Biomedical Informatics Commons^™

Emerging Therapeutics And Evolving Assessment Criteria For Intracranial Metastases In Patients With Oncogene-Driven Non-Small-Cell Lung Cancer, Kelsey Pan, Kyle Concannon, Jing Li, Jianjun Zhang, John V Heymach, Xiuning Le

Faculty, Staff and Student Publications

The improved survival outcomes of patients with non-small-cell lung cancer (NSCLC), largely owing to the improved control of systemic disease provided by immune-checkpoint inhibitors and novel targeted therapies, have highlighted the challenges posed by central nervous system (CNS) metastases as a devastating yet common complication, with up to 50% of patients developing such lesions during the course of the disease. Early-generation tyrosine-kinase inhibitors (TKIs) often provide robust systemic disease control in patients with oncogene-driven NSCLCs, although these agents are usually unable to accumulate to therapeutically relevant concentrations in the CNS owing to an inability to cross the blood-brain barrier. However, …

Kras G12c In Advanced Nsclc: Prevalence, Co-Mutations, And Testing, Tony Kiat Hon Lim, Ferdinandos Skoulidis, Keith M Kerr, Myung-Ju Ahn, Joshua R Kapp, Fernando A Soares, Yasushi Yatabe

Faculty, Staff and Student Publications

KRAS is the most commonly mutated oncogene in advanced, non-squamous, non-small cell lung cancer (NSCLC) in Western countries. Of the various KRAS mutants, KRAS G12C is the most common variant (~40%), representing 10-13% of advanced non-squamous NSCLC. Recent regulatory approvals of the KRASG12C-selective inhibitors sotorasib and adagrasib for patients with advanced or metastatic NSCLC harboring KRASG12C have transformed KRAS into a druggable target. In this review, we explore the evolving role of KRAS from a prognostic to a predictive biomarker in advanced NSCLC, discussing KRAS G12C biology, real-world prevalence, clinical relevance of co-mutations, and approaches to molecular testing. Real-world evidence …

International Association For The Study Of Lung Cancer Study Of Reproducibility In Assessment Of Pathologic Response In Resected Lung Cancers After Neoadjuvant Therapy, Sanja Dacic, William Travis, Mary Redman, Anjali Saqi, Wendy A Cooper, Alain Borczuk, Jin-Haeng Chung, Carolyn Glass, Javier Martin Lopez, Anja C Roden, Lynette Sholl, Annikka Weissferdt, Juan Posadas, Angela Walker, Hu Zhu, Manuja T Wijeratne, Casey Connolly, Murry Wynes, Neus Bota-Rabassedas, Beatriz Sanchez-Espiridion, J Jack Lee, Sabina Berezowska, Teh-Ying Chou, Keith Kerr, Andrew Nicholson, Claudia Poleri, Kurt A Schalper, Ming-Sound Tsao, David P Carbone, Neal Ready, Tina Cascone, John Heymach, Boris Sepesi, Catherine Shu, Naiyer Rizvi, Josuha Sonett, Nasser Altorki, Mariano Provencio, Paul A Bunn, Mark G Kris, Chandra P Belani, Karen Kelly, Ignacio Wistuba

Faculty, Staff and Student Publications

Introduction: Pathologic response has been proposed as an early clinical trial end point of survival after neoadjuvant treatment in clinical trials of NSCLC. The International Association for the Study of Lung Cancer (IASLC) published recommendations for pathologic evaluation of resected lung cancers after neoadjuvant therapy. The aim of this study was to assess pathologic response interobserver reproducibility using IASLC criteria.

Methods: An international panel of 11 pulmonary pathologists reviewed hematoxylin and eosin-stained slides from the lung tumors of resected NSCLC from 84 patients who received neoadjuvant immune checkpoint inhibitors in six clinical trials. Pathologic response was assessed for percent viable …

Renal Cell Carcinoma Of Variant Histology: Biology And Therapies, Pavlos Msaouel, Giannicola Genovese, Nizar M Tannir

Faculty, Staff and Student Publications

The term variant histology renal cell carcinomas (vhRCCs), also known as non-clear cell RCCs, refers to a diverse group of malignancies with distinct biologic and therapeutic considerations. The management of vhRCC subtypes is often based on extrapolating results from the more common clear cell RCC studies or basket trials that are not specific to each histology. The unique management of each vhRCC subtype necessitates accurate pathologic diagnosis and dedicated research efforts. Herein, we discuss tailored recommendations for each vhRCC histology informed by ongoing research and clinical experience.

