Oncology Commons^™

Neuroendocrine Gene Subsets Are Uniquely Dysregulated In Prostate Adenocarcinoma, Nicole M. Naranjo, Anne Kennedy, Anna Testa, Cecilia E. Verrillo, Adrian D. Altieri, Rhonda Kean, D. Craig Hooper, Jindan Yu, Jonathan Zhao, Oliver Abinader, Maxwell W. Pickles, Adam Hawkins, William Kevin Kelly, Ramkrishna Mitra, Lucia R. Languino

Department of Pharmacology, Physiology, and Cancer Biology Faculty Papers

Prostate cancer has heterogeneous growth patterns, and its prognosis is the poorest when it progresses to a neuroendocrine phenotype. Using bioinformatic analysis, we evaluated RNA expression of neuroendocrine genes in a panel of five different cancer types: prostate adenocarcinoma, breast cancer, kidney chromophobe, kidney renal clear cell carcinoma and kidney renal papillary cell carcinoma. Our results show that specific neuroendocrine genes are significantly dysregulated in these tumors, suggesting that they play an active role in cancer progression. Among others, synaptophysin (SYP), a conventional neuroendocrine marker, is upregulated in prostate adenocarcinoma (PRAD) and breast cancer (BRCA). Our analysis shows that SYP …

Loss Of Lpar6 And Cab39l Dysregulates The Basal-To-Luminal Urothelial Differentiation Program, Contributing To Bladder Carcinogenesis, Sangkyou Lee, Jolanta Bondaruk, Yishan Wang, Huiqin Chen, June Goo Lee, Tadeusz Majewski, Rachel D Mullen, David Cogdell, Jiansong Chen, Ziqiao Wang, Hui Yao, Pawel Kus, Joon Jeong, Ilkyun Lee, Woonyoung Choi, Neema Navai, Charles Guo, Colin Dinney, Keith Baggerly, Cathy Mendelsohn, David Mcconkey, Richard R Behringer, Marek Kimmel, Peng Wei, Bogdan Czerniak

Student and Faculty Publications

We describe a strategy that combines histologic and molecular mapping that permits interrogation of the chronology of changes associated with cancer development on a whole-organ scale. Using this approach, we present the sequence of alterations around RB1 in the development of bladder cancer. We show that RB1 is not involved in initial expansion of the preneoplastic clone. Instead, we found a set of contiguous genes that we term "forerunner" genes whose silencing is associated with the development of plaque-like field effects initiating carcinogenesis. Specifically, we identified five candidate forerunner genes (ITM2B, LPAR6, MLNR, CAB39L, and ARL11) mapping near RB1. Two …

Efficacy Of Intravesical Nadofaragene Firadenovec For Patients With Bacillus Calmette-Guérin-Unresponsive Nonmuscle-Invasive Bladder Cancer: 5-Year Follow-Up From A Phase 3 Trial, Vikram M. Narayan, Stephen A. Boorjian, Mehrdad Alemozaffar, Badrinath R. Konety, Neal D. Shore, Leonard G. Gomella, Ashish M. Kamat, Trinity J. Bivalacqua, Jeffrey S. Montgomery, Seth P. Lerner, Joseph E. Busby, Michael Poch, Paul L. Crispen, Gary D. Steinberg, Anne K. Schuckman, Tracy M. Downs, Joseph Mashni, Brian R. Lane, Thomas J. Guzzo, Gennady Bratslavsky, Lawrence I. Karsh, Michael E. Woods, Gordon Brown, Daniel Canter, Adam Luchey, Yair Lotan, Brant A. Inman, Michael B. Williams, Michael S. Cookson, Sam S. Chang, Alexander I. Sankin, Michael A. O'Donnell, David Sawutz, Richard Philipson, Nigel R. Parker, Seppo Yla-Herttuala, Dorte Rehm, Jørn S. Jakobsen, Kristian Juul, Colin P.N. Dinney

Department of Urology Faculty Papers

Purpose: Nadofaragene firadenovec-vncg is a nonreplicating adenoviral vector–based gene therapy for bacillus Calmette-Guérin (BCG)–unresponsive carcinoma in situ (CIS) with/without high-grade Ta/T1. We report outcomes following 5 years of planned follow-up.

