 [TP1]) and after cycles 2 or 3 (TP2). Cases were grouped into MRD negative (Neg)/Neg, positive (Pos)/Neg, or Pos/Pos at TP1 and TP2, respectively. Of 1980 patients with ND AML, 277 met the inclusion criteria and were included in this analysis. The median relapse-free survival (RFS) …

The Spatial Landscape Of Cancer Hallmarks Reveals Patterns Of Tumor Ecological Dynamics And Drug Sensitivity, Mustafa Sibai, Sergi Cervilla, Daniela Grases, Eva Musulen, Rossana Lazcano, Chia-Kuei Mo, Veronica Davalos, Arola Fortian, Adrià Bernat, Margarita Romeo, Collin Tokheim, Jordi Barretina, Alexander J Lazar, Li Ding, Dutreneo Study Investigators, Enrique Grande, Francisco X Real, Manel Esteller, Matthew H Bailey, Eduard Porta-Pardo

Faculty, Staff and Student Publications

Tumors are complex ecosystems of interacting cell types. The concept of cancer hallmarks distills this complexity into underlying principles that govern tumor growth. Here, we explore the spatial distribution of cancer hallmarks across 63 primary untreated tumors from 10 cancer types using spatial transcriptomics. We show that hallmark activity is spatially organized, with the cancer compartment contributing to the activity of seven out of 13 hallmarks, while the tumor microenvironment (TME) contributes to the activity of the rest. Additionally, we discover that genomic distance between tumor subclones correlates with differences in hallmark activity, even leading to clone-hallmark specialization. Finally, we …

Immunological Biomarkers Of Response And Resistance To Treatment With Cabozantinib And Nivolumab In Recurrent Endometrial Cancer, Vladimir Roudko, Diane Marie Del Valle, Emir Radkevich, Geoffrey Kelly, Xie Hui, Manishkumar Patel, Edgar Gonzalez-Kozlova, Kevin Tuballes, Howard Streicher, Swati Atale, Lisa Wang, Benito Czinczin, Seunghee Kim-Schulze, Ignacio I Wistuba, Cara L Haymaker, Gheath Al-Atrash, Ganiraju Manyam, Jianjun Zhang, Ryan Thompson, Mayte Suarez-Farinas, Stephanie Lheureux, Sacha Gnjatic

Faculty, Staff and Student Publications

Background: Antiangiogenics combined with immune checkpoint blockade have become standard of care for recurrent endometrial cancer after standard platinum-based chemotherapy. To dissect mechanisms and define biomarkers associated with clinical outcomes to these combinations, we applied multidimensional immune monitoring to peripheral blood specimens collected from a randomized phase 2 trial of nivolumab with or without cabozantinib in 75 evaluable patients with recurrent endometrial cancer (NCI ETCTN 10104, NCT03367741). This trial demonstrated superiority of the combination to nivolumab alone.

Methods and results: Using Olink proteomics, mass cytometry, tumor antigen-specific ELISA, and whole exome tumor sequencing, we identified longitudinal immune signatures specific …

Sequence Of Therapy Impact On Older Women With Comorbidities And Triple-Negative Or Her2-Positive Breast Cancer, Nina Tamirisa, Wenli Dong, Yu Shen, Heather Lin, Simona F Shaitelman, Gildy Babiera, Isabelle Bedrosian

Faculty, Staff and Student Publications

We sought to determine whether sequencing of treatment impacted outcomes in older, comorbid patients. Using the National Cancer Database(2010-2017), 2911 patients >70 with a Charleson Deyo Comorbidity(CCDM) score of 2/3 and cT1c-3/N0-3/HER2 positive or triple-negative breast cancer treated with chemotherapy,surgery,or both were included. Chi-square tests evaluated differences between groups. Multivariable models evaluated associations between overall survival and treatment. Majority 87.4%(n = 2544) underwent surgery first and 36.0%(n = 917) received adjuvant chemotherapy while 77.9%(n = 286) of chemotherapy first patients underwent surgery. Receipt of both modalities was associated with the best survival followed by surgery alone then chemotherapy alone. Additional …

Primary Intrathoracic Synovial Sarcoma: An Analysis Of Outcomes Of This Rare Disease, Riddhi R Patel, Andrew J Bishop, Alexander J Lazar, Patrick P Lin, Robert S Benjamin, Shreyaskumar R Patel, Joseph Ludwig, Vinod Ravi, Ara A Vaporciyan, Dejka M Araujo

Faculty, Staff and Student Publications

No abstract provided.