Cellular Responses After (Neratinib Plus Pemetrexed) Exposure In Nsclc Cells, Laurence Booth, Andrew Poklepovic, John F Hancock, Paul Dent

Faculty, Staff and Student Publications

We previously demonstrated that neratinib interacted with pemetrexed to kill non-small cell lung cancer (NSCLC) cells. From developing other drug combinations, we observed that several days following exposure, cells activated survival mechanisms to counteract drug toxicity. The present studies attempted to define mechanisms that evolve to reduce the efficacy of neratinib and pemetrexed. Neratinib and pemetrexed synergized to kill NSCLC cells expressing wild-type RAS proteins, mutant KRAS (G12S; Q61H; G12A and G12C) or mutant NRAS (Q61K) or mutant ERBB1 (L858R; L858R T790M and exon 19 deletion). Neratinib and pemetrexed interacted in a greater than additive fashion to kill after 24 …

Quantitative Multiplexed Imaging Technologies For Single-Cell Analysis To Assess Predictive Markers For Immunotherapy In Thoracic Immuno-Oncology: Promises And Challenges, Edwin Roger Parra, Marius Ilié, Ignacio I Wistuba, Paul Hofman

Faculty, Staff and Student Publications

The past decade has witnessed a revolution in cancer treatment by the shift from conventional drugs (chemotherapies) towards targeted molecular therapies and immune-based therapies, in particular the immune-checkpoint inhibitors (ICIs). These immunotherapies selectively release the host immune system against the tumour and have shown unprecedented durable remission for patients with cancers that were thought incurable such as advanced non-small cell lung cancer (aNSCLC). The prediction of therapy response is based since the first anti-PD-1/PD-L1 molecules FDA and EMA approvals on the level of PD-L1 tumour cells expression evaluated by immunohistochemistry, and recently more or less on tumour mutation burden in …

Germline Pathogenic Smarca4 Variants In Neuroblastoma, Leora Witkowski, Kim E Nichols, Marjolijn Jongmans, Nienke Van Engelen, Ronald R De Krijger, Jennifer Herrera-Mullar, Lieve Tytgat, Armita Bahrami, Helen Mar Fan, Aimee L Davidson, Thomas Robertson, Michael Anderson, Martin Hasselblatt, Sharon E Plon, William D Foulkes

Faculty, Staff and Students Publications

Heterozygous germline pathogenic variants (GPVs) in SMARCA4, the gene encoding the ATP-dependent chromatin remodeling protein SMARCA4 (previously known as BRG1), predispose to several rare tumour types, including small cell carcinoma of the ovary, hypercalcemic type, atypical teratoid and malignant rhabdoid tumor, and uterine sarcoma. The increase in germline testing of SMARCA4 in recent years has revealed putative GPVs affecting SMARCA4 in patients with other cancer types. Here we describe 11 patients with neuroblastoma, including four previously unreported cases, all of whom were found to harbour heterozygous germline variants in SMARCA4. Median age at diagnosis was 5 years (range 2 …

Differential Effects Of Pancreatic Cancer-Derived Extracellular Vesicles Driving A Suppressive Environment, Anurag Purushothaman, Jacqueline Oliva-Ramírez, Warapen Treekitkarnmongkol, Deivendran Sankaran, Mark W Hurd, Nagireddy Putluri, Anirban Maitra, Cara Haymaker, Subrata Sen

Faculty, Staff and Student Publications

Pancreatic ductal adenocarcinoma (PDAC) cells display extensive crosstalk with their surrounding environment to regulate tumor growth, immune evasion, and metastasis. Recent advances have attributed many of these interactions to intercellular communication mediated by small extracellular vesicles (sEVs), involving cancer-associated fibroblasts (CAF). To explore the impact of sEVs on monocyte lineage transition as well as the expression of checkpoint receptors and activation markers, peripheral blood monocytes from healthy subjects were exposed to PDAC-derived sEVs. Additionally, to analyze the role of sEV-associated HA in immune regulation and tissue-resident fibroblasts, monocytes and pancreatic stellate cells were cultured in the presence of PDAC sEVs …

Sepepquant Enhances The Detection Of Possible Isoform Regulations In Shotgun Proteomics, Yongchao Dou, Yuejia Liu, Xinpei Yi, Lindsey K Olsen, Hongwen Zhu, Qiang Gao, Hu Zhou, Bing Zhang

