Biomedical Informatics Commons^™

Mechanisms Of Response And Tolerance To Active Ras Inhibition In Kras-Mutant Non-Small Cell Lung Cancer, Haniel A Araujo, Ximo Pechuan-Jorge, Teng Zhou, Minh Truong Do, Xin Hu, Frank R Rojas Alvarez, Maria E Salvatierra, Heladio P Ibarguen, Richard Lee, Rashi Raghulan, Harshit Shah, Mariela A Moreno Ayala, Kevin Chen, Nataliya Tovbis Shifrin, Shuhong Wu, Luisa M Solis Soto, Marcelo V Negrao, Don L Gibbons, David S Hong, Jack A Roth, John V Heymach, Jianjun Zhang, Jingjing Jiang, Mallika Singh, Jacqueline A M Smith, Elsa Quintana, Ferdinandos Skoulidis

Faculty, Staff and Student Publications

Resistance to inactive state-selective RASG12C inhibitors frequently entails accumulation of RASGTP, rendering effective inhibition of active RAS potentially desirable. Here, we evaluated the antitumor activity of the RAS(ON) multiselective tricomplex inhibitor RMC-7977 and dissected mechanisms of response and tolerance in KRASG12C-mutant non-small cell lung cancer (NSCLC). Broad-spectrum reversible RASGTP inhibition with or without concurrent covalent targeting of active RASG12C yielded superior and differentiated antitumor activity across diverse comutational KRASG12C-mutant NSCLC mouse models of primary or acquired RASG12C(ON) or RASG12C(OFF) inhibitor resistance. Interrogation of time-resolved single-cell transcriptional responses established an in vivo atlas of multimodal acute and chronic RAS pathway inhibition …

Fractionated Photoimmunotherapy Stimulates An Anti-Tumour Immune Response: An Integrated Mathematical And In Vitro Study, Mohammad U Zahid, Matthew Waguespack, Rebecca C Harman, Eric M Kercher, Shubhankar Nath, Tayyaba Hasan, Imran Rizvi, Bryan Q Spring, Heiko Enderling

Faculty, Staff and Student Publications

Background: Advanced epithelial ovarian cancer (EOC) has high recurrence rates due to disseminated initial disease presentation. Cytotoxic phototherapies, such as photodynamic therapy (PDT) and photoimmunotherapy (PIT, cell-targeted PDT), have the potential to treat disseminated malignancies due to safe intraperitoneal delivery.

Methods: We use in vitro measurements of EOC tumour cell and T cell responses to chemotherapy, PDT, and epidermal growth factor receptor targeted PIT as inputs to a mathematical model of non-linear tumour and immune effector cell interaction. The model outputs were used to calculate how photoimmunotherapy could be utilised for tumour control.

Results: In vitro measurements of PIT dose …

Mechanisms Of Resistance To Oncogenic Kras Inhibition In Pancreatic Cancer, Julien Dilly, Megan T Hoffman, Laleh Abbassi, Ziyue Li, Francesca Paradiso, Brendan D Parent, Connor J Hennessey, Alexander C Jordan, Micaela Morgado, Shatavisha Dasgupta, Giselle A Uribe, Annan Yang, Kevin S Kapner, Felix P Hambitzer, Li Qiang, Hanrong Feng, Jacob Geisberg, Junning Wang, Kyle E Evans, Hengyu Lyu, Aislyn Schalck, Ningping Feng, Anastasia M Lopez, Christopher A Bristow, Michael P Kim, Kimal I Rajapakshe, Vahid Bahrambeigi, Jennifer A Roth, Kavita Garg, Paola A Guerrero, Ben Z Stanger, Simona Cristea, Scott W Lowe, Timour Baslan, Eliezer M Van Allen, Joseph D Mancias, Emily Chan, Abraham Anderson, Yuliya V Katlinskaya, Alex K Shalek, David S Hong, Shubham Pant, Jill Hallin, Kenna Anderes, Peter Olson, Timothy P Heffernan, Seema Chugh, James G Christensen, Anirban Maitra, Brian M Wolpin, Srivatsan Raghavan, Jonathan A Nowak, Peter S Winter, Stephanie K Dougan, Andrew J Aguirre

Faculty, Staff and Student Publications

KRAS inhibitors demonstrate clinical efficacy in pancreatic ductal adenocarcinoma (PDAC); however, resistance is common. Among patients with KRASG12C-mutant PDAC treated with adagrasib or sotorasib, mutations in PIK3CA and KRAS, and amplifications of KRASG12C, MYC, MET, EGFR, and CDK6 emerged at acquired resistance. In PDAC cell lines and organoid models treated with the KRASG12D inhibitor MRTX1133, epithelial-to-mesenchymal transition and PI3K-AKT-mTOR signaling associate with resistance to therapy. MRTX1133 treatment of the KrasLSL-G12D/+; Trp53LSL-R172H/+; p48-Cre (KPC) mouse model yielded deep tumor regressions, but drug resistance ultimately emerged, accompanied by amplifications of Kras, Yap1, Myc, Cdk6, and Abcb1a/b, and co-evolution of drug-resistant transcriptional programs. …

