Oncology Commons^™

In Vivo Characterization Of Glutamine Metabolism Identifies Therapeutic Targets In Clear Cell Renal Cell Carcinoma, Akash K Kaushik, Amy Tarangelo, Lindsey K Boroughs, Mukundan Ragavan, Yuanyuan Zhang, Cheng-Yang Wu, Xiangyi Li, Kristen Ahumada, Jui-Chung Chiang, Vanina T Tcheuyap, Faeze Saatchi, Quyen N Do, Cissy Yong, Tracy Rosales, Christina Stevens, Aparna D Rao, Brandon Faubert, Panayotis Pachnis, Lauren G Zacharias, Hieu Vu, Feng Cai, Thomas P Mathews, Giannicola Genovese, Barbara S Slusher, Payal Kapur, Xiankai Sun, Matthew Merritt, James Brugarolas, Ralph J Deberardinis

Student and Faculty Publications

Targeting metabolic vulnerabilities has been proposed as a therapeutic strategy in renal cell carcinoma (RCC). Here, we analyzed the metabolism of patient-derived xenografts (tumorgrafts) from diverse subtypes of RCC. Tumorgrafts from VHL-mutant clear cell RCC (ccRCC) retained metabolic features of human ccRCC and engaged in oxidative and reductive glutamine metabolism. Genetic silencing of isocitrate dehydrogenase-1 or isocitrate dehydrogenase-2 impaired reductive labeling of tricarboxylic acid (TCA) cycle intermediates in vivo and suppressed growth of tumors generated from tumorgraft-derived cells. Glutaminase inhibition reduced the contribution of glutamine to the TCA cycle and resulted in modest suppression of tumorgraft growth. Infusions with …

3d Imaging Analysis On An Organoid-Based Platform Guides Personalized Treatment In Pancreatic Ductal Adenocarcinoma, Ya'an Kang, Jenying Deng, Jianhua Ling, Xinqun Li, Yi-Ju Chiang, Eugene J Koay, Huamin Wang, Jared K Burks, Paul J Chiao, Mark W Hurd, Manoop S Bhutani, Jeffrey H Lee, Brian R Weston, Anirban Maitra, Naruhiko Ikoma, Ching-Wei D Tzeng, Jeffrey E Lee, Ronald A Depinho, Robert A Wolff, Shubham Pant, Florencia Mcallister, Matthew Hg Katz, Jason B Fleming, Michael P Kim

Student and Faculty Publications

BACKGROUNDPancreatic ductal adenocarcinoma (PDAC) is one of the most lethal malignancies, with unpredictable responses to chemotherapy. Approaches to assay patient tumors before treatment and identify effective treatment regimens based on tumor sensitivities are lacking. We developed an organoid-based platform (OBP) to visually quantify patient-derived organoid (PDO) responses to drug treatments and associated tumor-stroma modulation for personalized PDAC therapy.METHODSWe retrospectively quantified apoptotic responses and tumor-stroma cell proportions in PDOs via 3D immunofluorescence imaging through annexin A5, α-smooth muscle actin (α-SMA), and cytokeratin 19 (CK-19) levels. Simultaneously, an ex vivo organoid drug sensitivity assay (ODSA) was used to measure responses to standard-of-care …

Adjuvant Nab-Paclitaxel + Gemcitabine In Resected Pancreatic Ductal Adenocarcinoma: Results From A Randomized, Open-Label, Phase Iii Trial, Margaret A. Tempero, Uwe Pelzer, Eileen M. O'Reilly, Jordan Winter, Do-Youn Oh, Chung-Pin Li, Giampaolo Tortora, Heung-Moon Chang, Charles D. Lopez, Tanios Bekaii-Saab, Andrew H. Ko, Armando Santoro, Joon Oh Park, Marcus S. Noel, Giovanni Luca Frassineti, Yan-Shen Shan, Andrew Dean, Hanno Riess, Eric Van Cutsem, Jordan Berlin, Philip Philip, Malcolm Moore, David Goldstein, Josep Tabernero, Mingyu Li, Stefano Ferrara, Yvan Le Bruchec, George Zhang, Brian Lu, Andrew V. Biankin, Michele Reni