Faculty, Staff and Students Publications

Shotgun proteomics is essential for protein identification and quantification in biomedical research, but protein isoform characterization is challenging due to the extensive number of peptides shared across proteins, hindering our understanding of protein isoform regulation and their roles in normal and disease biology. We systematically assess the challenge and opportunities of shotgun proteomics-based protein isoform characterization using in silico and experimental data, and then present SEPepQuant, a graph theory-based approach to maximize isoform characterization. Using published data from one induced pluripotent stem cell study and two human hepatocellular carcinoma studies, we demonstrate the ability of SEPepQuant in addressing the key …

Elimination Of Oncogenic Kras In Genetic Mouse Models Eradicates Pancreatic Cancer By Inducing Fas-Dependent Apoptosis By Cd8+ T Cells, Krishnan K Mahadevan, Valerie S Lebleu, Elena V Ramirez, Yang Chen, Bingrui Li, Amari M Sockwell, Mihai Gagea, Hikaru Sugimoto, Lakshmi Kavitha Sthanam, Desiree Tampe, Michael Zeisberg, Haoqiang Ying, Abhinav K Jain, Ronald A Depinho, Anirban Maitra, Kathleen M Mcandrews, Raghu Kalluri

Faculty, Staff and Student Publications

Oncogenic KRASG12D (KRAS∗) is critical for the initiation and maintenance of pancreatic ductal adenocarcinoma (PDAC) and is a known repressor of tumor immunity. Conditional elimination of KRAS∗ in genetic mouse models of PDAC leads to the reactivation of FAS, CD8+ T cell-mediated apoptosis, and complete eradication of tumors. KRAS∗ elimination recruits activated CD4+ and CD8+ T cells and promotes the activation of antigen-presenting cells. Mechanistically, KRAS∗-mediated immune evasion involves the epigenetic regulation of Fas death receptor in cancer cells, via methylation of its promoter region. Furthermore, analysis of human RNA sequencing identifies that high KRAS expression in PDAC tumors shows …

Elimination Of Oncogenic Kras In Genetic Mouse Models Eradicates Pancreatic Cancer By Inducing Fas-Dependent Apoptosis By Cd8+ T Cells, Krishnan K Mahadevan, Valerie S Lebleu, Elena V Ramirez, Yang Chen, Bingrui Li, Amari M Sockwell, Mihai Gagea, Hikaru Sugimoto, Lakshmi Kavitha Sthanam, Desiree Tampe, Michael Zeisberg, Haoqiang Ying, Abhinav K Jain, Ronald A Depinho, Anirban Maitra, Kathleen M Mcandrews, Raghu Kalluri

Faculty, Staff and Student Publications

Oncogenic KrasG12D (Kras*) is critical for the initiation and maintenance of pancreatic ductal adenocarcinoma (PDAC), and a known repressor of tumor immunity. Conditional elimination of Kras* in genetic mouse models of PDAC leads to reactivation of Fas, CD8+ T cell mediated apoptosis, and complete eradication of tumors. Kras* elimination recruits activated CD4+ and CD8+ T cells and promotes the activation of antigen presenting cells. Mechanistically, Kras* mediated immune evasion involves epigenetic regulation of the Fas death receptor in cancer cells, via methylation of its promoter region. Further, analysis of human RNA sequencing identifies that high KRAS expressing PDAC tumors show …

Stereotactic Ablative Radiotherapy With Or Without Immunotherapy For Early-Stage Or Isolated Lung Parenchymal Recurrent Node-Negative Non-Small-Cell Lung Cancer: An Open-Label, Randomised, Phase 2 Trial, Joe Y Chang, Steven H Lin, Wenli Dong, Zhongxing Liao, Saumil J Gandhi, Carl M Gay, Jianjun Zhang, Stephen G Chun, Yasir Y Elamin, Frank V Fossella, George Blumenschein, Tina Cascone, Xiuning Le, Jenny V Pozadzides, Anne Tsao, Vivek Verma, James W Welsh, Aileen B Chen, Mehmet Altan, Reza J Mehran, Ara A Vaporciyan, Stephen G Swisher, Peter A Balter, Junya Fujimoto, Ignacio I Wistuba, Lei Feng, J Jack Lee, John V Heymach

Faculty, Staff and Student Publications

BACKGROUND: Stereotactic ablative radiotherapy (SABR) is the standard treatment for medically inoperable early-stage non-small-cell lung cancer (NSCLC), but regional or distant relapses, or both, are common. Immunotherapy reduces recurrence and improves survival in people with stage III NSCLC after chemoradiotherapy, but its utility in stage I and II cases is unclear. We therefore conducted a randomised phase 2 trial of SABR alone compared with SABR with immunotherapy (I-SABR) for people with early-stage NSCLC.

