Biomedical Informatics Commons^™

Impact Of Comorbidities On The Mortality Benefits Of Lung Cancer Screening: A Post-Hoc Analysis Of The Plco And Nlst Trials, Sebastien Gendarme, Ehsan Irajizad, James P Long, Johannes F Fahrmann, Jennifer B Dennison, Seyyed Mahmood Ghasemi, Rongzhang Dou, Robert J Volk, Rafael Meza, Iakovos Toumazis, Florence Canoui-Poitrine, Samir M Hanash, Edwin J Ostrin

Faculty, Staff and Student Publications

Objectives: To evaluate how comorbidities affect mortality benefits of lung cancer screening (LCS) with low-dose computed tomography.

Methods: We developed a comorbidity index (Prostate, Lung, Colorectal, and Ovarian comorbidity index [PLCO-ci]) using LCS-eligible participants' data from the Prostate, Lung, Colorectal, and Ovarian (PLCO) trial (training set) and the National Lung Screening Trial (NLST) (validation set). PLCO-ci predicts five-year non-lung cancer (LC) mortality using a regularized Cox model; with performance evaluated using the area under the receiver operating characteristics curve. In NLST, LC mortality (per original publication) was compared between low-dose computed tomography and chest radiograph arms across the PLCO-ci quintile …

Air Embolism After Percutaneous Lung Biopsy Or Ablation: A Report Of Six Cases, Rebecca Choi, Haylie Kieu-Mi Phan, Varshana Gurusamy, Rahul A Sheth, Bruno C Odisio, Kelvin Hong, Alda L Tam

Faculty, Staff and Student Publications

Systemic air embolism is a rare but potentially life-threatening complication of percutaneous lung biopsy and ablation. This report describes six patients (four male, two female) with air embolism following CT-guided lung interventions at two institutions between January 2021 and March 2024. Air embolisms were identified in locations such as the pulmonary vein, left ventricle, and coronary arteries, with clinical presentations ranging from asymptomatic to life-threatening events. Prompt intervention, including oxygen therapy, patient repositioning, and intravenous administration of epinephrine in cases of cardiac arrest, resulted in favorable outcomes. This series highlights the importance of early detection of systemic air embolism and …

Rnase1-Driven Alk-Activation Is An Oncogenic Driver And Therapeutic Target In Non-Small Cell Lung Cancer, Zhengyu Zha, Chunxiao Liu, Meisi Yan, Cong Chen, Cheng Yu, Yaohui Chen, Chenhao Zhou, Lu Li, Yi-Chuan Li, Hiro Yamaguchi, Leiguang Ye, Tong Liu, Ying-Nai Wang, Heng-Huan Lee, Wen-Hao Yang, Li-Chuan Chan, Baozhen Ke, Jennifer L Hsu, Lieming Ding, Dong Ji, Peng Pan, Yiran Meng, Yue Pu, Lunxu Liu, Mien-Chie Hung

Faculty, Staff and Student Publications

Targeted therapy has achieved significant success in the treatment of non-small cell lung cancer (NSCLC), particularly in patients harboring common oncogenic driver mutations such as EGFR, KRAS, and ALK rearrangement. However, ~35-50% of NSCLC patients without tyrosine kinase mutation or rearrangement (non-mutated) cannot benefit from these targeted treatments, highlighting the urgent need for novel therapeutic strategies for this patient population. In this study, we report a non-canonical role of human secretory ribonuclease 1 (RNase1), which binds to and activates wild-type ALK in lung cancer cells, thereby triggering its downstream signaling pathway. RNase1-driven ALK-activation (RDAA) cells exhibit enhanced cell proliferation, migration, …

Lysyl Hydroxylase 2 Glucosylates Collagen Vi To Drive Lung Cancer Progression, Shike Wang, Houfu Guo, Reo Fukushima, Masahiko Terajima, Min Liu, Guan-Yu Xiao, Lenka Koudelková, Chao Wu, Xin Liu, Jiang Yu, Emma Burris, Jun Xu, Alvise Schiavinato, William K Russell, Mitsuo Yamauchi, Xiaochao Tan, Jonathan M Kurie

Faculty, Staff and Student Publications

Lysyl hydroxylase 2 (LH2) is highly expressed in multiple tumor types and accelerates disease progression by hydroxylating lysine residues on fibrillar collagen telopeptides to generate stable collagen cross links in tumor stroma. Here, we show that a galactosylhydroxylysyl glucosyltransferase (GGT) domain on LH2-modified type-VI collagen (Col6) to promote lung adenocarcinoma (LUAD) growth and metastasis. In tumors generated by LUAD cells lacking LH2 GGT domain activity, stroma was less stiff, and stable types of collagen cross links were reduced. Mass spectrometric analysis of total and glycosylated peptides in parental and GGT-inactive tumor samples identified Col6 chain α3 (Col6a3), a component of …