Department of Surgery Faculty Papers

PURPOSE

This randomized, open-label trial compared the efficacy and safety of adjuvant nab-paclitaxel + gemcitabine with those of gemcitabine for resected pancreatic ductal adenocarcinoma (ClinicalTrials.gov identifier: NCT01964430). METHODS

We assigned 866 treatment-naive patients with pancreatic ductal adenocarcinoma to nab-paclitaxel (125 mg/m2) + gemcitabine (1,000 mg/m2) or gemcitabine alone to one 30-40 infusion on days 1, 8, and 15 of six 28-day cycles. The primary end point was independently assessed disease-free survival (DFS). Additional end points included investigator-assessed DFS, overall survival (OS), and safety. RESULTS

Two hundred eighty-seven of 432 patients and 310 of 434 patients completed nab …

Consensus Subtypes Of Hepatocellular Carcinoma Associated With Clinical Outcomes And Genomic Phenotypes, Sung Hwan Lee, Sun Young Yim, Yun Seong Jeong, Qi-Xiang Li, Sang-Hee Kang, Bo Hwa Sohn, Shwetha V Kumar, Ji-Hyun Shin, You Rhee Choi, Jae-Jun Shim, Hayeon Kim, Ji Hoon Kim, Shin Kim, Sheng Guo, Randy L Johnson, Ahmed Kaseb, Koo Jeong Kang, Yun Shin Chun, Hee Jin Jang, Byoung Gill Lee, Hyun Goo Woo, Min Jin Ha, Rehan Akbani, Lewis R Roberts, David A Wheeler, Ju-Seog Lee

Student and Faculty Publications

BACKGROUND AND AIMS: Although many studies revealed transcriptomic subtypes of HCC, concordance of the subtypes are not fully examined. We aim to examine a consensus of transcriptomic subtypes and correlate them with clinical outcomes.

APPROACH AND RESULTS: By integrating 16 previously established genomic signatures for HCC subtypes, we identified five clinically and molecularly distinct consensus subtypes. STM (STeM) is characterized by high stem cell features, vascular invasion, and poor prognosis. CIN (Chromosomal INstability) has moderate stem cell features, but high genomic instability and low immune activity. IMH (IMmune High) is characterized by high immune activity. BCM (Beta-Catenin with high Male …

Consensus Subtypes Of Hepatocellular Carcinoma Associated With Clinical Outcomes And Genomic Phenotypes, Sung Hwan Lee, Sun Young Yim, Yun Seong Jeong, Qi-Xiang Li, Sang-Hee Kang, Bo Hwa Sohn, Shwetha V Kumar, Ji-Hyun Shin, You Rhee Choi, Jae-Jun Shim, Hayeon Kim, Ji Hoon Kim, Shin Kim, Sheng Guo, Randy L Johnson, Ahmed Kaseb, Koo Jeong Kang, Yun Shin Chun, Hee Jin Jang, Byoung Gill Lee, Hyun Goo Woo, Min Jin Ha, Rehan Akbani, Lewis R Roberts, David A Wheeler, Ju-Seog Lee

Student and Faculty Publications

BACKGROUND AND AIMS: Although many studies revealed transcriptomic subtypes of HCC, concordance of the subtypes are not fully examined. We aim to examine a consensus of transcriptomic subtypes and correlate them with clinical outcomes.

APPROACH AND RESULTS: By integrating 16 previously established genomic signatures for HCC subtypes, we identified five clinically and molecularly distinct consensus subtypes. STM (STeM) is characterized by high stem cell features, vascular invasion, and poor prognosis. CIN (Chromosomal INstability) has moderate stem cell features, but high genomic instability and low immune activity. IMH (IMmune High) is characterized by high immune activity. BCM (Beta-Catenin with high Male …

Accuracy And Safety Of Scout Dose Resin Yttrium-90 Microspheres For Radioembolization Therapy Treatment Planning: A Prospective Single-Arm Clinical Trial, Nima Kokabi, Linzi A Webster, Mohammad Elsayed, Jeffrey M Switchenko, Bernard Chen, David Brandon, James Galt, Ila Sethi, Mircea Cristescu, S Cheenu Kappadath, David M Schuster