METHODS: We did an open-label, randomised, phase 2 trial comparing SABR to I-SABR, conducted at three different hospitals in TX, USA. People aged 18 years or older …

Low-Grade Serous Ovarian Cancer: Expert Consensus Report On The State Of The Science, Rachel N Grisham, Brian M Slomovitz, Nicole Andrews, Susana Banerjee, Jubilee Brown, Mark S Carey, Herman Chui, Robert L Coleman, Amanda N Fader, Stephanie Gaillard, Charlie Gourley, Anil K Sood, Bradley J Monk, Kathleen N Moore, Isabelle Ray-Coquard, Ie-Ming Shih, Shannon N Westin, Kwong-Kwok Wong, David M Gershenson

Faculty, Staff and Student Publications

Compared with high-grade serous carcinoma, low-grade serous carcinoma of the ovary or peritoneum is a less frequent epithelial ovarian cancer type that is poorly sensitive to chemotherapy and affects younger women, many of whom endure years of ineffective treatments and poor quality of life. The pathogenesis of this disease and its management remain incompletely understood. However, recent advances in the molecular characterization of the disease and identification of novel targeted therapies with activity in low-grade serous carcinoma offer the promise of improved outcomes. To update clinicians regarding recent scientific and clinical trial advancements and discuss unanswered questions related to low-grade …

Cytoreductive Nephrectomy For Patients With Metastatic Sarcomatoid And/Or Rhabdoid Renal Cell Carcinoma Treated With Immune Checkpoint Therapy, Andrew W Hahn, Ritesh R Kotecha, Paul V Viscuse, Alberto C Pieretti, Andrew J Wiele, Eric Jonasch, Chung-Han Lee, Jianjun Gao, Amado J Zurita, Amishi Y Shah, Matthew T Campbell, Padmanee Sharma, Robert J Motzer, Paul Russo, Christopher G Wood, Nizar M Tannir, Martin H Voss, Jose A Karam, A Ari Hakimi, Pavlos Msaouel

Faculty, Staff and Student Publications

BACKGROUND: Renal cell carcinoma (RCC) with sarcomatoid and/or rhabdoid (S/R) dedifferentiation is a highly aggressive tumor with a poor prognosis. Immune checkpoint therapy (ICT) has shown significant treatment efficacy in this subtype. There remains uncertainly regarding the role of cytoreductive nephrectomy (CN) for patients with metastatic RCC (mRCC) with S/R who received ICT.

OBJECTIVE: Here, we report the outcomes with ICT for patients with mRCC and S/R dedifferentiation by CN status.

DESIGN, SETTING, AND PARTICIPANTS: A retrospective review was conducted of 157 patients with sarcomatoid, rhabdoid, or sarcomatoid plus rhabdoid dedifferentiation who received an ICT-based regimen at two cancer centers. …

Association Between Duration Of Smoking Abstinence Before Non-Small-Cell Lung Cancer Diagnosis And Survival: A Retrospective, Pooled Analysis Of Cohort Studies, Aline F Fares, Yao Li, Mei Jiang, M Catherine Brown, Andrew C L Lam, Reenika Aggarwal, Sabine Schmid, Natasha B Leighl, Frances A Shepherd, Zhichao Wang, Nancy Diao, Angela S Wenzlaff, Juntao Xie, Takashi Kohno, Neil E Caporaso, Curtis Harris, Hongxia Ma, Matthew J Barnett, Leticia Ferro Leal, G Fernandez-Tardon, Mónica Pérez-Ríos, Michael P A Davies, Fiona Taylor, Ben Schöttker, Paul Brennan, David Zaridze, Ivana Holcatova, Jolanta Lissowska, Beata Świątkowska, Dana Mates, Milan Savic, Hermann Brenner, Angeline Andrew, Angela Cox, John K Field, Alberto Ruano-Ravina, Sanjay S Shete, Adonina Tardon, Ying Wang, Loic Le Marchand, Rui Manuel Reis, Matthew B Schabath, Chu Chen, Hongbing Shen, Brid M Ryan, Maria Teresa Landi, Kouya Shiraishi, Jie Zhang, Ann G Schwartz, Ming S Tsao, David C Christiani, Ping Yang, Rayjean J Hung, Wei Xu, Geoffrey Liu

Faculty, Staff and Student Publications

BACKGROUND: The association between duration of smoking abstinence before non-small-cell lung cancer (NSCLC) diagnosis and subsequent survival can influence public health messaging delivered in lung-cancer screening. We aimed to assess whether the duration of smoking abstinence before diagnosis of NSCLC is associated with improved survival.