Lesion Classification By Model-Based Feature Extraction: A Differential Affine Invariant Model Of Soft Tissue Elasticity In Ct Images, Weiguo Cao, Marc J Pomeroy, Zhengrong Liang, Yongfeng Gao, Yongyi Shi, Jiaxing Tan, Fangfang Han, Jing Wang, Jianhua Ma, Hongbin Lu, Almas F Abbasi, Perry J Pickhardt

Faculty, Staff and Student Publications

The elasticity of soft tissues has been widely considered a characteristic property for differentiation of healthy and lesions and, therefore, motivated the development of several elasticity imaging modalities, for example, ultrasound elastography, magnetic resonance elastography, and optical coherence elastography to directly measure the tissue elasticity. This paper proposes an alternative approach of modeling the elasticity for prior knowledge-based extraction of tissue elastic characteristic features for machine learning (ML) lesion classification using computed tomography (CT) imaging modality. The model describes a dynamic non-rigid (or elastic) soft tissue deformation in differential manifold to mimic the tissues’ elasticity under wave fluctuation in vivo. …

Receptor Tyrosine Kinase Fusion-Mediated Resistance To Egfr Tki In Egfr-Mutant Nsclc: A Multi-Center Analysis And Literature Review, Yang Xia, Kaiwen Wang, Jing Zhao, Zhaohui Arter, Yongchang Zhang, Jiaqi Zhou, Yuefei Lu, Liang Zeng, Robyn Du, Jennifer A Owens, Yasir Y Elamin, Carl M Gay, Ferdinandos Skoulidis, Anne S Tsao, Charles Lu, Tina Cascone, Don L Gibbons, Jianjun Zhang, Olivia Chen, Kevin K S Mok, Misako Nagasaka, Wen Li, John V Heymach, Sai-Hong Ignatius Ou, Molly Li, Xiuning Le

Faculty, Staff and Student Publications

Introduction: Drug resistance remains a major clinical challenge in EGFR-mutant NSCLC tumors owing to pathway reactivation, pathway bypass, and pathway indifference resistance mechanisms to evade tyrosine kinase inhibitor (TKI) suppression. Fusion of receptor tyrosine kinases (RTKs), such as RET, ALK, and FGFR3, has been reported to mediate EGFR TKI resistance. Given the rarity of these fusions and the heterogeneous nature of the condition, no prospective clinical trials evaluated the incidence, safety, and therapeutic benefit of dual EGFR-RTK inhibition.

Methods: We queried clinical databases from multiple institutions to identify patients who had RTK fusions detected on next-generation sequencing testing results from …

Cigarette Smoke Induces Angiogenic Activation In The Cancer Field Through Dysregulation Of An Endothelial Microrna, Asawari Korde, Anuradha Ramaswamy, Seth Anderson, Lei Jin, Jian-Ge Zhang, Buqu Hu, Walter V Velasco, Lixia Diao, Jing Wang, Margaret A Pisani, Maor Sauler, Daniel J Boffa, Jonathan T Puchalski, Xiting Yan, Seyed Javad Moghaddam, Shervin S Takyar

Faculty, Staff and Student Publications

Cigarette smoke (CS) creates a "cancer field" in the lung that promotes malignant transformation. The molecular changes within this field are not fully characterized. We examined the significance of microRNA-1 (miR-1) downregulation as one of these changes. We found that tumor miR-1 levels in three non-small cell lung cancer cohorts show inverse correlations with the smoking burden. Lung MiR-1 levels follow a spatial gradient, have prognostic significance, and correlate inversely with the molecular markers of injury. In CS-exposed lungs, miR-1 is specifically downregulated in the endothelium. Exposure to CS induces angiogenesis by selectively degrading mature miR-1 via a vascular endothelial …

Dna Damage Response Signatures Are Associated With Frontline Chemotherapy Response And Routes Of Tumor Evolution In Extensive Stage Small Cell Lung Cancer, Benjamin B Morris, Simon Heeke, Yuanxin Xi, Lixia Diao, Qi Wang, Pedro Rocha, Edurne Arriola, Myung Chang Lee, Darren R Tyson, Kyle Concannon, Kavya Ramkumar, C Allison Stewart, Robert J Cardnell, Runsheng Wang, Vito Quaranta, Jing Wang, John V Heymach, Barzin Y Nabet, David S Shames, Carl M Gay, Lauren A Byers

Faculty, Staff and Student Publications

Introduction: A hallmark of small cell lung cancer (SCLC) is its recalcitrance to therapy. While most SCLCs respond to frontline therapy, resistance inevitably develops. Identifying phenotypes potentiating chemoresistance and immune evasion is a crucial unmet need. Previous reports have linked upregulation of the DNA damage response (DDR) machinery to chemoresistance and immune evasion across cancers. However, it is unknown if SCLCs exhibit distinct DDR phenotypes.