Type I Met Inhibitors Cooperate With Pd-1 Blockade To Promote Rejection Of Hepatocellular Carcinoma, Ricardo Deazevedo, Madeline Steiner, Broderick X Turner, Arthur Liu, Sherwin Newton, Joanna Schmidt, Rachel Fleming, Angelica Tolentino, Ahmed O Kaseb, Michael A Curran

Faculty, Staff and Student Publications

Blockade of the immune checkpoints programmed death-1 (PD-1) and cytotoxic lymphocyte antigen 4 has improved outcomes for patients with hepatocellular carcinoma (HCC), yet most still fail to achieve objective clinical benefit. MET plays key roles in both HCC tumorigenesis and immunosuppressive conditioning; however, inhibition of MET causes upregulation of PD-ligand 1 (PD-L1) suggesting the use of these inhibitors in the context of PD-1 blockade. We sought to investigate across the Hepa1-6, HCA-1 and diethylnitrosamine (DEN) models of HCC whether the combination of more specific type I versus more pleiotropic type II MET inhibitors would confer superior outcomes in combination with …

Impact Of Select Actionable Genomic Alterations On Efficacy Of Neoadjuvant Immunotherapy In Resectable Non-Small Cell Lung Cancer, Nicolas Zhou, Cheuk H Leung, William N William, Annikka Weissferdt, Apar Pataer, Myrna C B Godoy, Brett W Carter, Frank V Fossella, Anne S Tsao, George R Blumenschein, Xiuning Le, Jianjun Zhang, Ferdinandos Skoulidis, Jonathan M Kurie, Mehmet Altan, Charles Lu, Bonnie S Glisson, Lauren A Byers, Yasir Y Elamin, Reza J Mehran, David C Rice, Garrett L Walsh, Wayne L Hofstetter, Jack A Roth, Hai T Tran, Jia Wu, Luisa M Solis Soto, Humam Kadara, Stephen G Swisher, Ara A Vaporciyan, Don L Gibbons, Heather Y Lin, J Jack Lee, John V Heymach, Marcelo V Negrao, Boris Sepesi, Tina Cascone

Faculty, Staff and Student Publications

Background: Neoadjuvant immune checkpoint inhibitors (ICIs) have improved survival outcomes compared with chemotherapy in resectable non-small cell lung cancer (NSCLC). However, the impact of actionable genomic alterations (AGAs) on the efficacy of neoadjuvant ICIs remains unclear. We report the influence of AGAs on treatment failure (TF) in patients with resectable NSCLC treated with neoadjuvant ICIs.

Methods: Tumor molecular profiles were obtained from patients with stage I-IIIA resectable NSCLC (American Joint Committee on Cancer seventh edition) treated with either neoadjuvant nivolumab (N, n=23) or nivolumab+ipilimumab (NI, n=21) followed by surgery in a previously reported phase-2 randomized study (NCT03158129). TF …

Unmasking Neuroendocrine Prostate Cancer With A Machine Learning-Driven Seven-Gene Stemness Signature That Predicts Progression, Agustina Sabater, Pablo Sanchis, Rocio Seniuk, Gaston Pascual, Nicolas Anselmino, Daniel F Alonso, Federico Cayol, Elba Vazquez, Marcelo Marti, Javier Cotignola, Ayelen Toro, Estefania Labanca, Juan Bizzotto, Geraldine Gueron

Faculty, Staff and Student Publications

Prostate cancer (PCa) poses a significant global health challenge, particularly due to its progression into aggressive forms like neuroendocrine prostate cancer (NEPC). This study developed and validated a stemness-associated gene signature using advanced machine learning techniques, including Random Forest and Lasso regression, applied to large-scale transcriptomic datasets. The resulting seven-gene signature (KMT5C, DPP4, TYMS, CDC25B, IRF5, MEN1, and DNMT3B) was validated across independent cohorts and patient-derived xenograft (PDX) models. This signature demonstrated strong prognostic value for progression-free, disease-free, relapse-free, metastasis-free, and overall survival. Importantly, the signature not only identified specific NEPC subtypes, …

