Medicine and Health Sciences Commons^™

Dna-Repair Defects And Olaparib In Metastatic Prostate Cancer., Joaquin Mateo, Suzanne Carreira, Shahneen Sandhu, Susana Miranda, Helen Mossop, Raquel Perez-Lopez, Daniel Nava Rodrigues, Dan Robinson, Aurelius Omlin, Nina Tunariu, Gunther Boysen, Nuria Porta, Penny Flohr, Alexa Gillman, Ines Figueiredo, Claire Paulding, George Seed, Suneil Jain, Christy Ralph, Andrew Protheroe, Syed Hussain, Robert Jones, Tony Elliott, Ursula Mcgovern, Diletta Bianchini, Jane Goodall, Zafeiris Zafeiriou, Chris T Williamson, Roberta Ferraldeschi, Ruth Riisnaes, Bernardette Ebbs, Gemma Fowler, Desamparados Roda, Wei Yuan, Yi-Mi Wu, Xuhong Cao, Rachel Brough, Helen Pemberton, Roger A'Hern, Amanda Swain, Lakshmi P Kunju, Rosalind Eeles, Gerhardt Attard, Christopher J Lord, Alan Ashworth, Mark A Rubin, Karen E Knudsen, Felix Y Feng, Arul M Chinnaiyan, Emma Hall, Johann S De Bono

Department of Medicine Faculty Papers

BACKGROUND: Prostate cancer is a heterogeneous disease, but current treatments are not based on molecular stratification. We hypothesized that metastatic, castration-resistant prostate cancers with DNA-repair defects would respond to poly(adenosine diphosphate [ADP]-ribose) polymerase (PARP) inhibition with olaparib.

METHODS: We conducted a phase 2 trial in which patients with metastatic, castration-resistant prostate cancer were treated with olaparib tablets at a dose of 400 mg twice a day. The primary end point was the response rate, defined either as an objective response according to Response Evaluation Criteria in Solid Tumors, version 1.1, or as a reduction of at least 50% in the …

A Phase 3 Trial Of 2 Years Of Androgen Suppression And Radiation Therapy With Or Without Adjuvant Chemotherapy For High-Risk Prostate Cancer: Final Results Of Radiation Therapy Oncology Group Phase 3 Randomized Trial Nrg Oncology Rtog 9902., Seth A. Rosenthal, Daniel Hunt, A. Oliver Sartor, Kenneth J. Pienta, Leonard G. Gomella, David Grignon, Raghu Rajan, Kevin J. Kerlin, Christopher U. Jones, Michael Dobelbower, William U Shipley, Kenneth Zeitzer, Daniel A. Hamstra, Viroon Donavanik, Marvin Rotman, Alan C. Hartford, Jeffrey Michalski, Michael Seider, Harold Kim, Deborah A. Kuban, Jennifer Moughan, Howard Sandler

Department of Urology Faculty Papers

PURPOSE: Long-term (LT) androgen suppression (AS) with radiation therapy (RT) is a standard treatment of high-risk, localized prostate cancer (PCa). Radiation Therapy Oncology Group 9902 was a randomized trial testing the hypothesis that adjuvant combination chemotherapy (CT) with paclitaxel, estramustine, and oral etoposide plus LT AS plus RT would improve overall survival (OS).

METHODS AND MATERIALS: Patients with high-risk PCa (prostate-specific antigen 20-100 ng/mL and Gleason score [GS] ≥ 7 or clinical stage ≥ T2 and GS ≥ 8) were randomized to RT and AS (AS + RT) alone or with adjuvant CT (AS + RT + CT). CT was …

Characterization Of 1577 Primary Prostate Cancers Reveals Novel Biological And Clinicopathologic Insights Into Molecular Subtypes., Scott A. Tomlins, Mohammed Alshalalfa, Elai Davicioni, Nicholas Erho, Kasra Yousefi, Shuang Zhao, Zaid Haddad, Robert B. Den, Adam P. Dicker, Bruce J. Trock, Angelo M. Demarzo, Ashley E. Ross, Edward M. Schaeffer, Eric A. Klein, Cristina Magi-Galluzzi, R. Jeffrey Karnes, Robert B. Jenkins, Felix Y. Feng

Department of Radiation Oncology Faculty Papers

BACKGROUND: Prostate cancer (PCa) molecular subtypes have been defined by essentially mutually exclusive events, including ETS gene fusions (most commonly involving ERG) and SPINK1 overexpression. Clinical assessment may aid in disease stratification, complementing available prognostic tests.

OBJECTIVE: To determine the analytical validity and clinicopatholgic associations of microarray-based molecular subtyping.

