2,146 results on '"Feng, Felix Y."'
Search Results
2. Integrative analysis of ultra-deep RNA-seq reveals alternative promoter usage as a mechanism of activating oncogenic programmes during prostate cancer progression
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Zhang, Meng, Sjöström, Martin, Cui, Xiekui, Foye, Adam, Farh, Kyle, Shrestha, Raunak, Lundberg, Arian, Dang, Ha X., Li, Haolong, Febbo, Phillip G., Aggarwal, Rahul, Alumkal, Joshi J., Small, Eric J., Maher, Christopher A., Feng, Felix Y., and Quigley, David A.
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- 2024
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3. The genomic and epigenomic landscape of double-negative metastatic prostate cancer
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Lundberg, Arian, Zhang, Meng, Aggarwal, Rahul, Li, Haolong, Zhang, Li, Foye, Adam, Sjöström, Martin, Chou, Jonathan, Chang, Kevin, Moreno-Rodriguez, Thaidy, Shrestha, Raunak, Baskin, Avi, Zhu, Xiaolin, Weinstein, Alana S, Younger, Noah, Alumkal, Joshi J, Beer, Tomasz M, N., Kim, Evans, Christopher P, Gleave, Martin, Lara, Primo N, Reiter, Rob E, Rettig, Matthew B, Witte, Owen N, Wyatt, Alexander W, Feng, Felix Y, Small, Eric J, and Quigley, David A
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Biological Sciences ,Biomedical and Clinical Sciences ,Clinical Sciences ,Oncology and Carcinogenesis ,Genetics ,Cancer Genomics ,Cancer ,Urologic Diseases ,Human Genome ,Precision Medicine ,Biotechnology ,Prostate Cancer ,Good Health and Well Being ,Humans ,Male ,Prostatic Neoplasms ,Castration-Resistant ,Receptors ,Androgen ,Epigenomics ,Androgen Antagonists ,Androgens ,Genomics ,Neuroendocrine Tumors ,Oncology & Carcinogenesis ,Biochemistry and cell biology ,Oncology and carcinogenesis - Abstract
Systemic targeted therapy in prostate cancer is primarily focused on ablating androgen signaling. Androgen deprivation therapy and second-generation androgen receptor (AR)-targeted therapy selectively favor the development of treatment-resistant subtypes of metastatic castration-resistant prostate cancer (mCRPC), defined by AR and neuroendocrine (NE) markers. Molecular drivers of double-negative (AR-/NE-) mCRPC are poorly defined. In this study, we comprehensively characterized treatment-emergent mCRPC by integrating matched RNA sequencing, whole-genome sequencing, and whole-genome bisulfite sequencing from 210 tumors. AR-/NE- tumors were clinically and molecularly distinct from other mCRPC subtypes, with the shortest survival, amplification of the chromatin remodeler CHD7, and PTEN loss. Methylation changes in CHD7 candidate enhancers were linked to elevated CHD7 expression in AR-/NE+ tumors. Genome-wide methylation analysis nominated Krüppel-like factor 5 (KLF5) as a driver of the AR-/NE- phenotype, and KLF5 activity was linked to RB1 loss. These observations reveal the aggressiveness of AR-/NE- mCRPC and could facilitate the identification of therapeutic targets in this highly aggressive disease.SignificanceComprehensive characterization of the five subtypes of metastatic castration-resistant prostate cancer identified transcription factors that drive each subtype and showed that the double-negative subtype has the worst prognosis.
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- 2023
4. Single cell-transcriptomic analysis informs the lncRNA landscape in metastatic castration resistant prostate cancer
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Saha, Debanjan, Dang, Ha X., Zhang, Meng, Quigley, David A., Feng, Felix Y., and Maher, Christopher A.
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- 2024
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5. Phase 1b study of enzalutamide plus CC-115, a dual mTORC1/2 and DNA-PK inhibitor, in men with metastatic castration-resistant prostate cancer (mCRPC)
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Zhao, Jimmy L., Antonarakis, Emmanuel S., Cheng, Heather H., George, Daniel J., Aggarwal, Rahul, Riedel, Elyn, Sumiyoshi, Takayuki, Schonhoft, Joseph D., Anderson, Amanda, Mao, Ninghui, Haywood, Samuel, Decker, Brooke, Curley, Tracy, Abida, Wassim, Feng, Felix Y., Knudsen, Karen, Carver, Brett, Lacouture, Mario E., Wyatt, Alexander W., and Rathkopf, Dana
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- 2024
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6. Prostate-Specific Antigen Level at the Time of Salvage Therapy After Radical Prostatectomy for Prostate Cancer and the Risk of Death
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Tilki, Derya, Chen, Ming-Hui, Wu, Jing, Huland, Hartwig, Graefen, Markus, Mohamad, Osama, Cowan, Janet E, Feng, Felix Y, Carroll, Peter R, and D'Amico, Anthony V
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Biomedical and Clinical Sciences ,Clinical Sciences ,Oncology and Carcinogenesis ,Urologic Diseases ,Cancer ,Prostate Cancer ,Aging ,Male ,Humans ,Prostate-Specific Antigen ,Prostatic Neoplasms ,Prostate ,Salvage Therapy ,Androgen Antagonists ,Prostatectomy ,Neoplasm Recurrence ,Local ,Retrospective Studies ,Oncology & Carcinogenesis ,Oncology and carcinogenesis - Abstract
PurposeBoth the performance characteristics of prostate-specific membrane antigen positron emission tomography and insurance approval improves with increasing prostate-specific antigen (PSA) level causing some physicians to delay post-radical prostatectomy salvage radiation therapy (sRT) after PSA failure. Yet, it is unknown for men with at most one high-risk factor (ie, pT3/4 or prostatectomy [p] Gleason score 8-10) whether a PSA level exists above which initiating sRT is associated with increased all-cause mortality (ACM)-risk and was investigated.MethodsUsing a multinational database of 25,551 patients with pT2-4N0 or NXM0 prostate cancer, multivariable Cox regression analysis evaluated whether an association with a significant increase in ACM-risk existed when sRT was delivered above a prespecified PSA level beginning at 0.10 ng/mL and in 0.05 increments up to 0.50 ng/mL versus at or below that level. The model was adjusted for age at and year of radical prostatectomy, established prostate cancer prognostic factors, institution, and the time-dependent use of androgen deprivation therapy.ResultsAfter a median follow-up of 6.00 years, patients who received sRT at a PSA level >0.25 ng/mL had a significantly higher ACM-risk (AHR, 1.49; 95% CI, 1.11 to 2.00; P = .008) compared with men who received sRT when the PSA was ≤0.25 mg/mL. This elevated ACM-risk remained significant for all PSA cutpoints up to 0.50 ng/mL but was not significant at PSA cutpoint values below 0.25 ng/mL.ConclusionAmong patients with at most one high-risk factor, initiating sRT above a PSA level of 0.25 ng/mL was associated with increased ACM-risk.
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- 2023
7. Theranostic Targeting of CUB Domain-Containing Protein 1 (CDCP1) in Multiple Subtypes of Bladder Cancer.
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Chopra, Shalini, Trepka, Kai, Sakhamuri, Sasank, Carretero-González, Alberto, Zhu, Jun, Egusa, Emily, Zhou, Jie, Leung, Kevin, Zhao, Ning, Hooshdaran, Nima, Feng, Felix Y, Wells, James A, Chou, Jonathan, and Evans, Michael J
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Biomedical and Clinical Sciences ,Oncology and Carcinogenesis ,Immunology ,Biotechnology ,Urologic Diseases ,Cancer ,5.1 Pharmaceuticals ,Development of treatments and therapeutic interventions ,Humans ,Animals ,Mice ,Radioisotopes ,Zirconium ,Neoplasm Proteins ,Precision Medicine ,Antigens ,CD ,Antigens ,Neoplasm ,Urinary Bladder Neoplasms ,Cell Line ,Tumor ,Cell Adhesion Molecules ,Oncology & Carcinogenesis ,Clinical sciences ,Oncology and carcinogenesis - Abstract
PurposeDespite recent approvals for checkpoint inhibitors and antibody-drug conjugates targeting NECTIN4 or TROP2, metastatic bladder cancer remains incurable and new treatment strategies are urgently needed. CUB domain-containing protein 1 (CDCP1) is a cell surface protein and promising drug target for many cancers. This study aimed to determine whether CDCP1 is expressed in bladder cancer and whether CDCP1 can be targeted for treatment with radiolabeled antibodies.Experimental designCDCP1 expression was evaluated in four bladder cancer datasets (n = 1,047 biopsies). A tissue microarray of primary bladder cancer biopsies was probed for CDCP1 by IHC. CDCP1 expression was evaluated in patient-derived xenografts and cell lysates by immunoblot, flow cytometry, and saturation binding assays. Tumor detection in mouse bladder cancer models was tested using 89Zr-labeled 4A06, a monoclonal antibody targeting the ectodomain of CDCP1. 177Lu-4A06 was applied to mice bearing UMUC3 or HT-1376 xenografts to evaluate antitumor effects (CDCP1 expression in UMUC3 is 10-fold higher than HT-1376).ResultsCDCP1 was highest in the basal/squamous subtype, and CDCP1 was expressed in 53% of primary biopsies. CDCP1 was not correlated with pathologic or tumor stage, metastatic site, or NECTIN4 and TROP2 at the mRNA or protein level. CDCP1 ranged from 105 to 106 receptors per cell. Mechanism studies showed that RAS signaling induced CDCP1 expression. 89Zr-4A06 PET detected five human bladder cancer xenografts. 177Lu-4A06 inhibited the growth of UMUC3 and HT-1376 xenografts, models with high and moderate CDCP1 expression, respectively.ConclusionsThese data establish that CDCP1 is expressed in bladder cancer, including TROP2 and NECTIN4-null disease, and suggest that bladder cancer can be treated with CDCP1-targeted radiotherapy.
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- 2023
8. Sequencing of Androgen-Deprivation Therapy of Short Duration With Radiotherapy for Nonmetastatic Prostate Cancer (SANDSTORM): A Pooled Analysis of 12 Randomized Trials
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Martin, Ting, Sun, Yilun, Malone, Shawn, Roach, Mack, Dearnaley, David, Pisansky, Thomas M, Feng, Felix Y, Sandler, Howard M, Efstathiou, Jason A, Syndikus, Isabel, Hall, Emma C, Tree, Alison C, Sydes, Matthew R, Cruickshank, Claire, Roy, Soumyajit, Bolla, Michel, Maingon, Philippe, De Reijke, Theo, Nabid, Abdenour, Carrier, Nathalie, Souhami, Luis, Zapatero, Almudena, Guerrero, Araceli, Alvarez, Ana, San-Segundo, Carmen Gonzalez, Maldonado, Xavier, Romero, Tahmineh, Steinberg, Michael L, Valle, Luca F, Rettig, Matthew B, Nickols, Nicholas G, Shoag, Jonathan E, Reiter, Robert E, Zaorsky, Nicholas G, Jia, Angela Y, Garcia, Jorge A, Spratt, Daniel E, Kishan, Amar U, and Investigators, on behalf of the Meta-Analysis of Randomized Trials in Cancer of the Prostate Consortium
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Biomedical and Clinical Sciences ,Clinical Sciences ,Oncology and Carcinogenesis ,Aging ,Clinical Research ,Patient Safety ,Urologic Diseases ,Cancer ,Prostate Cancer ,Evaluation of treatments and therapeutic interventions ,6.4 Surgery ,Good Health and Well Being ,Male ,Humans ,Prostatic Neoplasms ,Androgen Antagonists ,Androgens ,Randomized Controlled Trials as Topic ,Prostate-Specific Antigen ,Meta-Analysis of Randomized Trials in Cancer of the Prostate (MARCAP) Consortium Investigators ,Oncology & Carcinogenesis ,Oncology and carcinogenesis - Abstract
PurposeThe sequencing of androgen-deprivation therapy (ADT) with radiotherapy (RT) may affect outcomes for prostate cancer in an RT-field size-dependent manner. Herein, we investigate the impact of ADT sequencing for men receiving ADT with prostate-only RT (PORT) or whole-pelvis RT (WPRT).Materials and methodsIndividual patient data from 12 randomized trials that included patients receiving neoadjuvant/concurrent or concurrent/adjuvant short-term ADT (4-6 months) with RT for localized disease were obtained from the Meta-Analysis of Randomized trials in Cancer of the Prostate consortium. Inverse probability of treatment weighting (IPTW) was performed with propensity scores derived from age, initial prostate-specific antigen, Gleason score, T stage, RT dose, and mid-trial enrollment year. Metastasis-free survival (primary end point) and overall survival (OS) were assessed by IPTW-adjusted Cox regression models, analyzed independently for men receiving PORT versus WPRT. IPTW-adjusted Fine and Gray competing risk models were built to evaluate distant metastasis (DM) and prostate cancer-specific mortality.ResultsOverall, 7,409 patients were included (6,325 neoadjuvant/concurrent and 1,084 concurrent/adjuvant) with a median follow-up of 10.2 years (interquartile range, 7.2-14.9 years). A significant interaction between ADT sequencing and RT field size was observed for all end points (P interaction < .02 for all) except OS. With PORT (n = 4,355), compared with neoadjuvant/concurrent ADT, concurrent/adjuvant ADT was associated with improved metastasis-free survival (10-year benefit 8.0%, hazard ratio [HR], 0.65; 95% CI, 0.54 to 0.79; P < .0001), DM (subdistribution HR, 0.52; 95% CI, 0.33 to 0.82; P = .0046), prostate cancer-specific mortality (subdistribution HR, 0.30; 95% CI, 0.16 to 0.54; P < .0001), and OS (HR, 0.69; 95% CI, 0.57 to 0.83; P = .0001). However, in patients receiving WPRT (n = 3,049), no significant difference in any end point was observed in regard to ADT sequencing except for worse DM (HR, 1.57; 95% CI, 1.20 to 2.05; P = .0009) with concurrent/adjuvant ADT.ConclusionADT sequencing exhibits a significant impact on clinical outcomes with a significant interaction with field size. Concurrent/adjuvant ADT should be the standard of care where short-term ADT is indicated in combination with PORT.
