Medical Specialties Commons^™

The Fibro-Adipogenic Progenitor Apod+Dcn+Llum+ Cell Population In Aggressive Carcinomas, Lingyi Cai, Mikhail G Kolonin, Dimitris Anastassiou

Faculty, Staff and Student Publications

We identified a progenitor cell population highly enriched in samples from invasive and chemo-resistant carcinomas, characterized by a well-defined multigene signature including APOD, DCN, and LUM. This cell population has previously been labeled as consisting of inflammatory cancer-associated fibroblasts (iCAFs). The same signature characterizes naturally occurring fibro-adipogenic progenitors (FAPs) as well as stromal cells abundant in normal adipose tissue. Our analysis of human gene expression databases provides evidence that adipose stromal cells (ASCs) are recruited by tumors and undergo differentiation into CAFs during cancer progression to invasive and chemotherapy-resistant stages.

Mitochondrial Complex I Promotes Kidney Cancer Metastasis, Divya Bezwada, Luigi Perelli, Nicholas P Lesner, Ling Cai, Bailey Brooks, Zheng Wu, Hieu S Vu, Varun Sondhi, Daniel L Cassidy, Stacy Kasitinon, Sherwin Kelekar, Feng Cai, Arin B Aurora, Mckenzie Patrick, Ashley Leach, Rashed Ghandour, Yuanyuan Zhang, Duyen Do, Phyllis Mcdaniel, Jessica Sudderth, Dennis Dumesnil, Sara House, Tracy Rosales, Alan M Poole, Yair Lotan, Solomon Woldu, Aditya Bagrodia, Xiaosong Meng, Jeffrey A Cadeddu, Prashant Mishra, Javier Garcia-Bermudez, Ivan Pedrosa, Payal Kapur, Kevin D Courtney, Craig R Malloy, Giannicola Genovese, Vitaly Margulis, Ralph J Deberardinis

Faculty, Staff and Student Publications

Most kidney cancers are metabolically dysfunctional1-4, but how this dysfunction affects cancer progression in humans is unknown. We infused 13C-labelled nutrients in over 80 patients with kidney cancer during surgical tumour resection. Labelling from [U-13C]glucose varies across subtypes, indicating that the kidney environment alone cannot account for all tumour metabolic reprogramming. Compared with the adjacent kidney, clear cell renal cell carcinomas (ccRCCs) display suppressed labelling of tricarboxylic acid (TCA) cycle intermediates in vivo and in ex vivo organotypic cultures, indicating that suppressed labelling is tissue intrinsic. [1,2-13C]acetate and [U-13C]glutamine infusions in patients, coupled with measurements of respiration in isolated human …

Resin-Based 90 Y Tumor Dose As A Predictor Of Duration Of Response And Survival In Patients With Surgically Unresectable Hepatocellular Carcinoma : A Prospective Single-Arm Study, Nima Kokabi, Linzi A Webster, Howard Dabbous, Anand Shah, David Brandon, James Galt, Minzhi Xing, Alexander Villalobos, Amir Davarpanahfakhr, S Cheenu Kappadath, David M Schuster

Faculty, Staff and Student Publications

Background: Personalized dosimetry improves overall survival (OS) in patients with hepatocellular carcinoma (HCC) treated with glass 90 Y radioembolization. This study evaluated personalized tumor dose (TD) as a predictor of OS, progression-free survival (PFS), and local duration of response (DOR) in patients with surgically unresectable HCC treated with resin 90 Y radioembolization.

Patients and methods: This prospective, single-center, single-arm clinical trial (NCT04172714) evaluated the efficacy of scout activity of resin 90 Y versus 99m Tc-MAA for treatment planning. A secondary aim of this study was to evaluate personalized dosimetry as a predictor of OS, PFS, and DOR. Partition …

Pnpla3, Obesity, And Heavy Alcohol Use In Cirrhosis Patients May Exert A Synergistic Increase Hepatocellular Carcinoma Risk, Aaron P Thrift, Fasiha Kanwal, Hyeyeun Lim, Hao Duong, Yanhong Liu, Amit G Singal, Saira Khaderi, Sumeet K Asrani, Christopher I Amos, Hashem B El-Serag

Faculty, Staff and Students Publications

BACKGROUND & AIMS: In patients with cirrhosis, continued heavy alcohol consumption and obesity may increase risk of hepatocellular carcinoma (HCC). We examined whether germline susceptibility to hepatic steatosis not only independently predisposes to HCC but may also act synergistically with other risk factors.

METHODS: We analyzed data from 1911 patients in 2 multicenter prospective cohort studies in the United States. We classified patients according to alcohol consumption (current heavy vs not current heavy), obesity (body mass index ≥30 vs/m2), and PNPLA3 I148M variant status (carrier of at least one G risk allele vs noncarrier). We examined the independent and joint …

Successful Management Of Pre-Existing Psoriatic Arthritis Through Targeting The Il-23/Il-17 Axis In Cancer Patients Receiving Immune Checkpoint Inhibitor Therapy: A Case Series, Yuanteng Jeff Li, Pavlos Msaouel, Matthew Campbell, Patrick Hwu, Adi Diab, Sang T Kim

Faculty, Staff and Student Publications

BACKGROUND: Immune checkpoint inhibitors (ICIs) have significantly improved outcomes for patients with cancer. However, these therapies are associated with adverse events including de novo immune-related adverse events or flare of pre-exiting autoimmune disorders. Up to 80% of patients with cancer and pre-existing psoriasis (PsO) or psoriatic arthritis (PsA) experience PsO/PsA flare after initiating ICIs. Targeting the interleukin (IL)-17/IL-23 axis is a mainstream of the PsO/PsA treatment. However, whether this treatment can effectively control PsO/PsA with ICI exposure while preserving anti-tumour efficacy remains unknown.