Perioperative Chemoimmunotherapy Induces Strong Immune Responses And Long-Term Survival In Patients With Hla Class I-Deficient Non-Small Cell Lung Cancer, Marta Molina-Alejandre, Francisco Perea, Virginia Calvo, Cristina Martinez-Toledo, Ernest Nadal, Belén Sierra-Rodero, Marta Casarrubios, Joaquín Casal-Rubio, Alex Martinez-Martí, Amelia Insa, Bartomeu Massuti, Santiago Viteri, Isidoro Barneto Aranda, Delvys Rodriguez-Abreu, Javier De Castro, Joaquín Mosquera Martínez, Manuel Cobo, Ignacio I Wistuba, Edwin R Parra, Javier Martín-López, Diego Megías, Rafael Muñoz-Viana, Federico Garrido, Natalia Aptsiauri, Francisco Ruiz-Cabello, Mariano Provencio, Alberto Cruz-Bermúdez

Faculty, Staff and Student Publications

BACKGROUND: Loss of human leukocyte antigen (HLA) class I expression and loss of heterozygosity (LOH) are common events implicated in the primary resistance of non-small cell lung cancer (NSCLC) to immunotherapy. However, there is no data on perioperative chemoimmunotherapy (ChIO) efficacy or response mechanisms in the context of HLA class I defects.

METHODS: Baseline HLA class I tumor status (HLA-deficient (HLA-DEF) or HLA-proficient (HLA-PRO)) was determined by DNA LOH combined with immunohistochemistry for protein levels in tissue of 24 patients with NSCLC treated with perioperative nivolumab plus chemotherapy from NADIM trial (NCT03081689). We integrated HLA tumor status with molecular data …

A Phase Ib/Ii Randomized Clinical Trial Of Oleclumab With Or Without Durvalumab Plus Chemotherapy In Patients With Metastatic Pancreatic Ductal Adenocarcinoma, Andrew L Coveler, Matthew J Reilley, Mark Zalupski, Teresa Macarulla, Christos Fountzilas, Mariano Ponz-Sarvisé, Adnan Nagrial, Nataliya V Uboha, Sophia Frentzas, Michael Overman, Anne Noonan, Wells A Messersmith, Nick Pavlakis, Niharika B Mettu, Ina Bisha, Ying Wang, Paul Smith, Elina Murtomaki, Agata A Bielska, Veronique Bragulat, Zachary A Cooper, Rakesh Kumar, David R Spigel

Faculty, Staff and Student Publications

Purpose: Pancreatic ductal adenocarcinoma upregulates CD73, potentially contributing to immune surveillance evasion. Combining oleclumab (CD73 inhibitor) and durvalumab with chemotherapy may identify an effective treatment option.

Patients and methods: We describe a multicenter phase Ib/II randomized clinical trial in patients with metastatic pancreatic ductal adenocarcinoma, untreated (cohort A) or previously received gemcitabine-based chemotherapy (cohort B; NCT03611556). During escalation, patients received oleclumab 1,500 or 3,000 mg, durvalumab 1,500 mg, and gemcitabine plus nab-paclitaxel (GnP; cohort A; n = 14) or modified FOLFOX (cohort B; n = 11). During expansion, cohort A patients (n = 170) were randomized to GnP (arm …

Yap1 Status Defines Two Intrinsic Subtypes Of Lcnec With Distinct Molecular Features And Therapeutic Vulnerabilities, C Allison Stewart, Lixia Diao, Yuanxin Xi, Runsheng Wang, Kavya Ramkumar, Alejandra G Serrano, Azusa Tanimoto, B Leticia Rodriguez, Benjamin B Morris, Li Shen, Bingnan Zhang, Yan Yang, Samera H Hamad, Robert J Cardnell, Alberto Duarte, Moushumi Sahu, Veronica Y Novegil, Bernard E Weissman, Michael Frumovitz, Neda Kalhor, Luisa Solis Soto, Pedro Da Rocha, Natalie Vokes, Don L Gibbons, Jing Wang, John V Heymach, Bonnie Glisson, Lauren Averett Byers, Carl M Gay

Faculty, Staff and Student Publications

Purpose: Large cell neuroendocrine carcinoma (LCNEC) is a high-grade neuroendocrine malignancy that, like small cell lung cancer (SCLC), is associated with the absence of druggable oncogenic drivers and dismal prognosis. In contrast to SCLC, however, there is little evidence to guide optimal treatment strategies, which are often adapted from SCLC and non-small cell lung cancer approaches.

Experimental design: To better define the biology of LCNEC, we analyzed cell line and patient genomic data and performed IHC and single-cell RNA sequencing of core needle biopsies from patients with LCNEC and preclinical models.