The Heterogeneity Of 13q Deletions In Chronic Lymphocytic Leukemia: Diagnostic Challenges And Clinical Implications, Changqing Xia, Guang Liu, Jinglan Liu, Arash Ronaghy, Saber Tadros, Wei Wang, Hong Fang, Shanxiang Zhang, Joseph D Khoury, Zhenya Tang

Faculty, Staff and Student Publications

Chronic lymphocytic leukemia (CLL) is the most common type of adult leukemia, particularly in Western countries. CLL can present indolently or aggressively, influenced by various factors, including chromosomal alterations. Fluorescent in situ hybridization (FISH), targeting specific genes/loci frequently affected in CLL patients, has established a standard for stratifying five CLL prognostic groups: del(11q)/ATM, trisomy 12, del(13q) as a sole aberration, del(17p)/TP53, and normal CLL FISH panel results. Among these, del(13q) as a sole aberration is associated with a favorable prognosis, while the others are considered intermediate (normal CLL FISH panel result and trisomy 12) or unfavorable …

Aberrant Choroid Plexus Formation Drives The Development Of Treatment-Related Brain Toxicity, Tamara Bender, Esther Schickel, Celine Schielke, Jürgen Debus, David R Grosshans, Marco Durante, Insa S Schroeder

Faculty, Staff and Student Publications

Brain tumors are commonly treated with radiotherapy, but the efficacy of the treatment is limited by its toxicity to the normal tissue including post-irradiation contrast enhanced lesions often linked to necrosis. The poorly understood mechanisms behind such brain lesions were studied using cerebral organoids. Here we show that irradiation of such organoids leads to dose-dependent growth retardation and formation of liquid-filled cavities but is not correlated with necrosis. Instead, the radiation-induced changes comprise of an enhancement of cortical hem markers, altered neuroepithelial stem cell differentiation, and an increase of ZO1+/AQP1+/CLDN3+-choroid plexus (CP)-like structures accompanied by an upregulation of IGF2 mRNA, …

Immune Checkpoint Inhibitors Plus Debulking Surgery For Patients With Metastatic Renal Cell Carcinoma: Clinical Outcomes And Immunological Correlates Of A Prospective Pilot Trial, Sangeeta Goswami, Jianjun Gao, Sreyashi Basu, Daniel D Shapiro, Jose A Karam, Rebecca Slack Tidwell, Kamran Ahrar, Matthew T Campbell, Yu Shen, Alexandro E Trevino, Aaron T Mayer, Alexsandra B Espejo, Christian Seua, Marc D Macaluso, Yulong Chen, Wenbin Liu, Zhong He, Shalini S Yadav, Ying Wang, Priya Rao, Li Zhao, Jianhua Zhang, Sonali Jindal, Nizar M Tannir, Andrew Futreal, Linghua Wang, Padmanee Sharma

Faculty, Staff and Student Publications

Surgical removal of primary tumors reverses tumor-mediated immune suppression in pre-clinical models with metastatic disease. However, how cytoreductive surgery in the metastatic setting modulates the immune responses in patients, especially in the context of immune checkpoint therapy (ICT), is not understood. We report the first prospective, pilot, non-comparative clinical trial (NCT02210117) to evaluate the feasibility, clinical benefits, and immunologic changes of combining three different ICT-containing strategies with cytoreductive surgery or biopsy for patients with metastatic clear cell renal cell carcinoma. Primary safety endpoint of this trial has been met, with 43 patients completing cytoreductive surgery, 36 patients undergoing …

The Bacterial Microbiome Modulates The Initiation Of Brain Metastasis By Impacting The Gut-To-Brain Axis, Matteo Massara, Michelle Ballabio, Bastien Dolfi, Golnaz Morad, Vladimir Wischnewski, Eleni Lamprou, Joao Lourenco, Stéphanie Claudinot, Hector Gallart-Ayala, Rui Santalla Méndez, Annamaria Kauzlaric, Nadine Fournier, Ashish V Damania, Matthew C Wong, Julijana Ivanisevic, Nadim J Ajami, Jennifer A Wargo, Johanna A Joyce

