Biomedical Informatics Commons^™

It Is Better To Light A Candle Than To Curse The Darkness: Single-Cell Transcriptomics Sheds New Light On Pancreas Biology And Disease, Amelia T Cephas, William L Hwang, Anirban Maitra, Oren Parnas, Kathleen E Delgiorno

Faculty, Staff and Student Publications

Recent advances in single-cell RNA sequencing and bioinformatics have drastically increased our ability to interrogate the cellular composition of traditionally difficult to study organs, such as the pancreas. With the advent of these technologies and approaches, the field has grown, in just a few years, from profiling pancreas disease states to identifying molecular mechanisms of therapy resistance in pancreatic ductal adenocarcinoma, a particularly deadly cancer. Single-cell transcriptomics and related spatial approaches have identified previously undescribed epithelial and stromal cell types and states, how these populations change with disease progression, and potential mechanisms of action which will serve as the basis …

Clinical Implications Of Tumor-Based Next-Generation Sequencing In High-Grade Epithelial Ovarian Cancer, Katherine I Foster, Kenna R M Shaw, Jeff Jin, Shannon N Westin, Timothy A Yap, Deanna M Glassman, Amir A Jazaeri, Jose A Rauh-Hain, Sanghoon Lee, Bryan M Fellman, Zhenlin Ju, Yuexin Liu, Nicole D Fleming, Anil K Sood

Faculty, Staff and Student Publications

Background: Tumor-based next-generation sequencing is used inconsistently as a tool to tailor treatment of ovarian cancer, yet beyond detection of somatic BRCA1 and BRCA2 mutations, the clinical benefit is not well established. This study aimed to assess the clinical relevance of tumor-based next-generation sequencing (tbNGS) in patients with ovarian cancer.

Methods: This retrospective study included patients with high-grade epithelial ovarian carcinoma. tbNGS results were identified in the electronic medical record using optical character recognition and natural language processing. Genetic, clinical, and demographic information was collected. Progression-free survival (PFS) and overall survival were calculated and compared using log-rank tests. Multivariate Cox …

Efficacy And Safety Of Nivolumab Plus Ipilimumab Vs Nivolumab Alone For Treatment Of Recurrent Or Metastatic Squamous Cell Carcinoma Of The Head And Neck: The Phase 2 Checkmate 714 Randomized Clinical Trial, Kevin J Harrington, Robert L Ferris, Maura Gillison, Makoto Tahara, Athanasios Argiris, Jérôme Fayette, Michael Schenker, Åse Bratland, John W T Walker, Peter Grell, Caroline Even, Christine H Chung, Rebecca Redman, Alexandre Coutte, Sébastien Salas, Cliona Grant, Sergio De Azevedo, Denis Soulières, Aaron R Hansen, Li Wei, Tariq Aziz Khan, Karen Miller-Moslin, Mustimbo Roberts, Robert Haddad

Faculty, Staff and Student Publications

IMPORTANCE: There remains an unmet need to improve clinical outcomes in patients with recurrent or metastatic squamous cell carcinoma of the head and neck (R/M SCCHN).

OBJECTIVE: To evaluate clinical benefit of first-line nivolumab plus ipilimumab vs nivolumab alone in patients with R/M SCCHN.

DESIGN, SETTING, AND PARTICIPANTS: The CheckMate 714, double-blind, phase 2 randomized clinical trial was conducted at 83 sites in 21 countries between October 20, 2016, and January 23, 2019. Eligible participants were aged 18 years or older and had platinum-refractory or platinum-eligible R/M SCCHN and no prior systemic therapy for R/M disease. Data were analyzed from …

Circulating Succinate-Modifying Metabolites Accurately Classify And Reflect The Status Of Fumarate Hydratase-Deficient Renal Cell Carcinoma, Liang Zheng, Zi-Ran Zhu, Tal Sneh, Wei-Tuo Zhang, Zao-Yu Wang, Guang-Yu Wu, Wei He, Hong-Gang Qi, Hang Wang, Xiao-Yu Wu, Jonatan Fernández-García, Ifat Abramovich, Yun-Ze Xu, Jin Zhang, Eyal Gottlieb

Faculty, Staff and Student Publications

Germline or somatic loss-of-function mutations of fumarate hydratase (FH) predispose patients to an aggressive form of renal cell carcinoma (RCC). Since other than tumor resection there is no effective therapy for metastatic FH-deficient RCC, an accurate method for early diagnosis is needed. Although MRI or CT scans are offered, they cannot differentiate FH-deficient tumors from other RCCs. Therefore, finding noninvasive plasma biomarkers suitable for rapid diagnosis, screening, and surveillance would improve clinical outcomes. Taking advantage of the robust metabolic rewiring that occurs in FH-deficient cells, we performed plasma metabolomics analysis and identified 2 tumor-derived metabolites, succinyl-adenosine and succinic-cysteine, as excellent …