Materials and Methods: This open-label phase 3 trial (NCT02773849) enrolled patients with BCG-unresponsive nonmuscle-invasive bladder cancer in 2 cohorts: CIS ± Ta/T1 (CIS; n = 107) and Ta/T1 without CIS (Ta/T1 cohort; n = 50). Patients received 75 mL (3 × 1011 vp/mL) nadofaragene firadenovec intravesically once every 3 months with cystoscopy and cytology assessments, with continued treatment offered to those remaining high grade recurrence–free (HGRF).

Results: One hundred fifty-seven …

High Expression Of Trop2 Is Associated With Aggressive Localized Prostate Cancer And Is A Candidate Urinary Biomarker, Shiqin Liu, Sarah J Hawley, Christian A Kunder, En-Chi Hsu, Michelle Shen, Lennart Westphalen, Heidi Auman, Lisa F Newcomb, Daniel W Lin, Peter S Nelson, Ziding Feng, Maria S Tretiakova, Lawrence D True, Funda Vakar-Lopez, Peter R Carroll, Jeffry Simko, Martin E Gleave, Dean A Troyer, Jesse K Mckenney, James D Brooks, Michael A Liss, Tanya Stoyanova

Student and Faculty Publications

Distinguishing indolent from clinically significant localized prostate cancer is a major clinical challenge and influences clinical decision-making between treatment and active surveillance. The development of novel predictive biomarkers will help with risk stratification, and clinical decision-making, leading to a decrease in over or under-treatment of patients with prostate cancer. Here, we report that Trop2 is a prognostic tissue biomarker for clinically significant prostate cancer by utilizing the Canary Prostate Cancer Tissue Microarray (CPCTA) cohort composed of over 1100 patients from a multi-institutional study. We demonstrate that elevated Trop2 expression is correlated with worse clinical features including Gleason score, age, and …

Master Transcription Factor Reprogramming Unleashes Selective Translation Promoting Castration Resistance And Immune Evasion In Lethal Prostate Cancer, Sandra Santasusagna, Shijia Zhu, Vijayakumar Jawalagatti, Marc Carceles-Cordon, Adam Ertel, Saioa Garcia-Longarte, Won-Min Song, Naoto Fujiwara, Peiyao Li, Isabel Mendizabal, Daniel P. Petrylak, William Kevin Kelly, E. Premkumar Reddy, Liguo Wang, Matthew J. Schiewer, Amaia Lujambio, Jeffrey Karnes, Karen E. Knudsen, Carlos Cordon-Cardo, Haidong Dong, Haojie Huang, Arkaitz Carracedo, Yujin Hoshida, Veronica Rodriguez-Bravo, Josep Domingo-Domenech

Department of Medical Oncology Faculty Papers

Signaling rewiring allows tumors to survive therapy. Here we show that the decrease of the master regulator microphthalmia transcription factor (MITF) in lethal prostate cancer unleashes eukaryotic initiation factor 3B (eIF3B)-dependent translation reprogramming of key mRNAs conferring resistance to androgen deprivation therapy (ADT) and promoting immune evasion. Mechanistically, MITF represses through direct promoter binding eIF3B, which in turn regulates the translation of specific mRNAs. Genome-wide eIF3B enhanced cross-linking immunoprecipitation sequencing (eCLIP-seq) showed specialized binding to a UC-rich motif present in subsets of 5' untranslated regions. Indeed, translation of the androgen receptor and major histocompatibility complex I (MHC-I) through this motif …

Targeting The Αvβ3/Ngr2 Pathway In Neuroendocrine Prostate Cancer, Anna Testa, Fabio Quaglia, Nicole M. Naranjo, Cecilia E. Verrillo, Christopher D. Shields, Stephen Lin, Maxwell W. Pickles, Drini F. Hamza, Tami Von Schalscha, David A. Cheresh, Benjamin E Leiby, Qin Liu, Jianyi Ding, William K. Kelly, D. Craig Hooper, Eva Corey, Edward F. Plow, Dario C. Altieri, Lucia R. Languino