CASE REPORTS: We report three patients with PsA and cancer, who received ICIs for their cancer treatment. …

Inhibition Of Ulk1/2 And Kras G12c Controls Tumor Growth In Preclinical Models Of Lung Cancer, Phaedra C Ghazi, Kayla T O'Toole, Sanjana Srinivas Boggaram, Michael T Scherzer, Mark R Silvis, Yun Zhang, Madhumita Bogdan, Bryan D Smith, Guillermina Lozano, Daniel L Flynn, Eric L Snyder, Conan G Kinsey, Martin Mcmahon

Faculty, Staff and Student Publications

Mutational activation of KRAS occurs commonly in lung carcinogenesis and, with the recent U.S. Food and Drug Administration approval of covalent inhibitors of KRASG12C such as sotorasib or adagrasib, KRAS oncoproteins are important pharmacological targets in non-small cell lung cancer (NSCLC). However, not all KRASG12C-driven NSCLCs respond to these inhibitors, and the emergence of drug resistance in those patients who do respond can be rapid and pleiotropic. Hence, based on a backbone of covalent inhibition of KRASG12C, efforts are underway to develop effective combination therapies. Here, we report that the inhibition of KRASG12C signaling increases autophagy in KRASG12C-expressing lung cancer …

Mif/Nr3c2 Axis Regulates Glucose Metabolism Reprogramming In Pancreatic Cancer Through Mapk-Erk And Ap-1 Pathways, Shouhui Yang, Wei Tang, Azadeh Azizian, Jochen Gaedcke, Yuuki Ohara, Helen Cawley, Nader Hanna, Michael Ghadimi, Trisha Lal, Subrata Sen, Chad J Creighton, Jianjun Gao, Nagireddy Putluri, Stefan Ambs, Perwez Hussain

Faculty, Staff and Student Publications

Inflammation and aberrant cellular metabolism are widely recognized as hallmarks of cancer. In pancreatic ductal adenocarcinoma (PDAC), inflammatory signaling and metabolic reprogramming are tightly interwoven, playing pivotal roles in the pathogenesis and progression of the disease. However, the regulatory functions of inflammatory mediators in metabolic reprogramming in pancreatic cancer have not been fully explored. Earlier, we demonstrated that pro-inflammatory mediator macrophage migration inhibitory factor (MIF) enhances disease progression by inhibiting its downstream transcriptional factor nuclear receptor subfamily 3 group C member 2 (NR3C2). Here, we provide evidence that MIF and NR3C2 interactively regulate metabolic reprogramming, resulting in MIF-induced cancer growth …

Dual Inhibition Of The Trka And Jak2 Pathways Using Entrectinib And Pacritinib Suppresses The Growth And Metastasis Of Her2-Positive And Triple-Negative Breast Cancers, Angelina T Regua, Shivani Bindal, Mariana K Najjar, Chuling Zhuang, Munazza Khan, Austin B J Arrigo, Anneliese O Gonzalez, Xinhai R Zhang, Jay-Jiguang Zhu, Kounosuke Watabe, Hui-Wen Lo

Faculty, Staff and Student Publications

HER2-positive and triple-negative breast cancers (TNBC) are difficult to treat and associated with poor prognosis. Despite showing initial response, HER2-positive breast cancers often acquire resistance to HER2-targeted therapies, and TNBC lack effective therapies. To overcome these clinical challenges, we evaluated the therapeutic utility of co-targeting TrkA and JAK2/STAT3 pathways in these breast cancer subtypes. Here, we report the novel combination of FDA-approved TrkA inhibitors (Entrectinib or Larotrectinib) and JAK2 inhibitors (Pacritinib or Ruxolitinib) synergistically inhibited in vitro growth of HER2-positive breast cancer cells and TNBC cells. The Entrectinib-Pacritinib combination inhibited the breast cancer stem cell subpopulation, reduced expression of stemness …

Pkd1 Mutant Clones Within Cirrhotic Livers Inhibit Steatohepatitis Without Promoting Cancer, Min Zhu, Yunguan Wang, Tianshi Lu, Jason Guo, Lin Li, Meng-Hsiung Hsieh, Purva Gopal, Yi Han, Naoto Fujiwara, Darren P Wallace, Alan S L Yu, Xiangyi Fang, Crystal Ransom, Sara Verschleisser, David Hsiehchen, Yujin Hoshida, Amit G Singal, Adam Yopp, Tao Wang, Hao Zhu

Faculty, Staff and Student Publications

Somatic mutations in non-malignant tissues are selected for because they confer increased clonal fitness. However, it is uncertain whether these clones can benefit organ health. Here, ultra-deep targeted sequencing of 150 liver samples from 30 chronic liver disease patients revealed recurrent somatic mutations. PKD1 mutations were observed in 30% of patients, whereas they were only detected in 1.3% of hepatocellular carcinomas (HCCs). To interrogate tumor suppressor functionality, we perturbed PKD1 in two HCC cell lines and six in vivo models, in some cases showing that PKD1 loss protected against HCC, but in most cases showing no impact. However, Pkd1 haploinsufficiency …