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- 2023
9. PLX038: A Long-Acting Topoisomerase I Inhibitor With Robust Antitumor Activity in ATM-Deficient Tumors and Potent Synergy With PARP Inhibitors.
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Thomas, Anish, Fontaine, Shaun D, Diolaiti, Morgan E, Desai, Parth, Kumar, Rajesh, Takahashi, Nobuyuki, Sciuto, Linda, Nichols, Samantha, Ashworth, Alan, Feng, Felix Y, Ashley, Gary W, Nguyen, Minh, Pommier, Yves, and Santi, Daniel V
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Biomedical and Clinical Sciences ,Oncology and Carcinogenesis ,Breast Cancer ,Cancer ,Biotechnology ,Rare Diseases ,Genetics ,Development of treatments and therapeutic interventions ,5.1 Pharmaceuticals ,Humans ,Poly(ADP-ribose) Polymerase Inhibitors ,Topoisomerase I Inhibitors ,Ataxia Telangiectasia Mutated Proteins ,Cell Line ,Tumor ,DNA Repair ,Pharmacology and Pharmaceutical Sciences ,Oncology & Carcinogenesis ,Biochemistry and cell biology ,Oncology and carcinogenesis - Abstract
Alterations in the ATM gene are among the most common somatic and hereditary cancer mutations, and ATM-deficient tumors are hypersensitive to DNA-damaging agents. A synthetic lethal combination of DNA-damaging agents and DNA repair inhibitors could have widespread utility in ATM-deficient cancers. However, overlapping normal tissue toxicities from these drug classes have precluded their clinical translation. We investigated PLX038, a releasable polyethylene glycol-conjugate of the topoisomerase I inhibitor SN-38, in ATM wild-type and null isogenic xenografts and in a BRCA1-deficient xenograft. PLX038 monotherapy and combination with PARP inhibition potently inhibited the growth of both BRCA1- and ATM-deficient tumors. A patient with an ATM-mutated breast cancer treated with PLX038 and the PARP inhibitor rucaparib achieved rapid, symptomatic, and radiographic complete response lasting 12 months. Single-agent PLX038 or PLX038 in combination with DNA damage response inhibitors are novel therapeutic paradigms for patients with ATM-loss cancers.
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- 2022
10. Resistance to ATR Inhibitors Is Mediated by Loss of the Nonsense-Mediated Decay Factor UPF2.
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O'Leary, Patrick C, Chen, Huadong, Doruk, Yagmur U, Williamson, Tess, Polacco, Benjamin, McNeal, Andrew S, Shenoy, Tanushree, Kale, Nupura, Carnevale, Julia, Stevenson, Erica, Quigley, David A, Chou, Jonathan, Feng, Felix Y, Swaney, Danielle L, Krogan, Nevan J, Kim, Minkyu, Diolaiti, Morgan E, and Ashworth, Alan
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Biological Sciences ,Biomedical and Clinical Sciences ,Oncology and Carcinogenesis ,Cancer ,Rare Diseases ,Genetics ,Biotechnology ,Digestive Diseases ,Infectious Diseases ,Aetiology ,Development of treatments and therapeutic interventions ,2.1 Biological and endogenous factors ,5.1 Pharmaceuticals ,Humans ,Stomach Neoplasms ,Proteomics ,Protein Kinase Inhibitors ,Nonsense Mediated mRNA Decay ,RNA-Binding Proteins ,Ataxia Telangiectasia Mutated Proteins ,Oncology & Carcinogenesis ,Biochemistry and cell biology ,Oncology and carcinogenesis - Abstract
Over one million cases of gastric cancer are diagnosed each year globally, and the metastatic disease continues to have a poor prognosis. A significant proportion of gastric tumors have defects in the DNA damage response pathway, creating therapeutic opportunities through synthetic lethal approaches. Several small-molecule inhibitors of ATR, a key regulator of the DNA damage response, are now in clinical development as targeted agents for gastric cancer. Here, we performed a large-scale CRISPR interference screen to discover genetic determinants of response and resistance to ATR inhibitors (ATRi) in gastric cancer cells. Among the top hits identified as mediators of ATRi response were UPF2 and other components of the nonsense-mediated decay (NMD) pathway. Loss of UPF2 caused ATRi resistance across multiple gastric cancer cell lines. Global proteomic, phosphoproteomic, and transcriptional profiling experiments revealed that cell-cycle progression and DNA damage responses were altered in UPF2-mutant cells. Further studies demonstrated that UPF2-depleted cells failed to accumulate in G1 following treatment with ATRi. UPF2 loss also reduced transcription-replication collisions, which has previously been associated with ATRi response, thereby suggesting a possible mechanism of resistance. Our results uncover a novel role for NMD factors in modulating response to ATRi in gastric cancer, highlighting a previously unknown mechanism of resistance that may inform the clinical use of these drugs.SignificanceLoss of NMD proteins promotes resistance to ATR inhibitors in gastric cancer cells, which may provide a combination of therapeutic targets and biomarkers to improve the clinical utility of these drugs.
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- 2022
11. The 5-Hydroxymethylcytosine Landscape of Prostate Cancer
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Sjöström, Martin, Zhao, Shuang G, Levy, Samuel, Zhang, Meng, Ning, Yuhong, Shrestha, Raunak, Lundberg, Arian, Herberts, Cameron, Foye, Adam, Aggarwal, Rahul, Hua, Junjie T, Li, Haolong, Bergamaschi, Anna, Maurice-Dror, Corinne, Maheshwari, Ashutosh, Chen, Sujun, Ng, Sarah WS, Ye, Wenbin, Petricca, Jessica, Fraser, Michael, Chesner, Lisa, Perry, Marc D, Moreno-Rodriguez, Thaidy, Chen, William S, Alumkal, Joshi J, Chou, Jonathan, Morgans, Alicia K, Beer, Tomasz M, Thomas, George V, Gleave, Martin, Lloyd, Paul, Phillips, Tierney, McCarthy, Erin, Haffner, Michael C, Zoubeidi, Amina, Annala, Matti, Reiter, Robert E, Rettig, Matthew B, Witte, Owen N, Fong, Lawrence, Bose, Rohit, Huang, Franklin W, Luo, Jianhua, Bjartell, Anders, Lang, Joshua M, Mahajan, Nupam P, Lara, Primo N, Evans, Christopher P, Tran, Phuoc T, Posadas, Edwin M, He, Chuan, Cui, Xiao-Long, Huang, Jiaoti, Zwart, Wilbert, Gilbert, Luke A, Maher, Christopher A, Boutros, Paul C, N., Kim, Ashworth, Alan, Small, Eric J, He, Housheng H, Wyatt, Alexander W, Quigley, David A, and Feng, Felix Y
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Biological Sciences ,Biomedical and Clinical Sciences ,Genetics ,Clinical Sciences ,Oncology and Carcinogenesis ,Urologic Diseases ,Cancer ,Prostate Cancer ,Human Genome ,Aging ,Cancer Genomics ,4.1 Discovery and preclinical testing of markers and technologies ,2.1 Biological and endogenous factors ,4.2 Evaluation of markers and technologies ,Good Health and Well Being ,Male ,Humans ,5-Methylcytosine ,Prostatic Neoplasms ,Prostate ,Biopsy ,Oncology & Carcinogenesis ,Biochemistry and cell biology ,Oncology and carcinogenesis - Abstract
Analysis of DNA methylation is a valuable tool to understand disease progression and is increasingly being used to create diagnostic and prognostic clinical biomarkers. While conversion of cytosine to 5-methylcytosine (5mC) commonly results in transcriptional repression, further conversion to 5-hydroxymethylcytosine (5hmC) is associated with transcriptional activation. Here we perform the first study integrating whole-genome 5hmC with DNA, 5mC, and transcriptome sequencing in clinical samples of benign, localized, and advanced prostate cancer. 5hmC is shown to mark activation of cancer drivers and downstream targets. Furthermore, 5hmC sequencing revealed profoundly altered cell states throughout the disease course, characterized by increased proliferation, oncogenic signaling, dedifferentiation, and lineage plasticity to neuroendocrine and gastrointestinal lineages. Finally, 5hmC sequencing of cell-free DNA from patients with metastatic disease proved useful as a prognostic biomarker able to identify an aggressive subtype of prostate cancer using the genes TOP2A and EZH2, previously only detectable by transcriptomic analysis of solid tumor biopsies. Overall, these findings reveal that 5hmC marks epigenomic activation in prostate cancer and identify hallmarks of prostate cancer progression with potential as biomarkers of aggressive disease.SignificanceIn prostate cancer, 5-hydroxymethylcytosine delineates oncogene activation and stage-specific cell states and can be analyzed in liquid biopsies to detect cancer phenotypes. See related article by Wu and Attard, p. 3880.
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- 2022
12. Drug-Induced Epigenomic Plasticity Reprograms Circadian Rhythm Regulation to Drive Prostate Cancer toward Androgen Independence.
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Linder, Simon, Hoogstraat, Marlous, Stelloo, Suzan, Eickhoff, Nils, Schuurman, Karianne, de Barros, Hilda, Alkemade, Maartje, Bekers, Elise M, Severson, Tesa M, Sanders, Joyce, Huang, Chia-Chi Flora, Morova, Tunc, Altintas, Umut Berkay, Hoekman, Liesbeth, Kim, Yongsoo, Baca, Sylvan C, Sjöström, Martin, Zaalberg, Anniek, Hintzen, Dorine C, de Jong, Jeroen, Kluin, Roelof JC, de Rink, Iris, Giambartolomei, Claudia, Seo, Ji-Heui, Pasaniuc, Bogdan, Altelaar, Maarten, Medema, René H, Feng, Felix Y, Zoubeidi, Amina, Freedman, Matthew L, Wessels, Lodewyk FA, Butler, Lisa M, Lack, Nathan A, van der Poel, Henk, Bergman, Andries M, and Zwart, Wilbert
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Biomedical and Clinical Sciences ,Clinical Sciences ,Oncology and Carcinogenesis ,Prostate Cancer ,Aging ,Urologic Diseases ,Biotechnology ,Cancer ,5.1 Pharmaceuticals ,Development of treatments and therapeutic interventions ,2.1 Biological and endogenous factors ,Aetiology ,ARNTL Transcription Factors ,Androgens ,Cell Line ,Tumor ,Circadian Rhythm ,Drug Resistance ,Neoplasm ,Epigenomics ,Humans ,Male ,Nitriles ,Prostatic Neoplasms ,Castration-Resistant ,Receptors ,Androgen ,Biochemistry and cell biology ,Oncology and carcinogenesis - Abstract
In prostate cancer, androgen receptor (AR)-targeting agents are very effective in various disease stages. However, therapy resistance inevitably occurs, and little is known about how tumor cells adapt to bypass AR suppression. Here, we performed integrative multiomics analyses on tissues isolated before and after 3 months of AR-targeting enzalutamide monotherapy from patients with high-risk prostate cancer enrolled in a neoadjuvant clinical trial. Transcriptomic analyses demonstrated that AR inhibition drove tumors toward a neuroendocrine-like disease state. Additionally, epigenomic profiling revealed massive enzalutamide-induced reprogramming of pioneer factor FOXA1 from inactive chromatin sites toward active cis-regulatory elements that dictate prosurvival signals. Notably, treatment-induced FOXA1 sites were enriched for the circadian clock component ARNTL. Posttreatment ARNTL levels were associated with patients' clinical outcomes, and ARNTL knockout strongly decreased prostate cancer cell growth. Our data highlight a remarkable cistromic plasticity of FOXA1 following AR-targeted therapy and revealed an acquired dependency on the circadian regulator ARNTL, a novel candidate therapeutic target.SignificanceUnderstanding how prostate cancers adapt to AR-targeted interventions is critical for identifying novel drug targets to improve the clinical management of treatment-resistant disease. Our study revealed an enzalutamide-induced epigenomic plasticity toward prosurvival signaling and uncovered the circadian regulator ARNTL as an acquired vulnerability after AR inhibition, presenting a novel lead for therapeutic development. See related commentary by Zhang et al., p. 2017. This article is highlighted in the In This Issue feature, p. 2007.