Smarcb1 Regulates A Tfcp2l1-Myc Transcriptional Switch Promoting Renal Medullary Carcinoma Transformation And Ferroptosis Resistance, Bujamin H Vokshi, Guillaume Davidson, Nassim Tawanaie Pour Sedehi, Alexandra Helleux, Marc Rippinger, Alexandre R Haller, Justine Gantzer, Jonathan Thouvenin, Philippe Baltzinger, Rachida Bouarich, Valeria Manriquez, Sakina Zaidi, Priya Rao, Pavlos Msaouel, Xiaoping Su, Hervé Lang, Thibault Tricard, Véronique Lindner, Didier Surdez, Jean-Emmanuel Kurtz, Franck Bourdeaut, Nizar M Tannir, Irwin Davidson, Gabriel G Malouf

Faculty, Staff and Student Publications

Renal medullary carcinoma (RMC) is an aggressive tumour driven by bi-allelic loss of SMARCB1 and tightly associated with sickle cell trait. However, the cell-of-origin and oncogenic mechanism remain poorly understood. Using single-cell sequencing of human RMC, we defined transformation of thick ascending limb (TAL) cells into an epithelial-mesenchymal gradient of RMC cells associated with loss of renal epithelial transcription factors TFCP2L1, HOXB9 and MITF and gain of MYC and NFE2L2-associated oncogenic and ferroptosis resistance programs. We describe the molecular basis for this transcriptional switch that is reversed by SMARCB1 re-expression repressing the oncogenic and ferroptosis resistance programs leading to ferroptotic …

Kras-Dependency In Pancreatic Ductal Adenocarcinoma: Mechanisms Of Escaping In Resistance To Kras Inhibitors And Perspectives Of Therapy, Enrico Gurreri, Giannicola Genovese, Luigi Perelli, Antonio Agostini, Geny Piro, Carmine Carbone, Giampaolo Tortora

Faculty, Staff and Student Publications

Pancreatic ductal adenocarcinoma (PDAC) is still one of the deadliest cancers in oncology because of its increasing incidence and poor survival rate. More than 90% of PDAC patients are KRAS mutated (KRASmu), with KRASG12D and KRASG12V being the most common mutations. Despite this critical role, its characteristics have made direct targeting of the RAS protein extremely difficult. KRAS regulates development, cell growth, epigenetically dysregulated differentiation, and survival in PDAC through activation of key downstream pathways, such as MAPK-ERK and PI3K-AKT-mammalian target of rapamycin (mTOR) signaling, in a KRAS-dependent manner. KRASmu induces the occurrence of acinar-to-ductal metaplasia (ADM) and pancreatic intraepithelial …

Phase Ii Clinical Trial Of Axitinib And Avelumab In Patients With Recurrent/Metastatic Adenoid Cystic Carcinoma, Renata Ferrarotto, Luana G Sousa, Lei Feng, Frank Mott, George Blumenschein, Mehmet Altan, Diana Bell, Flavia Bonini, Kaiyi Li, Mario L Marques-Piubelli, Eduardo A Dal Lago, Jason J Johnson, Yoshitsugu Mitani, Myrna Godoy, Anna Lee, Michael Kupferman, Ehab Hanna, Bonnie S Glisson, Yasir Elamin, Adel El-Naggar

Faculty, Staff and Student Publications

Purpose: We conducted a phase II trial evaluating the efficacy of VEGFR inhibitor axitinib and PD-L1 inhibitor avelumab in patients with recurrent/metastatic adenoid cystic carcinoma (R/M ACC).

Patients and methods: Eligible patients had R/M ACC with progression within 6 months before enrollment. Treatment consisted of axitinib and avelumab. The primary end point was objective response rate (ORR) per RECIST 1.1; secondary end points included progression-free survival (PFS), overall survival (OS), and toxicity. Simon's optimal two-stage design tested the null hypothesis of ORR ≤5% versus ORR ≥20% at 6 months; ≥4 responses in 29 patients would reject the null hypothesis.

Results: …

Phase Ii Trial Of Neoadjuvant Sitravatinib Plus Nivolumab In Patients Undergoing Nephrectomy For Locally Advanced Clear Cell Renal Cell Carcinoma, Jose A Karam, Pavlos Msaouel, Cara L Haymaker, Surena F Matin, Matthew T Campbell, Amado J Zurita, Amishi Y Shah, Ignacio I Wistuba, Enrica Marmonti, Dzifa Y Duose, Edwin R Parra, Luisa Maren Solis Soto, Caddie Laberiano-Fernandez, Marisa Lozano, Alice Abraham, Max Hallin, Curtis D Chin, Peter Olson, Hirak Der-Torossian, Xiaohong Yan, Nizar M Tannir, Christopher G Wood

Faculty, Staff and Student Publications

Sitravatinib is an immunomodulatory tyrosine kinase inhibitor that can augment responses when combined with programmed death-1 inhibitors such as nivolumab. We report a single-arm, interventional, phase 2 study of neoadjuvant sitravatinib in combination with nivolumab in patients with locally advanced clear cell renal cell carcinoma (ccRCC) prior to curative nephrectomy (NCT03680521). The primary endpoint was objective response rate (ORR) prior to surgery with a null hypothesis ORR = 5% and the alternative hypothesis set at ORR = 30%. Secondary endpoints were safety; pharmacokinetics (PK) of sitravatinib; immune effects, including changes in programmed cell death-ligand 1 expression; time-to-surgery; and disease-free survival …