DESIGN, SETTING, AND PARTICIPANTS: We analyzed Affymetrix GeneChip expression profiles for 1577 patients from eight radical prostatectomy cohorts, including 1351 cases assessed using the Decipher prognostic assay (GenomeDx Biosciences, San Diego, CA, USA) performed in a laboratory with Clinical Laboratory Improvements Amendment certification. A microarray-based (m-) random forest ERG classification model …

Pkcε Is An Essential Mediator Of Prostate Cancer Bone Metastasis., Alvaro Gutierrez-Uzquiza, Cynthia Lopez-Haber University Of Pennsylvania, Danielle L. Jernigan, Alessandro Fatatis, Marcelo G. Kazanietz

Kimmel Cancer Center Papers, Presentations, and Grand Rounds

UNLABELLED: The bone is a preferred site for metastatic homing of prostate cancer cells. Once prostate cancer patients develop skeletal metastases, they eventually succumb to the disease; therefore, it is imperative to identify key molecular drivers of this process. This study examines the involvement of protein kinase C epsilon (PKCε), an oncogenic protein that is abnormally overexpressed in human tumor specimens and cell lines, on prostate cancer cell bone metastasis. PC3-ML cells, a highly invasive prostate cancer PC3 derivative with bone metastatic colonization properties, failed to induce skeletal metastatic foci upon inoculation into nude mice when PKCε expression was silenced …

Expression Of The Il-11 Gene In Metastatic Cells Is Supported By Runx2-Smad And Runx2-Cjun Complexes Induced By Tgfβ1., Xuhui Zhang, Hai Wu, Jason R. Dobson, Gillian Browne, Deli Hong, Jacqueline Akech, Lucia R. Languino, Gary S. Stein, Jane B. Lian

Department of Cancer Biology Faculty Papers

In tumor cells, two factors are abnormally increased that contribute to metastatic bone disease: Runx2, a transcription factor that promotes expression of metastasis related and osteolytic genes; and IL-11, a secreted osteolytic cytokine. Here, we addressed a compelling question: Does Runx2 regulate IL-11 gene expression? We find a positive correlation between Runx2, IL-11 and TGFβ1, a driver of the vicious cycle of metastatic bone disease, in prostate cancer (PC) cell lines representing early (LNCaP) and late (PC3) stage disease. Further, like Runx2 knockdown, IL-11 knockdown significantly reduced expression of several osteolytic factors. Modulation of Runx2 expression results in corresponding changes …

Structure-Based Screen Identifies A Potent Small Molecule Inhibitor Of Stat5a/B With Therapeutic Potential For Prostate Cancer And Chronic Myeloid Leukemia., Zhiyong Liao, Lei Gu, Jenny Vergalli, Samanta A. Mariani, Marco De Dominici, Ravi K. Lokareddy, Ayush Dagvadorj, Puranik Purushottamachar, Peter A. Mccue, Edouard J. Trabulsi, Costas D. Lallas, Shilpa Gupta, Elyse Ellsworth, Shauna Blackmon, Adam Ertel, Paolo Fortina, Benjamin E. Leiby, Guanjun Xia, Hallgeir Rui, David T. Hoang, Leonard G Gomella, Gino Cingolani, Vincent Njar, Nagarajan Pattabiraman, Bruno Calabretta, Marja T. Nevalainen

Department of Cancer Biology Faculty Papers

Bypassing tyrosine kinases responsible for Stat5a/b phosphorylation would be advantageous for therapy development for Stat5a/b-regulated cancers. Here, we sought to identify small molecule inhibitors of Stat5a/b for lead optimization and therapy development for prostate cancer and Bcr-Abl-driven leukemias. In silico screening of chemical structure databases combined with medicinal chemistry was used for identification of a panel of small molecule inhibitors to block SH2 domain-mediated docking of Stat5a/b to the receptor-kinase complex and subsequent phosphorylation and dimerization. We tested the efficacy of the lead compound IST5-002 in experimental models and patient samples of two known Stat5a/b-driven cancers, prostate cancer and chronic …

Dna-Pkcs-Mediated Transcriptional Regulation Drives Prostate Cancer Progression And Metastasis., Jonathan F Goodwin, Vishal Kothari, Justin M Drake, Shuang Zhao, Emanuela Dylgjeri, Jeffry L. Dean, Matthew J. Schiewer, Christopher Mcnair, Jennifer K. Jones, Alvaro Aytes, Michael S. Magee, Adam E. Snook, Ziqi Zhu, Robert Den, Ruth C. Birbe, Leonard G. Gomella, Nicholas A. Graham, Ajay A. Vashisht, James A. Wohlschlegel, Thomas G. Graeber, R. Jeffrey Karnes, Mandeep Takhar, Elai Davicioni, Scott A. Tomlins, Cory Abate-Shen, Nima Sharifi, Owen N. Witte, Felix Y. Feng, Karen E. Knudsen