Methods: To study SCLC DDR phenotypes, we developed a new DDR gene analysis method and applied it to SCLC clinical samples, in vitro, and in vivo model systems. We then investigated how DDR regulation is …

Impact Of Co-Mutations And Transcriptional Signatures In Non-Small Cell Lung Cancer Patients Treated With Adagrasib In The Krystal-1 Trial, Marcelo V Negrao, Alvaro G Paula, David Molkentine, Laura Hover, Monique Nilsson, Natalie Vokes, Lars Engstrom, Andrew Calinisan, David M Briere, Laura Waters, Jill Hallin, Lixia Diao, Mehmet Altan, George R Blumenschein, Ferdinandos Skoulidis, Jing Wang, Scott E Kopetz, David S Hong, Don L Gibbons, Peter Olson, James G Christensen, John V Heymach

Faculty, Staff and Student Publications

Purpose: KRAS inhibitors are revolutionizing the treatment of non-small cell lung cancer (NSCLC), but clinico-genomic determinants of treatment efficacy warrant continued exploration.

Experimental design: Patients with advanced KRASG12C-mutant NSCLC treated with adagrasib [KRYSTAL-1 (NCT03785249)] were included in the analysis. Pretreatment next-generation sequencing data were collected per protocol. HTG EdgeSeq Transcriptome Panel was used for gene expression profiling. Clinical endpoints included objective response, progression-free survival (PFS), and overall survival (OS). KRASG12C-mutant NSCLC cell lines and xenograft models were used for sensitivity analyses and combination drug screens.

Results: KEAP1 MUT and STK11MUT were associated with shorter survival to adagrasib [KEAP1: …

Incidence And Correlates Of High-Grade Chemotherapy-Induced Peripheral Neuropathy In Patients With Lung Cancer, Mitchell S Von Itzstein, Sawsan Rashdan, Suzanne E Dahlberg, David E Gerber, Alan B Sandler, Joan H Schiller, David H Johnson, Yating Wang, Zhuoxin Sun, Suresh S Ramalingam

Faculty, Staff and Student Publications

Background: High-grade chemotherapy-induced peripheral neuropathy (CIPN) represents a dreaded toxicity of cancer treatments. In some cases, it may limit activities of daily living and become permanent. Because many prior studies of CIPN were conducted in breast cancer populations, less is known about CIPN in men. We therefore determined the incidence and correlates of high-grade CIPN in a large cohort of patients with lung cancer.

Methods: We collected data from the ECOG-ACRIN E1594 (comparison of 4 chemotherapy regimens: cisplatin-paclitaxel, cisplatin-gemcitabine, cisplatin-docetaxel, carboplatin-paclitaxel) and E4599 (carboplatin-paclitaxel ± concurrent and maintenance bevacizumab) clinical trials. We identified cases with grade ≥3 CIPN. Multivariable logistic …

Nprl2 Gene Therapy Induces Effective Antitumor Immunity In Kras/Stk11 Mutant Anti-Pd1 Resistant Metastatic Non-Small Cell Lung Cancer (Nsclc) In A Humanized Mouse Model, Ismail M Meraz, Mourad Majidi, Renduo Song, Feng Meng, Lihui Gao, Qi Wang, Jing Wang, Elizabeth J Shpall, Jack A Roth

Faculty, Staff and Student Publications

Expression of NPRL2/TUSC4, a tumor-suppressor gene, is reduced in many cancers including NSCLC. Restoration of NPRL2 induces DNA damage, apoptosis, and cell-cycle arrest. We investigated NPRL2 antitumor immune responses in aPD1R/KRAS/STK11^mt NSCLC in humanized-mice. Humanized-mice were generated by transplanting fresh human cord blood-derived CD34 stem cells into sub-lethally irradiated NSG mice. Lung-metastases were developed from KRAS/STK11^mt/aPD1R A549 cells and treated with NPRL2 w/wo pembrolizumab. NPRL2-treatment reduced lung metastases significantly, whereas pembrolizumab was ineffective. Antitumor effect was greater in humanized than non-humanized-mice. NPRL2 + pembrolizumab was not synergistic in KRAS/STK11^mt/aPD1R tumors but was …

Proceedings Of The 1st Biannual Bridging The Gaps In Lung Cancer Conference, Narjust Florez, Sandip P Patel, Heather Wakelee, Lyudmila Bazhenova, Erminia Massarelli, Ravi Salgia, Brendon Stiles, Solange Peters, Jyoti Malhotra, Shirish M Gadgeel, Jorge J Nieva, Michelle Afkhami, Fred R Hirsch, Matthew Gubens, Tina Cascone, Benjamin Levy, Joshua Sabari, Hatim Husain, Patrick C Ma, Leah M Backhus, Puneeth Iyengar, Percy Lee, Russell Miller, Jacob Sands, Edward Kim