METHODS: In this retrospective, pooled analysis of cohort studies, we used 26 cohorts participating in Clinical Outcomes Studies of the International Lung Cancer Consortium (COS-ILCCO) at 23 hospitals. 16 (62%) were from North America, six (23%) were from Europe, three (12%) were from Asia, and one (4%) was from South America. Patients enrolled were diagnosed …

Spatially-Aware Clustering Improves Ajcc-8 Risk Stratification Performance In Oropharyngeal Carcinomas, Guadalupe Canahuate, Andrew Wentzel, Abdallah S R Mohamed, Lisanne V Van Dijk, David M Vock, Baher Elgohari, Hesham Elhalawani, Clifton D Fuller, G Elisabeta Marai

Faculty, Staff and Student Publications

OBJECTIVE: Evaluate the effectiveness of machine learning tools that incorporate spatial information such as disease location and lymph node metastatic patterns-of-spread, for prediction of survival and toxicity in HPV+ oropharyngeal cancer (OPC).

MATERIALS & METHODS: 675 HPV+ OPC patients that were treated at MD Anderson Cancer Center between 2005 and 2013 with curative intent IMRT were retrospectively collected under IRB approval. Risk stratifications incorporating patient radiometric data and lymph node metastasis patterns via an anatomically-adjacent representation with hierarchical clustering were identified. These clusterings were combined into a 3-level patient stratification and included along with other known clinical features in a …

Autotaxin Suppresses Cytotoxic T Cells Via Lpar5 To Promote Anti-Pd-1 Resistance In Non-Small Cell Lung Cancer, Jessica M Konen, B Leticia Rodriguez, Haoyi Wu, Jared J Fradette, Laura Gibson, Lixia Diao, Jing Wang, Stephanie Schmidt, Ignacio I Wistuba, Jianjun Zhang, Don L Gibbons

Faculty, Staff and Student Publications

Non-small cell lung cancers that harbor concurrent KRAS and TP53 (KP) mutations are immunologically warm tumors with partial responsiveness to anti-PD-(L)1 blockade; however, most patients observe little or no durable clinical benefit. To identify novel tumor-driven resistance mechanisms, we developed a panel of KP murine lung cancer models with intrinsic resistance to anti-PD-1 and queried differential gene expression between these tumors and anti-PD-1-sensitive tumors. We found that the enzyme autotaxin (ATX), and the metabolite it produces, lysophosphatidic acid (LPA), were significantly upregulated in resistant tumors and that ATX directly modulated antitumor immunity, with its expression negatively correlating with total and …

Phase 2 Trial Of Stereotactic Ablative Radiotherapy For Patients With Primary Renal Cancer, Raquibul Hannan, Mark F Mclaughlin, Laurentiu M Pop, Ivan Pedrosa, Payal Kapur, Aurelie Garant, Chul Ahn, Alana Christie, James Zhu, Tao Wang, Liliana Robles, Deniz Durakoglugil, Solomon Woldu, Vitaly Margulis, Jeffrey Gahan, James Brugarolas, Robert Timmerman, Jeffrey Cadeddu

Faculty, Staff and Student Publications

Background: Most renal cell carcinomas (RCCs) are localized and managed by active surveillance, surgery, or minimally invasive techniques. Stereotactic ablative radiation (SAbR) may provide an innovative non-invasive alternative although prospective data are limited.

Objective: To investigate whether SAbR is effective in the management of primary RCCs.

Design, setting, and participants: Patients with biopsy-confirmed radiographically enlarging primary RCC (≤5 cm) were enrolled. SAbR was delivered in either three (12 Gy) or five (8 Gy) fractions.

Outcome measurements and statistical analysis: The primary endpoint was local control (LC) defined as a reduction in tumor growth rate (compared with a benchmark of 4 …

Outcomes Of Treatment With Neoadjuvant Cemiplimab For Patients With Advanced, Resectable Cutaneous Squamous Cell Carcinoma Of The Head And Neck: Secondary Analysis Of A Phase 2 Clinical Trial, Renata Ferrarotto, Priyadharsini Nagarajan, Jacob M Maronge, Jason M Johnson, David I Rosenthal, Jeffrey N Myers, Neil D Gross

Faculty, Staff and Student Publications

This secondary analysis of a phase 2 clinical trial examines long-term survival for resectable cutaneous squamous cell carcinoma of the head and neck according to pathologic response.