Department of Pharmacology, Physiology, and Cancer Biology Faculty Papers

Highly aggressive, metastatic, neuroendocrine prostate cancer, which typically develops from prostate cancer cells acquiring resistance to androgen deprivation therapy, is associated with limited treatment options and hence poor prognosis. We have previously demonstrated that the αVβ3 integrin is over-expressed in neuroendocrine prostate cancer. We now show that LM609, a monoclonal antibody that specifically targets the human αVβ3 integrin, hinders the growth of neuroendocrine prostate cancer patient-derived xenografts in vivo. Our group has recently identified a novel αVβ3 integrin binding partner, NgR2, responsible for regulating the expression of neuroendocrine markers and for inducing neuroendocrine differentiation in prostate cancer cells. Through in …

Xaluritamig, A Steap1 × Cd3 Xmab 2+1 Immune Therapy For Metastatic Castration-Resistant Prostate Cancer: Results From Dose Exploration In A First-In-Human Study, William K. Kelly, Daniel C. Danila, Chia-Chi Lin, Jae-Lyun Lee, Nobuaki Matsubara, Patrick J. Ward, Andrew J. Armstrong, David Pook, Miso Kim, Tanya B. Dorff, Stefanie Fischer, Yung-Chang Lin, Lisa G. Horvath, Christopher Sumey, Zhao Yang, Gabor Jurida, Kristen M. Smith, Jamie N. Connarn, Hweixian L. Penny, Julia Stieglmaier, Leonard J. Appleman

Kimmel Cancer Center Faculty Papers

ABSTRACT : Xaluritamig (AMG 509) is a six-transmembrane epithelial antigen of the prostate 1 (STEAP1)-targeted T-cell engager designed to facilitate lysis of STEAP1-expressing cancer cells, such as those in advanced prostate cancer. This first-in-human study reports monotherapy dose exploration for patients with metastatic castration-resistant prostate cancer (mCRPC), primarily taxane pretreated. Ninety-seven patients received ≥1 intravenous dose ranging from 0.001 to 2.0 mg weekly or every 2 weeks. MTD was identified as 1.5 mg i.v. weekly via a 3-step dose. The most common treatment-related adverse events were cytokine release syndrome (CRS; 72%), fatigue (45%), and myalgia (34%). CRS occurred primarily during …

Evidence Of Novel Susceptibility Variants For Prostate Cancer And A Multiancestry Polygenic Risk Score Associated With Aggressive Disease In Men Of African Ancestry., Fei Chen, Ravi K Madduri, Alex A Rodriguez, Burcu F Darst, Alisha Chou, Xin Sheng, Anqi Wang, Jiayi Shen, Edward J Saunders, Suhn K Rhie, Jeannette T Bensen, Sue A Ingles, Rick A Kittles, Sara S Strom, Benjamin A Rybicki, Barbara Nemesure, William B Isaacs, Janet L Stanford, Wei Zheng, Maureen Sanderson, Esther M John, Jong Y Park, Jianfeng Xu, Ying Wang, Sonja I Berndt, Chad D Huff, Edward D Yeboah, Yao Tettey, Joseph Lachance, Wei Tang, Christopher T Rentsch, Kelly Cho, Benjamin H Mcmahon, Richard B Biritwum, Andrew A Adjei, Evelyn Tay, Ann Truelove, Shelley Niwa, Thomas A Sellers, Kosj Yamoah, Adam B Murphy, Dana C Crawford, Alpa V Patel, William S Bush, Melinda C Aldrich, Olivier Cussenot, Gyorgy Petrovics, Jennifer Cullen, Christine M Neslund-Dudas, Mariana C Stern, Zsofia Kote-Jarai, Koveela Govindasami, Michael B Cook, Anand P Chokkalingam, Ann W Hsing, Phyllis J Goodman, Thomas J Hoffmann, Bettina F Drake, Jennifer J Hu, Jacob M Keaton, Jacklyn N Hellwege, Peter E Clark, Mohamed Jalloh, Serigne M Gueye, Lamine Niang, Olufemi Ogunbiyi, Michael O Idowu, Olufemi Popoola, Akindele O Adebiyi, Oseremen I Aisuodionoe-Shadrach, Hafees O Ajibola, Mustapha A Jamda, Olabode P Oluwole, Maxwell Nwegbu, Ben Adusei, Sunny Mante, Afua Darkwa-Abrahams, James E Mensah, Halimatou Diop, Stephen K Van Den Eeden, Pascal Blanchet, Jay H Fowke, Graham Casey, Anselm J Hennis, Alexander Lubwama, Ian M Thompson, Robin Leach, Douglas F Easton, Michael H Preuss, Ruth J Loos, Susan M Gundell, Peggy Wan, James L Mohler, Elizabeth T Fontham, Gary J Smith, Jack A Taylor, Shiv Srivastava, Rosaline A Eeles, John D Carpten, Adam S Kibel, Luc Multigner, Marie-Élise Parent, Florence Menegaux, Geraldine Cancel-Tassin, Eric A Klein, Caroline Andrews, Timothy R Rebbeck, Laurent Brureau, Stefan Ambs, Todd L Edwards, Stephen Watya, Stephen J Chanock, John S Witte, William J Blot, J Michael Gaziano, Amy C Justice, David V Conti, Christopher A Haiman