Faculty, Staff and Student Publications

Lung cancer is the leading cause of cancer death in the US and globally. The mortality from lung cancer has been declining, due to a reduction in incidence and advances in treatment. Although recent success in developing targeted and immunotherapies for lung cancer has benefitted patients, it has also expanded the complexity of potential treatment options for health care providers. To aid in reducing such complexity, experts in oncology convened a conference (Bridging the Gaps in Lung Cancer) to identify current knowledge gaps and controversies in the diagnosis, treatment, and outcomes of various lung cancer scenarios, as described here. Such …

Brd7 Loss Reawakens Dormant Metastasis Initiating Cells In Lung By Forging An Immunosuppressive Niche, Jayanta Mondal, Junfeng Zhang, Feng Qing, Shunping Li, Dhiraj Kumar, Jason T Huse, Filippo G Giancotti

Faculty, Staff and Student Publications

Metastasis in cancer is influenced by epigenetic factors. Using an in vivo screen, we demonstrate that several subunits of the polybromo-associated BAF (PBAF) chromatin remodeling complex, particularly Brd7, are required for maintaining breast cancer metastatic dormancy in the lungs of female mice. Brd7 loss induces metastatic reawakening, along with modifications in epigenomic landscapes and upregulated oncogenic signaling. Breast cancer cells harboring Brd7 inactivation also reprogram the surrounding immune microenvironment by downregulating MHC-1 expression and promoting a pro-metastatic cytokine profile. Flow cytometric and single-cell analyses reveal increased levels of pro-tumorigenic inflammatory and transitional neutrophils, CD8+ exhausted T cells, and CD4+ stress …

Safety And Tolerability Of Letetresgene Autoleucel (Gsk3377794): Pilot Studies In Patients With Advanced Non-Small Cell Lung Cancer, Mehmet Altan, Gilberto Lopes, T Jeroen N Hiltermann, Ramaswamy Govindan, Liza C Villaruz, Emiliano Calvo, Martin J Edelman, Muhammad Furqan, Joel Neal, Enriqueta Felip, Jennifer W Carlisle, John V Heymach, Róisín Eilish O'Cearbhaill, Marjorie Zauderer, Michael Chisamore, Ellie Corigliano, Ioanna Eleftheriadou, Stefan Zajic, Ben Jenkins, Sophia Goodison, Sunil Suchindran, Natalia Ramos-Hernandez, Nidale Tarek, Adam J Schoenfeld

Faculty, Staff and Student Publications

Purpose: The study aims to evaluate the safety, tolerability, and antitumor response of letetresgene autoleucel (lete-cel), genetically modified autologous T cells expressing a T-cell receptor specific for New York esophageal squamous cell carcinoma 1 (NY-ESO-1)/LAGE-1a shared epitope, alone or in combination with pembrolizumab, in HLA-A*02-positive (HLA-A*02:01, HLA-A*02:05, and/or HLA-A*02:06) patients with NY-ESO-1- and/or LAGE-1a-positive non-small cell lung cancer.

Patients and methods: Study 208749 was a single-arm study of lete-cel alone. Study 208471 was a multiarm study of lete-cel alone or in combination with pembrolizumab in patients with advanced or recurrent non-small cell lung cancer.

Results: More than 2,500 patients were …

Rezilient3: Randomized Phase Iii Study Of First-Line Zipalertinib Plus Chemotherapy In Patients With Egfr Exon 20 Insertion-Mutated Nsclc, John V Heymach, Helena A Yu, Benjamin Besse, Ying Cheng, Daniel Sw Tan, Li Wei, Volker Wacheck, Makoto Nishio

Faculty, Staff and Student Publications

There remains a significant unmet need for effective and tolerable treatments for patients with non-small cell lung cancer (NSCLC) harboring epidermal growth factor receptor (

A Multicenter Open-Label Randomized Phase Ii Study Of Osimertinib With And Without Ramucirumab In Tyrosine Kinase Inhibitor–Naïve Egfr-Mutant Metastatic Non–Small Cell Lung Cancer (Ramose Trial), Xiuning Le, Jyoti D Patel, Elaine Shum, Christina Baik, Rachel E Sanborn, Catherine A Shu, Chul Kim, Mary Jo Fidler, Richard Hall, Yasir Y Elamin, Janet Tu, George Blumenschein, Jianjun Zhang, Don Gibbons, Carl Gay, Nisha A Mohindra, Young Chae, Yanis Boumber, Joshua Sabari, Rafael Santana-Davila, Shane Rogosin, Benjamin Herzberg, Ben Creelan, Bruna Pellini, Tawee Tanvetyanon, Simon Heeke, Mike Hernandez, Jhanelle E Gray, Andreas Saltos, John V Heymach

Faculty, Staff and Student Publications

Purpose: Preclinical studies demonstrated that dual inhibition of epidermal growth factor receptor (EGFR) and vascular endothelial growth factor (VEGF) pathways delay the emergence of resistance to EGFR tyrosine kinase inhibitors (TKIs), and in trials with first-generation EGFR TKIs, the combination of EGFR VEGF pathway inhibitors prolonged progression-free survival (PFS).