Adagrasib In Advanced Solid Tumors Harboring A Krasg12c Mutation, Tanios S Bekaii-Saab, Rona Yaeger, Alexander I Spira, Meredith S Pelster, Joshua K Sabari, Navid Hafez, Minal Barve, Karen Velastegui, Xiaohong Yan, Aditya Shetty, Hirak Der-Torossian, Shubham Pant

Faculty, Staff and Student Publications

Purpose: Adagrasib, a KRASG12C inhibitor, has demonstrated clinical activity in patients with KRASG12C-mutated non-small-cell lung cancer (NSCLC) and colorectal cancer (CRC). KRASG12C mutations occur rarely in other solid tumor types. We report evaluation of the clinical activity and safety of adagrasib in patients with other solid tumors harboring a KRASG12C mutation.

Methods: In this phase II cohort of the KRYSTAL-1 study (ClinicalTrials.gov identifier: NCT03785249; phase Ib cohort), we evaluated adagrasib (600 mg orally twice daily) in patients with KRASG12C-mutated advanced solid tumors (excluding NSCLC and CRC). The primary end point was objective response …

Stromal-Derived Nrg1 Enables Oncogenic Kras Bypass In Pancreas Cancer, Jincheng Han, Jiaqian Xu, Yonghong Liu, Shaoheng Liang, Kyle A Labella, Deepavali Chakravarti, Denise J Spring, Yan Xia, Ronald A Depinho

Faculty, Staff and Student Publications

Activating KRAS mutations (KRAS*) in pancreatic ductal adenocarcinoma (PDAC) drive anabolic metabolism and support tumor maintenance. KRAS* inhibitors show initial antitumor activity followed by recurrence due to cancer cell-intrinsic and immune-mediated paracrine mechanisms. Here, we explored the potential role of cancer-associated fibroblasts (CAFs) in enabling KRAS* bypass and identified CAF-derived NRG1 activation of cancer cell ERBB2 and ERBB3 receptor tyrosine kinases as a mechanism by which KRAS*-independent growth is supported. Genetic extinction or pharmacological inhibition of KRAS* resulted in up-regulation of ERBB2 and ERBB3 expression in human and murine models, which prompted cancer cell utilization of CAF-derived NRG1 as a …

Obesity And Renal Cell Carcinoma: Biological Mechanisms And Perspectives, Neha Venkatesh, Alberto Martini, Jennifer L Mcquade, Pavlos Msaouel, Andrew W Hahn

Faculty, Staff and Student Publications

Obesity, defined by body mass index (BMI), is an established risk factor for specific renal cell carcinoma (RCC) subtypes such as clear cell RCC, the most common RCC histology. Many studies have identified an association between obesity and improved survival after diagnosis of RCC, a potential "obesity paradox." Clinically, there is uncertainty whether improved outcomes observed after diagnosis are driven by stage, type of treatment received, or artifacts of longitudinal changes in weight and body composition. The biological mechanisms underlying obesity's influence on RCC are not fully established, but multiomic and mechanistic studies suggest an impact on tumor metabolism, particularly …

Key Genetic Determinants Driving Esophageal Squamous Cell Carcinoma Initiation And Immune Evasion, Kyung-Pil Ko, Yuanjian Huang, Shengzhe Zhang, Gengyi Zou, Bongjun Kim, Jie Zhang, Sohee Jun, Cecilia Martin, Karen J Dunbar, Gizem Efe, Anil K Rustgi, Hiroshi Nakagawa, Jae-Il Park

Faculty, Staff and Student Publications

BACKGROUND & AIMS: Despite recent progress in identifying aberrant genetic and epigenetic alterations in esophageal squamous cell carcinoma (ESCC), the mechanism of ESCC initiation remains unknown.

METHODS: Using CRISPR/Cas 9-based genetic ablation, we targeted 9 genes (TP53, CDKN2A, NOTCH1, NOTCH3, KMT2D, KMT2C, FAT1, FAT4, and AJUBA) in murine esophageal organoids. Transcriptomic phenotypes of organoids and chemokine released by organoids were analyzed by single-cell RNA sequencing. Tumorigenicity and immune evasion of organoids were monitored by allograft transplantation. Human ESCC single-cell RNA sequencing data sets were analyzed to classify patients and find subsets relevant to organoid models and immune evasion.