Student and Faculty Publications

BACKGROUND: Genetic factors play an important role in prostate cancer (PCa) susceptibility.

OBJECTIVE: To discover common genetic variants contributing to the risk of PCa in men of African ancestry.

DESIGN, SETTING, AND PARTICIPANTS: We conducted a meta-analysis of ten genome-wide association studies consisting of 19378 cases and 61620 controls of African ancestry.

OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Common genotyped and imputed variants were tested for their association with PCa risk. Novel susceptibility loci were identified and incorporated into a multiancestry polygenic risk score (PRS). The PRS was evaluated for associations with PCa risk and disease aggressiveness.

RESULTS AND LIMITATIONS: Nine …

Impact Of An Expanded Definition Of Family History On Outcomes Of Active Surveillance For Prostate Cancer, Adam C. Schneider, Thenappan Chandrasekar, Nicholas Bowler, Ryan Fogg, Joon Yau Leong, Andrew Gusev, Linda H. Rodgers, Shelley R. Mccormick, Douglas M. Dahl, Jason A. Efstathiou, Michael L. Blute, Anthony L. Zietman, Chin-Lee Wu, Matthew R. Smith, Eliezer M. Van Allen, Adam S. Feldman, Keyan Salari

Department of Urology Faculty Papers

PURPOSE: Despite family history being an established risk factor for prostate cancer, the role of a broader definition of family history inclusive of not just prostate cancer but other genetically related malignancies has not been investigated in the active surveillance population. Here, we evaluate the impact of an expanded definition of family history on active surveillance outcomes.

MATERIALS AND METHODS: Patients undergoing active surveillance for prostate cancer at Massachusetts General Hospital from 1997-2019 with detailed data available on family cancer history were identified. Primary outcome was biopsy progression-free survival, and secondary outcomes were treatment-free survival, adverse pathological features at prostatectomy, …

Comprehensive Proteomics And Platform Validation Of Urinary Biomarkers For Bladder Cancer Diagnosis And Staging, Kamala Vanarsa, Jessica Castillo, Long Wang, Kyung Hyun Lee, Claudia Pedroza, Yair Lotan, Chandra Mohan

Student and Faculty Publications

BACKGROUND: Bladder cancer (BC) is among the most common cancers diagnosed in men in the USA. The current gold standards for the diagnosis of BC are invasive or lack the sensitivity to correctly identify the disease.

METHODS: An aptamer-based screen analyzed the expression of 1317 proteins in BC compared to urology clinic controls. The top hits were subjected to systems biology analyses. Next, 30 urine proteins were ELISA-validated in an independent cohort of 68 subjects. Three of these proteins were next validated in an independent BC cohort of differing ethnicity.