Methods: The RAMOSE trial (ClinicalTrials.gov identifier: NCT03909334, HCRN LUN-18-335) is a randomized, open-label multicenter phase II study comparing osimertinib with ramucirumab (arm A) to osimertinib (arm B) for initial treatment of metastatic EGFR-mutant non-small cell lung cancer (NSCLC) with 2:1 random assignment. The primary end point is PFS for …

Imaging Lung Tumor Motion Using Integrated-Mode Proton Radiography-A Phantom Study Towards Tumor Tracking In Proton Radiotherapy, Ryan Fullarton, Mikaël Simard, Lennart Volz, Allison Toltz, Savanna Chung, Christoph Schuy, Daniel G Robertson, Gary Royle, Sam Beddar, Colin Baker, Christian Graeff, Charles-Antoine Collins-Fekete

Faculty, Staff and Student Publications

BACKGROUND: Motion of lung tumors during radiotherapy leads to decreased accuracy of the delivered dose distribution. This is especially true for proton radiotherapy due to the finite range of the proton beam. Methods for mitigating motion rely on knowing the position of the tumor during treatment.

PURPOSE: Proton radiography uses the treatment beam, at an energy high enough to traverse the patient, to produce a radiograph. This work shows the first results of using an integrated-mode proton radiography system to track the position of moving objects in an experimental phantom study; demonstrating the potential of using this method for measuring …

Statistical Identification Of Cell Type-Specific Spatially Variable Genes In Spatial Transcriptomics, Lulu Shang, Peijun Wu, Xiang Zhou

Faculty, Staff and Student Publications

An essential task in spatial transcriptomics is identifying spatially variable genes (SVGs). Here, we present Celina, a statistical method for systematically detecting cell type-specific SVGs (ct-SVGs)-a subset of SVGs exhibiting distinct spatial expression patterns within specific cell types. Celina utilizes a spatially varying coefficient model to accurately capture each gene's spatial expression pattern in relation to the distribution of cell types across tissue locations, ensuring effective type I error control and high power. Celina proves powerful compared to existing methods in single-cell resolution spatial transcriptomics and stands as the only effective solution for spot-resolution spatial transcriptomics. Applied to five real …

Real-Time Cbct Imaging And Motion Tracking Via A Single Arbitrarily-Angled X-Ray Projection By A Joint Dynamic Reconstruction And Motion Estimation (Dreme) Framework, Hua-Chieh Shao, Tielige Mengke, Tinsu Pan, You Zhang

Faculty, Staff and Student Publications

Objective: Real-time cone-beam computed tomography (CBCT) provides instantaneous visualization of patient anatomy for image guidance, motion tracking, and online treatment adaptation in radiotherapy. While many real-time imaging and motion tracking methods leveraged patient-specific prior information to alleviate under-sampling challenges and meet the temporal constraint (< 500 ms), the prior information can be outdated and introduce biases, thus compromising the imaging and motion tracking accuracy. To address this challenge, we developed a framework dynamic reconstruction and motion estimation (DREME) for real-time CBCT imaging and motion estimation, without relying on patient-specific prior knowledge.

Approach: DREME incorporates a deep learning-based real-time CBCT imaging and motion estimation method into a dynamic CBCT reconstruction framework. The reconstruction framework reconstructs a dynamic sequence of CBCTs in a data-driven manner from a standard pre-treatment scan, without requiring patient-specific prior knowledge. Meanwhile, a convolutional neural network-based motion encoder is jointly trained during the reconstruction …

Pooled Safety Analysis And Management Of Sotorasib-Related Adverse Events In Kras G12c-Mutated Advanced Non-Small Cell Lung Cancer, Ferdinandos Skoulidis, Bob T Li, Maximilian Hochmair, Ramaswamy Govindan, Mark Vincent, Anthonie J Van Der Wekken, Noemi Reguart Aransay, Kenneth J O'Byrne, Nicolas Girard, Frank Griesinger, Makoto Nishio, Simon Häfliger, Colin Lindsay, Niels Reinmuth, Astrid Paulus, Pavlos Papakotoulas, Sang-We Kim, Carlos Gil Ferreira, Giulia Pasello, Michael Duruisseaux, Spyridon Gennatas, Anastasios Dimou, Bhakti Mehta, William Kormany, Chidozie Nduka, Brooke E Sylvester, Christine Ardito-Abraham, Yang Wang, Adrianus Johannes De Langen

Faculty, Staff and Student Publications

Introduction: We describe the safety of sotorasib monotherapy in patients with KRAS G12C-mutated advanced non-small cell lung cancer (NSCLC) and discuss practical recommendations for managing key risks.