Results: In this study, we demonstrate that the presence …

Multi-Ancestry Gwas Meta-Analyses Of Lung Cancer Reveal Susceptibility Loci And Elucidate Smoking-Independent Genetic Risk, Bryan R Gorman, Sun-Gou Ji, Michael Francis, Anoop K Sendamarai, Yunling Shi, Poornima Devineni, Uma Saxena, Elizabeth Partan, Andrea K Devito, Jinyoung Byun, Younghun Han, Xiangjun Xiao, Don D Sin, Wim Timens, Jennifer Moser, Sumitra Muralidhar, Rachel Ramoni, Rayjean J Hung, James D Mckay, Yohan Bossé, Ryan Sun, Christopher I Amos, Va Million Veteran Program, Saiju Pyarajan

Faculty, Staff and Student Publications

Lung cancer remains the leading cause of cancer mortality, despite declining smoking rates. Previous lung cancer GWAS have identified numerous loci, but separating the genetic risks of lung cancer and smoking behavioral susceptibility remains challenging. Here, we perform multi-ancestry GWAS meta-analyses of lung cancer using the Million Veteran Program cohort (approximately 95% male cases) and a previous study of European-ancestry individuals, jointly comprising 42,102 cases and 181,270 controls, followed by replication in an independent cohort of 19,404 cases and 17,378 controls. We then carry out conditional meta-analyses on cigarettes per day and identify two novel, replicated loci, including the 19p13.11 …

Preventive Treatment With A Cd73 Small Molecule Inhibitor Enhances Immune Surveillance In K-Ras Mutant Pancreatic Intraepithelial Neoplasia, Lincoln N Strickland, Wendao Liu, Usama Hussein, Nicolette Mardik, Xian Chen, Tingting Mills, Lana A Vornik, Michelle I Savage, Shizuko Sei, John Clifford, Holger K Eltzschig, Powel H Brown, Zhongming Zhao, Florencia Mcallister, Jennifer M Bailey-Lundberg

Faculty, Staff and Student Publications

Immunoprevention is an emerging consideration for solid tumors, including pancreatic ductal adenocarcinoma (PDAC). We and others have shown that Kras mutations in genetic models of spontaneous pancreatic intraepithelial neoplasia (PanIN), which is a precursor to PDAC, results in CD73 expression in the neoplastic epithelium and some populations of infiltrating immune cells, including macrophages and CD8 T cells. CD73 is an ecto-enzyme that converts extracellular adenosine monophosphate to adenosine, a critical immune inhibitory molecule in PDAC. We hypothesized inhibition of CD73 would reduce the incidence of PanIN formation and alter the immune microenvironment. To test our hypothesis, we used the KrasG12D; …

Dcis Knowledge Of Women Choosing Between Active Surveillance And Surgery For Low-Risk Dcis, E G Engelhardt, R S J M Schmitz, M A Gerritsma, C M T Sondermeijer, E Verschuur, J H E Houtzager, R Griffioen, N Bijker, R M Mann, V Retèl, F H Van Duijnhoven, J Wesseling, E M A Bleiker

Faculty, Staff and Student Publications

BACKGROUND: Ductal carcinoma in situ (DCIS) can progress to invasive breast cancer (IBC), but often never will. As we cannot predict accurately which DCIS-lesions will or will not progress to IBC, almost all women with DCIS undergo breast-conserving surgery supplemented with radiotherapy, or even mastectomy. In some countries, endocrine treatment is prescribed as well. This implies many women with non-progressive DCIS undergo overtreatment. To reduce this, the LORD patient preference trial (LORD-PPT) tests whether mammographic active surveillance (AS) is safe by giving women with low-risk DCIS a choice between treatment and AS. For this, sufficient knowledge about DCIS is crucial. …

Genomic Biomarkers To Predict Response To Atezolizumab Plus Bevacizumab Immunotherapy In Hepatocellular Carcinoma: Insights From The Imbrave150 Trial, Sun Young Yim, Sung Hwan Lee, Seung-Woo Baek, Bohwa Sohn, Yun Seong Jeong, Sang-Hee Kang, Kena Park, Hyewon Park, Sunyoung S Lee, Ahmed O Kaseb, Young Nyun Park, Sun-Hee Leem, Michael A Curran, Ji Hoon Kim, Ju-Seog Lee

Faculty, Staff and Student Publications

Background/aims: Combination immunotherapy, exemplified by atezolizumab plus bevacizumab, has become the standard of care for inoperable hepatocellular carcinoma (HCC). However, the lack of predictive biomarkers and limited understanding of response mechanisms remain a challenge.

