1,458 results on '"Aggarwal, Rahul"'
Search Results
52. Abstract 15421: Cardiovascular Health of Middle-Aged US Adults by Income Level, 1999 to March 2020
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Liu, Michael, Aggarwal, Rahul, Zheng, ZhaoNian, and Wadhera, Rishi K
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- 2023
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53. Abstract 13696: Sotagliflozin is Associated With Early Clinical Benefit for Heart Failure and Atherosclerotic Events
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Aggarwal, Rahul, Bhatt, Deepak, Szarek, Michael, Davies, Michael J, Banks, Phillip, Pitt, Bertram, and Steg, Philippe G
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- 2023
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54. Large remodeling of the Myc-induced cell surface proteome in B cells and prostate cells creates new opportunities for immunotherapy
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Chen, Wentao, Mou, Kurt Yun, Solomon, Paige, Aggarwal, Rahul, Leung, Kevin K, and Wells, James A
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Biotechnology ,Prostate Cancer ,Immunization ,Urologic Diseases ,Vaccine Related ,Cancer ,2.1 Biological and endogenous factors ,Aetiology ,1.1 Normal biological development and functioning ,Underpinning research ,Generic health relevance ,Antibodies ,Bispecific ,B-Lymphocytes ,B7 Antigens ,Cell Engineering ,Cell Line ,Tumor ,Cytarabine ,Epithelial Cells ,Gene Expression Regulation ,Neoplastic ,Humans ,Immunosuppressive Agents ,Immunotherapy ,Male ,Molecular Targeted Therapy ,Plasmids ,Prostate ,Protein Binding ,Proto-Oncogene Proteins c-myc ,Receptors ,TNF-Related Apoptosis-Inducing Ligand ,Signal Transduction ,TNF-Related Apoptosis-Inducing Ligand ,Transfection ,oncogenes ,glycoproteomics ,surfaceome ,MYC ,antibody - Abstract
MYC is a powerful transcription factor overexpressed in many human cancers including B cell and prostate cancers. Antibody therapeutics are exciting opportunities to attack cancers but require knowledge of surface proteins that change due to oncogene expression. To identify how MYC overexpression remodels the cell surface proteome in a cell autologous fashion and in different cell types, we investigated the impact of MYC overexpression on 800 surface proteins in three isogenic model cell lines either of B cell or prostate cell origin engineered to have high or low MYC levels. We found that MYC overexpression resulted in dramatic remodeling (both up- and down-regulation) of the cell surfaceome in a cell type-dependent fashion. We found systematic and large increases in distinct sets of >80 transporters including nucleoside transporters and nutrient transporters making cells more sensitive to toxic nucleoside analogs like cytarabine, commonly used for treating hematological cancers. Paradoxically, MYC overexpression also increased expression of surface proteins driving cell turnover such as TNFRSF10B, also known as death receptor 5, and immune cell attacking signals such as the natural killer cell activating ligand NCR3LG1, also known as B7-H6. We generated recombinant antibodies to these two targets and verified their up-regulation in MYC overexpression cell lines and showed they were sensitive to bispecific T cell engagers (BiTEs). Our studies demonstrate how MYC overexpression leads to dramatic bidirectional remodeling of the surfaceome in a cell type-dependent but functionally convergent fashion and identify surface targets or combinations thereof as possible candidates for cytotoxic metabolite or immunotherapy.
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- 2021
55. Autoantibody Landscape in Patients with Advanced Prostate Cancer
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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
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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.
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- 2020
56. Accelerating precision medicine in metastatic prostate cancer
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Mateo, Joaquin, McKay, Rana, Abida, Wassim, Aggarwal, Rahul, Alumkal, Joshi, Alva, Ajjai, Feng, Felix, Gao, Xin, Graff, Julie, Hussain, Maha, Karzai, Fatima, Montgomery, Bruce, Oh, William, Patel, Vaibhav, Rathkopf, Dana, Rettig, Matthew, Schultz, Nikolaus, Smith, Matthew, Solit, David, Sternberg, Cora, Van Allen, Eliezer, VanderWeele, David, Vinson, Jake, Soule, Howard R, Chinnaiyan, Arul, Small, Eric, Simons, Jonathan W, Dahut, William, Miyahira, Andrea K, and Beltran, Himisha
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Clinical Research ,Human Genome ,Genetics ,Cancer ,Biotechnology ,Urologic Diseases ,Aging ,Health Services ,Prostate Cancer ,Good Health and Well Being ,Early Detection of Cancer ,Humans ,Male ,Medical Oncology ,Precision Medicine ,Prostate-Specific Antigen ,Prostatic Neoplasms - Abstract
Despite advances in prostate cancer screening and treatment, available therapy options, particularly in later stages of the disease, remain limited and the treatment-resistant setting represents a serious unmet medical need. Moreover, disease heterogeneity and disparities in patient access to medical advances result in significant variability in outcomes across patients. Disease classification based on genomic sequencing is a promising approach to identify patients whose tumors exhibit actionable targets and make more informed treatment decisions. Here we discuss how we can accelerate precision oncology to inform broader genomically-driven clinical decisions for men with advanced prostate cancer, drug development and ultimately contribute to new treatment paradigms.