Student and Faculty Publications

PURPOSE: To compare the accuracy and safety of 0.56 GBq resin yttrium-90 (

MATERIALS AND METHODS: This prospective single-arm clinical trial (Clinicaltrials.gov: NCT04172714) recruited patients with HCC. Patients underwent same-day mapping with MAA and scout

RESULTS: Thirty patients were treated using 19 segmental and 14 nonsegmental (ie, 2 contiguous segments or nonsegmental) therapies. MAA had weak LSF, moderate TNR, and moderate TD linear correlation with Rx

CONCLUSIONS: Compared with MAA, scout

Chemoradiation Therapy Alters The Pd-L1 Score In Locoregional Recurrent Squamous Cell Carcinomas Of The Head And Neck, Brian J Park, Austin K Mattox, Daniel Clayburgh, Mihir Patel, R Bryan Bell, Bevan Yueh, Rom Leidner, Hong Xiao, Marcus Couey, Shiting Li, Tingting Qin, Maureen A Sartor, Belinda Cairns, Tracy Macdonough, Kyle Halliwill, Daniel Deschler, Derrick T Lin, William C Faquin, Peter M Sadow, Sara I Pai

Student and Faculty Publications

PD-L1 testing guides therapeutic decision-making for head and neck squamous cell carcinoma (HNSCC). We sought to understand whether chemoradiation therapy (CRT) influences the PD-L1 combined positive score (CPS) and other biomarkers of response to immunotherapy. PD-L1 expression was assessed using immunohistochemistry, and bulk RNA sequencing was performed on 146 HNSCC patients (65 primary sites, 50 paired local recurrences, and 31 paired regional recurrences). PD-L1 was scored using the CPS of ≥1, ≥20, and ≥50. Overall, 98 %, 54 %, and 17 % of HNSCCs had a CPS ≥1, ≥20, and ≥50, respectively. When using a cut-off of ≥1, CRT did …

Inactivation Of Lats1/2 Drives Luminal-Basal Plasticity To Initiate Basal-Like Mammary Carcinomas, Joseph G Kern, Andrew M Tilston-Lunel, Anthony Federico, Boting Ning, Amy Mueller, Grace B Peppler, Eleni Stampouloglou, Nan Cheng, Randy L Johnson, Marc E Lenburg, Jennifer E Beane, Stefano Monti, Xaralabos Varelas

Student and Faculty Publications

Basal-like breast cancers, an aggressive breast cancer subtype that has poor treatment options, are thought to arise from luminal mammary epithelial cells that undergo basal plasticity through poorly understood mechanisms. Using genetic mouse models and ex vivo primary organoid cultures, we show that conditional co-deletion of the LATS1 and LATS2 kinases, key effectors of Hippo pathway signaling, in mature mammary luminal epithelial cells promotes the development of Krt14 and Sox9-expressing basal-like carcinomas that metastasize over time. Genetic co-deletion experiments revealed that phenotypes resulting from the loss of LATS1/2 activity are dependent on the transcriptional regulators YAP/TAZ. Gene expression analyses of …

Triple Blockade Of Ido-1, Pd-L1 And Mek As A Potential Therapeutic Strategy In Nsclc, Carminia Maria Della Corte, Vincenza Ciaramella, Kavya Ramkumar, Giovanni Vicidomini, Alfonso Fiorelli, Valerio Nardone, Salvatore Cappabianca, Immacolata Cozzolino, Federica Zito Marino, Gaetano Di Guida, Qi Wang, Robert Cardnell, Carl Michael Gay, Davide Ciardiello, Erika Martinelli, Teresa Troiani, Giulia Martini, Stefania Napolitano, Jing Wang, Lauren Averett Byers, Fortunato Ciardiello, Floriana Morgillo

Student and Faculty Publications

BACKGROUND: Despite the recent progress in the treatment and outcome of Non Small Cell Lung Cancer (NSCLC), immunotherapy has still significant limitations reporting a significant proportion of patients not benefiting from therapy, even in patients with high PD-L1 expression. We have previously demonstrated that the combined inhibition of MEK and PD-L1 in NSCLC patients derived three dimensional cultures exerted significant synergistic effect in terms of immune-dependent cancer cell death. However, subsequent experiments analyzing the expression of Indoleamine 2,3-dioxygenase-1 (Ido-1) gene expression demonstrated that Ido-1 resulted unaffected by the MEK inhibition and even increased after the combined inhibition of MEK and …