Methods: Incidence rates of treatment-related adverse events (TRAEs) were pooled from 4 clinical trials: CodeBreaK 100 (NCT03600883), CodeBreaK 101 (NCT04185883), CodeBreaK 105 (NCT04380753), and CodeBreaK 200 (NCT04303780) and graded according to CTCAE v5.0. Adverse events were deemed sotorasib-related per investigator causality assessment.

Results: In the pooled population (n = 549), TRAEs were reported in 388 (70.7%) patients (grade 1: 124 [22.6%]; grade 2: 117 [21.3%]; …

Zongertinib (Bi 1810631), An Irreversible Her2 Tki, Spares Egfr Signaling And Improves Therapeutic Response In Preclinical Models And Patients With Her2-Driven Cancers, Birgit Wilding, Lydia Woelflingseder, Anke Baum, Krzysztof Chylinski, Gintautas Vainorius, Neil Gibson, Irene C Waizenegger, Daniel Gerlach, Martin Augsten, Fiona Spreitzer, Yukina Shirai, Masachika Ikegami, Sylvia Tilandyová, Dirk Scharn, Mark A Pearson, Johannes Popow, Anna C Obenauf, Noboru Yamamoto, Shunsuke Kondo, Frans L Opdam, Annemarie Bruining, Shinji Kohsaka, Norbert Kraut, John V Heymach, Flavio Solca, Ralph A Neumüller

Faculty, Staff and Student Publications

Mutations in ERBB2 (encoding HER2) occur in 2% to 4% of non-small cell lung cancer (NSCLC) and confer poor prognosis. ERBB-targeting tyrosine kinase inhibitors, approved for treating other HER2-dependent cancers, are ineffective in HER2-mutant NSCLC due to dose-limiting toxicities or suboptimal potency. We report the discovery of zongertinib (BI 1810631), a covalent HER2 inhibitor. Zongertinib potently and selectively blocks HER2, while sparing EGFR, and inhibits the growth of cells dependent on HER2 oncogenic driver events, including HER2-dependent human cancer cells resistant to trastuzumab deruxtecan. Zongertinib displays potent antitumor activity in HER2-dependent human NSCLC xenograft models and enhances the activities of …

A Regularized Bayesian Dirichlet-Multinomial Regression Model For Integrating Single-Cell-Level Omics And Patient-Level Clinical Study Data, Yanghong Guo, Lei Yu, Lei Guo, Lin Xu, Qiwei Li

Faculty, Staff and Student Publications

The abundance of various cell types can vary significantly among patients with varying phenotypes and even those with the same phenotype. Recent scientific advancements provide mounting evidence that other clinical variables, such as age, gender, and lifestyle habits, can also influence the abundance of certain cell types. However, current methods for integrating single-cell-level omics data with clinical variables are inadequate. In this study, we propose a regularized Bayesian Dirichlet-multinomial regression framework to investigate the relationship between single-cell RNA sequencing data and patient-level clinical data. Additionally, the model employs a novel hierarchical tree structure to identify such relationships at different cell-type …

Selective Inhibition Of Canonical Stat3 Signaling Suppresses K-Ras Mutant Lung Tumorigenesis And Reinvigorates Anti-Tumor Immunity, Michael J Clowers, Zahraa Rahal, Sung-Nam Cho, Avantika Krishna, Bo Yuan, Leticia G Hamana Zorrilla, T Kris Eckols, Moses M Kasembeli, Samuel Liu, Stephen Peng, Marco Ramos-Castaneda, Annamarie L Thompson, Carlos Ignacio Rodriguez Reyna, Katherine E Larsen, Maria T Grimaldo, Shanshan Deng, Nastaran Karimi, Cody Chou, Walter V Velasco, Melody Zarghooni, Sayan Alekseev, Luisa M Solis Soto, Edwin J Ostrin, Humam Kadara, Suhendan Ekmekcioglu, David J Tweardy, Seyed Javad Moghaddam

Faculty, Staff and Student Publications

Introduction: K-ras mutant lung adenocarcinoma (KM-LUAD) is a difficult-to-treat cancer subtype in which chronic inflammation pervades the tumor immune microenvironment (TIME). Pro-inflammatory pathways dampen the response to treatments, including immune checkpoint inhibitors, necessitating therapies that target this inflammatory signaling network in the TIME. One of the lynchpins of chronic inflammation in KM-LUAD is signal transducer and activator of transcription 3 (STAT3).