Faculty, Staff and Student Publications

Brain metastases (BrMs) are the most common brain tumors in patients and are associated with poor prognosis. Investigating the systemic and environmental factors regulating BrM biology represents an important strategy to develop effective treatments. Toward this goal, we explored the contribution of the gut microbiome to BrM development by using in vivo breast-BrM models under germ-free conditions or antibiotic treatment. This revealed a detrimental role of gut microbiota in fostering BrM initiation. We thus evaluated the impact of antibiotics and BrM outgrowth on the gut-brain axis. We found the bacterial genus Alistipes was differentially present under antibiotic treatment and BrM …

Antibiotic-Induced Loss Of Gut Microbiome Metabolic Output Correlates With Clinical Responses To Car T-Cell Therapy, Rishika Prasad, Abdur Rehman, Lubna Rehman, Faezeh Darbaniyan, Viktoria Blumenberg, Maria-Luisa Schubert, Uria Mor, Eli Zamir, Sabine Schmidt, Tomo Hayase, Chia-Chi Chang, Lauren Mcdaniel, Ivonne Flores, Paolo Strati, Ranjit Nair, Dai Chihara, Luis E Fayad, Sairah Ahmed, Swaminathan P Iyer, Michael Wang, Preetesh Jain, Loretta J Nastoupil, Jason Westin, Reetakshi Arora, Joel Turner, Fareed Khawaja, Ranran Wu, Jennifer B Dennison, Meghan Menges, Melanie Hidalgo-Vargas, Kayla Reid, Marco L Davila, Peter Dreger, Felix Korell, Anita Schmitt, Mark R Tanner, Richard E Champlin, Christopher R Flowers, Elizabeth J Shpall, Samir Hanash, Sattva S Neelapu, Michael Schmitt, Marion Subklewe, Johannes Francois-Fahrmann, C K Stein-Thoeringer, Eran Elinav, Michael D Jain, Eiko Hayase, Robert R Jenq, Neeraj Y Saini

Faculty, Staff and Student Publications

Antibiotic (ABX)–induced microbiome dysbiosis is widespread in oncology, adversely affecting outcomes and side effects of various cancer treatments, including immune checkpoint inhibitors and chimeric antigen receptor T-cell (CAR-T) therapies. In this study, we observed that prior exposure to broad-spectrum ABXs with extended anaerobic coverage such as piperacillin-tazobactam and meropenem was associated with worse anti-CD19 CAR-T therapy survival outcomes in patients with large B-cell lymphoma (N = 422) than other ABX classes. In a discovery subset of these patients (n = 67), we found that the use of these ABXs was in turn associated with substantial dysbiosis of gut microbiome function, …

Aif3 Splicing Variant Elicits Mitochondrial Malfunction Via The Concurrent Dysregulation Of Electron Transport Chain And Glutathione-Redox Homeostasis, Mi Zhou, Shuiqiao Liu, Yanan Wang, Bo Zhang, Ming Zhu, Jennifer E Wang, Veena Rajaram, Yisheng Fang, Weibo Luo, Yingfei Wang

Faculty, Staff and Student Publications

Genetic mutations in apoptosis-inducing factor (AIF) have a strong association with mitochondrial disorders; however, little is known about the aberrant splicing variants in affected patients and how these variants contribute to mitochondrial dysfunction and brain development defects. We identified pathologic AIF3/AIF3-like splicing variants in postmortem brain tissues of pediatric individuals with mitochondrial disorders. Mutations in AIFM1 exon-2/3 increase splicing risks. AIF3-splicing disrupts mitochondrial complexes, membrane potential, and respiration, causing brain development defects. Mechanistically, AIF is a mammalian NAD(P)H dehydrogenase and possesses glutathione reductase activity controlling respiratory chain functions and glutathione regeneration. Conversely, AIF3, lacking these activities, disassembles mitochondrial complexes, increases …

Development Of A Conditional Plasmid For Gene Deletion In Non-Model Fusobacterium Nucleatum Strains, Peng Zhou, Bibek G C, Chenggang Wu