Angiotensin Ii Receptor Inhibition Ameliorates Liver Fibrosis And Enhances Hepatocellular Carcinoma Infiltration By Effector T Cells, Li Gu, Yahui Zhu, Maiya Lee, Albert Nguyen, Nicolas T Ryujin, Jian Yu Huang, Shusil K Pandit, Shadi Chamseddine, Lianchun Xiao, Yehia I Mohamed, Ahmed O Kaseb, Michael Karin, Shabnam Shalapour

Faculty, Staff and Student Publications

Although viral hepatocellular carcinoma (HCC) is declining, nonviral HCC, which often is the end stage of nonalcoholic or alcoholic steatohepatitis (NASH, ASH), is on an upward trajectory. Immune checkpoint inhibitors (ICIs) that block the T cell inhibitory receptor PD-1 were approved for treatment of all HCC types. However, only a minority of HCC patients show a robust and sustained response to PD-1 blockade, calling for improved understanding of factors that negatively impact response rate and duration and the discovery of new adjuvant treatments that enhance ICI responsiveness. Using a mouse model of NASH-driven HCC, we identified peritumoral fibrosis as a …

Lifetime Ovulatory Years And Risk Of Epithelial Ovarian Cancer: A Multinational Pooled Analysis, Zhuxuan Fu, Maria Mori Brooks, Sarah Irvin, Susan Jordan, Katja K H Aben, Hoda Anton-Culver, Elisa V Bandera, Matthias W Beckmann, Andrew Berchuck, Angela Brooks-Wilson, Jenny Chang-Claude, Linda S Cook, Daniel W Cramer, Kara L Cushing-Haugen, Jennifer A Doherty, Arif B Ekici, Peter A Fasching, Renée T Fortner, Simon A Gayther, Aleksandra Gentry-Maharaj, Graham G Giles, Ellen L Goode, Marc T Goodman, Holly R Harris, Alexander Hein, Rudolf Kaaks, Lambertus A Kiemeney, Martin Köbel, Joanne Kotsopoulos, Nhu D Le, Alice W Lee, Keitaro Matsuo, Valerie Mcguire, John R Mclaughlin, Usha Menon, Roger L Milne, Kirsten B Moysich, Celeste Leigh Pearce, Malcolm C Pike, Bo Qin, Susan J Ramus, Marjorie J Riggan, Joseph H Rothstein, Joellen M Schildkraut, Weiva Sieh, Rebecca Sutphen, Kathryn L Terry, Pamela J Thompson, Linda Titus, Anne M Van Altena, Emily White, Alice S Whittemore, Anna H Wu, Wei Zheng, Argyrios Ziogas, Sarah E Taylor, Lu Tang, Thomas Songer, Nicolas Wentzensen, Penelope M Webb, Aocs Group, Harvey A Risch, Francesmary Modugno

Faculty, Staff and Student Publications

BACKGROUND: The role of ovulation in epithelial ovarian cancer (EOC) is supported by the consistent protective effects of parity and oral contraceptive use. Whether these factors protect through anovulation alone remains unclear. We explored the association between lifetime ovulatory years (LOY) and EOC.

METHODS: LOY was calculated using 12 algorithms. Odds ratios (ORs) and 95% confidence intervals (CIs) estimated the association between LOY or LOY components and EOC among 26 204 control participants and 21 267 case patients from 25 studies. To assess whether LOY components act through ovulation suppression alone, we compared beta coefficients obtained from regression models with …

Immune Checkpoint Therapy Combinations In Adult Advanced Mit Family Translocation Renal Cell Carcinomas, Omar Alhalabi, Jonathan Thouvenin, Sylvie Négrier, Yann-Alexandre Vano, Luca Campedel, Elshad Hasanov, Ziad Bakouny, Andrew W Hahn, Mehmet Asim Bilen, Pavlos Msaouel, Toni K Choueiri, Srinivas R Viswanathan, Kanishka Sircar, Laurence Albiges, Gabriel G Malouf, Nizar M Tannir

Faculty, Staff and Student Publications

Background: There remains a paucity of data regarding the efficacy of immune checkpoint therapy (ICT) combinations ± vascular endothelial growth factor (VEGF) targeted therapy (TT) in translocation renal cell carcinoma (tRCC).

Methods: This is a retrospective study of patients with advanced tRCC treated with ICT combinations at 11 centers in the US, France, and Belgium. Only cases with confirmed fluorescence in situ hybridization (FISH) were included. Objective response rates (ORR) and progression-free survival (PFS) were assessed by RECIST, and overall survival (OS) was estimated by Kaplan-Meier methods.