Methods: Here, we tested the anti-tumor and early immunotherapeutic efficacy of TTI-101, a selective small-molecule inhibitor of canonical STAT3 signaling, in a K-rasG12D mutant lung cancer mouse model (CC-LR).

Results: Treatment of CC-LR mice with TTI-101 resulted in reduced …

Consolidation Alk Tyrosine Kinase Inhibitors Versus Durvalumab Or Observation After Chemoradiation In Unresectable Stage Iii Alk-Positive Nsclc, Amin H Nassar, Ritujith Jayakrishnan, Jamie Feng, Frances Shepherd, Elio Adib, Justin M Cheung, Jessica J Lin, Yufei Liu, Steven H Lin, Kaushal Parikh, Arthi Sridhar, Purnima Shakya, Thomas J Dilling, David Kaldas, Jhanelle E Gray, Anastasiya Lobachov, Jair Bar, Heike Luders, Christian Grohe, Shruti Gupta, Ticiana Leal, Bailey Fitzgerald, Fionnuala Crowley, Yu Fujiwara, Thomas U Marron, Molly Wilgucki, Joshua Reuss, Luxi Chen, Kamya Sankar, Jacqueline V Aredo, Joel W Neal, Heather A Wakelee, Rohit Thummalapalli, Helena Yu, Ryan Whitaker, Ana Velazquez, Meera Ragavan, Alessio Cortellini, David J Kwiatkowski, Abdul Rafeh Naqash, Sarah B Goldberg, So Yeon Kim

Faculty, Staff and Student Publications

Introduction: Patients with advanced ALK-positive NSCLC typically have poor response to immunotherapy; the benefit of consolidation durvalumab in patients with unresectable stage III ALK-positive NSCLC remains unclear. Herein, we compare the efficacy and safety of consolidation ALK tyrosine kinase inhibitor (TKI) versus durvalumab or observation after concurrent chemoradiation.

Methods: We conducted a retrospective study using a multicenter study of 17 institutions globally. Patients with unresectable stage III ALK-positive NSCLC treated between 2015 and 2022 were included. Patients received ALK TKI, durvalumab, or observation after concurrent chemoradiation. Real-world progression-free survival (rwPFS) and overall survival (OS) were estimated using Kaplan-Meier method. Treatment-related …

Integrative Multi-Omics Approach For Improving Causal Gene Identification, Austin King, Chong Wu

Faculty, Staff and Student Publications

Transcriptome-wide association studies (TWAS) have been widely used to identify thousands of likely causal genes for diseases and complex traits using predicted expression models. However, most existing TWAS methods rely on gene expression alone and overlook other regulatory mechanisms of gene expression, including DNA methylation and splicing, that contribute to the genetic basis of these complex traits and diseases. Here we introduce a multi-omics method that integrates gene expression, DNA methylation, and splicing data to improve the identification of associated genes with our traits of interest. Through simulations and by analyzing genome-wide association study (GWAS) summary statistics for 24 complex …

Efficacy Of A Smartphone Application Assisting Home-Based Rehabilitation And Symptom Management For Patients With Lung Cancer Undergoing Video-Assisted Thoracoscopic Lobectomy: A Prospective, Single-Blinded, Randomised Control Trial (Popper Study, Chao Lv, Fangliang Lu, Xiugeng Zhou, Xiang Li, Wenhua Yu, Chune Zhang, Kaishen Chen, Songtao Du, Chao Han, Jia Wang, Yuzhao Wang, Shaolei Li, Liang Wang, Yinan Liu, Shanyuan Zhang, Miao Huang, Dongdong Song, Dachuan Zhao, Bing Liu, Yaqi Wang, Xinrun Cui, Zhiwei Zhou, Shi Yan, Nan Wu

Faculty, Staff and Student Publications

Background: Video-assisted thoracoscopic (VATS) lobectomy can affect patients' pulmonary function and quality of life significantly. No optimal protocol combining patient-reported outcome-based symptom management and postdischarge rehabilitation programme has yet been established. This study aimed to assess the efficacy of a novel smartphone app designed for home-based symptom management and rehabilitation.

Methods: The app was developed based on three modules: a symptom reporting system with alerts, aerobic and respiratory training exercises, and educational material. Four core symptoms were selected based on a questionnaire survey of 201 patients and three rounds of Delphi voting by 30 experts. The authors screened 265 patients …

Stat3 Inhibition In Combination With Cd47 Blockade Inhibits Osteosarcoma Lung Metastasis, Pradeep Shrestha, Rejeena Shrestha, You Zhou, Rafal Zielinski, Waldemar Priebe, Eugenie S Kleinerman

Faculty, Staff and Student Publications

Background: New therapies are urgently needed for patients with osteosarcoma (OS). STAT3 and CD47 are potential therapeutic target in OS. Here we investigated the therapeutic activity of the orally bioavailable STAT3 inhibitor, WP1066, and anti-CD47 antibody using OS mouse models.