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- 2022
13. Transcriptional profiling of matched patient biopsies clarifies molecular determinants of enzalutamide-induced lineage plasticity.
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Westbrook, Thomas C, Guan, Xiangnan, Rodansky, Eva, Flores, Diana, Liu, Chia Jen, Udager, Aaron M, Patel, Radhika A, Haffner, Michael C, Hu, Ya-Mei, Sun, Duanchen, Beer, Tomasz M, Foye, Adam, Aggarwal, Rahul, Quigley, David A, Youngren, Jack F, Ryan, Charles J, Gleave, Martin, Wang, Yuzhuo, Huang, Jiaoti, Coleman, Ilsa, Morrissey, Colm, Nelson, Peter S, Evans, Christopher P, Lara, Primo, Reiter, Robert E, Witte, Owen, Rettig, Matthew, Wong, Christopher K, Weinstein, Alana S, Uzunangelov, Vlado, Stuart, Josh M, Thomas, George V, Feng, Felix Y, Small, Eric J, Yates, Joel A, Xia, Zheng, and Alumkal, Joshi J
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Cell Line ,Tumor ,Humans ,Benzamides ,Nitriles ,Phenylthiohydantoin ,Receptors ,Androgen ,RNA ,Biopsy ,Drug Resistance ,Neoplasm ,Male ,E2F1 Transcription Factor ,Androgen Receptor Antagonists ,Prostatic Neoplasms ,Castration-Resistant ,Prostate Cancer ,Genetics ,Urologic Diseases ,Cancer ,Clinical Research ,2.1 Biological and endogenous factors ,Aetiology - Abstract
The androgen receptor (AR) signaling inhibitor enzalutamide (enza) is one of the principal treatments for metastatic castration-resistant prostate cancer (CRPC). Several emergent enza clinical resistance mechanisms have been described, including lineage plasticity in which the tumors manifest reduced dependency on the AR. To improve our understanding of enza resistance, herein we analyze the transcriptomes of matched biopsies from men with metastatic CRPC obtained prior to treatment and at progression (n = 21). RNA-sequencing analysis demonstrates that enza does not induce marked, sustained changes in the tumor transcriptome in most patients. However, three patients' progression biopsies show evidence of lineage plasticity. The transcription factor E2F1 and pathways linked to tumor stemness are highly activated in baseline biopsies from patients whose tumors undergo lineage plasticity. We find a gene signature enriched in these baseline biopsies that is strongly associated with poor survival in independent patient cohorts and with risk of castration-induced lineage plasticity in patient-derived xenograft models, suggesting that tumors harboring this gene expression program may be at particular risk for resistance mediated by lineage plasticity and poor outcomes.
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- 2022
14. Addition of Enzalutamide to Leuprolide and Definitive Radiation Therapy Is Tolerable and Effective in High-Risk Localized or Regional Nonmetastatic Prostate Cancer: Results From a Phase 2 Trial.
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Shee, Kevin, de la Calle, Claire M, Chang, Albert J, Wong, Anthony C, Feng, Felix Y, Gottschalk, Alexander R, Carroll, Peter R, and Nguyen, Hao G
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Clinical Trials and Supportive Activities ,Clinical Research ,Prostate Cancer ,Aging ,Cancer ,Urologic Diseases ,Evaluation of treatments and therapeutic interventions ,6.1 Pharmaceuticals - Abstract
BackgroundEnzalutamide is an antiandrogen used to treat both metastatic and nonmetastatic prostate cancer. Here we present results from a phase 2 trial designed to determine the safety, tolerability, and efficacy of adding enzalutamide to standard androgen deprivation therapy with radiation therapy in high-risk localized or regional, nonmetastatic patients with prostate cancer.Methods and materialsEnrollment criteria included at least 2 of the following: stage cT3a/b, prostate specific antigen (PSA) ≥20 ng/mL, Gleason grade 8 to 10, ≥33% core involvement on biopsy, or pelvic lymph node involvement on computed tomography or magnetic resonance imaging. Patients with metastatic disease were excluded. All patients received 24 months of leuprolide and enzalutamide, and 5 weeks of intensity modulated radiation therapy followed by a brachytherapy boost. Adverse events (AE), PSA, testosterone, and basic laboratory tests were then followed for up to 36 months. Primary outcomes were safety and tolerability and PSA complete response rate (PSA-CR, defined as PSA ≤0.3). Secondary outcomes included time to biochemical recurrence (BCR; nadir + 2 ng/mL).ResultsSixteen patients were enrolled; 2 were ineligible and 3 withdrew before starting treatment. Median age at enrollment was 69.0 years (interquartile range [IQR] 11.5). Median treatment duration was 24.0 months (IQR 11.9). Median follow-up time was 35.5 months (IQR 11.2), and 9 of 11 (81.8%) patients completed the 36 months of follow-up. One of 11 (9%) patients had grade 4 AE (seizure), and no grade 5 AE were reported. Four of 11 (36.4%) patients had grade 3 AE, such as erectile dysfunction and hot flashes. All patients achieved PSA-CR, and median time to PSA-CR was 4.2 months (IQR 1.4). At 24 months follow-up, 0 of 11 (0%) patients had a biochemical recurrence. At 36 months, 1 of 9 (11.1%) patient had a biochemical recurrence. Of note, this patient did not complete the full 24 months of enzalutamide and leuprolide due to AEs.ConclusionsEnzalutamide in combination with standard androgen deprivation therapy and radiation therapy was well-tolerated and effective warranting further study in a randomized controlled trial.
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- 2022
15. CUB Domain-Containing Protein 1 (CDCP1) Is a Target for Radioligand Therapy in Castration-Resistant Prostate Cancer, including PSMA Null Disease.
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Zhao, Ning, Chopra, Shalini, Trepka, Kai, Wang, Yung-Hua, Sakhamuri, Sasank, Hooshdaran, Nima, Kim, Hyunjung, Zhou, Jie, Lim, Shion A, Leung, Kevin K, Egusa, Emily A, Zhu, Jun, Zhang, Li, Foye, Adam, Sriram, Renuka, Chan, Emily, Seo, Youngho, Feng, Felix Y, Small, Eric J, Chou, Jonathan, Wells, James A, Aggarwal, Rahul, and Evans, Michael J
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Biomedical and Clinical Sciences ,Oncology and Carcinogenesis ,Biotechnology ,Cancer ,Urologic Diseases ,Prostate Cancer ,Good Health and Well Being ,Animals ,Antigens ,Neoplasm ,Cell Adhesion Molecules ,Dipeptides ,Heterocyclic Compounds ,1-Ring ,Humans ,Male ,Mice ,Prostate-Specific Antigen ,Prostatic Neoplasms ,Castration-Resistant ,Radioisotopes ,Radiopharmaceuticals ,Treatment Outcome ,Zirconium ,Oncology & Carcinogenesis ,Clinical sciences ,Oncology and carcinogenesis - Abstract
PurposeWith the improvement in overall survival with 177Lu-PSMA 617, radioligand therapy (RLT) is now a viable option for patients with metastatic castration-resistant prostate cancer (mCRPC). However, responses are variable, in part due to low PSMA expression in 30% of patients. Herein, we evaluated whether the cell surface protein CUB domain-containing protein 1 (CDCP1) can be exploited to treat mCRPC with RLT, including in PSMA-low subsets.Experimental designCDCP1 levels were evaluated using RNA sequencing from 119 mCRPC biopsies. CDCP1 levels were assessed in 17 post-enzalutamide- or abiraterone-treated mCRPC biopsies, 12 patient-derived xenografts (PDX), and prostate cancer cell lines. 4A06, a recombinant human antibody that targets the CDCP1 ectodomain, was labeled with Zr-89 or Lu-177 and tested in tumor-bearing mice.ResultsCDCP1 expression was observed in 90% of mCRPC biopsies, including small-cell neuroendocrine (SCNC) and adenocarcinomas with low FOLH1 (PSMA) levels. Fifteen of 17 evaluable mCRPC biopsies (85%) demonstrated membranous CDCP1 expression, and 4 of 17 (23%) had higher CDCP1 H-scores compared with PSMA. CDCP1 was expressed in 10 of 12 PDX samples. Bmax values of approximately 22,000, 6,200, and 2,800 fmol/mg were calculated for PC3, DU145, and C4-2B human prostate cancer cells, respectively. 89Zr-4A06 PET detected six human prostate cancer xenografts, including PSMA-low tumors. 177Lu-4A06 significantly suppressed growth of DU145 and C4-2B xenografts.ConclusionsThe data provide the first evidence supporting CDCP1-directed RLT to treat mCRPC. Expanded studies are warranted to determine whether CDCP1 is a viable drug target for patients with mCPRC.
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- 2022
16. Transcriptomic Heterogeneity of Expansile Cribriform and Other Gleason Pattern 4 Prostate Cancer Subtypes
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Chappidi, Meera R., Sjöström, Martin, Greenland, Nancy Y., Cowan, Janet E., Baskin, Avi S., Shee, Kevin, Simko, Jeffry P., Chan, Emily, Stohr, Bradley A., Washington, Samuel L., 3rd, Nguyen, Hao G., Quigley, David A., Davicioni, Elai, Feng, Felix Y., Carroll, Peter R., and Cooperberg, Matthew R.
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- 2024
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17. Histone H2A Lys130 acetylation epigenetically regulates androgen production in prostate cancer
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Nguyen, Thanh, Sridaran, Dhivya, Chouhan, Surbhi, Weimholt, Cody, Wilson, Audrey, Luo, Jingqin, Li, Tiandao, Koomen, John, Fang, Bin, Putluri, Nagireddy, Sreekumar, Arun, Feng, Felix Y., Mahajan, Kiran, and Mahajan, Nupam P.
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- 2023
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18. Author Correction: Histone H2A Lys130 acetylation epigenetically regulates androgen production in prostate cancer
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Nguyen, Thanh, Sridaran, Dhivya, Chouhan, Surbhi, Weimholt, Cody, Wilson, Audrey, Luo, Jingqin, Li, Tiandao, Koomen, John, Fang, Bin, Putluri, Nagireddy, Sreekumar, Arun, Feng, Felix Y., Mahajan, Kiran, and Mahajan, Nupam P.
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- 2023
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19. Author Correction: Prostate cancer therapy personalization via multi-modal deep learning on randomized phase III clinical trials
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Esteva, Andre, Feng, Jean, van der Wal, Douwe, Huang, Shih-Cheng, Simko, Jeffry P., DeVries, Sandy, Chen, Emmalyn, Schaeffer, Edward M., Morgan, Todd M., Sun, Yilun, Ghorbani, Amirata, Naik, Nikhil, Nathawani, Dhruv, Socher, Richard, Michalski, Jeff M., Roach, III, Mack, Pisansky, Thomas M., Monson, Jedidiah M., Naz, Farah, Wallace, James, Ferguson, Michelle J., Bahary, Jean-Paul, Zou, James, Lungren, Matthew, Yeung, Serena, Ross, Ashley E., Sandler, Howard M., Tran, Phuoc T., Spratt, Daniel E., Pugh, Stephanie, Feng, Felix Y., and Mohamad, Osama
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- 2023
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20. Targeting a splicing-mediated drug resistance mechanism in prostate cancer by inhibiting transcriptional regulation by PKCβ1.
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Melnyk, James E, Steri, Veronica, Nguyen, Hao G, Hwang, Y Christina, Gordan, John D, Hann, Byron, Feng, Felix Y, and Shokat, Kevan M
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Humans ,Prostatic Neoplasms ,Androgen Antagonists ,Receptors ,Androgen ,Gene Expression Regulation ,Neoplastic ,RNA Splicing ,Drug Resistance ,Male ,Protein Kinase C beta ,Prostatic Neoplasms ,Castration-Resistant ,Human Genome ,Aging ,Urologic Diseases ,Cancer ,Prostate Cancer ,Genetics ,5.1 Pharmaceuticals ,Development of treatments and therapeutic interventions ,Clinical Sciences ,Oncology and Carcinogenesis ,Oncology & Carcinogenesis - Abstract
The androgen receptor (AR) is a central driver of aggressive prostate cancer. After initial treatment with androgen receptor signaling inhibitors (ARSi), reactivation of AR signaling leads to resistance. Alternative splicing of AR mRNA yields the AR-V7 splice variant, which is currently an undruggable mechanism of ARSi resistance: AR-V7 lacks a ligand binding domain, where hormones and anti-androgen antagonists act, but still activates AR signaling. We reveal PKCβ as a druggable regulator of transcription and splicing at the AR genomic locus. We identify a clinical PKCβ inhibitor in combination with an FDA-approved anti-androgen as an approach for repressing AR genomic locus expression, including expression of AR-V7, while antagonizing full-length AR. PKCβ inhibition reduces total AR gene expression, thus reducing AR-V7 protein levels and sensitizing prostate cancer cells to current anti-androgen therapies. We demonstrate that this combination may be a viable therapeutic strategy for AR-V7-positive prostate cancer.