Results: There were 29 patients identified with median age of 38 (21-70) years, …

Immune Checkpoint Therapy Combinations In Adult Advanced Mit Family Translocation Renal Cell Carcinomas, Omar Alhalabi, Jonathan Thouvenin, Sylvie Négrier, Yann-Alexandre Vano, Luca Campedel, Elshad Hasanov, Ziad Bakouny, Andrew W Hahn, Mehmet Asim Bilen, Pavlos Msaouel, Toni K Choueiri, Srinivas R Viswanathan, Kanishka Sircar, Laurence Albiges, Gabriel G Malouf, Nizar M Tannir

Faculty, Staff and Student Publications

Background: There remains a paucity of data regarding the efficacy of immune checkpoint therapy (ICT) combinations ± vascular endothelial growth factor (VEGF) targeted therapy (TT) in translocation renal cell carcinoma (tRCC).

Methods: This is a retrospective study of patients with advanced tRCC treated with ICT combinations at 11 centers in the US, France, and Belgium. Only cases with confirmed fluorescence in situ hybridization (FISH) were included. Objective response rates (ORR) and progression-free survival (PFS) were assessed by RECIST, and overall survival (OS) was estimated by Kaplan-Meier methods.

Results: There were 29 patients identified with median age of 38 (21-70) years, …

P53 And Ovarian Carcinoma Survival: An Ovarian Tumor Tissue Analysis Consortium Study, Martin Köbel, Eun-Young Kang, Ashley Weir, Peter F Rambau, Cheng-Han Lee, Gregg S Nelson, Prafull Ghatage, Nicola S Meagher, Marjorie J Riggan, Jennifer Alsop, Michael S Anglesio, Matthias W Beckmann, Christiani Bisinotto, Michelle Boisen, Jessica Boros, Alison H Brand, Angela Brooks-Wilson, Michael E Carney, Penny Coulson, Madeleine Courtney-Brooks, Kara L Cushing-Haugen, Cezary Cybulski, Suha Deen, Mona A El-Bahrawy, Esther Elishaev, Ramona Erber, Sian Fereday, Aocs Group, Anna Fischer, Simon A Gayther, Arantzazu Barquin-Garcia, Aleksandra Gentry-Maharaj, C Blake Gilks, Helena Gronwald, Marcel Grube, Paul R Harnett, Holly R Harris, Andreas D Hartkopf, Arndt Hartmann, Alexander Hein, Joy Hendley, Brenda Y Hernandez, Yajue Huang, Anna Jakubowska, Mercedes Jimenez-Linan, Michael E Jones, Catherine J Kennedy, Tomasz Kluz, Jennifer M Koziak, Jaime Lesnock, Jenny Lester, Jan Lubiński, Teri A Longacre, Maria Lycke, Constantina Mateoiu, Bryan M Mccauley, Valerie Mcguire, Britta Ney, Alexander Olawaiye, Sandra Orsulic, Ana Osorio, Luis Paz-Ares, Teresa Ramón Y Cajal, Joseph H Rothstein, Matthias Ruebner, Minouk J Schoemaker, Mitul Shah, Raghwa Sharma, Mark E Sherman, Yurii B Shvetsov, Naveena Singh, Helen Steed, Sarah J Storr, Aline Talhouk, Nadia Traficante, Chen Wang, Alice S Whittemore, Martin Widschwendter, Lynne R Wilkens, Stacey J Winham, Javier Benitez, Andrew Berchuck, David D Bowtell, Francisco J Candido Dos Reis, Ian Campbell, Linda S Cook, Anna Defazio, Jennifer A Doherty, Peter A Fasching, Renée T Fortner, María J García, Marc T Goodman, Ellen L Goode, Jacek Gronwald, David G Huntsman, Beth Y Karlan, Linda E Kelemen, Stefan Kommoss, Nhu D Le, Stewart G Martin, Usha Menon, Francesmary Modugno, Paul Dp Pharoah, Joellen M Schildkraut, Weiva Sieh, Annette Staebler, Karin Sundfeldt, Anthony J Swerdlow, Susan J Ramus, James D Brenton

Faculty, Staff and Student Publications

Our objective was to test whether p53 expression status is associated with survival for women diagnosed with the most common ovarian carcinoma histotypes (high-grade serous carcinoma [HGSC], endometrioid carcinoma [EC], and clear cell carcinoma [CCC]) using a large multi-institutional cohort from the Ovarian Tumor Tissue Analysis (OTTA) consortium. p53 expression was assessed on 6,678 cases represented on tissue microarrays from 25 participating OTTA study sites using a previously validated immunohistochemical (IHC) assay as a surrogate for the presence and functional effect of TP53 mutations. Three abnormal expression patterns (overexpression, complete absence, and cytoplasmic) and the normal (wild type) pattern were …

Neural Network Based Ensemble Model To Predict Radiation Induced Lymphopenia After Concurrent Chemo-Radiotherapy For Non-Small Cell Lung Cancer From Two Institutions, Yejin Kim, Ibrahim Chamseddine, Yeona Cho, Jin Sung Kim, Radhe Mohan, Nadya Shusharina, Harald Paganetti, Steven Lin, Hong In Yoon, Seungryong Cho, Clemens Grassberger