Methods: Using data from the IMbrave150plus cohort, we applied an immune signature score (ISS) predictor to stratify HCC patients treated with atezolizumab plus bevacizumab or with sorafenib alone into potential high and low response groups. By applying multiple statistical approaches including a Bayesian covariate prediction algorithm, we refined the signature to 10 key genes (ISS10) for clinical use while maintaining similar predictive power to the full …

Mhc Hammer Reveals Genetic And Non-Genetic Hla Disruption In Cancer Evolution, Clare Puttick, Thomas P Jones, Michelle M Leung, Felipe Galvez-Cancino, Jiali Liu, Manuel Varas-Godoy, Andrew Rowan, Oriol Pich, Carlos Martinez-Ruiz, Robert Bentham, Krijn K Dijkstra, James R M Black, Rachel Rosenthal, Nnennaya Kanu, Kevin Litchfield, Roberto Salgado, David A Moore, Peter Van Loo, Mariam Jamal-Hanjani, Sergio A Quezada, Tracerx Consortium, Charles Swanton, Nicholas Mcgranahan

Faculty, Staff and Student Publications

Disruption of the class I human leukocyte antigen (HLA) molecules has important implications for immune evasion and tumor evolution. We developed major histocompatibility complex loss of heterozygosity (LOH), allele-specific mutation and measurement of expression and repression (MHC Hammer). We identified extensive variability in HLA allelic expression and pervasive HLA alternative splicing in normal lung and breast tissue. In lung TRACERx and lung and breast TCGA cohorts, 61% of lung adenocarcinoma (LUAD), 76% of lung squamous cell carcinoma (LUSC) and 35% of estrogen receptor-positive (ER+) cancers harbored class I HLA transcriptional repression, while HLA tumor-enriched alternative splicing occurred in 31%, 11% …

Neoadjuvant And Adjuvant Treatments For Early Stage Resectable Nsclc: Consensus Recommendations From The International Association For The Study Of Lung Cancer, Jonathan D Spicer, Tina Cascone, Murry W Wynes, Myung-Ju Ahn, Sanja Dacic, Enriqueta Felip, Patrick M Forde, Kristin A Higgins, Mark G Kris, Tetsuya Mitsudomi, Mariano Provencio, Suresh Senan, Benjamin J Solomon, Ming Sound Tsao, Masahiro Tsuboi, Heather A Wakelee, Yi-Long Wu, James Chih-Hsin Yang, Caicun Zhou, David H Harpole, Karen L Kelly

Faculty, Staff and Student Publications

Advances in the multidisciplinary care of early stage resectable NSCLC (rNSCLC) are emerging at an unprecedented pace. Numerous phase 3 trials produced results that have transformed patient outcomes for the better, yet these findings also require important modifications to the patient treatment journey trajectory and reorganization of care pathways. Perhaps, most notably, the need for multispecialty collaboration for this patient population has never been greater. These rapid advances have inevitably left us with important gaps in knowledge for which definitive answers will only become available in several years. To this end, the International Association for the Study of Lung Cancer …

Artificial Intelligence Applications In Oral Cancer And Oral Dysplasia, Chi T Viet, Michael Zhang, Neeraja Dharmaraj, Grace Y Li, Alexander T Pearson, Victoria A Manon, Anupama Grandhi, Ke Xu, Bradley E Aouizerat, Simon Young

Faculty, Staff and Student Publications

Oral squamous cell carcinoma (OSCC) is a highly unpredictable disease with devastating mortality rates that have not changed over the past decades, in the face of advancements in treatments and biomarkers, which have improved survival for other cancers. Delays in diagnosis are frequent, leading to more disfiguring treatments and poor outcomes for patients. The clinical challenge lies in identifying those patients at the highest risk of developing OSCC. Oral epithelial dysplasia (OED) is a precursor of OSCC with highly variable behavior across patients. There is no reliable clinical, pathological, histological, or molecular biomarker to determine individual risk in OED patients. …

Targeting Multiple Receptor Tyrosine Kinases With Sitravatinib: A Phase 1b Study In Advanced Renal Cell Carcinoma And Castrate-Resistant Prostate Cancer, Shubham Pant, Byoung Chul Cho, Christos E Kyriakopoulos, Alexander Spira, Nizar Tannir, Theresa L Werner, Xiaohong Yan, Saskia Neuteboom, Richard Chao, Sanjay Goel

Faculty, Staff and Student Publications

Sitravatinib (MGCD516) is an oral inhibitor of several closely related oncogenic tyrosine kinase receptors that include VEGFR-2 (vascular endothelial growth factor receptor-2), AXL, and MET (mesenchymal-epithelial transition). The safety and antitumor activity of sitravatinib are reported in patients from two histologic cohorts (anti-angiogenesis-refractory clear cell renal cell carcinoma [RCC] and castrate-resistant prostate cancer [CRPC] with bone metastases) who participated in a Phase 1/1b study. The patients were enrolled using a 3-stage design that was based on observed objective responses. Objective response rate (ORR) was the primary endpoint. Duration of response, progression-free survival (PFS), overall survival (OS), and safety were also …