The Nogo Receptor Ngr2, A Novel Αvβ3 Integrin Effector, Induces Neuroendocrine Differentiation In Prostate Cancer, Fabio Quaglia, Shiv Ram Krishn, Khalid Sossey-Alaoui, Priyanka Shailendra Rana, Elzbieta Pluskota, Pyung Hun Park, Christopher D. Shields, Stephen Lin, Peter Mccue, Andrew V. Kossenkov, Yanqing Wang, David W. Goodrich, Sheng-Yu Ku, Himisha Beltran, William K. Kelly, Eva Corey, Maja Klose, Christine Bandtlow, Qin Liu, Dario C. Altieri, Edward F. Plow, Lucia R. Languino

Department of Cancer Biology Faculty Papers

Androgen deprivation therapies aimed to target prostate cancer (PrCa) are only partially successful given the occurrence of neuroendocrine PrCa (NEPrCa), a highly aggressive and highly metastatic form of PrCa, for which there is no effective therapeutic approach. Our group has demonstrated that while absent in prostate adenocarcinoma, the αVβ3 integrin expression is increased during PrCa progression toward NEPrCa. Here, we show a novel pathway activated by αVβ3 that promotes NE differentiation (NED). This novel pathway requires the expression of a GPI-linked surface molecule, NgR2, also known as Nogo-66 receptor homolog 1. We show here that NgR2 is upregulated by αVβ3, …

Metformin Increases Natural Killer Cell Functions In Head And Neck Squamous Cell Carcinoma Through Cxcl1 Inhibition, Mckenzie Crist, Benyamin Yaniv, Sarah Palackdharry, Maria A. Lehn, Mario Medvedovic, Timothy Stone, Shuchi Gulati, Vidhya Karivedu, Michael Borchers, Bethany Fuhrman, Audrey Crago, Joseph Curry, Ubaldo Martinez-Outschoorn, Vinita Takiar, Trisha M. Wise-Draper

Department of Otolaryngology - Head and Neck Surgery Faculty Papers

BACKGROUND: Metformin slows tumor growth and progression in vitro, and in combination with chemoradiotherapy, resulted in high overall survival in patients with head and neck cancer squamous cell carcinoma (HNSCC) in our phase 1 clinical trial (NCT02325401). Metformin is also postulated to activate an antitumor immune response. Here, we investigate immunologic effects of metformin on natural killer (NK) and natural killer T cells, including results from two phase I open-label studies in patients with HNSCC treated with metformin (NCT02325401, NCT02083692).

METHODS: Peripheral blood was collected before and after metformin treatment or from newly diagnosed patients with HNSCC. Peripheral immune cell …

Prognostic Significance Of Preoperative And Postoperative Ca 19–9 Normalization In Pancreatic Adenocarcinoma Treated With Neoadjuvant Therapy Or Surgery First, Timothy P Diperi, Timothy E Newhook, Laura R Prakash, Naruhiko Ikoma, Jessica E Maxwell, Michael P Kim, Jeffrey E Lee, Matthew H G Katz, Ching-Wei D Tzeng

Student and Faculty Publications

BACKGROUND: Normal(ization) of serum carbohydrate 19-9 (CA19-9) before/after surgery has not been compared in patients with pancreatic adenocarcinoma (PDAC) treated with neoadjuvant therapy (NT) versus surgery-first (SF).

METHODS: Characteristics for patients with PDAC who underwent resection from July 2011 to October 2018 were collected. Patients with pre-/postoperative CA19-9, bilirubin/dL, and initial CA19-9 > 1 U/ml were included. Overall survival (OS) and recurrence-free survival (RFS) were compared by pre-/postoperative CA19-9.