Faculty, Staff and Student Publications

The use of adjuvant Immune Checkpoint Inhibitors (ICI) after concurrent chemo-radiation therapy (CCRT) has become the standard of care for locally advanced non-small cell lung cancer (LA-NSCLC). However, prolonged radiotherapy regimens are known to cause radiation-induced lymphopenia (RIL), a long-neglected toxicity that has been shown to correlate with response to ICIs and survival of patients treated with adjuvant ICI after CCRT. In this study, we aim to develop a novel neural network (NN) approach that integrates patient characteristics, treatment related variables, and differential dose volume histograms (dDVH) of lung and heart to predict the incidence of RIL at the end …

Noninvasive Genomic Profiling Of Somatic Mutations In Oral Cavity Cancers, Yuanxin Xi, Marcelo V Negrao, Keiko Akagi, Weihong Xiao, Bo Jiang, Sarah C Warner, Joe Dan Dunn, Jing Wang, David E Symer, Maura L Gillison

Faculty, Staff and Student Publications

OBJECTIVES: Somatic mutations may predict prognosis, therapeutic response, or cancer progression. We evaluated targeted sequencing of oral rinse samples (ORS) for non-invasive mutational profiling of oral squamous cell carcinomas (OSCC).

MATERIALS AND METHODS: A custom hybrid capture panel targeting 42 frequently mutated genes in OSCC was used to identify DNA sequence variants in matched ORS and fresh-frozen tumors from 120 newly-diagnosed patients. Receiver operating characteristic (ROC) curves determined the optimal variant allele fraction (VAF) cutoff for variant discrimination in ORS. Behavioral, clinical, and analytical factors were evaluated for impacts on assay performance.

RESULTS: Half of tumors involved oral tongue (50 …

Integrated Circulating Tumor Dna And T Cell Repertoire Predict Radiotherapeutic Response And Outcome In Non-Small Cell Lung Cancer Patients With Brain Metastasis, Ling Peng, Yawen Bin, Peng Ding, Lingjuan Chen, Hao Zeng, Zelong Xu, Liyan Ji, Xuan Gao, Pian Liu, Ye Wang, Sheng Zhang, Zhongxing Liao, Xuefeng Xia, Ruiguang Zhang, Fan Tong, Xiaorong Dong

Faculty, Staff and Student Publications

No abstract provided.

Potent Antitumor Activity Of Ensartinib In Met Exon 14 Skipping-Mutated Non-Small Cell Lung Cancer, Yang Xia, Rui Jin, Miao Li, Fen Lan, Hao Zhu, Yinghui Yu, Da Miao, Qiyuan Wang, Yi Zhou, Giovanni Selvaggi, Songmin Ying, Jianjun Zhang, Huahao Shen, Xiuning Le, Wen Li

Faculty, Staff and Student Publications

Met proto-oncogene exon 14 skipping (METex14) mutations are targetable driver genes in approximately 3% of non-small-cell lung cancers (NSCLCs). Ensartinib, a type Ia MET inhibitor, is a multi-kinase inhibitor that has been approved for ALK-positive NSCLCs. Ensartinib was administered for compassionate use (cohort 1) and in a phase II clinical trial (cohort 2) to patients with METex14 mutant NSCLCs, with ORR as a primary endpoint. Molecular simulation was conducted to evaluate ensartinib c-MET interaction, and cell lines, patient-derived organoids (PDOs), and xenograft models were used to test the effectiveness of ensartinib. Among 29 evaluable patients, the ORR and DCR of …

Genomic And Transcriptomic Analysis Of Checkpoint Blockade Response In Advanced Non-Small Cell Lung Cancer, Arvind Ravi, Matthew D Hellmann, Monica B Arniella, Mark Holton, Samuel S Freeman, Vivek Naranbhai, Chip Stewart, Ignaty Leshchiner, Jaegil Kim, Yo Akiyama, Aaron T Griffin, Natalie I Vokes, Mustafa Sakhi, Vashine Kamesan, Hira Rizvi, Biagio Ricciuti, Patrick M Forde, Valsamo Anagnostou, Jonathan W Riess, Don L Gibbons, Nathan A Pennell, Vamsidhar Velcheti, Subba R Digumarthy, Mari Mino-Kenudson, Andrea Califano, John V Heymach, Roy S Herbst, Julie R Brahmer, Kurt A Schalper, Victor E Velculescu, Brian S Henick, Naiyer Rizvi, Pasi A Jänne, Mark M Awad, Andrew Chow, Benjamin D Greenbaum, Marta Luksza, Alice T Shaw, Jedd Wolchok, Nir Hacohen, Gad Getz, Justin F Gainor

Faculty, Staff and Student Publications

Anti-PD-1/PD-L1 agents have transformed the treatment landscape of advanced non-small cell lung cancer (NSCLC). To expand our understanding of the molecular features underlying response to checkpoint inhibitors in NSCLC, we describe here the first joint analysis of the Stand Up To Cancer-Mark Foundation cohort, a resource of whole exome and/or RNA sequencing from 393 patients with NSCLC treated with anti-PD-(L)1 therapy, along with matched clinical response annotation. We identify a number of associations between molecular features and outcome, including (1) favorable (for example, ATM altered) and unfavorable (for example, TERT amplified) genomic subgroups, (2) a prominent association between expression of …