Translational Modeling-Based Evidence For Enhanced Efficacy Of Standard-Of-Care Drugs In Combination With Anti-Microrna-155 In Non-Small-Cell Lung Cancer, Prashant Dogra, Vrushaly Shinglot, Javier Ruiz-Ramírez, Joseph Cave, Joseph D Butner, Carmine Schiavone, Dan G Duda, Ahmed O Kaseb, Caroline Chung, Eugene J Koay, Vittorio Cristini, Bulent Ozpolat, George A Calin, Zhihui Wang

Faculty, Staff and Student Publications

BACKGROUND: Elevated microRNA-155 (miR-155) expression in non-small-cell lung cancer (NSCLC) promotes cisplatin resistance and negatively impacts treatment outcomes. However, miR-155 can also boost anti-tumor immunity by suppressing PD-L1 expression. Therapeutic targeting of miR-155 through its antagonist, anti-miR-155, has proven challenging due to its dual molecular effects.

METHODS: We developed a multiscale mechanistic model, calibrated with in vivo data and then extrapolated to humans, to investigate the therapeutic effects of nanoparticle-delivered anti-miR-155 in NSCLC, alone or in combination with standard-of-care drugs.

RESULTS: Model simulations and analyses of the clinical scenario revealed that monotherapy with anti-miR-155 at a dose of 2.5 mg/kg …

Safety And Efficacy Outcomes Of Early Cessation Of Anti-Pd1 Therapy In Patients 80 Years Or Older: A Retrospective Cohort Study, Kylie Fletcher, Alessio Cortellini, Teja Ganta, Roma Kankaria, Haocan Song, Fei Ye, Rebecca Irlmeier, Neha Debnath, Anwaar Saeed, Maluki Radford, Asrar Alahmadi, Akiva Diamond, Christopher Hoimes, Carolyn J Presley, Dwight H Owen, Sarah Abou Alaiwi, Amin H Nassar, Giuseppe Lamberti, Fabiana Perrone, Sebastiano Buti, Raffaele Giusti, Marco Filetti, Vito Vanella, Domenico Mallardo, Tamara A Sussman, Domenico Galetta, Foteini Kalofonou, Ella Daniels, Paolo A Ascierto, David J Pinato, Caroline Nebhan, Stephanie Berg, Toni K Choueiri, Thomas U Marron, Yinghong Wang, Abdul Rafeh Naqash, Douglas B Johnson

Faculty, Staff and Students Publications

Older patients have similar immune checkpoint inhibitor efficacy and rates of adverse events as younger patients, but appear to have decreased tolerability, particularly in the oldest patient cohort (>80 years), often leading to early cessation of therapy. We aimed to determine whether early discontinuation impacts efficacy of anti-PD-1 therapy in patients ≥80 years old. In this retrospective, multicenter, international cohort study, we examined 773 patients with 4 tumor types who were at least 80 years old and treated with anti-PD-1 therapy. We determined response rate, overall survival (OS), and progression-free survival (PFS) in patients who discontinued therapy early (< 12 months) for reasons other than progression or death. We used descriptive statistics for demographics, response, and toxicity rates. Survival statistics were described using Kaplan Meier curves. Median (range) age at anti-PD-1 initiation was 83.0 (75.8-97.0) years. The cancer types included were melanoma (n = 286), non-small cell lung cancer (NSCLC) (n = 345), urothelial cell carcinoma (UCC) (n = 108), and renal cell carcinoma (RCC) (n = 34). Of these, 102 met the primary endpoint of < 12 months to discontinuation for reasons other than death or progression. Median PFS and OS, respectively, for these patients were 34.4 months and 46.6 months for melanoma, 15.8 months and 23.4 months for NSCLC, and 10.4 months and 15.8 months for UCC. This study suggests geriatric patients who have demonstrated therapeutic benefit and discontinued anti-PD-1 therapy at less than 12 months of duration for reasons other than progression may have durable clinical benefit without additional therapy.

In Utero Exposure To Antihistamines And Risk Of Hepatocellular Carcinoma In A Multigenerational Cohort, Caitlin C Murphy, Karim Seif El Dahan, Amit G Singal, Piera M Cirillo, Nickilou Y Krigbaum, Barbara A Cohn

Faculty, Staff and Student Publications

BACKGROUND: Growing evidence suggests that liver disease originates in early life. Antihistamines cross the placenta and are frequently prescribed to pregnant women to treat nausea and vomiting, as well as allergy and asthma symptoms. Exposure to antihistamines in utero may impact the developing liver by reprogramming or inducing epigenetic changes in fetal hepatocytes.