Antiangiogenic Tyrosine Kinase Inhibitors Have Differential Efficacy In Clear Cell Renal Cell Carcinoma In Bone, Stefan Maksimovic, Nina C Boscolo, Ludovica La Posta, Sergio Barrios, Mohammad Jad Moussa, Emanuela Gentile, Pedro I Pesquera, Wenjiao Li, Jianfeng Chen, Javier A Gomez, Akshay Basi, Jared K Burks, Christopher Alvarez-Breckenridge, Jianjun Gao, Matthew T Campbell, Eleonora Dondossola

Faculty, Staff and Student Publications

Clear cell renal cell carcinoma (ccRCC) is the most prevalent kidney neoplasm; bone metastasis (BM) develops in 35% to 40% of metastatic patients and results in substantial morbidity and mortality, as well as medical costs. A key feature of ccRCC is the loss of function of the von Hippel-Lindau protein, which enhances angiogenesis via vascular endothelial growth factor release. Consequently, antiangiogenic tyrosine kinase inhibitors (TKI) emerged as a treatment for ccRCC. However, limited data about their efficacy in BM is available, and no systematic comparisons have been performed. We developed mouse models of bone and lung ccRCC tumors and compared …

Imageable Radioembolization Microspheres For Treatment Of Unresectable Hepatocellular Carcinoma: Interim Results From A First-In-Human Trial, Robert J Abraham, Aravind Arepally, David Liu, Robert Lewandowski, S Cheenu Kappadath, Amit Verma, David Dobrowski, Andrew Holden

Faculty, Staff and Student Publications

Purpose: To determine 6-month interim safety, effectiveness, and multimodal imageability of imageable glass microsphere yttrium-90 (90Y) radioembolization for unresectable hepatocellular carcinoma (HCC) in a first-in-human trial.

Materials and methods: Imageable microspheres (Eye90 Microspheres; ABK Biomedical, Halifax, Nova Scotia, Canada), a U.S. Food and Drug Administration (FDA) Breakthrough-Designated Device consisting of glass radiopaque 90Y microspheres visible on computed tomography (CT) and single photon emission CT (SPECT), were used to treat 6 subjects with unresectable HCC. Patients underwent selective (≤2 segments) treatment in a prospective open-label pilot trial. Key inclusion criteria included liver-only HCC, performance status ≤1, total lesion diameter ≤9 cm, …

Neoadjuvant And Adjuvant Treatments For Early Stage Resectable Nsclc: Consensus Recommendations From The International Association For The Study Of Lung Cancer, Jonathan D Spicer, Tina Cascone, Murry W Wynes, Myung-Ju Ahn, Sanja Dacic, Enriqueta Felip, Patrick M Forde, Kristin A Higgins, Mark G Kris, Tetsuya Mitsudomi, Mariano Provencio, Suresh Senan, Benjamin J Solomon, Ming Sound Tsao, Masahiro Tsuboi, Heather A Wakelee, Yi-Long Wu, James Chih-Hsin Yang, Caicun Zhou, David H Harpole, Karen L Kelly

Faculty, Staff and Student Publications

Advances in the multidisciplinary care of early stage resectable NSCLC (rNSCLC) are emerging at an unprecedented pace. Numerous phase 3 trials produced results that have transformed patient outcomes for the better, yet these findings also require important modifications to the patient treatment journey trajectory and reorganization of care pathways. Perhaps, most notably, the need for multispecialty collaboration for this patient population has never been greater. These rapid advances have inevitably left us with important gaps in knowledge for which definitive answers will only become available in several years. To this end, the International Association for the Study of Lung Cancer …

Reconstructing Oral Cavity Tumor Evolution Through Brush Biopsy, Evit John, Tom Lesluyes, Toby M Baker, Maxime Tarabichi, Ann Gillenwater, Jennifer R Wang, Peter Van Loo, Xiao Zhao

Faculty, Staff and Student Publications

Oral potentially malignant disorders (OPMDs) with genomic alterations have a heightened risk of evolving into oral squamous cell carcinoma (OSCC). Currently, genomic data are typically obtained through invasive tissue biopsy. However, brush biopsy is a non-invasive method that has been utilized for identifying dysplastic cells in OPMD but its effectiveness in reflecting the genomic landscape of OPMDs remains uncertain. This pilot study investigates the potential of brush biopsy samples in accurately reconstructing the genomic profile and tumor evolution in a patient with both OPMD and OSCC. We analyzed single nucleotide variants (SNVs), copy number aberrations (CNAs), and subclonal architectures in …