Faculty, Staff and Student Publications

Fusobacterium nucleatum is an opportunistic pathogen with four subspecies: nucleatum (FNN), vincentii (FNV), polymorphum (FNP), and animalis (FNA), each with distinct disease potentials. Research on fusobacterial pathogenesis has mainly focused on the model strain ATCC 23726 from FNN. However, this narrow focus may overlook significant behaviors of other FNN strains and those from other subspecies, given the genetic and phenotypic diversity within F. nucleatum. While ATCC 23726 is highly transformable, most other Fusobacterium strains exhibit low transformation efficiency, complicating traditional gene deletion methods that rely on non-replicating plasmids. To address this, we developed a conditional plasmid system in which …

Early Application Value Of Flexible Laryngoscope Swallowing Function Assessment In Patients After Partial Laryngectomy, Lina Jia, Chenxu Yan, Run Liu, Pengfei He, Ailing Liu, Fei Yang, Hui Huangfu, Sen Zhang

Faculty, Staff and Student Publications

To investigate the influence of early dysphagia on quality of life in patients with partial laryngectomy, and to investigate the application value of Flexible Endoscopic Evaluation of Swallowing (FEES). This study included 30 inpatients who underwent partial laryngectomy due to laryngeal cancer. In the early postoperative period, a comprehensive assessment was conducted on each patient, encompassing Videofluoroscopic Swallowing Study (VFSS), Flexible Endoscopic Evaluation of Swallowing (FEES), and MD Anderson Dysphagia Inventory (MDADI). Each patient underwent two evaluations at different time points following the surgical procedure, all conducted on the same day. The patients' first MDADI assement score after surgery was …

Iroc Phantoms Accurately Detect Mlc Delivery Errors, Sharbacha S Edward, Julianne M Pollard-Larkin, Peter A Balter, Rebecca M Howell, Christine B Peterson, Stephen F Kry

Faculty, Staff and Student Publications

Purpose: We evaluated the impact of random and whole-bank multileaf collimator (MLC) delivery errors on dosimetric delivery accuracy in the Imaging and Radiation Oncology Core (IROC) phantom audits, as well as differences in delivery accuracy between the IROC phantom prescription and typical clinical fraction sizes.

Methods and materials: Plans were created for the IROC IMRT head and neck (H&N) and SBRT spine phantoms. MLC leaf errors were introduced into the plans: random shifts between -2 and 2 mm, and whole bank shifts of 0.5, 1, and 2 mm. Plans were recalculated and delivered on a Varian Truebeam, and the log …

Nanrilkefusp Alfa (Sot101), An Il-15 Receptor Βγ Superagonist, As A Single Agent Or With Anti-Pd-1 In Patients With Advanced Cancers, Stephane Champiat, Elena Garralda, Vladimir Galvao, Philippe A Cassier, Carlos Gomez-Roca, Iphigenie Korakis, Peter Grell, Aung Naing, Patricia Lorusso, Romana Mikyskova, Nada Podzimkova, Milan Reinis, Kaissa Ouali, Andreu Schoenenberger, Joachim Kiemle-Kallee, Sascha Tillmanns, Richard Sachse, Ulrich Moebius, Radek Spisek, David Bechard, Lenka Palova Jelinkova, Irena Adkins, Aurelien Marabelle

Faculty, Staff and Student Publications

Nanrilkefusp alfa (nanril; SOT101) is an interleukin (IL)-15 receptor βγ superagonist that stimulates natural killer (NK) and CD8

Single-Cell Analysis Of Neoplastic Plasma Cells Identifies Myeloma Pathobiology Mediators And Potential Targets, Luz Yurany Moreno Rueda, Hua Wang, Keiko Akagi, Minghao Dang, Amishi Vora, Li Qin, Hans C Lee, Krina K Patel, Pei Lin, David E Mery, Fenghuang Zhan, John D Shaughnessy, Qing Yi, Yang Song, Bo Jiang, Maura L Gillison, Sheeba K Thomas, Donna M Weber, Lixia Diao, Jing Wang, Isere Kuiatse, Elisabet E Manasanch, David E Symer, Robert Z Orlowski