RESULTS: We …

Safety, Tolerability, And Clinical Activity Of Selinexor In Combination With Pembrolizumab In Treatment Of Metastatic Non-Small Cell Lung Cancer, Mehmet Altan, Janet Tu, Denái R Milton, Bulent Yilmaz, Yanyan Tian, Frank V Fossella, Frank E Mott, George R Blumenschein, Bettzy Stephen, Daniel D Karp, Funda Meric-Bernstam, John V Heymach, Aung Naing

Faculty, Staff and Student Publications

Background: In lung cancer, overexpression of nuclear export proteins can result in inactivation of critical tumor suppressor proteins and cell-cycle regulators. Selective suppression of nuclear export proteins has immunomodulatory activities. Here, clinical safety and early efficacy data are presented on the combination of pembrolizumab and an oral selective nuclear export inhibitor, selinexor, for the treatment of metastatic non-small cell lung cancer (mNSCLC).

Methods: The primary objective of this prospective investigator-initiated study was to determine the safety and tolerability of selinexor in combination with pembrolizumab in patients with mNSCLC. Secondary objectives included determination of objective tumor response rate, disease control rate, …

Archival Single-Cell Genomics Reveals Persistent Subclones During Dcis Progression, Kaile Wang, Tapsi Kumar, Junke Wang, Darlan Conterno Minussi, Emi Sei, Jianzhuo Li, Tuan M Tran, Aatish Thennavan, Min Hu, Anna K Casasent, Zhenna Xiao, Shanshan Bai, Lei Yang, Lorraine M King, Vandna Shah, Petra Kristel, Carolien L Van Der Borden, Jeffrey R Marks, Yuehui Zhao, Amado J Zurita, Ana Aparicio, Brian Chapin, Jie Ye, Jianjun Zhang, Don L Gibbons, Ellinor Sawyer, Alastair M Thompson, Andrew Futreal, E Shelley Hwang, Jelle Wesseling, Esther H Lips, Nicholas E Navin

Faculty, Staff and Student Publications

Ductal carcinoma in situ (DCIS) is a common precursor of invasive breast cancer. Our understanding of its genomic progression to recurrent disease remains poor, partly due to challenges associated with the genomic profiling of formalin-fixed paraffin-embedded (FFPE) materials. Here, we developed Arc-well, a high-throughput single-cell DNA-sequencing method that is compatible with FFPE materials. We validated our method by profiling 40,330 single cells from cell lines, a frozen tissue, and 27 FFPE samples from breast, lung, and prostate tumors stored for 3-31 years. Analysis of 10 patients with matched DCIS and cancers that recurred 2-16 years later show that many primary …

Spatial Immunoprofiling Of Adenoid Cystic Carcinoma Reveals B7-H4 Is A Therapeutic Target For Aggressive Tumors, Luana Guimaraes Sousa, Daniel J Mcgrail, Felippe Lazar Neto, Kaiyi Li, Mario L Marques-Piubelli, Sammy Ferri-Borgogno, Hui Dai, Yoshitsugu Mitani, Nicole Spardy Burr, Zachary A Cooper, Krista Kinneer, Maria Angelica Cortez, Shiaw-Yih Lin, Diana Bell, Adel El Naggar, Jared Burks, Renata Ferrarotto

Faculty, Staff and Student Publications

PURPOSE: Adenoid cystic carcinoma (ACC) is a heterogeneous malignancy, and no effective systemic therapy exists for metastatic disease. We previously described two prognostic ACC molecular subtypes with distinct therapeutic vulnerabilities, ACC-I and ACC-II. In this study, we explored the ACC tumor microenvironment (TME) using RNA-sequencing and spatial biology to identify potential therapeutic targets.

EXPERIMENTAL DESIGN: Tumor samples from 62 ACC patients with available RNA-sequencing data that had been collected as part of previous studies were stained with a panel of 28 validated metal-tagged antibodies. Imaging mass cytometry (IMC) was performed using the Fluidigm Helios CyTOF instrument and analyzed with Visiopharm …

Perioperative Pembrolizumab For Early-Stage Non-Small-Cell Lung Cancer, Heather Wakelee, Moishe Liberman, Terufumi Kato, Masahiro Tsuboi, Se-Hoon Lee, Shugeng Gao, Ke-Neng Chen, Christophe Dooms, Margarita Majem, Ekkehard Eigendorff, Gastón L Martinengo, Olivier Bylicki, Delvys Rodríguez-Abreu, Jamie E Chaft, Silvia Novello, Jing Yang, Steven M Keller, Ayman Samkari, Jonathan D Spicer, Keynote-671 Investigators

Faculty, Staff and Student Publications

BACKGROUND: Among patients with resectable early-stage non-small-cell lung cancer (NSCLC), a perioperative approach that includes both neoadjuvant and adjuvant immune checkpoint inhibition may provide benefit beyond either approach alone.