The P-Myh9/Usp22/Hif-1Α Axis Promotes Lenvatinib Resistance And Cancer Stemness In Hepatocellular Carcinoma, Qiaonan Shan, Lu Yin, Qifan Zhan, Jiongjie Yu, Sheng Pan, Jianyong Zhuo, Wei Zhou, Jiaqi Bao, Lincheng Zhang, Jiachen Hong, Jianan Xiang, Qingyang Que, Kangchen Chen, Shengjun Xu, Jingrui Wang, Yangbo Zhu, Bin He, Jingbang Wu, Haiyang Xie, Shusen Zheng, Tingting Feng, Sunbin Ling, Xiao Xu

Faculty, Staff and Student Publications

Lenvatinib is a targeted drug used for first-line treatment of hepatocellular carcinoma (HCC). A deeper insight into the resistance mechanism of HCC against lenvatinib is urgently needed. In this study, we aimed to dissect the underlying mechanism of lenvatinib resistance (LR) and provide effective treatment strategies. We established an HCC model of acquired LR. Cell counting, migration, self-renewal ability, chemoresistance and expression of stemness genes were used to detect the stemness of HCC cells. Molecular and biochemical strategies such as RNA-sequencing, immunoprecipitation, mass spectrometry and ubiquitination assays were used to explore the underlying mechanisms. Patient-derived HCC models and HCC samples …

Impact Of An Online Decision Support Tool For Ductal Carcinoma In Situ (Dcis) Using A Pre-Post Design (Aft-25), Elissa Ozanne, Kellyn Maves, Angela Tramontano, Thomas Lynch, Alastair Thompson, Ann Partridge, Elizabeth Frank, Deborah Collyar, Desiree Basila, Donna Pinto, Terry Hyslop, Marc Ryser, Shoshana Rosenberg, E. Shelley Hwang, Rinaa Punglia

Department of Pharmacology and Experimental Therapeutics Faculty Papers

BACKGROUND: The heterogeneous biology of ductal carcinoma in situ (DCIS), as well as the variable outcomes, in the setting of numerous treatment options have led to prognostic uncertainty. Consequently, making treatment decisions is challenging and necessitates involved communication between patient and provider about the risks and benefits. We developed and investigated an interactive decision support tool (DST) designed to improve communication of treatment options and related long-term risks for individuals diagnosed with DCIS.

FINDINGS: The DST was developed for use by individuals aged > 40 years with DCIS and is based on a disease simulation model that integrates empirical data and …

Loss Of P53 And Smad4 Induces Adenosquamous Subtype Pancreatic Cancer In The Absence Of An Oncogenic Kras Mutation, Daowei Yang, Xinlei Sun, Rohan Moniruzzaman, Hua Wang, Citu Citu, Zhongming Zhao, Ignacio I Wistuba, Huamin Wang, Anirban Maitra, Yang Chen

Faculty, Staff and Student Publications

Pancreatic cancer is associated with an oncogenic KRAS mutation in approximately 90% of cases. However, a non-negligible proportion of pancreatic cancer cases harbor wild-type KRAS (KRAS-WT). This study establishes genetically engineered mouse models that develop spontaneous pancreatic cancer in the context of KRAS-WT. The Trp53

Targeting Prmt3 Impairs Methylation And Oligomerization Of Hsp60 To Boost Anti-Tumor Immunity By Activating Cgas/Sting Signaling, Yunxing Shi, Zongfeng Wu, Shaoru Liu, Dinglan Zuo, Yi Niu, Yuxiong Qiu, Liang Qiao, Wei He, Jiliang Qiu, Yunfei Yuan, Guocan Wang, Binkui Li

Faculty, Staff and Student Publications

Immune checkpoint blockade (ICB) has emerged as a promising therapeutic option for hepatocellular carcinoma (HCC), but resistance to ICB occurs and patient responses vary. Here, we uncover protein arginine methyltransferase 3 (PRMT3) as a driver for immunotherapy resistance in HCC. We show that PRMT3 expression is induced by ICB-activated T cells via an interferon-gamma (IFNγ)-STAT1 signaling pathway, and higher PRMT3 expression levels correlate with reduced numbers of tumor-infiltrating CD8+ T cells and poorer response to ICB. Genetic depletion or pharmacological inhibition of PRMT3 elicits an influx of T cells into tumors and reduces tumor size in HCC mouse models. Mechanistically, …

The Kras Mutational Spectrum And Its Clinical Implications In Pancreatic Cancer, Luigi Perelli, Giannicola Genovese, Giulio F Draetta

Faculty, Staff and Student Publications

In this issue of Cancer Cell, McIntyre et al. show that specific mutations in the KRAS proto-oncogene shape clinical progression of pancreatic ductal adenocarcinoma (PDAC). Importantly, they find that the KRASG12R mutation is enriched in early-stage PDAC, and it is characterized by distinctly activated molecular programs.