Faculty, Staff and Student Publications

Multiple myeloma is a clonal plasma cell (PC) dyscrasia that arises from precursors and has been studied utilizing approaches focused on CD138+ cells. By combining single-cell RNA sequencing (scRNA-seq) with scB-cell receptor sequencing (scBCR-seq), we differentiate monoclonal/neoplastic from polyclonal/normal PCs and find more dysregulated genes, especially in precursor patients, than we would have by analyzing bulk PCs. To determine whether this approach can identify oncogenes that contribute to disease pathobiology, mitotic arrest deficient-2 like-1 (MAD2L1) and S-adenosylmethionine synthase isoform type-2 (MAT2A) are validated as targets with drug-like molecules that suppress myeloma growth in preclinical models. Moreover, functional studies show a …

An Integrative Multiparametric Approach Stratifies Putative Distinct Phenotypes Of Blast Phase Chronic Myelomonocytic Leukemia, Kristian Gurashi, Yu-Hung Wang, Fabio M R Amaral, Katherine Spence, Rachel Cant, Chi-Yuan Yao, Chien-Chin Lin, Christopher Wirth, David C Wedge, Guillermo Montalban-Bravo, Simona Colla, Hwei-Fang Tien, Tim C P Somervaille, Kiran Batta, Daniel H Wiseman

Faculty, Staff and Student Publications

Approximately 30% of patients with chronic myelomonocytic leukemia (CMML) undergo transformation to a chemo-refractory blastic phase (BP-CMML). Seeking novel therapeutic approaches, we profiled blast transcriptomes from 42 BP-CMMLs, observing extensive transcriptional heterogeneity and poor alignment to current acute myeloid leukemia (AML) classifications. BP-CMMLs display distinctive transcriptomic profiles, including enrichment for quiescence and variability in drug response signatures. Integrating clinical, immunophenotype, and transcriptome parameters, Random Forest unsupervised clustering distinguishes immature and mature subtypes characterized by differential expression of transcriptional modules, oncogenes, apoptotic regulators, and patterns of surface marker expression. Subtypes differ in predicted response to AML drugs, validated ex vivo in …

Mitochondrial Defects And Metabolic Vulnerabilities In Lynch Syndrome-Associated Msh2-Deficient Endometrial Cancer, Mikayla Borthwick Bowen, Brenda Melendez, Qian Zhang, Diana Moreno, Leah Peralta, Wai Kin Chan, Collene Jeter, Lin Tan, M Anna Zal, Philip L Lorenzi, Kenneth Dunner, Richard K Yang, Russell R Broaddus, Joseph Celestino, Nisha Gokul, Elizabeth Whitley, Deena M Scoville, Tae Hoon Kim, Jae-Wook Jeong, Rosemarie Schmandt, Karen Lu, Hyun-Eui Kim, Melinda S Yates

Faculty, Staff and Student Publications

Lynch syndrome (LS), caused by inherited mutations in DNA mismatch repair genes, including MSH2, carries a 60% lifetime risk of developing endometrial cancer (EC). Beyond hypermutability, mechanisms driving LS-associated EC (LS-EC) remain unclear. We investigated MSH2 loss in EC pathogenesis using a mouse model (PR-Cre Msh2LoxP/LoxP, abbreviated Msh2KO), primary cell lines, human tissues, and human EC cells with isogenic MSH2 knockdown. By 8 months, 58% of Msh2KO mice developed endometrial atypical hyperplasia (AH), a precancerous lesion. At 12-16 months, 50% of Msh2KO mice exhibited either AH or ECs with histologic similarities to human LS-ECs. Transcriptomic profiling of EC from Msh2KO …

Natural And Bioengineered Extracellular Vesicles In Diagnosis, Monitoring And Treatment Of Cancer, Xin Luo, Kathleen M Mcandrews, Raghu Kalluri

Faculty, Staff and Student Publications

Extracellular vesicles (EVs) are cell derived nanovesicles which are implicated in both physiological and pathological intercellular communication, including the initiation, progression, and metastasis of cancer. The exchange of biomolecules between stromal cells and cancer cells via EVs can provide a window to monitor cancer development in real time for better diagnostic and interventional strategies. In addition, the process of secretion and internalization of EVs by stromal and cancer cells in the tumor microenvironment (TME) can be exploited for delivering therapeutics. EVs have the potential to provide a targeted, biocompatible, and efficient delivery platform for the treatment of cancer and other …