RESULTS: In patients receiving NT, normal pre/postoperative CA19-9 ("NT

CONCLUSIONS: While a normal(ized) postoperative CA19-9 may result in similar survival as preoperative normal(ization), postoperative normalization failed to occur in nearly 30% of …

A Blood-Based Metabolite Panel For Distinguishing Ovarian Cancer From Benign Pelvic Masses, Ehsan Irajizad, Chae Y Han, Joseph Celestino, Ranran Wu, Eunice Murage, Rachelle Spencer, Jennifer B Dennison, Jody Vykoukal, James P Long, Kim Anh Do, Charles Drescher, Karen Lu, Zhen Lu, Robert C Bast, Sam Hanash, Johannes F Fahrmann

Student and Faculty Publications

PURPOSE: To assess the contributions of circulating metabolites for improving upon the performance of the risk of ovarian malignancy algorithm (ROMA) for risk prediction of ovarian cancer among women with ovarian cysts.

EXPERIMENTAL DESIGN: Metabolomic profiling was performed on an initial set of sera from 101 serous and nonserous ovarian cancer cases and 134 individuals with benign pelvic masses (BPM). Using a deep learning model, a panel consisting of seven cancer-related metabolites [diacetylspermine, diacetylspermidine, N-(3-acetamidopropyl)pyrrolidin-2-one, N-acetylneuraminate, N-acetyl-mannosamine, N-acetyl-lactosamine, and hydroxyisobutyric acid] was developed for distinguishing early-stage ovarian cancer from BPM. The performance of the metabolite panel was evaluated in an …

Nab-Paclitaxel, Capecitabine, And Radiation Therapy After Induction Chemotherapy In Treating Patients With Locally Advanced And Borderline Resectable Pancreatic Cancer: Phase 1 Trial And Imaging-Based Biomarker Validation., Eugene J Koay, Mohamed Zaid, Maureen Aliru, Polycarpe Bagereka, Arie Van Wieren, Maria Jovie Rodriguez, Galia Jacobson, Robert A Wolff, Michael Overman, Gauri Varadhachary, Shubham Pant, Huamin Wang, Ching-Wei Tzeng, Naruhiko Ikoma, Michael Kim, Jeffrey E Lee, Matthew Hg Katz, Eric Tamm, Priya Bhosale, Cullen M Taniguchi, Emma B Holliday, Grace L Smith, Ethan B Ludmir, Bruce D Minsky, Christopher H Crane, Albert C Koong, Prajnan Das, Xuemei Wang, Milind Javle, Sunil Krishnan

Student and Faculty Publications

PURPOSE: Effective consolidative chemoradiation (CRT) regimens are lacking. In this phase 1 trial, we evaluated the safety and efficacy of nab-paclitaxel, capecitabine, and radiation therapy after induction chemotherapy in patients with locally advanced and borderline-resectable pancreatic cancer (LAPC and BRPC). Also, we evaluated a computed tomography (CT)-based biomarker of response.

METHODS AND MATERIALS: Eligible patients had pathologically confirmed pancreatic ductal adenocarcinoma, underwent computed tomography-imaging, received a diagnosis of LAPC or BRPC, and received induction chemotherapy. Standard 3 + 3 study design was used, with 3 escalating nab-paclitaxel dose levels (50, 75, and 100 mg/m

RESULTS: Twenty-three patients started and finished …

Therapeutic Efficacy Of The Humanized Jaa-F11 Anti-Thomsen-Friedenreich Antibody Constructs H2al2a And H3l3 In Human Breast And Lung Cancer Xenograft Models, Diala Ghazal, Fatma Zalzala, John C Fisk, Swetha Tati, Loukia G Karacosta, Susan Morey, James R Olson, Sally Quataert, Grace K Dy, Kate Rittenhouse-Olson

Student and Faculty Publications

The Thomsen-Friedenreich antigen (TF-Ag-α) is found on ~85% of human carcinomas but is cryptic on normal tissue. The humanized highly specific hJAA-F11-H2aL2a and -H3L3 antibodies target TF-Ag-α without binding to TF-Ag-beta (found on surface glycolipids of some normal cells). The relative affinity of H3L3 is 17 times that of H2aL2a, which would seem to favor superior efficacy, however, increased affinity can result in less tumor penetration. To assess the potential therapeutic efficacy of these antibodies, four human cancer- mouse xenograft models were treated with H2aL2a and H3L3. The tumor xenograft models used were human non-small cell lung cancer, H520, and …