Voxel-Based Dosimetry Predicting Treatment Response And Related Toxicity In Hcc Patients Treated With Resin-Based Y90 Radioembolization: A Prospective, Single-Arm Study, Nima Kokabi, Linzi Arndt-Webster, Bernard Chen, David Brandon, Ila Sethi, Amir Davarpanahfakhr, James Galt, Mohammad Elsayed, Zachary Bercu, Mircea Cristescu, S Cheenu Kappadath, David M Schuster

Faculty, Staff and Student Publications

BACKGROUND: There is an increasing body of evidence indicating Y90 dose thresholds for tumor response and treatment-related toxicity. These thresholds are poorly studied in resin Y90, particularly in hepatocellular carcinoma (HCC).

PURPOSE: To evaluate the efficacy of prospective voxel-based dosimetry for predicting treatment response and adverse events (AEs) in patients with HCC undergoing resin-based Y90 radioembolization.

MATERIALS AND METHODS: This correlative study was based on a prospective single-arm clinical trial (NCT04172714), which evaluated the efficacy of low/scout (555 MBq) activity of resin-based Y90 for treatment planning. Partition model was used with goal of tumor dose (TD) > 200 Gy and non-tumoral …

Current Treatment Strategies And Risk Stratification For Oral Carcinoma, Issa Mohamad, Mica D E Glaun, Kumar Prabhash, Ahmed Busheri, Stephen Y Lai, Vanita Noronha, Ali Hosni

Faculty, Staff and Student Publications

Management of oral cavity squamous cell carcinoma (OSCC) involves a multidisciplinary team approach. Surgery is ideally the primary treatment option for nonmetastatic OSCC, and less invasive curative surgical approaches are preferred in early-stage disease to minimize surgical-related morbidity. For patients at high risk of recurrence, adjuvant treatment using radiation therapy or chemoradiation is often used. Systemic therapy may also be used in the neoadjuvant setting (for advanced-stage disease with the intent of mandibular preservation) or in the palliative setting (for nonsalvageable locoregional recurrence and/or distant metastases). Patient involvement in treatment decision is the key for patient-driven management, particularly in clinical …

Neddylation Inhibition Sensitises Renal Medullary Carcinoma Tumours To Platinum Chemotherapy, Daniel D Shapiro, Niki Millward Zacharias, Durga N Tripathi, Menuka Karki, Jean-Philippe Bertocchio, Melinda Soeung, Rong He, Mary E Westerman, Jianjun Gao, Priya Rao, Truong N A Lam, Eric Jonasch, Luigi Perelli, Emily H Cheng, Alessandro Carugo, Timothy P Heffernan, Cheryl L Walker, Giannicola Genovese, Nizar M Tannir, Jose A Karam, Pavlos Msaouel

Faculty, Staff and Student Publications

BACKGROUND: Renal medullary carcinoma (RMC) is a highly aggressive cancer in need of new therapeutic strategies. The neddylation pathway can protect cells from DNA damage induced by the platinum-based chemotherapy used in RMC. We investigated if neddylation inhibition with pevonedistat will synergistically enhance antitumour effects of platinum-based chemotherapy in RMC.

METHODS: We evaluated the IC50 concentrations of the neddylation‐activating enzyme inhibitor pevonedistat in vitro in RMC cell lines. Bliss synergy scores were calculated using growth inhibition assays following treatment with varying concentrations of pevonedistat and carboplatin. Protein expression was assessed by western blot and immunofluorescence assays. The efficacy of pevonedistat …

Cdk5-Prmt1-Wdr24 Signaling Cascade Promotes Mtorc1 Signaling And Tumor Growth, Shasha Yin, Liu Liu, Lauren E Ball, Yalong Wang, Mark T Bedford, Stephen A Duncan, Haizhen Wang, Wenjian Gan

Faculty, Staff and Student Publications

The mammalian target of rapamycin complex1 (mTORC1) is a central regulator of metabolism and cell growth by sensing diverse environmental signals, including amino acids. The GATOR2 complex is a key component linking amino acid signals to mTORC1. Here, we identify protein arginine methyltransferase 1 (PRMT1) as a critical regulator of GATOR2. In response to amino acids, cyclin-dependent kinase 5 (CDK5) phosphorylates PRMT1 at S307 to promote PRMT1 translocation from nucleus to cytoplasm and lysosome, which in turn methylates WDR24, an essential component of GATOR2, to activate the mTORC1 pathway. Disruption of the CDK5-PRMT1-WDR24 axis suppresses hepatocellular carcinoma (HCC) cell proliferation …

Immune Cellular Patterns Of Distribution Affect Outcomes Of Patients With Non-Small Cell Lung Cancer, Edwin Roger Parra, Jiexin Zhang, Mei Jiang, Auriole Tamegnon, Renganayaki Krishna Pandurengan, Carmen Behrens, Luisa Solis, Cara Haymaker, John Victor Heymach, Cesar Moran, Jack J Lee, Don Gibbons, Ignacio Ivan Wistuba