METHODS: We examined in utero exposure to antihistamines and the risk of HCC in the Child Health and Development Studies, a multigenerational cohort that enrolled pregnant women in the East Bay, CA, between 1959 and 1966 (n=14,507 mothers and 18,751 liveborn offspring). We reviewed mothers' medical records …

Impact Of Pretreatment Body Mass Index On The Survival Of Head And Neck Cancer Patients, Zheng Yang, Jobran Mansour, Peng Sun, Peng Wei, Kristina R Dahlstrom, Mark Zafereo, Guojun Li, Neil D Gross

Faculty, Staff and Student Publications

Background: Differences in pretreatment body mass index (BMI) have been associated with survival in squamous cell carcinoma of head and neck (SCCHN). We examined effects of BMI on survival in SCCHN patients after stratifying patients by tumor human papillomavirus (HPV) status and subsite.

Methods: Totally 2204 SCCHN patients in a prospective study were included in this secondary analysis. Multivariable Cox models were used to evaluate associations between pretreatment BMI and overall survival, disease-specific survival, and disease-free survival.

Results: BMI was significantly higher among patients with HPV-positive tumors than HPV-negative tumors. BMI >25 kg/m2 was associated with improved survival, while BMI …

Perioperative Nivolumab Versus Observation In Patients With Renal Cell Carcinoma Undergoing Nephrectomy (Prosper Ecog-Acrin Ea8143): An Open-Label, Randomised, Phase 3 Study, Mohamad E Allaf, Se-Eun Kim, Viraj Master, David F Mcdermott, Lauren C Harshman, Suzanne M Cole, Charles G Drake, Sabina Signoretti, Mahmut Akgul, Nicholas Baniak, Elsa Li-Ning, Matthew B Palmer, Hamid Emamekhoo, Nabil Adra, Hristos Kaimakliotis, Yasser Ged, Phillip M Pierorazio, E Jason Abel, Mehmet A Bilen, Kenneth Ogan, Helen H Moon, Krishna A Ramaswamy, Eric A Singer, Tina M Mayer, Jay Lohrey, Vitaly Margulis, Jessie Gills, Scott E Delacroix, Mark J Waples, Andrew C James, Peng Wang, Toni Choueiri, M Dror Michaelson, Anil Kapoor, Daniel Y Heng, Brian Shuch, Bradley C Leibovich, Primo N Lara, Judith Manola, Deborah Maskens, Dena Battle, Robert Uzzo, Gennady Bratslavsky, Naomi B Haas, Michael A Carducci

Faculty, Staff and Student Publications

Background: The standard of care for patients with intermediate-to-high risk renal cell carcinoma is partial or radical nephrectomy followed by surveillance. We aimed to investigate use of nivolumab before nephrectomy followed by adjuvant nivolumab in patients with high-risk renal cell carcinoma to determine recurrence-free survival compared with surgery only.

Methods: In this open-label, randomised, phase 3 trial (PROSPER EA8143), patients were recruited from 183 community and academic sites across the USA and Canada. Eligible patients were aged 18 years or older with an Eastern Cooperative Oncology Group performance status of 0-1, with previously untreated clinical stage T2 or greater or …

Bigh3 Mediates Apoptosis And Gap Junction Failure In Osteocytes During Renal Cell Carcinoma Bone Metastasis Progression, Tianhong Pan, Fengshuo Liu, Xiaoxin Hao, Shubo Wang, Murtaza Wasi, Jian H Song, Valerae O Lewis, Patrick P Lin, Bryan Moon, Justin E Bird, Theocharis Panaretakis, Sue-Hwa Lin, Danielle Wu, Mary C Farach-Carson, Liyun Wang, Ningyan Zhang, Zhiqiang An, Xiang H-F Zhang, Robert L Satcher

Faculty, Staff and Student Publications

Renal cell carcinoma (RCC) bone metastatis progression is driven by crosstalk between tumor cells and the bone microenvironment, which includes osteoblasts, osteoclasts, and osteocytes. RCC bone metastases (RCCBM) are predominantly osteolytic and resistant to antiresorptive therapy. The molecular mechanisms underlying pathologic osteolysis and disruption of bone homeostasis remain incompletely understood. We previously reported that BIGH3/TGFBI (transforming growth factor-beta-induced protein ig-h3, shortened to BIGH3 henceforth) secreted by colonizing RCC cells drives osteolysis by inhibiting osteoblast differentiation, impairing healing of osteolytic lesions, which is reversible with osteoanabolic agents. Here, we report that BIGH3 induces osteocyte apoptosis in both human RCCBM tissue specimens …

Long-Term Prospective Outcomes Of Intensity Modulated Radiotherapy For Locally Advanced Lung Cancer: A Secondary Analysis Of A Randomized Clinical Trial, Stephen G Chun, Chen Hu, Ritsuko U Komaki, Robert D Timmerman, Steven E Schild, Jeffrey A Bogart, Michael C Dobelbower, Walter Bosch, Vivek S Kavadi, Samir Narayan, Puneeth Iyengar, Clifford Robinson, Jan Rothman, Adam Raben, Mark E Augspurger, Robert M Macrae, Rebecca Paulus, Jeffrey D Bradley

Faculty, Staff and Students Publications

Importance: The optimal radiotherapy technique for unresectable locally advanced non-small cell lung cancer (NSCLC) is controversial, so evaluating long-term prospective outcomes of intensity-modulated radiotherapy (IMRT) is important.

Objective: To compare long-term prospective outcomes of patients receiving IMRT and 3-dimensional conformal radiotherapy (3D-CRT) with concurrent carboplatin/paclitaxel for locally advanced NSCLC.