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- 2022
21. Interplay Between Duration of Androgen Deprivation Therapy and External Beam Radiotherapy With or Without a Brachytherapy Boost for Optimal Treatment of High-risk Prostate Cancer
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Kishan, Amar U, Steigler, Alison, Denham, James W, Zapatero, Almudena, Guerrero, Araceli, Joseph, David, Maldonado, Xavier, Wong, Jessica K, Stish, Bradley J, Dess, Robert T, Pilar, Avinash, Reddy, Chandana, Wedde, Trude B, Lilleby, Wolfgang A, Fiano, Ryan, Merrick, Gregory S, Stock, Richard G, Demanes, D Jeffrey, Moran, Brian J, Tran, Phuoc T, Martin, Santiago, Martinez-Monge, Rafael, Krauss, Daniel J, Abu-Isa, Eyad I, Pisansky, Thomas M, Choo, C Richard, Song, Daniel Y, Greco, Stephen, Deville, Curtiland, McNutt, Todd, DeWeese, Theodore L, Ross, Ashley E, Ciezki, Jay P, Tilki, Derya, Karnes, R Jeffrey, Tosoian, Jeffrey J, Nickols, Nicholas G, Bhat, Prashant, Shabsovich, David, Juarez, Jesus E, Jiang, Tommy, Ma, T Martin, Xiang, Michael, Philipson, Rebecca, Chang, Albert, Kupelian, Patrick A, Rettig, Matthew B, Feng, Felix Y, Berlin, Alejandro, Tward, Jonathan D, Davis, Brian J, Reiter, Robert E, Steinberg, Michael L, Elashoff, David, Boutros, Paul C, Horwitz, Eric M, Tendulkar, Rahul D, Spratt, Daniel E, and Romero, Tahmineh
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Cancer ,Clinical Research ,Prostate Cancer ,Urologic Diseases ,Clinical Trials and Supportive Activities ,Evaluation of treatments and therapeutic interventions ,6.1 Pharmaceuticals ,Androgen Antagonists ,Androgens ,Brachytherapy ,Data Analysis ,Humans ,Male ,Middle Aged ,Prostatic Neoplasms ,Retrospective Studies ,Oncology and Carcinogenesis ,Public Health and Health Services - Abstract
ImportanceRadiotherapy combined with androgen deprivation therapy (ADT) is a standard of care for high-risk prostate cancer. However, the interplay between radiotherapy dose and the required minimum duration of ADT is uncertain.ObjectiveTo determine the specific ADT duration threshold that provides a distant metastasis-free survival (DMFS) benefit in patients with high-risk prostate cancer receiving external beam radiotherapy (EBRT) or EBRT with a brachytherapy boost (EBRT+BT).Design, settings, and participantsThis was a cohort study of 3 cohorts assembled from a multicenter retrospective study (2000-2013); a post hoc analysis of the Randomized Androgen Deprivation and Radiotherapy 03/04 (RADAR; 2003-2007) randomized clinical trial (RCT); and a cross-trial comparison of the RADAR vs the Deprivación Androgénica y Radio Terapía (Androgen Deprivation and Radiation Therapy; DART) 01/05 RCT (2005-2010). In all, the study analyzed 1827 patients treated with EBRT and 1108 patients treated with EBRT+BT from the retrospective cohort; 181 treated with EBRT and 203 with EBRT+BT from RADAR; and 91 patients treated with EBRT from DART. The study was conducted from October 15, 2020, to July 1, 2021, and the data analyses, from January 5 to June 15, 2021.ExposuresHigh-dose EBRT or EBRT+BT for an ADT duration determined by patient-physician choice (retrospective) or by randomization (RCTs).Main outcomes and measuresThe primary outcome was DMFS; secondary outcome was overall survival (OS). Natural cubic spline analysis identified minimum thresholds (months).ResultsThis cohort study of 3 studies totaling 3410 men (mean age [SD], 68 [62-74] years; race and ethnicity not collected) with high-risk prostate cancer found a significant interaction between the treatment type (EBRT vs EBRT+BT) and ADT duration (binned to
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- 2022
22. Adding Short-Term Androgen Deprivation Therapy to Radiation Therapy in Men With Localized Prostate Cancer: Long-Term Update of the NRG/RTOG 9408 Randomized Clinical Trial
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Jones, Christopher U, Pugh, Stephanie L, Sandler, Howard M, Chetner, Michael P, Amin, Mahul B, Bruner, Deborah W, Zietman, Anthony L, Den, Robert B, Leibenhaut, Mark H, Longo, John M, Bahary, Jean-Paul, Rosenthal, Seth A, Souhami, Luis, Michalski, Jeff M, Hartford, Alan C, Amin, Pradip P, Roach, Mack, Yee, Don, Efstathiou, Jason A, Rodgers, Joseph P, Feng, Felix Y, and Shipley, William U
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Biomedical and Clinical Sciences ,Clinical Sciences ,Oncology and Carcinogenesis ,Prostate Cancer ,Clinical Trials and Supportive Activities ,Clinical Research ,Cancer ,Urologic Diseases ,Evaluation of treatments and therapeutic interventions ,6.4 Surgery ,Androgen Antagonists ,Androgens ,Follow-Up Studies ,Humans ,Male ,Prostate-Specific Antigen ,Prostatic Neoplasms ,Other Physical Sciences ,Oncology & Carcinogenesis ,Oncology and carcinogenesis ,Theoretical and computational chemistry ,Medical and biological physics - Abstract
PurposeFor men with localized prostate cancer, NRG Oncology/Radiation Therapy Oncology Group (RTOG) 9408 demonstrated that adding short-term androgen deprivation therapy (ADT) to radiation therapy (RT) improved the primary endpoint of overall survival (OS) and improved disease-specific mortality (DSM), biochemical failure (BF), local progression, and freedom from distant metastases (DM). This study was performed to determine whether the short-term ADT continued to improve OS, DSM, BF, and freedom from DM with longer follow-up.Methods and materialsFrom 1994 to 2001, NRG/RTOG 9408 randomized 2028 men from 212 North American institutions with T1b-T2b, N0 prostate adenocarcinoma and prostate-specific antigen (PSA) ≤20ng/mL to RT alone or RT plus short-term ADT. Patients were stratified by PSA, tumor grade, and surgical versus clinical nodal staging. ADT was flutamide with either goserelin or leuprolide for 4 months. Prostate RT (66.6 Gy) was started after 2 months. OS was calculated at the date of death from any cause or at last follow-up. Secondary endpoints were DSM, BF, local progression, and DM. Acute and late toxic effects were assessed using RTOG toxicity scales.ResultsMedian follow-up in surviving patients was 14.8 years (range, 0.16-21.98). The 10-year and 18-year OS was 56% and 23%, respectively, with RT alone versus 63% and 23% with combined therapy (HR 0.94; 95% confidence interval [CI], 0.85-1.05; P = .94). The hazards were not proportional (P = .003). Estimated restricted mean survival time at 18 years was 11.8 years (95% CI, 11.4-12.1) with combined therapy versus 11.3 years with RT alone (95% CI, 10.9-11.6; P = .05). The 10-year and 18-year DSM was 7% and 14%, respectively, with RT alone versus 3% and 8% with combined therapy (HR 0.56; 95% CI, 0.41-0.75; P < .01). DM and BF favored combined therapy at 18 years. Rates of late grade ≥3 hepatic, gastrointestinal, and genitourinary toxicity were ≤1%, 3%, and 8%, respectively, with combined therapy versus ≤1%, 2%, and 5% with RT alone.ConclusionsFurther follow-up demonstrates that OS converges at approximately 15 years, by which point the administration of 4 months of ADT had conferred an estimated additional 6 months of life.
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- 2022
23. The CIC-ERF co-deletion underlies fusion-independent activation of ETS family member, ETV1, to drive prostate cancer progression
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Gupta, Nehal, Song, Hanbing, Wu, Wei, Ponce, Rovingaile K, Lin, Yone K, Kim, Ji Won, Small, Eric J, Feng, Felix Y, Huang, Franklin W, and Okimoto, Ross A
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Biological Sciences ,Biomedical and Clinical Sciences ,Clinical Sciences ,Oncology and Carcinogenesis ,Cancer ,Biotechnology ,Aging ,Urologic Diseases ,Cancer Genomics ,Human Genome ,Prostate Cancer ,Genetics ,2.1 Biological and endogenous factors ,Aetiology ,Humans ,Male ,Carcinogenesis ,DNA-Binding Proteins ,Prostate ,Prostatic Neoplasms ,Repressor Proteins ,Transcription Factors ,Gene Deletion ,prostate cancer ,Capicua ,ERF ,ETS transcription factors ,Human ,cancer biology ,human ,Biochemistry and Cell Biology ,Biological sciences ,Biomedical and clinical sciences ,Health sciences - Abstract
Human prostate cancer can result from chromosomal rearrangements that lead to aberrant ETS gene expression. The mechanisms that lead to fusion-independent ETS factor upregulation and prostate oncogenesis remain relatively unknown. Here, we show that two neighboring transcription factors, Capicua (CIC) and ETS2 repressor factor (ERF), which are co-deleted in human prostate tumors can drive prostate oncogenesis. Concurrent CIC and ERF loss commonly occur through focal genomic deletions at chromosome 19q13.2. Mechanistically, CIC and ERF co-bind the proximal regulatory element and mutually repress the ETS transcription factor, ETV1. Targeting ETV1 in CIC and ERF-deficient prostate cancer limits tumor growth. Thus, we have uncovered a fusion-independent mode of ETS transcriptional activation defined by concurrent loss of CIC and ERF.
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- 2022
24. Impact of radiopharmaceutical therapy (177Lu, 225Ac) microdistribution in a cancer-associated fibroblasts model
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Tranel, Jonathan, Palm, Stig, Graves, Stephen A, Feng, Felix Y, and Hope, Thomas A
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Cancer ,Cancer-associated fibroblasts ,Dose voxel kernel ,Radiopharmaceutical therapy ,Monte Carlo simulation - Abstract
BackgroundThe aim of this study is to elucidate the difference in absorbed dose (Dabs) patterns in radiopharmaceutical therapies between alpha emitters (225Ac) and beta emitters (177Lu) when targeting cancer-associated fibroblasts (CAF) or tumor cells. Five spherical models with 3 mm diameter were created, representing spherical tumor masses that contain tumor clusters, interspersed with CAFs. The mean distance from a tumor cell to the nearest CAF (Lmean) varied throughout these models from 92 to 1030 µm. Dabs calculations were performed while selecting either CAFs or tumor cells as sources, with Convolution/Superposition with 177Lu and Monte Carlo simulations (GATE) with 225Ac. Analyses were conducted with Dose Volume Histograms and efficacy ratios (ER), which represents the ratio of mean Dabs that is deposited in the target volume.Results225Ac is the most optimal radionuclide when CAFs are both targeted and irradiating themselves, as ERs increase from 1.5 to 3.7 when Lmean increases from 92 to 1030 µm. With 177Lu, these numbers vary from 1.2 to 2.7. Conversely, when CAFs are sources and tumors are targets with 225Ac, ERs decreased from 0.8 to 0.1 when Lmean increases from 92 to 1030 µm. With 177Lu, these numbers vary from 0.9 to 0.3 CONCLUSION: When targeting CAFs to irradiate tumors, the efficacy of using 225Ac decreases as the average size of the tumor clusters (or Lmean) increases. In such situations, 177Lu will be more effective than 225Ac when targeting CAFs due to the longer beta particle range.