Single-Cell Sequencing Reveals Trajectory Of Tumor-Infiltrating Lymphocyte States In Pancreatic Cancer, Aislyn Schalck, Donastas Sakellariou-Thompson, Marie-Andrée Forget, Emi Sei, Tara G Hughes, Alexandre Reuben, Shanshan Bai, Min Hu, Tapsi Kumar, Mark W Hurd, Matthew H G Katz, Ching-Wei D Tzeng, Shubham Pant, Milind Javle, David R Fogelman, Anirban Maitra, Cara L Haymaker, Michael P Kim, Nicholas E Navin, Chantale Bernatchez

Student and Faculty Publications

Pancreatic ductal adenocarcinoma (PDAC) has few effective treatments. Immunotherapy, an attractive alternative strategy, remains challenging with the lack of knowledge on the tumor-infiltrating lymphocyte (TIL) landscape in PDAC. To generate a reference of T-cell subpopulations, we profiled 80,000 T cells from 57 PDAC samples, 22 uninvolved/normal samples, and cultured TIL using single-cell transcriptomic and T-cell receptor analysis. These data revealed 20 cell states and heterogeneous distributions of TIL populations. The CD8+ TIL contained a putative transitional GZMK+ population based on T-cell receptor clonotype sharing, and cell-state trajectory analysis showed similarity to a GZMB+PRF1+ cytotoxic and a CXCL13+ dysfunctional population. Statistical …

Role Of Sam68 In Sunitinib Induced Renal Cell Carcinoma Apoptosis, Zeshen Wu, Yulu Peng, Longbin Xiong, Jun Wang, Zhen Li, Kang Ning, Minhua Deng, Ning Wang, Wensu Wei, Zhiyong Li, Pei Dong, Chunping Yu, Fangjian Zhou, Zhiling Zhang

Student and Faculty Publications

Sunitinib is one of the first-line targeted drugs for metastatic renal cell carcinoma (RCC) with dual effects of antiangiogensis and proapoptosis. Sam68 (Src-associated in mitosis, 68 KDa), is found being involved in cell apoptosis. This article reveals that Sam68 impacts the sensitivity to sunitinib by mediating the apoptosis of RCC cells. Immunohistochemical staining indicated that the Sam68 expression levels in sunitinib sensitive tumor tissues were markedly higher than those in sunitinib resistant tumor tissues. Sunitinib induced RCC cell apoptosis in a concentration-dependent manner and inhibited the expression of total and phosphorylated Sam68 (p-Sam68). Downregulation of Sam68 expression inhibited RCC cell …

Preoperative Inflammatory Markers As Prognostic Predictors After Hepatocellular Carcinoma Resection: Data From A Western Referral Center, João Paulo Maciel Silva, Fabricio Ferreira Coelho, Alex Jones Flores Cassenote, Vagner Birk Jeismann, Gilton Marques Fonseca, Jaime Arthur Pirola Kruger, José Donizeti De Meira Júnior, Sérgio Carlos Nahas, Paulo Herman

Faculty and Staff Publications

BACKGROUND: Recent studies from eastern centers have demonstrate an association between inflammatory response and long-term outcomes after hepatocellular carcinoma (HCC) resection. However, the prognostic impact of inflammatory markers in western patients, with distinct tumor and epidemiologic features, is still unknown.

AIM: To evaluate the prognostic impact of preoperative neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), and monocyte-to-lymphocyte ratio (MLR), as well as their impact according to tumor size (< 5 cm, 5-10 cm, > 10 cm) in patients undergoing HCC resection with curative intent.

METHODS: Optimal cut-off values for NLR, PLR, and MLR were determined by plotting the receiver operator curves. Overall survival (OS) and disease-free …

Libretto-531: A Phase Iii Study Of Selpercatinib In Multikinase Inhibitor-Naïve, Lori J Wirth, Marcia S Brose, Rossella Elisei, Jaume Capdevila, Ana O Hoff, Mimi I Hu, Makoto Tahara, Bruce Robinson, Ming Gao, Meng Xia, Patricia Maeda, Eric Sherman