Next-Generation Sequencing-Based Msi Scoring Predicts Benefit In Mismatch Repair-Deficient Tumors Treated With Nivolumab: Follow-Up On Nci-Match Arm Z1d, Jonathan D Schoenfeld, Nilofer S Azad, Jacob Gross, Li Chen, Michael J Overman, Katrina Kao, Latifa Jackson, Donna Brunnquell, Xiangning Bu, Christina Coppola, Ping Guan, Jennifer Lee, David Sims, Rebecca Fuchs, Jason L Weirather, Kathleen L Pfaff, Lauren Gunasti, Srin Ranasinghe, Stanley R Hamilton, Victoria Wang, Peter J O'Dwyer, Catherine J Wu, Scott J Rodig, David R Patton, Lyndsay Harris

Faculty, Staff and Student Publications

Purpose: Mismatch repair-deficient (dMMR) tumors have demonstrated favorable responses to immune checkpoint inhibition targeting PD-1. However, more in-depth identification of predictors of response could further refine patient selection for immunotherapy treatment.

Patients and methods: We undertook integrated evaluation performed on samples collected from 28 of 42 patients enrolled on the NCI-Molecular Analysis for Therapy Choice arm Z1D trial that evaluated PD-1 inhibition treatment with nivolumab in patients with noncolorectal dMMR tumors. Genomic analyses were performed using next-generation sequencing (NGS), whole-exome sequencing, and RNA sequencing and supplemented by multiplex immunofluorescence performed on tissue samples.

Results: In this dMMR population, more extensive …

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, …

Reassessing Estrogen Receptor Expression Thresholds For Breast Cancer Prognosis In Her2-Negative Patients Using Shape Restricted Modeling, Wenli Dong, Takeo Fujii, Jing Ning, Toshiaki Iwase, Jing Qin, Naoto T Ueno, Yu Shen

Faculty, Staff and Student Publications

We used a novel shape-restricted Cox model to determine the desirable ER expression cutoff to predict breast cancer prognoses. Our model treats ER as a continuous variable using a flexible monotone-shaped Cox regression to assess its association with survival outcomes holistically. The study included 3055 patients with stage II/III HER2-negative breast cancer. The primary outcomes were time to recurrence or death (TTR) and overall survival (OS). The shape-restricted Cox model identified 10% ER as the preferred cutoff to predict TTR. The finding was confirmed by the log-rank test and standard Cox model that patients with ER ≥ 10% had TTR …

Structure-Activity Relationship Studies Of Dna Methyltransferase 1 Monovalent Degraders, Chao Qian, Youngeun Lee, Yulin Han, Yue Zhong, Jujun Zhou, Joel Hrit, Ling Xie, Qin Chen, H Ümit Kaniskan, Xian Chen, Scott Rothbart, Xiaodong Cheng, Yan Xiong, Jian Jin

Faculty, Staff and Student Publications

DNA methyltransferase 1 (DNMT1), which catalyzes maintenance methylation of hemimethylated DNA during DNA replication, is overexpressed in cancer. Recently, the first-in-class DNMT1-selective noncovalent small-molecule inhibitors, GSK3484862 and GSK3685032, were discovered. These inhibitors were also reported to degrade DNMT1. However, structure–activity relationship (SAR) studies of these monovalent DNMT1 degraders are lacking. Here, we report our SAR studies of this scaffold on degrading DNMT1, which led to the discovery of multiple lead degraders, including compound 4 (MS9024). Compound 4 potently and selectively degraded DNMT1 in multiple cancer cell lines in a concentration-, time-, and proteasome-dependent manner without altering DNMT1 transcription. Further mechanism-of-action …

Inhibition Of Histone Methyltransferase Ezh2 For Immune Interception Of Colorectal Cancer In Lynch Syndrome, Charles M Bowen, Fahriye Duzagac, Abel Martel-Martel, Laura Reyes-Uribe, Mahira Zaheer, Jacklyn Thompson, Nan Deng, Ria Sinha, Soham Mazumdar, Melissa W Taggart, Abhinav K Jain, Elena Tosti, Winfried Edelmann, Krishna M Sinha, Eduardo Vilar