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- 2022
25. Prostate cancer therapy personalization via multi-modal deep learning on randomized phase III clinical trials
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Esteva, Andre, Feng, Jean, van der Wal, Douwe, Huang, Shih-Cheng, Simko, Jeffry P, DeVries, Sandy, Chen, Emmalyn, Schaeffer, Edward M, Morgan, Todd M, Sun, Yilun, Ghorbani, Amirata, Naik, Nikhil, Nathawani, Dhruv, Socher, Richard, Michalski, Jeff M, Roach, Mack, Pisansky, Thomas M, Monson, Jedidiah M, Naz, Farah, Wallace, James, Ferguson, Michelle J, Bahary, Jean-Paul, Zou, James, Lungren, Matthew, Yeung, Serena, Ross, Ashley E, Sandler, Howard M, Tran, Phuoc T, Spratt, Daniel E, Pugh, Stephanie, Feng, Felix Y, and Mohamad, Osama
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Clinical Trials and Supportive Activities ,Prostate Cancer ,Urologic Diseases ,Patient Safety ,Cancer ,Clinical Research ,4.2 Evaluation of markers and technologies ,Detection ,screening and diagnosis ,Good Health and Well Being ,NRG Prostate Cancer AI Consortium - Abstract
Prostate cancer is the most frequent cancer in men and a leading cause of cancer death. Determining a patient's optimal therapy is a challenge, where oncologists must select a therapy with the highest likelihood of success and the lowest likelihood of toxicity. International standards for prognostication rely on non-specific and semi-quantitative tools, commonly leading to over- and under-treatment. Tissue-based molecular biomarkers have attempted to address this, but most have limited validation in prospective randomized trials and expensive processing costs, posing substantial barriers to widespread adoption. There remains a significant need for accurate and scalable tools to support therapy personalization. Here we demonstrate prostate cancer therapy personalization by predicting long-term, clinically relevant outcomes using a multimodal deep learning architecture and train models using clinical data and digital histopathology from prostate biopsies. We train and validate models using five phase III randomized trials conducted across hundreds of clinical centers. Histopathological data was available for 5654 of 7764 randomized patients (71%) with a median follow-up of 11.4 years. Compared to the most common risk-stratification tool-risk groups developed by the National Cancer Center Network (NCCN)-our models have superior discriminatory performance across all endpoints, ranging from 9.2% to 14.6% relative improvement in a held-out validation set. This artificial intelligence-based tool improves prognostication over standard tools and allows oncologists to computationally predict the likeliest outcomes of specific patients to determine optimal treatment. Outfitted with digital scanners and internet access, any clinic could offer such capabilities, enabling global access to therapy personalization.
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- 2022
26. Single-cell analysis of human primary prostate cancer reveals the heterogeneity of tumor-associated epithelial cell states.
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Song, Hanbing, Weinstein, Hannah NW, Allegakoen, Paul, Wadsworth, Marc H, Xie, Jamie, Yang, Heiko, Castro, Ethan A, Lu, Kevin L, Stohr, Bradley A, Feng, Felix Y, Carroll, Peter R, Wang, Bruce, Cooperberg, Matthew R, Shalek, Alex K, and Huang, Franklin W
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Prostate ,Organoids ,Epithelial Cells ,Humans ,Prostatic Neoplasms ,Neoplasm Proteins ,Prostatectomy ,Gene Expression Profiling ,Signal Transduction ,Gene Expression Regulation ,Neoplastic ,Cell Lineage ,Genetic Heterogeneity ,Male ,Molecular Sequence Annotation ,Single-Cell Analysis ,Tumor Microenvironment ,Primary Cell Culture ,Carcinogenesis ,Gene Ontology ,Transcriptional Regulator ERG ,Prostate Cancer ,Urologic Diseases ,Clinical Research ,Cancer ,Aging ,2.1 Biological and endogenous factors ,Aetiology - Abstract
Prostate cancer is the second most common malignancy in men worldwide and consists of a mixture of tumor and non-tumor cell types. To characterize the prostate cancer tumor microenvironment, we perform single-cell RNA-sequencing on prostate biopsies, prostatectomy specimens, and patient-derived organoids from localized prostate cancer patients. We uncover heterogeneous cellular states in prostate epithelial cells marked by high androgen signaling states that are enriched in prostate cancer and identify a population of tumor-associated club cells that may be associated with prostate carcinogenesis. ERG-negative tumor cells, compared to ERG-positive cells, demonstrate shared heterogeneity with surrounding luminal epithelial cells and appear to give rise to common tumor microenvironment responses. Finally, we show that prostate epithelial organoids harbor tumor-associated epithelial cell states and are enriched with distinct cell types and states from their parent tissues. Our results provide diagnostically relevant insights and advance our understanding of the cellular states associated with prostate carcinogenesis.
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- 2022
27. Race-dependent association of clinical trial participation with improved outcomes for high-risk prostate cancer patients treated in the modern era
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Ma, Ting Martin, Feng, Felix Y., Rosenthal, Seth A., Rettig, Matthew B., Raldow, Ann C., Spratt, Daniel E., Xiang, Michael, and Kishan, Amar U.
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- 2023
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28. Cardiovascular Mortality and Duration of Androgen Deprivation in Locally Advanced Prostate Cancer: Long-term Update of NRG/RTOG 9202
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Mak, Kimberley S., Scannell Bryan, Molly, Dignam, James J., Shipley, William U., Lin, Yue, Peters, Christopher A., Gore, Elizabeth M., Rosenthal, Seth A., Zeitzer, Kenneth L., D'Souza, David P., Horwitz, Eric M., Pisansky, Thomas M., Maier, Jordan M., Chafe, Susan M., Robin, Tyler P., Roach, Mack, III, Tran, Phuoc T., Souhami, Luis, Michalski, Jeff M., Hartford, Alan C., Feng, Felix Y., Sandler, Howard M., and Efstathiou, Jason A.
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- 2024
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29. The Impact of Positron Emission Tomography Imaging and Tumor Molecular Profiling on Risk Stratification, Treatment Choice, and Oncological Outcomes of Patients with Primary or Relapsed Prostate Cancer: An International Collaborative Review of the Existing Literature
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Sood, Akshay, Kishan, Amar U., Evans, Christopher P., Feng, Felix Y., Morgan, Todd M., Murphy, Declan G., Padhani, Anwar R., Pinto, Peter, Van der Poel, Henk G., Tilki, Derya, Briganti, Alberto, and Abdollah, Firas
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- 2024
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30. Long-term Outcomes of Chemoradiation for Muscle-invasive Bladder Cancer in Noncystectomy Candidates. Final Results of NRG Oncology RTOG 0524—A Phase 1/2 Trial of Paclitaxel + Trastuzumab with Daily Radiation or Paclitaxel Alone with Daily Irradiation
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Dahl, Douglas M., Karrison, Theodore G., Michaelson, M. Dror, Pham, Huong T., Wu, Chin-Lee, Swanson, Gregory P., Shipley, William U., Vuky, Jacqueline, Lee, R. Jeffrey, Zietman, Anthony L., Souhami, Luis, Chang, Brian K., Deming, Richard L., Ellerton, John A., Sandler, Howard M., Rodgers, Joseph P., Feng, Felix Y., and Efstathiou, Jason A.
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- 2024
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31. Multi-institutional Development and External Validation of a Machine Learning Model for the Prediction of Distant Metastasis in Patients Treated by Salvage Radiotherapy for Biochemical Failure After Radical Prostatectomy
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Sabbagh, Ali, Tilki, Derya, Feng, Jean, Huland, Hartwig, Graefen, Markus, Wiegel, Thomas, Böhmer, Dirk, Hong, Julian C., Valdes, Gilmer, Cowan, Janet E., Cooperberg, Matthew, Feng, Felix Y., Mohammad, Tarek, Shelan, Mohamed, D'Amico, Anthony V., Carroll, Peter R., and Mohamad, Osama
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- 2024
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32. Comparison of Response to Definitive Radiotherapy for Localized Prostate Cancer in Black and White Men
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Martin, Ting, Romero, Tahmineh, Nickols, Nicholas G, Rettig, Matthew B, Garraway, Isla P, Roach, Mack, Michalski, Jeff M, Pisansky, Thomas M, Lee, W Robert, Jones, Christopher U, Rosenthal, Seth A, Wang, Chenyang, Hartman, Holly, Nguyen, Paul L, Feng, Felix Y, Boutros, Paul C, Saigal, Christopher, Chamie, Karim, Jackson, William C, Morgan, Todd M, Mehra, Rohit, Salami, Simpa S, Vince, Randy, Schaeffer, Edward M, Mahal, Brandon A, Dess, Robert T, Steinberg, Michael L, Elashoff, David, Sandler, Howard M, Spratt, Daniel E, and Kishan, Amar U
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Clinical Trials and Supportive Activities ,Cancer ,Prostate Cancer ,Urologic Diseases ,Clinical Research ,Good Health and Well Being ,Black People ,Humans ,Male ,Prostatic Neoplasms ,Randomized Controlled Trials as Topic ,Treatment Outcome ,White People - Abstract
ImportanceBlack men have a 2-fold increased risk of dying from prostate cancer compared with White men. However, race-specific differences in response to initial treatment remain unknown.ObjectiveTo compare overall and treatment-specific outcomes of Black and White men with localized prostate cancer receiving definitive radiotherapy (RT).Data sourcesA systematic search was performed of relevant published randomized clinical trials conducted by the NRG Oncology/Radiation Therapy Oncology Group between January 1, 1990, and December 31, 2010. This meta-analysis was performed from July 1, 2019, to July 1, 2021.Study selectionRandomized clinical trials of definitive RT for patients with localized prostate cancer comprising a substantial number of Black men (self-identified race) enrolled that reported on treatment-specific and overall outcomes.Data extraction and synthesisIndividual patient data were obtained from 7 NRG Oncology/Radiation Therapy Oncology Group randomized clinical trials evaluating definitive RT with or without short- or long-term androgen deprivation therapy. Unadjusted Fine-Gray competing risk models, with death as a competing risk, were developed to evaluate the cumulative incidences of end points. Cox proportional hazards models were used to evaluate differences in all-cause mortality and the composite outcome of distant metastasis (DM) or death. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guideline was followed.Main outcomes and measuresSubdistribution hazard ratios (sHRs) of biochemical recurrence (BCR), DM, and prostate cancer-specific mortality (PCSM).ResultsA total of 8814 patients (1630 [18.5%] Black and 7184 [81.5%] White) were included; mean (SD) age was 69.1 (6.8) years. Median follow-up was 10.6 (IQR, 8.0-17.8) years for surviving patients. At enrollment, Black men were more likely to have high-risk disease features. However, even without adjustment, Black men were less likely to experience BCR (sHR, 0.88; 95% CI, 0.58-0.91), DM (sHR, 0.72; 95% CI, 0.58-0.91), or PCSM (sHR, 0.72; 95% CI, 0.54-0.97). No significant differences in all-cause mortality were identified (HR, 0.99; 95% CI, 0.92-1.07). Upon adjustment, Black race remained significantly associated with improved BCR (adjusted sHR, 0.79; 95% CI, 0.72-0.88; P
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- 2021
33. The Mutational Landscape of Metastatic Castration-sensitive Prostate Cancer: The Spectrum Theory Revisited
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Deek, Matthew P, Van der Eecken, Kim, Phillips, Ryan, Parikh, Neil R, Velho, Pedro Isaacsson, Lotan, Tamara L, Kishan, Amar U, Maurer, Tobias, Consortium, GAP6, Boutros, Paul C, Hovens, Christopher, Abramowtiz, Matthew, Pollack, Alan, Desai, Neil, Stish, Bradley, Feng, Felix Y, Eisenberger, Mario, Carducci, Michael, Pienta, Kenneth J, Markowski, Mark, Paller, Channing J, Antonarakis, Emmanuel S, Berlin, Alejandro, Ost, Piet, and Tran, Phuoc T
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Biomedical and Clinical Sciences ,Clinical Sciences ,Oncology and Carcinogenesis ,Urologic Diseases ,Genetics ,Prostate Cancer ,Aging ,Cancer ,High-Throughput Nucleotide Sequencing ,Humans ,Male ,Mutation ,Neoplasm Metastasis ,Neoplasm Recurrence ,Local ,Prostatic Neoplasms ,Castration-Resistant ,Retrospective Studies ,Treatment Outcome ,Oligometastatic prostate cancer ,Next Generation Sequencing ,GAP6 Consortium ,Urology & Nephrology ,Clinical sciences - Abstract
BackgroundEmerging data suggest that metastasis is a spectrum of disease burden rather than a binary state, and local therapies, such as radiation, might improve outcomes in oligometastasis. However, current definitions of oligometastasis are solely numerical.ObjectiveTo characterize the somatic mutational landscape across the disease spectrum of metastatic castration-sensitive prostate cancer (mCSPC) to elucidate a biological definition of oligometastatic CSPC.Design, setting, and participantsThis was a retrospective study of men with mCSPC who underwent clinical-grade sequencing of their tumors (269 primary tumor, 25 metastatic sites). Patients were classified as having biochemically recurrent (ie, micrometastatic), metachronous oligometastatic (≤5 lesions), metachronous polymetastatic (>5 lesions), or de novo metastatic (metastasis at diagnosis) disease.Outcome measurements and statistical analysisWe measured the frequency of driver mutations across metastatic classifications and the genomic associations with radiographic progression-free survival (rPFS) and time to castrate-resistant prostate cancer (CRPC).Results and limitationsThe frequency of driver mutations in TP53 (p = 0.01), WNT (p = 0.08), and cell cycle (p = 0.04) genes increased across the mCSPC spectrum. TP53 mutation was associated with shorter rPFS (26.7 vs 48.6 mo; p = 0.002), and time to CRPC (95.6 vs 155.8 mo; p = 0.02) in men with oligometastasis, and identified men with polymetastasis with better rPFS (TP53 wild-type, 42.7 mo; TP53 mutated, 18.5 mo; p = 0.01). Mutations in TP53 (incidence rate ratio [IRR] 1.45; p = 0.004) and DNA double-strand break repair (IRR 1.61; p
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- 2021
34. Heterogeneity in NECTIN4 Expression Across Molecular Subtypes of Urothelial Cancer Mediates Sensitivity to Enfortumab Vedotin
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Chu, Carissa E, Sjöström, Martin, Egusa, Emily A, Gibb, Ewan A, Badura, Michelle L, Zhu, Jun, Koshkin, Vadim S, Stohr, Bradley A, Meng, Maxwell V, Pruthi, Raj S, Friedlander, Terence W, Lotan, Yair, Black, Peter C, Porten, Sima P, Feng, Felix Y, and Chou, Jonathan
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Biomedical and Clinical Sciences ,Oncology and Carcinogenesis ,Clinical Research ,Cancer ,Biotechnology ,Urologic Diseases ,Development of treatments and therapeutic interventions ,5.1 Pharmaceuticals ,Good Health and Well Being ,Antibodies ,Monoclonal ,Carcinoma ,Transitional Cell ,Cell Adhesion Molecules ,Female ,Gene Expression Regulation ,Neoplastic ,Humans ,Immunoconjugates ,Tumor Cells ,Cultured ,Urinary Bladder Neoplasms ,Oncology & Carcinogenesis ,Clinical sciences ,Oncology and carcinogenesis - Abstract
PurposeEnfortumab vedotin (EV) is an antibody-drug conjugate (ADC) targeting NECTIN4 (encoded by the PVRL4/NECTIN4 gene) approved for treatment-refractory metastatic urothelial cancer. Factors that mediate sensitivity or resistance to EV are unknown. In this study, we sought to (i) examine heterogeneity of NECTIN4 gene expression across molecular subtypes of bladder cancer and (ii) determine whether NECTIN4 expression mediates EV sensitivity or resistance.Experimental designMolecular subtyping and NECTIN4 expression data from seven muscle-invasive bladder cancer clinical cohorts (n = 1,915 total specimens) were used to assess NECTIN4 expression across molecular subtypes. The outcome of the transcriptomic analysis was relative NECTIN4 expression in the consensus molecular subtypes of bladder cancer. Expression of NECTIN4 was validated in bladder cancer cell lines. NECTIN4 was stably overexpressed or knocked down in basal and luminal bladder cancer cell lines and EV drug sensitivity assays were performed, as measured by cell proliferation and clonogenic assays.ResultsNECTIN4 expression is heterogenous across molecular subtypes of bladder cancer and significantly enriched in luminal subtypes. NECTIN4 expression is positively correlated with luminal markers GATA3, FOXA1, and PPARG across all cohorts. NECTIN4 expression is both necessary and sufficient for EV sensitivity in luminal and basal subtypes of urothelial bladder cancer cells. Downregulation of NECTIN4 leads to EV resistance.ConclusionsSensitivity to EV is mediated by expression of NECTIN4, which is enriched in luminal subtypes of bladder cancer. These findings may have implications for biomarker development, patient selection, and the inclusion of molecular subtyping in ongoing and future EV clinical trials.See related commentary by Teo and Rosenberg, p. 4950.