Methods: Cytotoxic effect of WP1066 against OS cell lines and its immunomodulatory effects were evaluated in vitro. Experimental metastasis and orthotopic syngeneic mouse models were used to investigate the therapeutic efficacy of WP1066 and anti-CD47 antibody. Further flow cytometric analysis was performed.

Results: STAT3 was constitutively activated in multiple human and mouse OS cell lines. WP1066 suppressed STAT3 activation …

High Peripheral T Cell Diversity Is Associated With Lower Risk Of Toxicity And Superior Response To Dual Immune Checkpoint Inhibitor Therapy In Patients With Metastatic Nsclc, Mehmet Altan, Ruoxing Li, Ziyi Li, Runzhe Chen, Ajay Sheshadri, Hai T Tran, Latasha Little, Joshua Baguley, Jefferson Sinson, Natalie Vokes, Saumil Gandhi, Mara B Antonoff, Stephen G Swisher, Greg Lizee, Alexandre Reuben, John V Heymach, Jianjun Zhang

Faculty, Staff and Student Publications

INTRODUCTION: Despite significant successes, immune checkpoint blockade fails to achieve clinical responses in a significant proportion of patients, predictive markers for responses are imperfect and immune-related adverse events (irAEs) are unpredictable. We used T-cell receptor (TCR) sequencing to systematically analyze prospectively collected patient blood samples from a randomized clinical trial of dual immune checkpoint inhibitor therapy to evaluate changes in the T-cell repertoire and their association with response and irAEs.

METHODS: Patients with immunotherapy-naïve metastatic non-small cell lung cancer (NSCLC) were treated with ipilimumab and nivolumab according to trial protocol (LONESTAR, NCT03391869). Blood samples were systematically obtained at baseline (n=107), …

Targeted Degradation Of Oncogenic Krasg12v Triggers Antitumor Immunity In Lung Cancer Models, Dezhi Li, Ke Geng, Yuan Hao, Jiajia Gu, Saurav Kumar, Annabel T Olson, Christina C Kuismi, Hye Mi Kim, Yuanwang Pan, Fiona Sherman, Asia M Williams, Yiting Li, Fei Li, Ting Chen, Cassandra Thakurdin, Michela Ranieri, Mary Meynardie, Daniel S Levin, Janaye Stephens, Alison Chafitz, Joy Chen, Mia S Donald-Paladino, Jaylen M Powell, Ze-Yan Zhang, Wei Chen, Magdalena Ploszaj, Han Han, Shengqing Stan Gu, Tinghu Zhang, Baoli Hu, Benjamin A Nacev, Medard Ernest Kaiza, Alice H Berger, Xuerui Wang, Jing Li, Xuejiao Sun, Yang Liu, Xiaoyang Zhang, Tullia C Bruno, Nathanael S Gray, Behnam Nabet, Kwok-Kin Wong, Hua Zhang

Faculty, Staff and Student Publications

Kirsten rat sarcoma viral oncogene homolog (KRAS) is the most frequently mutated oncogene in lung adenocarcinoma, with G12C and G12V being the most predominant forms. Recent breakthroughs in KRASG12C inhibitors have transformed the clinical management of patients with the G12C mutation and advanced our understanding of the function of this mutation. However, little is known about the targeted disruption of KRASG12V, partly due to a lack of specific inhibitors. Here, we leverage the degradation tag (dTAG) system to develop a KRASG12V-transgenic mouse model. We explored the therapeutic potential of KRASG12V degradation and characterized its effect on the tumor microenvironment (TME). …

Enhancer Reprogramming Underlies Therapeutic Utility Of A Smarca2 Degrader In Smarca4 Mutant Cancer, Sasikumar Kotagiri, Nicholas Blazanin, Yuanxin Xi, Yanyan Han, Md Qudratullah, Xiaobing Liang, Yawen Wang, Poonam Pandey, Hira Mazhar, Truong Nguyen Lam, Anand Kamal Singh, Jing Wang, Yonathan Lissanu

Faculty, Staff and Student Publications

Genomic studies have identified frequent mutations in subunits of the SWI/SNF (switch/sucrose non-fermenting) chromatin remodeling complex including SMARCA4 and ARID1A in non-small cell lung cancer (NSCLC). Genetic evidence indicates that the paralog SMARCA2 is synthetic lethal to SMARCA4 suggesting SMARCA2 is a valuable therapeutic target. However, the discovery of selective inhibitors of SMARCA2 has been challenging. Here, we utilized structure-activity relationship (SAR) studies to develop YD23, a potent and selective proteolysis targeting chimera (PROTAC) targeting SMARCA2. Mechanistically, we show that SMARCA2 degradation induces reprogramming of the enhancer landscape in SMARCA4-mutant cells with loss of chromatin accessibility at enhancers of genes …