Design, setting, and participants: A secondary analysis of a prospective phase 3 randomized clinical trial NRG Oncology-RTOG 0617 assessed 483 patients receiving chemoradiotherapy (3D-CRT vs IMRT) for locally advanced NSCLC based on stratification.

Main outcomes and measures: Long-term outcomes were analyzed, including overall survival (OS), progression-free survival (PFS), time to local …

Efficacy, Safety, And Tolerability Of Tivozanib In Heavily Pretreated Patients With Advanced Clear Cell Renal Cell Carcinoma, Andrew C Johns, Matthew T Campbell, Mamie Gao, Andrew W Hahn, Zita Lim, Emily Wang, Jianjun Gao, Amishi Y Shah, Pavlos Msaouel, Nizar M Tannir

Faculty, Staff and Student Publications

BACKGROUND: Tivozanib has been approved as a third-line or later therapy for advanced renal cell carcinoma based on the TIVO-3 trial, which was conducted before immune checkpoint therapies (ICT), cabozantinib, and lenvatinib/everolimus became incorporated in the current sequential treatment paradigm for advanced clear cell RCC (ccRCC).

METHODS: We performed a retrospective study of patients with advanced ccRCC treated with tivozanib at MD Anderson Cancer Center during 6/2021-7/2023. A blinded radiologist assessed tumor response by RECIST v1.1. We assessed overall response rate (ORR), clinical benefit rate (CBR) [percentage of all treated patients who achieved radiologic response or stable disease (SD) for …

Epigenetic Activation Of Sox11 Is Associated With Recurrence And Progression Of Ductal Carcinoma In Situ To Invasive Breast Cancer, Warapen Treekitkarnmongkol, Vandna Shah, Kazuharu Kai, Hiroshi Katayama, Justin Wong, Farah A Ladha, Tristian Nguyen, Brian Menegaz, Wei Lu, Fei Yang, Barbara Mino, Ximing Tang, Mihai Gagea, Harsh Batra, Maria Gabriela Raso, Ignacio I Wistuba, Savitri Krishnamurthy, Sarah E Pinder, Elinor J Sawyer, Alastair M Thompson, Subrata Sen

Faculty, Staff and Student Publications

Background: Risk of recurrence and progression of ductal carcinoma in situ (DCIS) to invasive cancer remains uncertain, emphasizing the need for developing predictive biomarkers of aggressive DCIS.

Methods: Human cell lines and mouse models of disease progression were analyzed for candidate risk predictive biomarkers identified and validated in two independent DCIS cohorts.

Results: RNA profiling of normal mammary and DCIS tissues (n = 48) revealed that elevated SOX11 expression correlates with MKI67, EZH2, and DCIS recurrence score. The 21T human cell line model of DCIS progression to invasive cancer and two mouse models developing mammary intraepithelial neoplasia confirmed the findings. …

Machine Learning Identifies Prognostic Subtypes Of The Tumor Microenvironment Of Nsclc, Duo Yu, Michael J Kane, Eugene J Koay, Ignacio I Wistuba, Brian P Hobbs

Faculty, Staff and Student Publications

The tumor microenvironment (TME) plays a fundamental role in tumorigenesis, tumor progression, and anti-cancer immunity potential of emerging cancer therapeutics. Understanding inter-patient TME heterogeneity, however, remains a challenge to efficient drug development. This article applies recent advances in machine learning (ML) for survival analysis to a retrospective study of NSCLC patients who received definitive surgical resection and immune pathology following surgery. ML methods are compared for their effectiveness in identifying prognostic subtypes. Six survival models, including Cox regression and five survival machine learning methods, were calibrated and applied to predict survival for NSCLC patients based on PD-L1 expression, CD3 expression, …

Lacrimal Gland Adenocarcinoma Clinicopathologic Features And Outcomes Compared With Those Of Lacrimal Gland Adenoid Cystic Carcinoma, Hila Goldberg, Xinyang Jiang, Janet Fan, Jiawei Zhao, Jing Ning, Michelle Williams, Steven Frank, Amy Moreno, Brandon Gunn, Renata Ferrarotto, Bita Esmaeli

Faculty, Staff and Student Publications

Purpose: Lacrimal gland (LG) adenocarcinomas (ACs) are rare, with limited data. We compared clinicopathologic features and local recurrence, distant metastasis, and survival rates between LG AC and LG adenoid cystic carcinoma (ACC).

Methods: The records of LG AC patients treated from 2008 to 2022 and LG ACC patients treated from 1998 to 2022 at the same center were retrospectively reviewed.

Results: The study included 20 patients with AC; 10 de-novo AC, 10 ex-pleomorphic AC; and 51 ACC patients. The median age at diagnosis was 61 years for de-novo AC, 54 years for ex-pleomorphic AC, and 45 years for ACC. All …

Genetic Deletion Of Galectin-3 Inhibits Pancreatic Cancer Progression And Enhances The Efficacy Of Immunotherapy, 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

Background & aims: Pancreatic ductal adenocarcinoma (PDAC) has a desmoplastic tumor stroma and immunosuppressive microenvironment. Galectin-3 (GAL3) is enriched in PDAC, highly expressed by cancer cells and myeloid cells. However, the functional roles of GAL3 in the PDAC microenvironment remain elusive.