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- 2021
35. An androgen receptor switch underlies lineage infidelity in treatment-resistant prostate cancer
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Davies, Alastair, Nouruzi, Shaghayegh, Ganguli, Dwaipayan, Namekawa, Takeshi, Thaper, Daksh, Linder, Simon, Karaoğlanoğlu, Fatih, Omur, Meltem E, Kim, Soojin, Kobelev, Maxim, Kumar, Sahil, Sivak, Olena, Bostock, Chiara, Bishop, Jennifer, Hoogstraat, Marlous, Talal, Amina, Stelloo, Suzan, van der Poel, Henk, Bergman, Andries M, Ahmed, Musaddeque, Fazli, Ladan, Huang, Haojie, Tilley, Wayne, Goodrich, David, Feng, Felix Y, Gleave, Martin, He, Housheng Hansen, Hach, Faraz, Zwart, Wilbert, Beltran, Himisha, Selth, Luke, and Zoubeidi, Amina
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Prostate Cancer ,Genetics ,Cancer ,Stem Cell Research ,Urologic Diseases ,Aetiology ,1.1 Normal biological development and functioning ,Underpinning research ,2.1 Biological and endogenous factors ,Cell Line ,Tumor ,Enhancer of Zeste Homolog 2 Protein ,Gene Expression Regulation ,Neoplastic ,Gene Regulatory Networks ,Humans ,Male ,Prostatic Neoplasms ,Receptors ,Androgen ,Signal Transduction ,Biological Sciences ,Medical and Health Sciences ,Developmental Biology - Abstract
Cancers adapt to increasingly potent targeted therapies by reprogramming their phenotype. Here we investigated such a phenomenon in prostate cancer, in which tumours can escape epithelial lineage confinement and transition to a high-plasticity state as an adaptive response to potent androgen receptor (AR) antagonism. We found that AR activity can be maintained as tumours adopt alternative lineage identities, with changes in chromatin architecture guiding AR transcriptional rerouting. The epigenetic regulator enhancer of zeste homologue 2 (EZH2) co-occupies the reprogrammed AR cistrome to transcriptionally modulate stem cell and neuronal gene networks-granting privileges associated with both fates. This function of EZH2 was associated with T350 phosphorylation and establishment of a non-canonical polycomb subcomplex. Our study provides mechanistic insights into the plasticity of the lineage-infidelity state governed by AR reprogramming that enabled us to redirect cell fate by modulating EZH2 and AR, highlighting the clinical potential of reversing resistance phenotypes.
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- 2021
36. Predicting cancer drug TARGETS - TreAtment Response Generalized Elastic-neT Signatures
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Rydzewski, Nicholas R, Peterson, Erik, Lang, Joshua M, Yu, Menggang, Laura Chang, S, Sjöström, Martin, Bakhtiar, Hamza, Song, Gefei, Helzer, Kyle T, Bootsma, Matthew L, Chen, William S, Shrestha, Raunak M, Zhang, Meng, Quigley, David A, Aggarwal, Rahul, Small, Eric J, Wahl, Daniel R, Feng, Felix Y, and Zhao, Shuang G
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Biotechnology ,Genetic Testing ,Genetics ,Human Genome ,Prostate Cancer ,Urologic Diseases ,Cancer ,5.1 Pharmaceuticals ,Development of treatments and therapeutic interventions ,4.1 Discovery and preclinical testing of markers and technologies ,Detection ,screening and diagnosis ,Good Health and Well Being - Abstract
We are now in an era of molecular medicine, where specific DNA alterations can be used to identify patients who will respond to specific drugs. However, there are only a handful of clinically used predictive biomarkers in oncology. Herein, we describe an approach utilizing in vitro DNA and RNA sequencing and drug response data to create TreAtment Response Generalized Elastic-neT Signatures (TARGETS). We trained TARGETS drug response models using Elastic-Net regression in the publicly available Genomics of Drug Sensitivity in Cancer (GDSC) database. Models were then validated on additional in-vitro data from the Cancer Cell Line Encyclopedia (CCLE), and on clinical samples from The Cancer Genome Atlas (TCGA) and Stand Up to Cancer/Prostate Cancer Foundation West Coast Prostate Cancer Dream Team (WCDT). First, we demonstrated that all TARGETS models successfully predicted treatment response in the separate in-vitro CCLE treatment response dataset. Next, we evaluated all FDA-approved biomarker-based cancer drug indications in TCGA and demonstrated that TARGETS predictions were concordant with established clinical indications. Finally, we performed independent clinical validation in the WCDT and found that the TARGETS AR signaling inhibitors (ARSI) signature successfully predicted clinical treatment response in metastatic castration-resistant prostate cancer with a statistically significant interaction between the TARGETS score and PSA response (p = 0.0252). TARGETS represents a pan-cancer, platform-independent approach to predict response to oncologic therapies and could be used as a tool to better select patients for existing therapies as well as identify new indications for testing in prospective clinical trials.
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- 2021
37. Development and External Validation of a Machine Learning Model for Prediction of Lymph Node Metastasis in Patients with Prostate Cancer
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Sabbagh, Ali, Washington, Samuel L., 3rd, Tilki, Derya, Hong, Julian C., Feng, Jean, Valdes, Gilmer, Chen, Ming-Hui, Wu, Jing, Huland, Hartwig, Graefen, Markus, Wiegel, Thomas, Böhmer, Dirk, Cowan, Janet E., Cooperberg, Matthew, Feng, Felix Y., Roach, Mack, 3rd, Trock, Bruce J., Partin, Alan W., D'Amico, Anthony V., Carroll, Peter R., and Mohamad, Osama
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- 2023
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38. Genomic Classifier Performance in Intermediate-Risk Prostate Cancer: Results From NRG Oncology/RTOG 0126 Randomized Phase 3 Trial
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Spratt, Daniel E., Liu, Vinnie Y.T., Michalski, Jeff, Davicioni, Elai, Berlin, Alejandro, Simko, Jeffry P., Efstathiou, Jason A., Tran, Phuoc T., Sandler, Howard M., Hall, William A., Thompson, Darby J.S., Parliament, Matthew B., Dayes, Ian S., Correa, Rohann Jonathan Mark, Robertson, John M., Gore, Elizabeth M., Doncals, Desiree E., Vigneault, Eric, Souhami, Luis, Karrison, Theodore G., and Feng, Felix Y.
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- 2023
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39. CRISPRi screens reveal a DNA methylation-mediated 3D genome dependent causal mechanism in prostate cancer.
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Ahmed, Musaddeque, Soares, Fraser, Xia, Ji-Han, Yang, Yue, Li, Jing, Guo, Haiyang, Su, Peiran, Tian, Yijun, Lee, Hyung Joo, Wang, Miranda, Akhtar, Nayeema, Houlahan, Kathleen E, Bosch, Almudena, Zhou, Stanley, Mazrooei, Parisa, Hua, Junjie T, Chen, Sujun, Petricca, Jessica, Zeng, Yong, Davies, Alastair, Fraser, Michael, Quigley, David A, Feng, Felix Y, Boutros, Paul C, Lupien, Mathieu, Zoubeidi, Amina, Wang, Liang, Walsh, Martin J, Wang, Ting, Ren, Shancheng, Wei, Gong-Hong, and He, Housheng Hansen
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Cell Line ,Tumor ,Animals ,Mice ,Inbred NOD ,Humans ,Mice ,SCID ,Prostatic Neoplasms ,Genetic Predisposition to Disease ,Proto-Oncogene Proteins c-myc ,Risk Factors ,DNA Methylation ,Polymorphism ,Single Nucleotide ,Quantitative Trait Loci ,Male ,Regulatory Elements ,Transcriptional ,Promoter Regions ,Genetic ,Genome-Wide Association Study ,Carcinogenesis ,CRISPR-Cas Systems ,Gene Editing ,CCCTC-Binding Factor ,Human Genome ,Aging ,Prostate Cancer ,Urologic Diseases ,Cancer ,Genetics ,2.1 Biological and endogenous factors - Abstract
Prostate cancer (PCa) risk-associated SNPs are enriched in noncoding cis-regulatory elements (rCREs), yet their modi operandi and clinical impact remain elusive. Here, we perform CRISPRi screens of 260 rCREs in PCa cell lines. We find that rCREs harboring high risk SNPs are more essential for cell proliferation and H3K27ac occupancy is a strong indicator of essentiality. We also show that cell-line-specific essential rCREs are enriched in the 8q24.21 region, with the rs11986220-containing rCRE regulating MYC and PVT1 expression, cell proliferation and tumorigenesis in a cell-line-specific manner, depending on DNA methylation-orchestrated occupancy of a CTCF binding site in between this rCRE and the MYC promoter. We demonstrate that CTCF deposition at this site as measured by DNA methylation level is highly variable in prostate specimens, and observe the MYC eQTL in the 8q24.21 locus in individuals with low CTCF binding. Together our findings highlight a causal mechanism synergistically driven by a risk SNP and DNA methylation-mediated 3D genome architecture, advocating for the integration of genetics and epigenetics in assessing risks conferred by genetic predispositions.