RESULTS: Systems biology analysis implicated molecular functions related to the …

Downregulation Of Cenpf Remodels Prostate Cancer Cells And Alters Cellular Metabolism., Muhammad Shahid, Minhyung Kim, Min Young Lee, Austin Yeon, Sungyong You, Hyung L Kim, Jayoung Kim

Articles, Abstracts, and Reports

Metabolic alterations in prostate cancer (PC) are associated with progression and aggressiveness. However, the underlying mechanisms behind PC metabolic functions are unknown. The authors' group recently reported on the important role of centromere protein F (CENPF), a protein associated with the centromere-kinetochore complex and chromosomal segregation during mitosis, in PC MRI visibility. This study focuses on discerning the role of CENPF in metabolic perturbation in human PC3 cells. A series of bioinformatics analyses shows that CENPF is one gene that is strongly associated with aggressive PC and that its expression is positively correlated with metastasis. By identifying and reconstructing the …

A Clinician's Guide To Next Generation Imaging In Patients With Advanced Prostate Cancer (Radar Iii)., E. David Crawford, Phillip J. Koo, Neal Shore, Susan F. Slovin, Raoul S. Concepcion, Stephen J. Freedland, Leonard G. Gomella, Lawrence Karsh, Thomas E. Keane, Paul Maroni, David Penson, Daniel P. Petrylak, Ashley Ross, Vlad Mouraviev, Robert E. Reiter, Chaitanya Divgi, Evan Y. Yu

Department of Urology Faculty Papers

PURPOSE: The advanced prostate cancer therapeutic landscape has changed dramatically in the last several years, resulting in improved overall survival of patients with castration naïve and castration resistant disease. The evolution and development of novel next generation imaging techniques will affect diagnostic and therapeutic decision making. Clinicians must navigate when and which next generation imaging techniques to use and how to adjust treatment strategies based on the results, often in the absence of correlative therapeutic data. Therefore, guidance is needed based on best available information and current clinical experience.

MATERIALS AND METHODS: The RADAR (Radiographic Assessments for Detection of Advanced …

First Report Of Nrg Oncology/Radiation Therapy Oncology Group 0622: A Phase 2 Trial Of Samarium-153 Followed By Salvage Prostatic Fossa Irradiation In High-Risk Clinically Nonmetastatic Prostate Cancer After Radical Prostatectomy., Richard K. Valicenti, Stephanie L. Pugh, Edouard J. Trabulsi, Oliver Sartor, Eric C. Ko, Michael R. Girvigian, Seth A. Rosenthal, Mark E. Shaves, Jean Hoffman-Censits, John Schallenkamp, Howard M. Sandler

Department of Urology Faculty Papers

PURPOSE: To investigate the utility of ¹⁵³Sm lexidronam (Quadramet) in the setting of men with prostate cancer status post radical prostatectomy who develop biochemical failure with no clinical evidence of osseous metastases.

PATIENTS AND METHODS: Trial NRG Oncology RTOG 0622 is a single-arm phase 2 trial that enrolled men with pT2-T4, N0-1, M0 prostate cancer status post radical prostatectomy, who meet at least 1 of these biochemical failure criteria: (1) prostate-specific antigen (PSA) > 1.0 ng/mL; (2) PSA > 0.2 ng/mL if Gleason score 9 to 10; or (3) PSA > 0.2 ng/mL if N1. Patients received ¹⁵³Sm (2.0 mCi/kg intravenously …

Mechanisms Of Therapeutic Resistance In Prostate Cancer, Mary Nakazawa, Channing Paller, Natasha Kyprianou

Urology Faculty Publications

Prostate cancer is the second leading cause of cancer deaths in the USA. The challenge in managing castration-resistant prostate cancer (CRPC) stems not from the lack of therapeutic options but from the limited duration of clinical and survival benefit offered by treatments in this setting due to primary and acquired resistance. The remarkable molecular heterogeneity and tumor adaptability in advanced prostate cancer necessitate optimization of such treatment strategies. While the future of CRPC management will involve newer targeted therapies in deliberately biomarker-selected patients, interventions using current approaches may exhibit improved clinical benefit if employed in the context of optimal sequencing …