Faculty, Staff and Student Publications

Studying the cellular geographic distribution in non-small cell lung cancer is essential to understand the roles of cell populations in this type of tumor. In this study, we characterize the spatial cellular distribution of immune cell populations using 23 makers placed in five multiplex immunofluorescence panels and their associations with clinicopathologic variables and outcomes. Our results demonstrate two cellular distribution patterns-an unmixed pattern mostly related to immunoprotective cells and a mixed pattern mostly related to immunosuppressive cells. Distance analysis shows that T-cells expressing immune checkpoints are closer to malignant cells than other cells. Combining the cellular distribution patterns with cellular …

Nivolumab Plus Ipilimumab Versus Extreme Regimen As First-Line Treatment For Recurrent/Metastatic Squamous Cell Carcinoma Of The Head And Neck: The Final Results Of Checkmate 651, Robert I Haddad, Kevin Harrington, Makoto Tahara, Robert L Ferris, Maura Gillison, Jerome Fayette, Amaury Daste, Piotr Koralewski, Bogdan Zurawski, Miren Taberna, Nabil F Saba, Milena Mak, Andrzej Kawecki, Gustavo Girotto, Miguel Angel Alvarez Avitia, Caroline Even, Joaquin Gabriel Reinoso Toledo, Alexander Guminski, Urs Müller-Richter, Naomi Kiyota, Mustimbo Roberts, Tariq Aziz Khan, Karen Miller-Moslin, Li Wei, Athanassios Argiris

Faculty, Staff and Student Publications

PURPOSE: CheckMate 651 (ClinicalTrials.gov identifier: NCT02741570) evaluated first-line nivolumab plus ipilimumab versus EXTREME (cetuximab plus cisplatin/carboplatin plus fluorouracil ≤ six cycles, then cetuximab maintenance) in recurrent/metastatic squamous cell carcinoma of the head and neck (R/M SCCHN).

METHODS: Patients without prior systemic therapy for R/M SCCHN were randomly assigned 1:1 to nivolumab plus ipilimumab or EXTREME. Primary end points were overall survival (OS) in the all randomly assigned and programmed death-ligand 1 combined positive score (CPS) ≥ 20 populations. Secondary end points included OS in the programmed death-ligand 1 CPS ≥ 1 population, and progression-free survival, objective response rate, and duration …

A Reduced Pancreatic Polypeptide Response Is Associated With New-Onset Pancreatogenic Diabetes Versus Type 2 Diabetes, Phil A Hart, Yogish C Kudva, Dhiraj Yadav, Dana K Andersen, Yisheng Li, Frederico G S Toledo, Fuchenchu Wang, Melena D Bellin, David Bradley, Randall E Brand, Kenneth Cusi, William Fisher, Kieren Mather, Walter G Park, Zeb Saeed, Robert V Considine, Sarah C Graham, Jo Ann Rinaudo, Jose Serrano, Mark O Goodarzi

Faculty, Staff and Student Publications

PURPOSE: Pancreatogenic diabetes refers to diabetes mellitus (DM) that develops in the setting of a disease of the exocrine pancreas, including pancreatic ductal adenocarcinoma (PDAC) and chronic pancreatitis (CP). We sought to evaluate whether a blunted nutrient response of pancreatic polypeptide (PP) can differentiate these DM subtypes from type 2 DM (T2DM).

METHODS: Subjects with new-onset DM (<3 >years' duration) in the setting of PDAC (PDAC-DM, n = 28), CP (CP-DM, n = 38), or T2DM (n = 99) completed a standardized mixed meal tolerance test, then serum PP concentrations were subsequently measured at a central laboratory. Two-way comparisons of …

Pancreatic Cancer: Advances And Challenges, Christopher J Halbrook, Costas A Lyssiotis, Marina Pasca Di Magliano, Anirban Maitra

Faculty, Staff and Student Publications

Pancreatic ductal adenocarcinoma (PDAC) remains one of the deadliest cancers. Significant efforts have largely defined major genetic factors driving PDAC pathogenesis and progression. Pancreatic tumors are characterized by a complex microenvironment that orchestrates metabolic alterations and supports a milieu of interactions among various cell types within this niche. In this review, we highlight the foundational studies that have driven our understanding of these processes. We further discuss the recent technological advances that continue to expand our understanding of PDAC complexity. We posit that the clinical translation of these research endeavors will enhance the currently dismal survival rate of this recalcitrant …

Targeting The Mevalonate Pathway Suppresses Arid1a-Inactivated Cancers By Promoting Pyroptosis, Wei Zhou, Heng Liu, Zhe Yuan, Joseph Zundell, Martina Towers, Jianhuang Lin, Simona Lombardi, Hao Nie, Brennah Murphy, Tyler Yang, Chen Wang, Liping Liao, Aaron R Goldman, Toshitha Kannan, Andrew V Kossenkov, Ronny Drapkin, Luis J Montaner, Daniel T Claiborne, Nan Zhang, Shuai Wu, Rugang Zhang