Faculty, Staff and Student Publications

Colorectal precancers in Lynch syndrome (LS) exhibit a distinct immune profile, presenting unique opportunities for developing immune-interception strategies to prevent carcinogenesis. Epigenetic modulation by EZH2 of immune-related genes is implicated in the carcinogenesis of different cancer types, including colorectal cancer. This study utilizes a mouse model of LS and ex vivo colonic organoids to assess the effects of the EZH2 inhibitor GSK503 on immune regulatory pathways, tumorigenesis, and epigenetic reprogramming. Our findings revealed that GSK503 significantly increased CD4+ and CD8+ T cells in both splenocytes and colonic mucosa of treated mice compared with controls. Additionally, a preventive dose of GSK503 …

Contribution Of Rare Chromosome 22q112 Copy Number Variants To Non-Syndromic Bicuspid Aortic Valve, Helene Digregorio, Sara Mansoorshahi, Steven G Carlisle, Catherina Tovar Pensa, Abi Watts, Courtney Mcneely, Anna Sabate-Rotes, Anji Yetman, Hector I Michelena, Julie F A De Backer, Laura Muiño Mosquera, Malenka M Bissell, Maria Grazia Andreassi, Ilenia Foffa, Dawn S Hui, Anthony Caffarelli, Yuli Y Kim, Rodolfo Citro, Margot De Marco, Justin T Tretter, Kim L Mcbride, Simon C Body, Dianna M Milewicz, Siddharth K Prakash, Ebav Investigators

Faculty, Staff and Student Publications

Background: Bicuspid aortic valve (BAV) is the most common congenital heart defect in adults, often leading to complications such as thoracic aortic aneurysms and aortic stenosis. While BAV is frequently associated with 22q11.2 deletion syndrome (22q11.2DS), the contribution of rare copy number variants (CNVs) in this region to non-syndromic BAV is less clear. This study is aimed to assess the role of rare 22q11.2 CNVs in patients with early-onset BAV (EBAV) and to determine whether these variants are linked to an increased risk of complications.

Methods: Whole genome microarray genotyping was conducted on 272 patients with BAV with early onset …

Efficacy And Safety Of Nivolumab Plus Ipilimumab In Patients With Metastatic Variant Histology (Non-Clear Cell) Renal Cell Carcinoma, Mohammad Jad Moussa, Jaanki Khandelwal, Nathaniel R Wilson, Kiran L Malikayil, Devaki Shilpa Surasi, Tharakeswara K Bathala, Yiyun Lin, Priya Rao, Pheroze Tamboli, Kanishka Sircar, Helen Ajufo, Khaled M Elsayes, Amishi Shah, Andrew C Johns, Sangeeta Goswami, Elshad Hasanov, Eric Jonasch, Pavlos Msaouel, Matthew T Campbell, Omar Alhalabi, Nizar M Tannir

Faculty, Staff and Student Publications

Background: Nivolumab plus ipilimumab (nivo/ipi) is a standard of care first-line (1 L) therapy for patients with metastatic clear-cell renal cell carcinoma (ccRCC), but its role in patients with metastatic, non-ccRCC has not been fully defined. We report a single-institution experience with nivo/ipi in non-ccRCC.

Methods: Between November 2017 and February 2024, 55 patients with metastatic non-ccRCC received nivo/ipi at MD Anderson Cancer Center. The tumor response was assessed by blinded radiologists using RECIST v1.1. The overall response rate (ORR), progression-free survival (PFS), PFS milestone, duration of response (DoR), and overall survival (OS) were determined. Next-generation sequencing (NGS) was performed …

Repeat Expansion In A Fragile X Model Is Independent Of Double Strand Break Repair Mediated By Pol Θ, Rad52, Rad54 Or Rad54b, Bruce E Hayward, Geum-Yi Kim, Carson J Miller, Cai Mccann, Megan G Lowery, Richard D Wood, Karen Usdin

Faculty, Staff and Student Publications

Microsatellite instability is responsible for the human repeat expansion diseases (REDs). The mutagenic process differs from classical cancer-associated microsatellite instability (MSI) in that it requires the mismatch repair proteins that normally protect against MSI. LIG4, an enzyme essential for non-homologous end-joining (NHEJ), the major pathway for double-strand break repair (DSBR) in mammalian cells, protects against expansion in mouse models. Thus, NHEJ may compete with the expansion pathway for access to a common intermediate. This raises the possibility that expansion involves an NHEJ-independent form of DSBR. Pol θ, a polymerase involved in the theta-mediated end joining (TMEJ) DSBR pathway, has been …