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- 2020
57. Phase 1 Study of Safety and Preliminary Clinical Activity of JNJ-63898081, a PSMA and CD3 Bispecific Antibody, for Metastatic Castration-Resistant Prostate Cancer
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Lim, Emerson A., Schweizer, Michael T., Chi, Kim N., Aggarwal, Rahul, Agarwal, Neeraj, Gulley, James, Attiyeh, Edward, Greger, James, Wu, Shujian, Jaiprasart, Pharavee, Loffredo, John, Bandyopadhyay, Nibedita, Xie, Hong, and Hansen, Aaron R.
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- 2023
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58. A Phase Ib/IIa Study of the Pan-BET Inhibitor ZEN-3694 in Combination with Enzalutamide in Patients with Metastatic Castration-resistant Prostate Cancer
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Aggarwal, Rahul R, Schweizer, Michael T, Nanus, David M, Pantuck, Allan J, Heath, Elisabeth I, Campeau, Eric, Attwell, Sarah, Norek, Karen, Snyder, Margo, Bauman, Lisa, Lakhotia, Sanjay, Feng, Felix Y, Small, Eric J, Abida, Wassim, and Alumkal, Joshi J
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Biomedical and Clinical Sciences ,Clinical Sciences ,Oncology and Carcinogenesis ,Urologic Diseases ,Cancer ,Clinical Research ,Prostate Cancer ,Evaluation of treatments and therapeutic interventions ,6.1 Pharmaceuticals ,Aged ,Aged ,80 and over ,Androstenes ,Antineoplastic Agents ,Antineoplastic Combined Chemotherapy Protocols ,Benzamides ,Disease-Free Survival ,Drug Resistance ,Neoplasm ,Humans ,Male ,Middle Aged ,Neoplasm Metastasis ,Nitriles ,Phenylthiohydantoin ,Progression-Free Survival ,Prostatic Neoplasms ,Castration-Resistant ,Receptors ,Androgen ,Treatment Outcome ,Oncology & Carcinogenesis ,Clinical sciences ,Oncology and carcinogenesis - Abstract
PurposeZEN-3694 is a bromodomain extraterminal inhibitor (BETi) with activity in androgen-signaling inhibitor (ASI)-resistant models. The safety and efficacy of ZEN-3694 plus enzalutamide was evaluated in a phase Ib/IIa study in metastatic castration-resistant prostate cancer (mCRPC).Patients and methodsPatients had progressive mCRPC with prior resistance to abiraterone and/or enzalutamide. 3+3 dose escalation was followed by dose expansion in parallel cohorts (ZEN-3694 at 48 and 96 mg orally once daily, respectively).ResultsSeventy-five patients were enrolled (N = 26 and 14 in dose expansion at low- and high-dose ZEN-3694, respectively). Thirty (40.0%) patients were resistant to abiraterone, 34 (45.3%) to enzalutamide, and 11 (14.7%) to both. ZEN-3694 dosing ranged from 36 to 144 mg daily without reaching an MTD. Fourteen patients (18.7%) experienced grade ≥3 toxicities, including three patients with grade 3 thrombocytopenia (4%). An exposure-dependent decrease in whole-blood RNA expression of BETi targets was observed (up to fourfold mean difference at 4 hours post-ZEN-3694 dose; P ≤ 0.0001). The median radiographic progression-free survival (rPFS) was 9.0 months [95% confidence interval (CI), 4.6-12.9] and composite median radiographic or clinical progression-free survival (PFS) was 5.5 months (95% CI, 4.0-7.8). Median duration of treatment was 3.5 months (range, 0-34.7+). Lower androgen receptor (AR) transcriptional activity in baseline tumor biopsies was associated with longer rPFS (median rPFS 10.4 vs. 4.3 months).ConclusionsZEN-3694 plus enzalutamide demonstrated acceptable tolerability and potential efficacy in patients with ASI-resistant mCRPC. Further prospective study is warranted including in mCRPC harboring low AR transcriptional activity.