Methods: We generated a novel transgenic mouse model (LSL-KrasG12D/+;Trp53loxP/loxP;Pdx1-Cre;Lgals3-/- [KPPC;Lgals3-/-]) that allows the genetic depletion of GAL3 from both cancer cells and myeloid cells in spontaneous PDAC formation. Single-cell RNA-sequencing analysis was used to identify the alterations in the tumor microenvironment upon GAL3 depletion. We investigated both the cancer cell-intrinsic function and immunosuppressive function of GAL3. We also evaluated …

Evaluation Of Major Pathologic Response And Pathologic Complete Response As Surrogate End Points For Survival In Randomized Controlled Trials Of Neoadjuvant Immune Checkpoint Blockade In Resectable In Nsclc, Jacobi B Hines, Robert B Cameron, Alessandra Esposito, Leeseul Kim, Luca Porcu, Antonio Nuccio, Giuseppe Viscardi, Roberto Ferrara, Giulia Veronesi, Patrick M Forde, Janis Taube, Everett Vokes, Christine M Bestvina, James M Dolezal, Matteo Sacco, Marta Monteforte, Tina Cascone, Marina C Garassino, Valter Torri

Faculty, Staff and Student Publications

Introduction: Controversy remains as to whether pathologic complete response (pCR) and major pathologic response (MPR) represent surrogate end points for event-free survival (EFS) and overall survival (OS) in neoadjuvant trials for resectable NSCLC.

Methods: A search of PubMed and archives of international conference abstracts was performed from June 2017 through October 31, 2023. Studies incorporating a neoadjuvant arm with immune checkpoint blockade alone or in combination with chemotherapy were included. Those not providing information regarding pCR, MPR, EFS, or OS were excluded. For trial-level surrogacy, log ORs for pCR and MPR and log hazard ratios for EFS and OS were …

Delivery Of Hereditary Cancer Genetics Services To Patients Newly Diagnosed With Ovarian And Endometrial Cancers At Three Gynecologic Oncology Clinics In The Usa, Brazil, And Mexico, Erica M Bednar, Keiry A Paiz, Karen H Lu, Aline Patricia Soares Dias De Souza, Gabriela Oliveira, Carlos E Eduardo Mattos Da Cunha Andrade, Lenny Gallardo, Jairo Rubio-Cordero, David Cantu-De-León, Jose Alejandro Rauh-Hain

Faculty, Staff and Student Publications

Objective: Three gynecologic oncology clinics located in the USA, Brazil, and Mexico collaborated to evaluate their delivery of hereditary cancer genetics services. This descriptive retrospective review study aimed to establish baseline rates and timeliness of guideline-recommended genetics service delivery to patients with ovarian, fallopian tube, primary peritoneal (ovarian), and endometrial cancers at each clinic.

Methods: Patients who were newly diagnosed with ovarian and endometrial cancers between September 1, 2018 and December 31, 2020 were identified from the medical records of the clinics. Genetics service delivery metrics included the rates of mismatch repair deficiency tumor testing for patients with endometrial cancer …

Global Prevalence Of Metabolic Dysfunction-Associated Fatty Liver Disease-Related Hepatocellular Carcinoma: A Systematic Review And Meta-Analysis, Harry Crane, Guy D Eslick, Cameron Gofton, Anjiya Shaikh, George Cholankeril, Mark Cheah, Jian-Hong Zhong, Gianluca Svegliati-Baroni, Alessandro Vitale, Beom Kyung Kim, Sang Hoon Ahn, Mi Na Kim, Simone I Strasser, Jacob George

Faculty, Staff and Students Publications

BACKGROUND/AIMS: The global proportion of hepatocellular carcinoma (HCC) attributable to metabolic dysfunction-associated fatty liver disease (MAFLD) is unclear. The MAFLD diagnostic criteria allows objective diagnosis in the presence of steatosis plus defined markers of metabolic dysfunction, irrespective of concurrent liver disease. We aimed to determine the total global prevalence of MAFLD in HCC cohorts (total-MAFLD), including the proportion with MAFLD as their sole liver disease (single-MAFLD), and the proportion of those with concurrent liver disease where MAFLD was a contributary factor (mixed-MAFLD).

METHODS: This systematic review and meta-analysis included studies systematically ascertaining MAFLD in HCC cohorts, defined using international expert …

Homozygous Missense Variants In Ykt6 Result In Loss Of Function And Are Associated With Developmental Delay, With Or Without Severe Infantile Liver Disease And Risk For Hepatocellular Carcinoma, Mengqi Ma, Mythily Ganapathi, Yiming Zheng, Kai-Li Tan, Oguz Kanca, Kevin E Bove, Norma Quintanilla, Sebnem O Sag, Sehime G Temel, Charles A Leduc, Amanda J Mcpartland, Elaine M Pereira, Yufeng Shen, Jacob Hagen, Christie P Thomas, Nhu Thao Nguyen Galván, Xueyang Pan, Shenzhao Lu, Jill A Rosenfeld, Daniel G Calame, Michael F Wangler, James R Lupski, Davut Pehlivan, Paula M Hertel, Wendy K Chung, Hugo J Bellen

Faculty, Staff and Students Publications

PURPOSE: YKT6 plays important roles in multiple intracellular vesicle trafficking events but has not been associated with Mendelian diseases.