Department of Cancer Biology Faculty Papers

Emerging evidence demonstrates that the DNA repair kinase DNA-PKcs exerts divergent roles in transcriptional regulation of unsolved consequence. Here, in vitro and in vivo interrogation demonstrate that DNA-PKcs functions as a selective modulator of transcriptional networks that induce cell migration, invasion, and metastasis. Accordingly, suppression of DNA-PKcs inhibits tumor metastases. Clinical assessment revealed that DNA-PKcs is significantly elevated in advanced disease and independently predicts for metastases, recurrence, and reduced overall survival. Further investigation demonstrated that DNA-PKcs in advanced tumors is highly activated, independent of DNA damage indicators. Combined, these findings reveal unexpected DNA-PKcs functions, identify DNA-PKcs as a potent driver …

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. …

Risk Analysis Of Prostate Cancer In Practical, A Multinational Consortium, Using 25 Known Prostate Cancer Susceptibility Loci., Ali Amin Al Olama, Sara Benlloch, Antonis C Antoniou, Graham G Giles, Gianluca Severi, David E Neal, Freddie C Hamdy, Jenny L Donovan, Kenneth Muir, Johanna Schleutker, Brian E Henderson, Christopher Haiman, Fredrick R Schumacher, Nora Pashayan, Paul D P Pharoah, Elaine A Ostrander, Janet L Stanford, Jyotsna Batra, Judith A Clements, Suzanne K Chambers, Maren Weischer, Børge G Nordestgaard, Sue A Ingles, Karina D Sorensen, Torben F Orntoft, Jong Y Park, Cezary Cybulski, Christiane Maier, Thilo Doerk, Joanne L Dickinson, Lisa Cannon-Albright, Hermann Brenner, Timothy R Rebbeck, Charnita Zeigler-Johnson, Tomonori Habuchi, Stephen N Thibodeau, Kathleen A Cooney, Pierre O Chappuis, Pierre Hutter, Radka P Kaneva, William D Foulkes, Maurice P Zeegers, Yong-Jie Lu, Hong-Wei Zhang, Robert Stephenson, Angela Cox, Melissa C Southey, Amanda B Spurdle, Liesel Fitzgerald, Daniel Leongamornlert, Edward Saunders, Malgorzata Tymrakiewicz, Michelle Guy, Tokhir Dadaev, Sarah J Little, Koveela Govindasami, Emma Sawyer, Rosemary Wilkinson, Kathleen Herkommer, John L Hopper, Aritaya Lophatonanon, Antje E Rinckleb, Zsofia Kote-Jarai, Rosalind A Eeles, Douglas F Easton

Department of Medical Oncology Faculty Papers

BACKGROUND: Genome-wide association studies have identified multiple genetic variants associated with prostate cancer risk which explain a substantial proportion of familial relative risk. These variants can be used to stratify individuals by their risk of prostate cancer.

METHODS: We genotyped 25 prostate cancer susceptibility loci in 40,414 individuals and derived a polygenic risk score (PRS). We estimated empirical odds ratios (OR) for prostate cancer associated with different risk strata defined by PRS and derived age-specific absolute risks of developing prostate cancer by PRS stratum and family history.

RESULTS: The prostate cancer risk for men in the top 1% of the …

Quantifying Unnecessary Normal Tissue Complication Risks Due To Suboptimal Planning: A Secondary Study Of Rtog 0126., Kevin L. Moore, Rachel Schmidt, Vitali Moiseenko, Lindsey A. Olsen, Jun Tan, Ying Xiao, James Galvin, Stephanie Pugh, Michael J Seider, Adam P. Dicker, Walter Bosch, Jeff Michalski, Sasa Mutic

Department of Radiation Oncology Faculty Papers

PURPOSE: The purpose of this study was to quantify the frequency and clinical severity of quality deficiencies in intensity modulated radiation therapy (IMRT) planning in the Radiation Therapy Oncology Group 0126 protocol.