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- 2021
40. Molecular Imaging of Prostate Cancer Targeting CD46 Using ImmunoPET
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Wang, Sinan, Li, Jun, Hua, Jun, Su, Yang, Beckford-Vera, Denis R, Zhao, Walter, Jayaraman, Mayuri, Huynh, Tony L, Zhao, Ning, Wang, Yung-hua, Huang, Yangjie, Qin, Fujun, Shen, Sui, Gioeli, Daniel, Dreicer, Robert, Sriram, Renuka, Egusa, Emily A, Chou, Jonathan, Feng, Felix Y, Aggarwal, Rahul, Evans, Michael J, Seo, Youngho, Liu, Bin, Flavell, Robert R, and He, Jiang
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Biomedical and Clinical Sciences ,Clinical Sciences ,Oncology and Carcinogenesis ,Prostate Cancer ,Biotechnology ,Urologic Diseases ,Biomedical Imaging ,Cancer ,Adenocarcinoma ,Animals ,Apoptosis ,Cell Proliferation ,Humans ,Immunoconjugates ,Male ,Membrane Cofactor Protein ,Mice ,Mice ,Inbred NOD ,Mice ,Nude ,Mice ,SCID ,Molecular Imaging ,Neuroendocrine Tumors ,Positron-Emission Tomography ,Prostatic Neoplasms ,Radiopharmaceuticals ,Tissue Distribution ,Tumor Cells ,Cultured ,Xenograft Model Antitumor Assays ,Zirconium ,Oncology & Carcinogenesis ,Clinical sciences ,Oncology and carcinogenesis - Abstract
PurposeWe recently identified CD46 as a novel therapeutic target in prostate cancer. In this study, we developed a CD46-targeted PET radiopharmaceutical, [89Zr]DFO-YS5, and evaluated its performance for immunoPET imaging in murine prostate cancer models.Experimental design[89Zr]DFO-YS5 was prepared and its in vitro binding affinity for CD46 was measured. ImmunoPET imaging was conducted in male athymic nu/nu mice bearing DU145 [AR-, CD46+, prostate-specific membrane antigen-negative (PSMA-)] or 22Rv1 (AR+, CD46+, PSMA+) tumors, and in NOD/SCID gamma mice bearing patient-derived adenocarcinoma xenograft, LTL-331, and neuroendocrine prostate cancers, LTL-331R and LTL-545.Results[89Zr]DFO-YS5 binds specifically to the CD46-positive human prostate cancer DU145 and 22Rv1 xenografts. In biodistribution studies, the tumor uptake of [89Zr]DFO-YS5 was 13.3 ± 3.9 and 11.2 ± 2.5 %ID/g, respectively, in DU145 and 22Rv1 xenografts, 4 days postinjection. Notably, [89Zr]DFO-YS5 demonstrated specific uptake in the PSMA- and AR-negative DU145 model. [89Zr]DFO-YS5 also showed uptake in the patient-derived LTL-331 and -331R models, with particularly high uptake in the LTL-545 neuroendocrine prostate cancer tumors (18.8 ± 5.3, 12.5 ± 1.8, and 32 ± 5.3 %ID/g in LTL-331, LTL-331R, and LTL-545, respectively, at 4 days postinjection).Conclusions[89Zr]DFO-YS5 is an excellent PET imaging agent across a panel of prostate cancer models, including in both adenocarcinoma and neuroendocrine prostate cancer, both cell line- and patient-derived xenografts, and both PSMA-positive and -negative tumors. It demonstrates potential for clinical translation as an imaging agent, theranostic platform, and companion biomarker in prostate cancer.
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- 2021
41. Effect of microdistribution of alpha and beta-emitters in targeted radionuclide therapies on delivered absorbed dose in a GATE model of bone marrow
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Tranel, Jonathan, Feng, Felix Y, St James, Sara, and Hope, Thomas A
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Rare Diseases ,Alpha Particles ,Beta Particles ,Bone Marrow ,Bone Marrow Neoplasms ,Cancellous Bone ,Half-Life ,Humans ,Monte Carlo Method ,Phantoms ,Imaging ,Radiotherapy Dosage ,cell-scale dosimetry ,alpha emitters ,bone marrow toxicities ,targeted radionuclide therapy ,Monte Carlo simulation ,Other Physical Sciences ,Biomedical Engineering ,Clinical Sciences ,Nuclear Medicine & Medical Imaging - Abstract
Acute hematologic toxicity is a frequent adverse effect of beta-emitter targeted radionuclide therapies (TRTs). Alpha emitters have the potential of delivering high linear energy transfer (LET) radiation to the tumor attributed to its shorter range. Antibody-based TRTs have increased blood-pool half-lives, and therefore increased marrow toxicity, which is a particular concern with alpha emitters. Accurate 3D absorbed dose calculations focusing on the interface region of blood vessels and bone can elucidate energy deposition patterns. Firstly, a cylindrical geometry model with a central blood vessel embedded in the trabecular tissue was modeled. Monte Carlo simulations in GATE were performed considering beta (177Lu, 90Y) and alpha emitters (211At, 225Ac) as sources restricted to the blood pool. Subsequently, the radioactive sources were added in the trabecular bone compartment in order to model bone marrow metastases infiltration (BMMI). Radial profiles, dose-volume histograms and voxel relative differences were used to evaluate the absorbed dose results. We demonstrated that alpha emitters have a higher localized energy deposition compared to beta emitters. In the cylindrical geometry model, when the sources are confined to the blood pool, the dose to the trabecular bone is greater for beta emitting radionuclides, as alpha emitters deposit the majority of their energy within 70 μm of the vessel wall. In the BMMI model, alpha emitters have a lower dose to untargeted trabecular bone. Our results suggest that when alpha emitters are restricted to the blood pool, as when labeled to antibodies, hematologic toxicities may be lower than expected due to differences in the microdistribution of delivered absorbed dose.
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- 2021
42. False positive PSMA PET for tumor remnants in the irradiated prostate and other interpretation pitfalls in a prospective multi-center trial
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Fendler, Wolfgang P, Calais, Jeremie, Eiber, Matthias, Simko, Jeffrey P, Kurhanewicz, John, Santos, Romelyn Delos, Feng, Felix Y, Reiter, Robert E, Rettig, Matthew B, Nickols, Nicholas G, Kishan, Amar U, Slavik, Roger, Carroll, Peter R, Lawhn-Heath, Courtney, Herrmann, Ken, Czernin, Johannes, and Hope, Thomas A
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Biomedical and Clinical Sciences ,Clinical Sciences ,Oncology and Carcinogenesis ,Radiation Oncology ,Clinical Research ,Clinical Trials and Supportive Activities ,Cancer ,Prostate Cancer ,Biomedical Imaging ,Urologic Diseases ,Edetic Acid ,Humans ,Male ,Neoplasm Recurrence ,Local ,Positron Emission Tomography Computed Tomography ,Prospective Studies ,Prostate ,Prostatectomy ,Prostatic Neoplasms ,PSMA ,PET ,Pitfall ,Recurrence ,Interpretation ,Radiotherapy ,PSMA PET Reader Group ,Other Physical Sciences ,Nuclear Medicine & Medical Imaging ,Clinical sciences - Abstract
PurposeReaders need to be informed about potential pitfalls of [68Ga]Ga-PSMA-11 PET interpretation.MethodsHere we report [68Ga]Ga-PSMA-11 PET findings discordant with the histopathology/composite reference standard in a recently published prospective trial on 635 patients with biochemically recurrent prostate cancer.ResultsConsensus reads were false positive in 20 regions of 17/217 (8%) patients with lesion validation. Majority of the false positive interpretations (13 of 20, 65%) occurred in the context of suspected prostate (bed) relapse (T) after radiotherapy (n = 11); other false positive findings were noted for prostate bed post prostatectomy (T, n = 2), pelvic nodes (N, n = 2), or extra pelvic lesions (M, n = 5). Major sources of false positive findings were PSMA-expressing residual adenocarcinoma with marked post-radiotherapy treatment effect. False negative interpretation occurred in 8 regions of 6/79 (8%) patients with histopathology validation, including prostate (bed) (n = 5), pelvic nodes (n = 1), and extra pelvic lesions (n = 2). Lesions were missed mostly due to small metastases or adjacent bladder/urine uptake.Conclusion[68Ga]Ga-PSMA-11 PET at biochemical recurrence resulted in less than 10% false positive interpretations. Post-radiotherapy prostate uptake was a major source of [68Ga]Ga-PSMA-11 PET false positivity. In few cases, PET correctly detects residual PSMA expression post-radiotherapy, originating however from treated, benign tissue or potentially indolent tumor remnants.Trial registration numberClinicalTrials.gov Identifiers: NCT02940262 and NCT03353740.
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- 2021
43. Prostate Radiotherapy With Adjuvant Androgen Deprivation Therapy (ADT) Improves Metastasis-Free Survival Compared to Neoadjuvant ADT: An Individual Patient Meta-Analysis.
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Spratt, Daniel E, Malone, Shawn, Roy, Soumyajit, Grimes, Scott, Eapen, Libni, Morgan, Scott C, Malone, Julia, Craig, Julia, Dess, Robert T, Jackson, William C, Hartman, Holly E, Kishan, Amar U, Mehra, Rohit, Kaffenberger, Samuel, Morgan, Todd M, Reichert, Zachery R, Alumkal, Joshi J, Michalski, Jeff, Lee, W Robert, Pisansky, Thomas M, Feng, Felix Y, Shipley, William, Sandler, Howard M, Schipper, Mathew J, Roach, Mack, Sun, Yilun, and Lawton, Colleen AF
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Clinical Research ,Aging ,Urologic Diseases ,Prostate Cancer ,Cancer ,Clinical Trials and Supportive Activities ,Good Health and Well Being ,Androgen Antagonists ,Clinical Trials ,Phase III as Topic ,Humans ,Male ,Neoadjuvant Therapy ,Neoplasm Metastasis ,Prostatic Neoplasms ,Randomized Controlled Trials as Topic ,Clinical Sciences ,Oncology and Carcinogenesis ,Oncology & Carcinogenesis - Abstract
PurposeThere remains a lack of clarity regarding the influence of sequencing of androgen deprivation therapy (ADT) and radiotherapy (RT) on outcomes in prostate cancer (PCa). Herein, we evaluate the optimal sequencing of ADT with prostate-directed RT in localized PCa.MethodsMEDLINE (1966-2018), Embase (1982-2018), ClinicalTrials.gov, and conference proceedings (1990-2018) were searched to identify randomized trials evaluating the sequencing, but not duration, of ADT with RT. Two randomized phase III trials were identified, and individual patient data were obtained: Ottawa 0101 and NRG Oncology's Radiation Therapy Oncology Group 9413. Ottawa 0101 randomly assigned patients to neoadjuvant or concurrent versus concurrent or adjuvant short-term ADT. Radiation Therapy Oncology Group 9413, a 2 × 2 factorial trial, included a random assignment of neoadjuvant or concurrent versus adjuvant short-term ADT. The neoadjuvant or concurrent ADT arms of both trials were combined into the neoadjuvant group, and the arms receiving adjuvant ADT were combined into the adjuvant group. The primary end point of this meta-analysis was progression-free survival (PFS).ResultsThe median follow-up was 14.9 years. Overall, 1,065 patients were included (531 neoadjuvant and 534 adjuvant). PFS was significantly improved in the adjuvant group (15-year PFS, 29% v 36%, hazard ratio [HR], 1.25 [95% CI, 1.07 to 1.47], P = .01). Biochemical failure (subdistribution HR [sHR], 1.37 [95% CI, 1.12 to 1.68], P = .002), distant metastasis (sHR, 1.40 [95% CI, 1.00 to 1.95], P = .04), and metastasis-free survival (HR, 1.17 [95% CI, 1.00 to 1.37], P = .050) were all significantly improved in the adjuvant group. There were no differences in late grade ≥ 3 gastrointestinal (2% v 3%, P = .33) or genitourinary toxicity (5% v 5%, P = .76) between groups.ConclusionThe sequencing of ADT with prostate-directed RT has significant association with long-term PFS and MFS in localized PCa. Our findings favor use of an adjuvant over a neoadjuvant approach, without any increase in long-term toxicity.