The Kras Mutational Spectrum And Its Clinical Implications In Pancreatic Cancer, Luigi Perelli, Giannicola Genovese, Giulio F Draetta

Faculty, Staff and Student Publications

In this issue of Cancer Cell, McIntyre et al. show that specific mutations in the KRAS proto-oncogene shape clinical progression of pancreatic ductal adenocarcinoma (PDAC). Importantly, they find that the KRASG12R mutation is enriched in early-stage PDAC, and it is characterized by distinctly activated molecular programs.

Racial And Ethnic Differences In Epithelial Ovarian Cancer Risk: An Analysis From The Ovarian Cancer Association Consortium, Nicola S Meagher, Kami K White, Lynne R Wilkens, Elisa V Bandera, Andrew Berchuck, Michael E Carney, Daniel W Cramer, Kara L Cushing-Haugen, Susan Jordan, Scott H Kaufmann, Nhu D Le, Malcolm C Pike, Marjorie Riggan, Bo Qin, Joseph H Rothstein, Linda Titus, Stacey J Winham, Hoda Anton-Culver, Jennifer A Doherty, Ellen L Goode, Celeste Leigh Pearce, Harvey A Risch, Penelope M Webb, Linda S Cook, Marc T Goodman, Holly R Harris, Loic Le Marchand, Valerie Mcguire, Paul D P Pharoah, Danja Sarink, Joellen M Schildkraut, Weiva Sieh, Kathryn L Terry, Pamela J Thompson, Alice S Whittemore, Anna H Wu, Lauren C Peres, Melissa A Merritt

Faculty, Staff and Student Publications

Limited estimates exist on risk factors for epithelial ovarian cancer (EOC) in Asian, Hispanic, and Native Hawaiian/Pacific Islander women. Participants in this study included 1734 Asian (n = 785 case and 949 control participants), 266 Native Hawaiian/Pacific Islander (n = 99 case and 167 control participants), 1149 Hispanic (n = 505 case and 644 control participants), and 24 189 White (n = 9981 case and 14 208 control participants) from 11 studies in the Ovarian Cancer Association Consortium. Logistic regression models estimated odds ratios (ORs) and 95% CIs for risk associations by race and ethnicity. Heterogeneity in EOC risk associations …

Prognostic Impact Of Notch1 Intracellular Domain, P63, And C-Myc In Lacrimal Gland Adenoid Cystic Carcinoma, Jiawei Zhao, Michelle D Williams, Mike Hernandez, Grace Kuang, Hila Goldberg, Janet Fan, Jing Ning, Renata Ferrarotto, Bita Esmaeli

Faculty, Staff and Student Publications

PURPOSE: We assessed whether NICD1 expression, c-MYC expression, and P63 expression by immunohistochemistry (IHC) correlate with prognosis and high-risk clinicopathological features in lacrimal gland adenoid cystic carcinoma (ACC).

METHODS: Records of patients with lacrimal gland ACC who underwent surgery between 1998 to 2018 were reviewed. Clinicopathologic and treatment data were collected. Tumor tissues were subjected to light microscopy and IHC.

RESULTS: Of 43 patients treated during the study period, 21 had archived tumor tissue available and were included. The median age at diagnosis was 47 years, and 13 patients (62%) were male. Thirteen patients (62%) had T2 disease, and none …

Premalignant Progression In The Lung: Knowledge Gaps And Novel Opportunities For Interception Of Non-Small Cell Lung Cancer An Official American Thoracic Society Research Statement, Seyed Javad Moghaddam, Rajkumar Savai, Ramin Salehi-Rad, Shreoshi Sengupta, Michael N Kammer, Pierre Massion, Jennifer E Beane, Edwin J Ostrin, Carmen Priolo, Meredith A Tennis, Laura P Stabile, Alison K Bauer, Catherine R Sears, Eva Szabo, M Patricia Rivera, Charles A Powell, Humam Kadara, Brendan J Jenkins, Steven M Dubinett, A Mcgarry Houghton, Carla F Kim, Robert L Keith

Faculty, Staff and Student Publications

Rationale: Despite significant advances in precision treatments and immunotherapy, lung cancer is the most common cause of cancer death worldwide. To reduce incidence and improve survival rates, a deeper understanding of lung premalignancy and the multistep process of tumorigenesis is essential, allowing timely and effective intervention before cancer development. Objectives: To summarize existing information, identify knowledge gaps, formulate research questions, prioritize potential research topics, and propose strategies for future investigations into the premalignant progression in the lung. Methods: An international multidisciplinary team of basic, translational, and clinical scientists reviewed available data to develop and refine research questions pertaining to the …