METHODS AND MATERIALS: A total of 219 IMRT patients from the high-dose arm (79.2 Gy) of RTOG 0126 were analyzed. To quantify plan quality, we used established knowledge-based methods for patient-specific dose-volume histogram (DVH) prediction of organs at risk and a Lyman-Kutcher-Burman (LKB) model for grade ≥2 rectal complications to convert DVHs into normal tissue complication probabilities (NTCPs). The LKB model was validated by fitting dose-response parameters relative …

The Endogenous Cell-Fate Factor Dachshund Restrains Prostate Epithelial Cell Migration Via Repression Of Cytokine Secretion Via A Cxcl Signaling Module., Ke Chen, Kongming Wu, Xuanmao Jiao, Liping Wang, Xiaoming Ju, Min Wang, Gabriele Disante, Shaohua Xu, Qiong Wang, Kevin Li, Xin Sun, Chongwen Xu, Zhiping Li, Mathew C. Casimiro, Adam Ertel, Sankar Addya, Peter Mccue, Michael P. Lisanti, Chenguang Wang, Richard J. Davis, Graeme Mardon, Richard Pestell

Department of Cancer Biology Faculty Papers

Prostate cancer is the second leading form of cancer-related death in men. In a subset of prostate cancer patients, increased chemokine signaling IL8 and IL6 correlates with castrate-resistant prostate cancer (CRPC). IL8 and IL6 are produced by prostate epithelial cells and promote prostate cancer cell invasion; however, the mechanisms restraining prostate epithelial cell cytokine secretion are poorly understood. Herein, the cell-fate determinant factor DACH1 inhibited CRPC tumor growth in mice. Using Dach1(fl/fl)/Probasin-Cre bitransgenic mice, we show IL8 and IL6 secretion was altered by approximately 1,000-fold by endogenous Dach1. Endogenous Dach1 is shown to serve as a key endogenous restraint to …

Novel Actions Of Next-Generation Taxanes Benefit Advanced Stages Of Prostate Cancer., Renée De Leeuw, Lisa D. Berman-Booty, Matthew J. Schiewer, Stephen J Ciment, Robert Den, Adam P. Dicker, William Kelly, Edouard J. Trabulsi, Costas D. Lallas, Leonard G. Gomella, Karen E. Knudsen

Department of Cancer Biology Faculty Papers

PURPOSE: To improve the outcomes of patients with castration-resistant prostate cancer (CRPC), there is an urgent need for more effective therapies and approaches that individualize specific treatments for patients with CRPC. These studies compared the novel taxane cabazitaxel with the previous generation docetaxel, and aimed to determine which tumors are most likely to respond.

EXPERIMENTAL DESIGN: Cabazitaxel and docetaxel were compared via in vitro modeling to determine the molecular mechanism, biochemical and cell biologic impact, and cell proliferation, which was further assessed ex vivo in human tumor explants. Isogenic pairs of RB knockdown and control cells were interrogated in vitro …

On Voxel-By-Voxel Accumulated Dose For Prostate Radiation Therapy Using Deformable Image Registration., Jialu Yu, Nicholas Hardcastle, Kyoungkeun Jeong, Edward T. Bender, Mark A. Ritter, Wolfgang A. Tomé

Department of Radiation Oncology Faculty Papers

Since delivered dose is rarely the same with planned, we calculated the delivered total dose to ten prostate radiotherapy patients treated with rectal balloons using deformable dose accumulation (DDA) and compared it with the planned dose. The patients were treated with TomoTherapy using two rectal balloon designs: five patients had the Radiadyne balloon (balloon A), and five patients had the EZ-EM balloon (balloon B). Prostate and rectal wall contours were outlined on each pre-treatment MVCT for all patients. Delivered fractional doses were calculated using the MVCT taken immediately prior to delivery. Dose grids were accumulated to the last MVCT using …

African American Men With Low-Grade Prostate Cancer Have Increased Disease Recurrence After Prostatectomy Compared With Caucasian Men., Kosj Yamoah, Curtiland Deville, Neha Vapiwala, Elaine Spangler, Charnita M. Zeigler-Johnson, Bruce Malkowicz, David I Lee, Michael Kattan, Adam P. Dicker, Timothy R. Rebbeck

Department of Radiation Oncology Faculty Papers

PURPOSE: To explore whether disparities in outcomes exist between African American (AA) and Caucasian (CS) men with low-grade prostate cancer and similar cancer of the prostate risk assessment-postsurgery (CAPRA-S) features following prostatectomy (RP).

METHODS: The overall cohort consisted of 1,265 men (234 AA and 1,031 CS) who met the National comprehensive cancer network criteria for low- to intermediate-risk prostate cancer and underwent RP between 1990 and 2012. We first evaluated whether clinical factors were associated with adverse pathologic outcomes and freedom from biochemical failure (FFbF) using the entire cohort. Next, we studied a subset of 705 men (112 AA and …