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- 2021
44. An integrated functional and clinical genomics approach reveals genes driving aggressive metastatic prostate cancer
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Das, Rajdeep, Sjöström, Martin, Shrestha, Raunak, Yogodzinski, Christopher, Egusa, Emily A, Chesner, Lisa N, Chen, William S, Chou, Jonathan, Dang, Donna K, Swinderman, Jason T, Ge, Alex, Hua, Junjie T, Kabir, Shaheen, Quigley, David A, Small, Eric J, Ashworth, Alan, Feng, Felix Y, and Gilbert, Luke A
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Genetics ,Biotechnology ,Prostate Cancer ,Pediatric Research Initiative ,Cancer ,Human Genome ,Urologic Diseases ,Aging ,2.1 Biological and endogenous factors ,Aetiology ,Good Health and Well Being ,Animals ,CRISPR-Cas Systems ,Cell Cycle ,Cell Cycle Proteins ,Cell Movement ,Cells ,Cultured ,Databases ,Genetic ,Gene Expression Regulation ,Neoplastic ,Heterografts ,Humans ,Kinesins ,Male ,Mice ,Inbred NOD ,Mice ,SCID ,Neoplasm Metastasis ,Neoplasm Staging ,Nerve Tissue Proteins ,Prostatic Neoplasms ,Survival Rate - Abstract
Genomic sequencing of thousands of tumors has revealed many genes associated with specific types of cancer. Similarly, large scale CRISPR functional genomics efforts have mapped genes required for cancer cell proliferation or survival in hundreds of cell lines. Despite this, for specific disease subtypes, such as metastatic prostate cancer, there are likely a number of undiscovered tumor specific driver genes that may represent potential drug targets. To identify such genetic dependencies, we performed genome-scale CRISPRi screens in metastatic prostate cancer models. We then created a pipeline in which we integrated pan-cancer functional genomics data with our metastatic prostate cancer functional and clinical genomics data to identify genes that can drive aggressive prostate cancer phenotypes. Our integrative analysis of these data reveals known prostate cancer specific driver genes, such as AR and HOXB13, as well as a number of top hits that are poorly characterized. In this study we highlight the strength of an integrated clinical and functional genomics pipeline and focus on two top hit genes, KIF4A and WDR62. We demonstrate that both KIF4A and WDR62 drive aggressive prostate cancer phenotypes in vitro and in vivo in multiple models, irrespective of AR-status, and are also associated with poor patient outcome.
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- 2021
45. Dose–response with stereotactic body radiotherapy for prostate cancer: A multi-institutional analysis of prostate-specific antigen kinetics and biochemical control
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Levin-Epstein, Rebecca G, Jiang, Naomi Y, Wang, Xiaoyan, Upadhyaya, Shrinivasa K, Collins, Sean P, Suy, Simeng, Aghdam, Nima, Mantz, Constantine, Katz, Alan J, Miszczyk, Leszek, Napieralska, Aleksandra, Namysl-Kaletka, Agnieszka, Prionas, Nicholas, Bagshaw, Hilary, Buyyounouski, Mark K, Cao, Minsong, Agazaryan, Nzhde, Dang, Audrey, Yuan, Ye, Kupelian, Patrick A, Zaorsky, Nicholas G, Spratt, Daniel E, Mohamad, Osama, Feng, Felix Y, Mahal, Brandon A, Boutros, Paul C, Kishan, Arun U, Juarez, Jesus, Shabsovich, David, Jiang, Tommy, Kahlon, Sartajdeep, Patel, Ankur, Patel, Jay, Nickols, Nicholas G, Steinberg, Michael L, Fuller, Donald B, and Kishan, Amar U
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Biomedical and Clinical Sciences ,Clinical Sciences ,Oncology and Carcinogenesis ,Clinical Trials and Supportive Activities ,Clinical Research ,Cancer ,Radiation Oncology ,Aging ,Urologic Diseases ,Prostate Cancer ,6.5 Radiotherapy and other non-invasive therapies ,Humans ,Kinetics ,Male ,Prospective Studies ,Prostate-Specific Antigen ,Prostatic Neoplasms ,Radiosurgery ,Prostate cancer ,Stereotactic body radiation therapy ,SBRT ,Dose-escalation ,Dose-response ,Biochemical control ,Dose–response ,Other Physical Sciences ,Oncology & Carcinogenesis ,Clinical sciences ,Oncology and carcinogenesis ,Medical and biological physics - Abstract
Background and purposeThe optimal dose for prostate stereotactic body radiotherapy (SBRT) is still unknown. This study evaluated the dose-response relationships for prostate-specific antigen (PSA) decay and biochemical recurrence (BCR) among 4 SBRT dose regimens.Materials and methodsIn 1908 men with low-risk (50.0%), favorable intermediate-risk (30.9%), and unfavorable intermediate-risk (19.1%) prostate cancer treated with prostate SBRT across 8 institutions from 2003 to 2018, we examined 4 regimens (35 Gy/5 fractions [35/5, n = 265, 13.4%], 36.25 Gy/5 fractions [36.25/5, n = 711, 37.3%], 40 Gy/5 fractions [40/5, n = 684, 35.8%], and 38 Gy/4 fractions [38/4, n = 257, 13.5%]). Between dose groups, we compared PSA decay slope, nadir PSA (nPSA), achievement of nPSA ≤0.2 and ≤0.5 ng/mL, and BCR-free survival (BCRFS).ResultsMedian follow-up was 72.3 months. Median nPSA was 0.01 ng/mL for 38/4, and 0.17-0.20 ng/mL for 5-fraction regimens (p
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- 2021
46. Androgen Deprivation and Radiotherapy with or Without Docetaxel for Localized High-risk Prostate Cancer: Long-term Follow-up from the Randomized NRG Oncology RTOG 0521 Trial
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Sartor, Oliver, Karrison, Theodore G., Sandler, Howard M., Gomella, Leonard G., Amin, Mahul B., Purdy, James, Michalski, Jeff M., Garzotto, Mark G., Pervez, Nadeem, Balogh, Alexander G., Rodrigues, George B., Souhami, Luis, Reaume, M. Neil, Williams, Scott G., Hannan, Raquibul, Jones, Christopher U., Horwitz, Eric M., Rodgers, Joseph P., Feng, Felix Y., and Rosenthal, Seth A.
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- 2023
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47. Five-Year Patient-Reported Outcomes in NRG Oncology RTOG 0938, Evaluating Two Ultrahypofractionated Regimens for Prostate Cancer
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Lukka, Himanshu R., Deshmukh, Snehal, Bruner, Deborah W., Bahary, Jean-Paul, Lawton, Colleen A.F., Efstathiou, Jason A., Kudchadker, Rajat J., Ponsky, Lee E., Seaward, Samantha A., Dayes, Ian S., Gopaul, Darindra D., Michalski, Jeff M., Delouya, Guila, Kaplan, Irving D., Horwitz, Eric M., Roach, Mack, III, Feng, Felix Y., Pugh, Stephanie L., Sandler, Howard M., and Kachnic, Lisa A.
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- 2023
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48. Analysis of a Biopsy-Based Genomic Classifier in High-Risk Prostate Cancer: Meta-Analysis of the NRG Oncology/Radiation Therapy Oncology Group 9202, 9413, and 9902 Phase 3 Randomized Trials
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Nguyen, Paul L., Huang, Huei-Chung (Rebecca), Spratt, Daniel E., Davicioni, Elai, Sandler, Howard M., Shipley, William U., Efstathiou, Jason A., Simko, Jeffry P., Pollack, Alan, Dicker, Adam P., Roach, Mack, Rosenthal, Seth A., Zeitzer, Kenneth L., Mendez, Lucas C., Hartford, Alan C., Hall, William A., Desai, Anand B., Rabinovitch, Rachel A., Peters, Christopher A., Rodgers, Joseph P., Tran, Phuoc, and Feng, Felix Y.
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- 2023
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49. Performance of clinicopathologic models in men with high risk localized prostate cancer: impact of a 22-gene genomic classifier
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Tosoian, Jeffrey J, Birer, Samuel R, Jeffrey Karnes, R, Zhang, Jingbin, Davicioni, Elai, Klein, Eric E, Freedland, Stephen J, Weinmann, Sheila, Trock, Bruce J, Dess, Robert T, Zhao, Shuang G, Jackson, William C, Yamoah, Kosj, Dal Pra, Alan, Mahal, Brandon A, Morgan, Todd M, Mehra, Rohit, Kaffenberger, Samuel, Salami, Simpa S, Kane, Christopher, Pollack, Alan, Den, Robert B, Berlin, Alejandro, Schaeffer, Edward M, Nguyen, Paul L, Feng, Felix Y, and Spratt, Daniel E
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Biomedical and Clinical Sciences ,Clinical Sciences ,Oncology and Carcinogenesis ,Prostate Cancer ,Prevention ,Patient Safety ,Cancer ,Aging ,Urologic Diseases ,Biotechnology ,Aged ,Biomarkers ,Tumor ,Cohort Studies ,Disease Progression ,Humans ,Kallikreins ,Male ,Middle Aged ,Models ,Statistical ,Neoplasm Metastasis ,Nomograms ,Prognosis ,Prostate-Specific Antigen ,Prostatectomy ,Prostatic Neoplasms ,ROC Curve ,Retrospective Studies ,Risk Factors ,Transcriptome ,Urology & Nephrology ,Clinical sciences ,Oncology and carcinogenesis - Abstract
BackgroundProstate cancer exhibits biological and clinical heterogeneity even within established clinico-pathologic risk groups. The Decipher genomic classifier (GC) is a validated method to further risk-stratify disease in patients with prostate cancer, but its performance solely within National Comprehensive Cancer Network (NCCN) high-risk disease has not been undertaken to date.MethodsA multi-institutional retrospective study of 405 men with high-risk prostate cancer who underwent primary treatment with radical prostatectomy (RP) or radiation therapy (RT) with androgen-deprivation therapy (ADT) at 11 centers from 1995 to 2005 was performed. Cox proportional hazards models were used to determine the hazard ratios (HR) for the development of metastatic disease based on clinico-pathologic variables, risk groups, and GC score. The area under the receiver operating characteristic curve (AUC) was determined for regression models without and with the GC score.ResultsOver a median follow-up of 82 months, 104 patients (26%) developed metastatic disease. On univariable analysis, increasing GC score was significantly associated with metastatic disease ([HR]: 1.34 per 0.1 unit increase, 95% confidence interval [CI]: 1.19-1.50, p 0.05). On multivariable analysis, GC score (HR: 1.33 per 0.1 unit increase, 95% CI: 1.19-1.48, p
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- 2020
50. Autoantibody Landscape in Patients with Advanced Prostate Cancer
- Author
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Chen, William S, Haynes, Winston A, Waitz, Rebecca, Kamath, Kathy, Vega-Crespo, Agustin, Shrestha, Raunak, Zhang, Minlu, Foye, Adam, Carretero, Ignacio Baselga, Garcilazo, Ivan Perez, Zhang, Meng, Zhao, Shuang G, Sjöström, Martin, Quigley, David A, Chou, Jonathan, Beer, Tomasz M, Rettig, Matthew, Gleave, Martin, Evans, Christopher P, Lara, Primo, N., Kim, Reiter, Robert E, Alumkal, Joshi J, Ashworth, Alan, Aggarwal, Rahul, Small, Eric J, Daugherty, Patrick S, Ribas, Antoni, Oh, David Y, Shon, John C, and Feng, Felix Y
- Subjects
Biomedical and Clinical Sciences ,Oncology and Carcinogenesis ,Immunology ,Cancer ,Human Genome ,Cancer Genomics ,Clinical Research ,Biotechnology ,Prostate Cancer ,Vaccine Related ,Immunization ,Urologic Diseases ,Genetics ,2.1 Biological and endogenous factors ,Aetiology ,Good Health and Well Being ,Aged ,Antigens ,Neoplasm ,Autoantibodies ,Biomarkers ,Tumor ,Case-Control Studies ,Epitopes ,Follow-Up Studies ,Humans ,Male ,Mutation ,Prognosis ,Prospective Studies ,Prostatic Neoplasms ,Oncology & Carcinogenesis ,Clinical sciences ,Oncology and carcinogenesis - Abstract
PurposeAutoantibody responses in cancer are of great interest, as they may be concordant with T-cell responses to cancer antigens or predictive of response to cancer immunotherapies. Thus, we sought to characterize the antibody landscape of metastatic castration-resistant prostate cancer (mCRPC).Experimental designSerum antibody epitope repertoire analysis (SERA) was performed on patient serum to identify tumor-specific neoepitopes. Somatic mutation-specific neoepitopes were investigated by associating serum epitope enrichment scores with whole-genome sequencing results from paired solid tumor metastasis biopsies and germline blood samples. A protein-based immunome-wide association study (PIWAS) was performed to identify significantly enriched epitopes, and candidate serum antibodies enriched in select patients were validated by ELISA profiling. A distinct cohort of patients with melanoma was evaluated to validate the top cancer-specific epitopes.ResultsSERA was performed on 1,229 serum samples obtained from 72 men with mCRPC and 1,157 healthy control patients. Twenty-nine of 6,636 somatic mutations (0.44%) were associated with an antibody response specific to the mutated peptide. PIWAS analyses identified motifs in 11 proteins, including NY-ESO-1 and HERVK-113, as immunogenic in mCRPC, and ELISA confirmed serum antibody enrichment in candidate patients. Confirmatory PIWAS, Identifying Motifs Using Next-generation sequencing Experiments (IMUNE), and ELISA analyses performed on serum samples from 106 patients with melanoma similarly revealed enriched cancer-specific antibody responses to NY-ESO-1.ConclusionsWe present the first large-scale profiling of autoantibodies in advanced prostate cancer, utilizing a new antibody profiling approach to reveal novel cancer-specific antigens and epitopes. Our study recovers antigens of known importance and identifies novel tumor-specific epitopes of translational interest.
- Published
- 2020
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