Faculty, Staff and Student Publications

ARID1A, encoding a subunit of the SWI/SNF complex, is mutated in ∼50% of clear cell ovarian carcinoma (OCCC) cases. Here we show that inhibition of the mevalonate pathway synergizes with immune checkpoint blockade (ICB) by driving inflammasome-regulated immunomodulating pyroptosis in ARID1A-inactivated OCCCs. SWI/SNF inactivation downregulates the rate-limiting enzymes in the mevalonate pathway such as HMGCR and HMGCS1, which creates a dependence on the residual activity of the pathway in ARID1A-inactivated cells. Inhibitors of the mevalonate pathway such as simvastatin suppresses the growth of ARID1A mutant, but not wild-type, OCCCs. In addition, simvastatin synergizes with anti-PD-L1 antibody in a genetic OCCC …

Prmt3-Mediated Arginine Methylation Of Igf2bp1 Promotes Oxaliplatin Resistance In Liver Cancer, Yunxing Shi, Yi Niu, Yichuan Yuan, Kai Li, Chengrui Zhong, Zhiyu Qiu, Keren Li, Zhu Lin, Zhiwen Yang, Dinglan Zuo, Jiliang Qiu, Wei He, Chenwei Wang, Yadi Liao, Guocan Wang, Yunfei Yuan, Binkui Li

Faculty, Staff and Student Publications

Although oxaliplatin-based chemotherapy has been effective in the treatment of hepatocellular carcinoma (HCC), primary or acquired resistance to oxaliplatin remains a major challenge in the clinic. Through functional screening using CRISPR/Cas9 activation library, transcriptomic profiling of clinical samples, and functional validation in vitro and in vivo, we identify PRMT3 as a key driver of oxaliplatin resistance. Mechanistically, PRMT3-mediated oxaliplatin-resistance is in part dependent on the methylation of IGF2BP1 at R452, which is critical for the function of IGF2BP1 in stabilizing the mRNA of HEG1, an effector of PRMT3-IGF2BP1 axis. Also, PRMT3 overexpression may serve as a biomarker for oxaliplatin resistance …

Il6 Mediates Suppression Of T- And Nk-Cell Function In Emt-Associated Tki-Resistant Egfr-Mutant Nsclc, Sonia A Patel, Monique B Nilsson, Yan Yang, Xiuning Le, Hai T Tran, Yasir Y Elamin, Xiaoxing Yu, Fahao Zhang, Alissa Poteete, Xiaoyang Ren, Li Shen, Jing Wang, Seyed Javad Moghaddam, Tina Cascone, Michael Curran, Don L Gibbons, John V Heymach

Faculty, Staff and Student Publications

Purpose: Patients with advanced non-small cell lung cancer (NSCLC) harboring activating EGFR mutations are initially responsive to tyrosine kinase inhibitors (TKI). However, therapeutic resistance eventually emerges, often via secondary EGFR mutations or EGFR-independent mechanisms such as epithelial-to-mesenchymal transition. Treatment options after EGFR-TKI resistance are limited as anti-PD-1/PD-L1 inhibitors typically display minimal benefit. Given that IL6 is associated with worse outcomes in patients with NSCLC, we investigate whether IL6 in part contributes to this immunosuppressed phenotype.

Experimental design: We utilized a syngeneic genetically engineered mouse model (GEMM) of EGFR-mutant NSCLC to investigate the effects of IL6 on the tumor microenvironment and …

Inhibition Of Stat6 With Antisense Oligonucleotides Enhances The Systemic Antitumor Effects Of Radiotherapy And Anti-Pd-1 In Metastatic Non-Small Cell Lung Cancer, Kewen He, Hampartsoum B Barsoumian, Nahum Puebla-Osorio, Yun Hu, Duygu Sezen, Mark D Wasley, Genevieve Bertolet, Jie Zhang, Carola Leuschner, Liangpeng Yang, Claudia S Kettlun Leyton, Natalie Wall Fowlkes, Morgan Maureen Green, Lisa Hettrick, Dawei Chen, Fatemeh Masrorpour, Meidi Gu, Hadi Maazi, Alexey S Revenko, Maria Angelica Cortez, James W Welsh

Faculty, Staff and Student Publications

Diverse factors contribute to the limited clinical response to radiotherapy (RT) and immunotherapy in metastatic non-small cell lung cancer (NSCLC), among which is the ability of these tumors to recruit a retinue of suppressive immune cells-such as M2 tumor-associated macrophages (TAM)-thereby establishing an immunosuppressive tumor microenvironment that contributes to tumor progression and radio resistance. M2 TAMs are activated by the STAT6 signaling pathway. Therefore, we targeted STAT6 using an antisense oligonucleotide (ASO) along with hypofractionated RT (hRT; 3 fractions of 12 Gy each) to primary tumors in three bilateral murine NSCLC models (Lewis lung carcinoma, 344SQ-parental, and anti-PD-1-resistant 344SQ lung …