Department of Medicine Faculty Papers

Selpercatinib is a first-in-class, highly selective and potent, central nervous system-active RET kinase inhibitor. In the phase I/II trial, selpercatinib demonstrated clinically meaningful antitumor activity with manageable toxicity in heavily pre-treated and treatment-naive patients with RET-mutant medullary thyroid cancer (MTC). LIBRETTO-531 (NCT04211337) is a multicenter, open-label, randomized, controlled, phase III trial comparing selpercatinib to cabozantinib or vandetanib in patients with advanced/metastatic RET-mutant MTC. The primary objective is to compare progression-free survival (per RECIST 1.1) by blinded independent central review of patients with progressive, advanced, multikinase inhibitor-naive, RET-mutant MTC treated with selpercatinib versus cabozantinib or vandetanib. …

Interleukin-8 Produced From Cancer-Associated Fibroblasts Suppresses Proliferation Of The Ocuch-Lm1 Cancer Cell Line, Ryota Tanaka, Kenjiro Kimura, Shimpei Eguchi, Go Ohira, Shogo Tanaka, Ryosuke Amano, Hiroaki Tanaka, Masakazu Yashiro, Masaichi Ohira, Shoji Kubo

Department of Medical Oncology Faculty Papers

Background: Cancer-associated fibroblasts (CAFs) play an important role in cancer growth by interacting with cancer cells, but their effects differ depending on the type of cancer. This study investigated the role of CAFs in biliary tract cancers (BTCs), compared with pancreatic ductal adenocarcinoma (PDAC) as a comparison cohort.

Methods: We retrospectively evaluated alpha-smooth muscle actin (αSMA) expression in CAFs from 114 cases of PDAC and 154 cases of BTCs who underwent surgical treatment at our institution from 1996 to 2017. CAFs were isolated from resected specimens of BTC and PDAC, and tested for the effects of their supernatants and cytokines …

Efficacy Of Niraparib By Time Of Surgery And Postoperative Residual Disease Status: A Post Hoc Analysis Of Patients In The Prima/Engot-Ov26/Gog-3012 Study, Roisin E O'Cearbhaill, Jose-Alejandro Pérez-Fidalgo, Bradley J Monk, Ignacio Tusquets, Colleen Mccormick, Jose Fuentes, Richard G Moore, Christof Vulsteke, Mark S Shahin, Frédéric Forget, William H Bradley, Sakari Hietanen, David M O'Malley, Anne Dørum, Brian M Slomovitz, Klaus Baumann, Frédéric Selle, Paula M Calvert, Grazia Artioli, Tally Levy, Aalok Kumar, Izabela A Malinowska, Yong Li, Divya Gupta, Antonio González-Martín

Faculty and Staff Publications

OBJECTIVE: To evaluate the association between surgical timing and postoperative residual disease status on the efficacy of niraparib first-line maintenance therapy in patients with newly diagnosed advanced ovarian cancer at high risk of recurrence.

METHODS: Post hoc analysis of the phase 3 PRIMA/ENGOT-OV26/GOG-3012 (NCT02655016) study of niraparib in patients with newly diagnosed primary advanced ovarian, primary peritoneal, or fallopian tube cancer with a complete/partial response to first-line platinum-based chemotherapy. Progression-free survival (PFS) was assessed by surgical status (primary debulking surgery [PDS] vs neoadjuvant chemotherapy/interval debulking surgery [NACT/IDS]) and postoperative residual disease status (no visible residual disease [NVRD] vs visible residual …

Opposing Roles Of Hdac6 In Liver Regeneration And Hepatocarcinogenesis, Sophors Phorl, Azra Memon, Yuri Seo, Thi Oanh Hoang, Trung Nghia Tran, Le Minh Tri Nguyen, Chang Hoon Lee, Woon Kyu Lee, Joo-Yong Lee

Faculty and Staff Publications

Histone deacetylase 6 (HDAC6), a deacetylase of p53, has emerged as a privileged inhibitory target for cancer therapy because of its deacetylating activity for p53 at K120 and K373/382. However, intricate roles of HDAC6 in hepatocellular carcinogenesis have been suggested by recent evidence, namely that HDAC6 ablation suppresses innate immunity, which plays critical roles in tumor immunosurveillance and antitumor immune responses. Therefore, it is valuable to determine whether HDAC6 ablation inhibits hepatocellular carcinogenesis using in vivo animal models. Here, we firstly showed that HDAC6 ablation increased K320 acetylation of p53, known as pro-survival acetylation, in all tested animal models but …