An Approach Using Psa Levels Of 1.5 Ng/Ml As The Cutoff For Prostate Cancer Screening In Primary Care., E. David Crawford, Matt T. Rosenberg, Alan W. Partin, Matthew R. Cooperberg, Michael Maccini, Stacy Loeb, Curtis A. Pettaway, Neal D. Shore, Paul Arangua, John Hoenemeyer, Mike Leveridge, Michael Leapman, Peter Pinto, Ian M. Thompson, Peter Carroll, James Eastham, Leonard G. Gomella, Eric A. Klein

Department of Urology Faculty Papers

No abstract provided.

Long-Term Oncological Outcomes Of A Phase Ii Trial Of Neoadjuvant Chemohormonal Therapy Followed By Radical Prostatectomy For Patients With Clinically Localised, High-Risk Prostate Cancer., Jonathan L. Silberstein, Stephen A. Poon, Daniel D. Sjoberg, Alexandra C. Maschino, Andrew J. Vickers, Aaron Bernie, Badrinath R. Konety, William Kevin Kelly, James A. Eastham

Department of Urology Faculty Papers

OBJECTIVE: To determine long-term oncological outcomes of radical prostatectomy (RP) after neoadjuvant chemohormonal therapy (CHT) for clinically localised, high-risk prostate cancer.

PATIENTS AND METHODS: In this phase II multicentre trial of patients with high-risk prostate cancer (PSA level >20 ng/mL, Gleason ≥8, or clinical stage ≥T3), androgen-deprivation therapy (goserelin acetate depot) and paclitaxel, carboplatin and estramustine were administered before RP. We report the long-term oncological outcomes of these patients and compared them to a contemporary cohort who met oncological inclusion criteria but received RP only.

RESULTS: In all, 34 patients were enrolled and followed for a median of 13.1 years. …

Mitostatin Is Down-Regulated In Human Prostate Cancer And Suppresses The Invasive Phenotype Of Prostate Cancer Cells., Matteo Fassan, Domenico D'Arca, Juraj Letko, Andrea Vecchione, Marina P Gardiman, Peter Mccue, Bernadette Wildemore, Massimo Rugge, Dolores Shupp-Byrne, Leonard G Gomella, Andrea Morrione, Renato V Iozzo, Raffaele Baffa

Kimmel Cancer Center Faculty Papers

MITOSTATIN, a novel putative tumor suppressor gene induced by decorin overexpression, is expressed in most normal human tissues but is markedly down-regulated in advanced stages of mammary and bladder carcinomas. Mitostatin negatively affects cell growth, induces cell death and regulates the expression and activation levels of Hsp27. In this study, we demonstrated that ectopic expression of Mitostatin in PC3, DU145, and LNCaP prostate cancer cells not only induced a significant reduction in cell growth, but also inhibited migration and invasion. Moreover, Mitostatin inhibited colony formation in soft-agar of PC3 and LNCaP cells as well as tumorigenicity of LNCaP cells in …

Microrna Expression Profiling Of Male Breast Cancer., Matteo Fassan, Raffaele Baffa, Juan P Palazzo, Joshua Lloyd, Marco Crosariol, Chang-Gong Liu, Stefano Volinia, Hannes Alder, Massimo Rugge, Carlo M Croce, Anne Rosenberg

Department of Urology Faculty Papers

INTRODUCTION : MicroRNAs (miRNAs) are a class of small noncoding RNAs that control gene expression by targeting mRNAs and triggering either translation repression or RNA degradation. Their aberrant expression may be involved in human diseases, including cancer. To test the hypothesis that there is a specific miRNA expression signature which characterizes male breast cancers, we performed miRNA microarray analysis in a series of male breast cancers and compared them with cases of male gynecomastia and female breast cancers. METHODS : Paraffin blocks were obtained at the Department of Pathology of Thomas Jefferson University from 28 male patients including 23 breast …