METHODS: We report 3 unrelated individuals with rare homozygous missense variants in YKT6 who exhibited neurological disease with or without a progressive infantile liver disease. We modeled the variants in Drosophila. We generated wild-type and variant genomic rescue constructs of the fly ortholog dYkt6 and compared their ability in rescuing the loss-of-function phenotypes in mutant flies. We also generated a dYkt6

RESULTS: Two individuals are homozygous for YKT6 [NM_006555.3:c.554A>G p.(Tyr185Cys)] and exhibited normal prenatal course followed by failure to thrive, …

Type I Conventional Dendritic Cells Facilitate Immunotherapy In Pancreatic Cancer, Krishnan K Mahadevan, Allison M Dyevoich, Yang Chen, Bingrui Li, Hikaru Sugimoto, Amari M Sockwell, Kathleen M Mcandrews, Lakshmi Kavitha Sthanam, Huamin Wang, Shabnam Shalapour, Stephanie S Watowich, Raghu Kalluri

Faculty, Staff and Student Publications

Inflammation and tissue damage associated with pancreatitis can precede or occur concurrently with pancreatic ductal adenocarcinoma (PDAC). We demonstrate that in PDAC coupled with pancreatitis (ptPDAC), antigen-presenting type I conventional dendritic cells (cDC1s) are specifically activated. Immune checkpoint blockade therapy (iCBT) leads to cytotoxic CD8+ T cell activation and elimination of ptPDAC with restoration of life span even upon PDAC rechallenge. Using PDAC antigen-loaded cDC1s as a vaccine, immunotherapy-resistant PDAC was rendered sensitive to iCBT with elimination of tumors. cDC1 vaccination coupled with iCBT identified specific CDR3 sequences in the tumor-infiltrating CD8+ T cells with potential therapeutic importance. This study …

Durable Objective Response To Lurbinectedin In Small Cell Bladder Cancer With Tp53 Mutation: A Molecular-Directed Strategy, Mohammad Jad Moussa, Jaanki Khandelwal, Nathaniel R Wilson, Sagar A Naik, Vivek Subbiah, Matthew T Campbell, Pavlos Msaouel, Parminder Singh, Omar Alhalabi

Faculty, Staff and Student Publications

Small cell bladder cancer (SCBC) is a rare and aggressive disease, often treated with platinum/etoposide-based chemotherapy. Key molecular drivers include the inactivation of onco-suppressor genes (TP53, RB1) and amplifications in proto-oncogenes (MYC). We report a patient with SCBC who achieved an objective and prolonged response to lurbinectedin, which has been approved for metastatic small cell lung cancer, after developing disease progression on cisplatin/etoposide and nivolumab/ipilimumab. A genomic analysis of a metastatic biopsy prior to lurbinectedin initiation revealed a TP53 mutation and amplification of the cell cycle regulators E2F3 and MYCL. A repeat biopsy following …

Defining The Kras- And Erk-Dependent Transcriptome In Kras-Mutant Cancers, Jeffrey A Klomp, Jennifer E Klomp, Clint A Stalnecker, Kirsten L Bryant, A Cole Edwards, Kristina Drizyte-Miller, Priya S Hibshman, J Nathaniel Diehl, Ye S Lee, Alexis J Morales, Khalilah E Taylor, Sen Peng, Nhan L Tran, Laura E Herring, Alex W Prevatte, Natalie K Barker, Laura D Hover, Jill Hallin, Alexey Sorokin, Preeti Marie Kanikarla, Saikat Chowdhury, Oluwadara Coker, Hey Min Lee, Craig M Goodwin, Prson Gautam, Peter Olson, James G Christensen, John P Shen, Scott Kopetz, Lee M Graves, Kian-Huat Lim, Andrea Wang-Gillam, Krister Wennerberg, Adrienne D Cox, Channing J Der

Faculty, Staff and Student Publications

How the KRAS oncogene drives cancer growth remains poorly understood. Therefore, we established a systemwide portrait of KRAS- and ERK-dependent gene transcription in KRAS-mutant cancer to delineate the molecular mechanisms of growth and of inhibitor resistance. Unexpectedly, our KRAS-dependent gene signature diverges significantly from the frequently cited Hallmark KRAS signaling gene signature, is driven predominantly through the ERK mitogen-activated protein kinase (MAPK) cascade, and accurately reflects KRAS- and ERK-regulated gene transcription in KRAS-mutant cancer patients. Integration with our ERK-regulated phospho- and total proteome highlights ERK deregulation of the anaphase promoting complex/cyclosome and other components of the cell cycle machinery as …