Ros And Mirna Dysregulation In Ovarian Cancer Development, Angiogenesis And Therapeutic Resistance, David C Stieg, Yifang Wang, Ling-Zhi Liu, Bing-Hua Jiang

Kimmel Cancer Center Faculty Papers

The diverse repertoires of cellular mechanisms that progress certain cancer types are being uncovered by recent research and leading to more effective treatment options. Ovarian cancer (OC) is among the most difficult cancers to treat. OC has limited treatment options, especially for patients diagnosed with late-stage OC. The dysregulation of miRNAs in OC plays a significant role in tumorigenesis through the alteration of a multitude of molecular processes. The development of OC can also be due to the utilization of endogenously derived reactive oxygen species (ROS) by activating signaling pathways such as PI3K/AKT and MAPK. Both miRNAs and ROS are …

The Hispanic Paradox In Non-Small Cell Lung Cancer, Rohit Kumar, Franklin Castillero, Shruti Bhandari, Sindhu Malapati, Goetz Kloecker

Hematology/Oncology and Stem Cell Therapy

Objective/Background: According to the U.S. Census Bureau, 18% of the total population in the United States identified themselves as Hispanic in 2016 making it the largest minority group. This study aimed to evaluate the effect of Hispanic ethnicity on the overall survival of patients with non-small cell lung cancer (NSCLC) using a large national cancer database. Methods: We used the National Cancer Database to identify patients diagnosed with NSCLC between 2010 and 2015. The two comparative groups for this study were non-Hispanic Whites (NHWs) and Hispanics. The primary outcome was overall survival. Results: Of the 555,475 patients included in the …

Impact Of Homologous Recombination Status And Responses With Veliparib Combined With First-Line Chemotherapy In Ovarian Cancer In The Phase 3 Velia/Gog-3005 Study, Elizabeth M Swisher, Carol Aghajanian, David M O'Malley, Gini F Fleming, Scott H Kaufmann, Douglas A Levine, Michael J Birrer, Kathleen N Moore, Nick M Spirtos, Mark S Shahin, Thomas J Reid, Michael Friedlander, Karina Dahl Steffensen, Aikou Okamoto, Vasudha Sehgal, Peter J Ansell, Minh H Dinh, Michael A Bookman, Robert L Coleman

Kimmel Cancer Center Faculty Papers

Objective: In the Phase 3 VELIA trial (NCT02470585), PARP inhibitor (PARPi) veliparib was combined with first-line chemotherapy and continued as maintenance for patients with ovarian carcinoma enrolled regardless of chemotherapy response or biomarker status. Here, we report exploratory analyses of the impact of homologous recombination deficient (HRD) or proficient (HRP) status on progression-free survival (PFS) and objective response rates during chemotherapy.

Methods: Women with Stage III-IV ovarian carcinoma were randomized to veliparib-throughout, veliparib-combination-only, or placebo. Stratification factors included timing of surgery and germline BRCA mutation status. HRD status was dichotomized at genomic instability score 33. During combination therapy, …

18 Fdg Pet/Ct Imaging In Carcinoma Cesophagus, Maseeh Uz Zaman, Nosheen Fatima

Department of Radiology

No abstract provided.

Machine Learning Analyses Of Highly-Multiplexed Immunofluorescence Identifies Distinct Tumor And Stromal Cell Populations In Primary Pancreatic Tumors, Krysten Vance, Alphan Alitinok, Seth Winfree, Heather Jensen Smith, Benjamin Swanson Md, Phd, Paul M. Grandgenett, Kelsey Klute, Daniel J Crichton, Michael A. Hollingsworth

Journal Articles: Eppley Institute

BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is a formidable challenge for patients and clinicians.

OBJECTIVE: To analyze the distribution of 31 different markers in tumor and stromal portions of the tumor microenvironment (TME) and identify immune cell populations to better understand how neoplastic, non-malignant structural, and immune cells, diversify the TME and influence PDAC progression.

METHODS: Whole slide imaging (WSI) and cyclic multiplexed-immunofluorescence (MxIF) was used to collect 31 different markers over the course of nine distinctive imaging series of human PDAC samples. Image registration and machine learning algorithms were developed to largely automate an imaging analysis pipeline identifying distinct cell …