METHODS: We conducted a randomized, double-blind, phase 3 trial to evaluate perioperative pembrolizumab in patients with early-stage NSCLC. Participants with resectable stage II, IIIA, or IIIB (N2 stage) NSCLC were assigned in a 1:1 ratio to receive neoadjuvant pembrolizumab (200 mg) or placebo once every 3 weeks, each of which was given with cisplatin-based chemotherapy for 4 cycles, followed by surgery and adjuvant pembrolizumab (200 mg) or placebo once every 3 …

Metabolic Liver Cancer: Associations Of Rare And Common Germline Variants In One-Carbon Metabolism And Dna Methylation Genes, Samuel O Antwi, Michael Heckman, Launia White, Irene Yan, Vivekananda Sarangi, Kimberly P Lauer, Joseph Reddy, Fowsiyo Ahmed, Swathi Veliginti, Ellis D Mejías Febres, Rikita I Hatia, Ping Chang, Laura Izquierdo-Sanchez, Loreto Boix, Angela Rojas, Jesus M Banales, Maria Reig, Per Stål, Manuel Romero Gómez, Amit G Singal, Donghui Li, Manal M Hassan, Lewis R Roberts, Tushar Patel

Faculty, Staff and Student Publications

Animal studies implicate one-carbon metabolism and DNA methylation genes in hepatocellular carcinoma (HCC) development in the setting of metabolic perturbations. Using human samples, we investigated the associations between common and rare variants in these closely related biochemical pathways and risk for metabolic HCC development in a multicenter international study. We performed targeted exome sequencing of 64 genes among 556 metabolic HCC cases and 643 cancer-free controls with metabolic conditions. Multivariable logistic regression was used to calculate odds ratios (ORs) and 95% confidence intervals (CIs), adjusting for multiple comparisons. Gene-burden tests were used for rare variant associations. Analyses were performed in …

Metabolic Liver Cancer: Associations Of Rare And Common Germline Variants In One-Carbon Metabolism And Dna Methylation Genes, Samuel O Antwi, Michael Heckman, Launia White, Irene Yan, Vivekananda Sarangi, Kimberly P Lauer, Joseph Reddy, Fowsiyo Ahmed, Swathi Veliginti, Ellis D Mejías Febres, Rikita I Hatia, Ping Chang, Laura Izquierdo-Sanchez, Loreto Boix, Angela Rojas, Jesus M Banales, Maria Reig, Per Stål, Manuel Romero Gómez, Amit G Singal, Donghui Li, Manal M Hassan, Lewis R Roberts, Tushar Patel

Faculty, Staff and Student Publications

Animal studies implicate one-carbon metabolism and DNA methylation genes in hepatocellular carcinoma (HCC) development in the setting of metabolic perturbations. Using human samples, we investigated the associations between common and rare variants in these closely related biochemical pathways and risk for metabolic HCC development in a multicenter international study. We performed targeted exome sequencing of 64 genes among 556 metabolic HCC cases and 643 cancer-free controls with metabolic conditions. Multivariable logistic regression was used to calculate odds ratios (ORs) and 95% confidence intervals (CIs), adjusting for multiple comparisons. Gene-burden tests were used for rare variant associations. Analyses were performed in …

Spatial Transcriptomics Of Intraductal Papillary Mucinous Neoplasms Of The Pancreas Identifies Nkx6-2 As A Driver Of Gastric Differentiation And Indolent Biological Potential, Marta Sans, Yuki Makino, Jimin Min, Kimal I Rajapakshe, Michele Yip-Schneider, C Max Schmidt, Mark W Hurd, Jared K Burks, Javier A Gomez, Fredrik I Thege, Johannes F Fahrmann, Robert A Wolff, Michael P Kim, Paola A Guerrero, Anirban Maitra

Faculty, Staff and Student Publications

Intraductal Papillary Mucinous Neoplasms (IPMNs) of the pancreas are bona fide precursor lesions of pancreatic ductal adenocarcinoma (PDAC). The most common subtype of IPMNs harbor a gastric foveolar-type epithelium, and these low-grade mucinous neoplasms are harbingers of IPMNs with high-grade dysplasia and cancer. The molecular underpinning of gastric differentiation in IPMNs is unknown, although identifying drivers of this indolent phenotype might enable opportunities for intercepting progression to high-grade IPMN and cancer. We conducted spatial transcriptomics on a cohort of IPMNs, followed by orthogonal and cross species validation studies, which established the transcription factor NKX6-2 as a key determinant of gastric …