Integrative Multi-Omics Analyses To Identify The Genetic And Functional Mechanisms Underlying Ovarian Cancer Risk Regions, Eileen O Dareng, Simon G Coetzee, Jonathan P Tyrer, Pei-Chen Peng, Will Rosenow, Stephanie Chen, Brian D Davis, Felipe Segato Dezem, Ji-Heui Seo, Robbin Nameki, Alberto L Reyes, Katja K H Aben, Hoda Anton-Culver, Natalia N Antonenkova, Gerasimos Aravantinos, Elisa V Bandera, Laura E Beane Freeman, Matthias W Beckmann, Alicia Beeghly-Fadiel, Javier Benitez, Marcus Q Bernardini, Line Bjorge, Amanda Black, Natalia V Bogdanova, Kelly L Bolton, James D Brenton, Agnieszka Budzilowska, Ralf Butzow, Hui Cai, Ian Campbell, Rikki Cannioto, Jenny Chang-Claude, Stephen J Chanock, Kexin Chen, Georgia Chenevix-Trench, Aocs Group, Yoke-Eng Chiew, Linda S Cook, Anna Defazio, Joe Dennis, Jennifer A Doherty, Thilo Dörk, Andreas Du Bois, Matthias Dürst, Diana M Eccles, Gabrielle Ene, Peter A Fasching, James M Flanagan, Renée T Fortner, Florentia Fostira, Aleksandra Gentry-Maharaj, Graham G Giles, Marc T Goodman, Jacek Gronwald, Christopher A Haiman, Niclas Håkansson, Florian Heitz, Michelle A T Hildebrandt, Estrid Høgdall, Claus K Høgdall, Ruea-Yea Huang, Allan Jensen, Michael E Jones, Daehee Kang, Beth Y Karlan, Anthony N Karnezis, Linda E Kelemen, Catherine J Kennedy, Elza K Khusnutdinova, Lambertus A Kiemeney, Susanne K Kjaer, Jolanta Kupryjanczyk, Marilyne Labrie, Diether Lambrechts, Melissa C Larson, Nhu D Le, Jenny Lester, Lian Li, Jan Lubiński, Michael Lush, Jeffrey R Marks, Keitaro Matsuo, Taymaa May, John R Mclaughlin, Iain A Mcneish, Usha Menon, Stacey Missmer, Francesmary Modugno, Melissa Moffitt, Alvaro N Monteiro, Kirsten B Moysich, Steven A Narod, Tu Nguyen-Dumont, Kunle Odunsi, Håkan Olsson, N Charlotte Onland-Moret, Sue K Park, Tanja Pejovic, Jennifer B Permuth, Anna Piskorz, Darya Prokofyeva, Marjorie J Riggan, Harvey A Risch, Cristina Rodríguez-Antona, Mary Anne Rossing, Dale P Sandler, V Wendy Setiawan, Kang Shan, Honglin Song, Melissa C Southey, Helen Steed, Rebecca Sutphen, Anthony J Swerdlow, Soo Hwang Teo, Kathryn L Terry, Pamela J Thompson, Liv Cecilie Vestrheim Thomsen, Linda Titus, Britton Trabert, Ruth Travis, Shelley S Tworoger, Ellen Valen, Els Van Nieuwenhuysen, Digna Velez Edwards, Robert A Vierkant, Penelope M Webb, Opal Study Group, Clarice R Weinberg, Rayna Matsuno Weise, Nicolas Wentzensen, Emily White, Stacey J Winham, Alicja Wolk, Yin-Ling Woo, Anna H Wu, Li Yan, Drakoulis Yannoukakos, Nur Zeinomar, Wei Zheng, Argyrios Ziogas, Andrew Berchuck, Ellen L Goode, David G Huntsman, Celeste L Pearce, Susan J Ramus, Thomas A Sellers, Ovarian Cancer Association Consortium (Ocac), Matthew L Freedman, Kate Lawrenson, Joellen M Schildkraut, Dennis Hazelett, Jasmine T Plummer, Siddhartha Kar, Michelle R Jones, Paul D P Pharoah, Simon A Gayther

Faculty, Staff and Student Publications

To identify credible causal risk variants (CCVs) associated with different histotypes of epithelial ovarian cancer (EOC), we performed genome-wide association analysis for 470,825 genotyped and 10,163,797 imputed SNPs in 25,981 EOC cases and 105,724 controls of European origin. We identified five histotype-specific EOC risk regions (p value < 5 × 10-8) and confirmed previously reported associations for 27 risk regions. Conditional analyses identified an additional 11 signals independent of the primary signal at six risk regions (p value < 10-5). Fine mapping identified 4,008 CCVs in these regions, of which 1,452 CCVs were located in ovarian cancer-related chromatin marks with significant enrichment in active enhancers, active promoters, and active regions for CCVs from each EOC histotype. Transcriptome-wide association and colocalization analyses across histotypes using tissue-specific and cross-tissue datasets identified 86 candidate susceptibility genes in known EOC risk regions and 32 genes in 23 additional genomic regions that may represent novel EOC risk loci (false discovery rate < 0.05). Finally, by integrating genome-wide HiChIP interactome analysis with transcriptome-wide association study (TWAS), variant effect predictor, transcription factor ChIP-seq, and motifbreakR data, we identified candidate gene-CCV interactions at each locus. This included risk loci where TWAS identified one or more candidate susceptibility genes (e.g., HOXD-AS2, HOXD8, and HOXD3 at 2q31) and other loci where no candidate gene was identified (e.g., MYC and PVT1 at 8q24) by TWAS. In summary, this study describes a functional framework and provides a greater understanding of the biological significance of risk alleles and candidate gene targets at EOC susceptibility loci identified by a genome-wide association study.

Primary Cytoreduction And Survival For Patients With Less-Common Epithelial Ovarian Cancer, Koji Matsuo, Ling Chen, Maximilian Klar, Lynda D Roman, Anil K Sood, David M Gershenson, Jason D Wright

Faculty, Staff and Student Publications

This cohort study examines the association between primary cytoreduction status and survival for patients with less-common, advanced-stage epithelial ovarian carcinoma.