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- 2020
59. Tipifarnib in recurrent, metastatic HRAS‐mutant salivary gland cancer
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Hanna, Glenn J, Guenette, Jeffrey P, Chau, Nicole G, Sayehli, Cyrus M, Wilhelm, Christian, Metcalf, Robert, Wong, Deborah J, Brose, Marcia, Razaq, Mohammad, Pérez‐Ruiz, Elisabeth, Cohen, Ezra EW, Aggarwal, Rahul, Scholz, Catherine, Gualberto, Antonio, and Ho, Alan L
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Biomedical and Clinical Sciences ,Clinical Sciences ,Oncology and Carcinogenesis ,Cancer ,Genetics ,Clinical Research ,Adult ,Aged ,Female ,Humans ,Male ,Middle Aged ,Neoplasm Metastasis ,Neoplasm Recurrence ,Local ,Progression-Free Survival ,Proto-Oncogene Proteins p21(ras) ,Quinolones ,Salivary Gland Neoplasms ,Treatment Outcome ,HRAS ,rare cancers ,salivary cancer ,targeted therapy ,tipifarnib ,HRAS ,Public Health and Health Services ,Oncology & Carcinogenesis ,Oncology and carcinogenesis ,Public health - Abstract
BackgroundTo the authors' knowledge, there are no approved therapies for recurrent, metastatic (R/M) salivary gland carcinoma (SGC), but molecularly targeted therapies warrant ongoing investigation. In the current study, the authors have reported on the efficacy of tipifarnib in patients with aggressive HRAS-mutant, R/M SGC.MethodsThe current prospective, nonrandomized, multicenter, international cohort study involved 8 centers and was conducted from May 2015 to June 2019. The median follow-up was 22 months (range, 6-55 months). Subjects with HRAS-mutant R/M SGC (any histology) and disease progression within the last 6 months were enrolled. Tipifarnib was dosed orally twice daily. The authors determined the objective response rate using Response Evaluation Criteria in Solid Tumors (version 1.1), duration of response, and molecular predictors of response.ResultsA total of 13 patients with R/M SGC were enrolled; all had received prior systemic therapy (1-3 regimens). One objective response was observed; an additional 7 of 12 evaluable patients (58%) had stable disease as their best response with a median duration of 9 months (range, 3-14 months). Five of 7 patients had >10% tumor regression and 6 of 7 had stable disease lasting >6 months. Q61R was the most frequent activating HRAS mutation noted (7 of 13 patients; 54%), but gene variant and allele frequency did not correlate with outcomes. The median progression-free survival was 7 months (95% confidence interval, 5.9-10.1 months), and the median overall survival was 18 months (95% confidence interval, 9.6-22.4 months) with approximately 58.6% of patients alive at 1 year. Survival was similar regardless of HRAS mutant variant or co-occurring PIK3CA alterations. No participant discontinued treatment because of toxicity.ConclusionsTipifarnib resulted in modest clinical activity with a promising disease control rate among patients with HRAS-mutant, R/M SGC who developed disease progression within the last 6 months.
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- 2020
60. Copy Number Loss of 17q22 Is Associated with Enzalutamide Resistance and Poor Prognosis in Metastatic Castration-Resistant Prostate Cancer
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Guan, Xiangnan, Sun, Duanchen, Lu, Eric, Urrutia, Joshua A, Reiter, Robert Evan, Rettig, Matthew, Evans, Christopher P, Lara, Primo, Gleave, Martin, Beer, Tomasz M, Thomas, George V, Huang, Jiaoti, Aggarwal, Rahul R, Quigley, David A, Foye, Adam, Chen, William S, Youngren, Jack, Weinstein, Alana S, Stuart, Joshua M, Feng, Felix Y, Small, Eric J, Xia, Zheng, and Alumkal, Joshi J
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Biomedical and Clinical Sciences ,Clinical Sciences ,Oncology and Carcinogenesis ,Human Genome ,Urologic Diseases ,Cancer ,Biotechnology ,Prostate Cancer ,Genetics ,Benzamides ,Biomarkers ,Tumor ,Biopsy ,Chromosomes ,Human ,Pair 17 ,DNA Copy Number Variations ,Disease-Free Survival ,Drug Resistance ,Neoplasm ,Humans ,Male ,Nitriles ,Phenylthiohydantoin ,Prostate ,Prostatic Neoplasms ,Castration-Resistant ,RNA-Seq ,Survival Analysis ,Oncology & Carcinogenesis ,Clinical sciences ,Oncology and carcinogenesis - Abstract
PurposeThe purpose of this study was to measure genomic changes that emerge with enzalutamide treatment using analyses of whole-genome sequencing and RNA sequencing.Experimental designOne hundred and one tumors from men with metastatic castration-resistant prostate cancer (mCRPC) who had not been treated with enzalutamide (n = 64) or who had enzalutamide-resistant mCRPC (n = 37) underwent whole genome sequencing. Ninety-nine of these tumors also underwent RNA sequencing. We analyzed the genomes and transcriptomes of these mCRPC tumors.ResultsCopy number loss was more common than gain in enzalutamide-resistant tumors. Specially, we identified 124 protein-coding genes that were more commonly lost in enzalutamide-resistant samples. These 124 genes included eight putative tumor suppressors located at nine distinct genomic regions. We demonstrated that focal deletion of the 17q22 locus that includes RNF43 and SRSF1 was not present in any patient with enzalutamide-naïve mCRPC but was present in 16% (6/37) of patients with enzalutamide-resistant mCRPC. 17q22 loss was associated with lower RNF43 and SRSF1 expression and poor overall survival from time of biopsy [median overall survival of 19.3 months in 17q22 intact vs. 8.9 months in 17q22 loss, HR, 3.44 95% confidence interval (CI), 1.338-8.867, log-rank P = 0.006]. Finally, 17q22 loss was linked with activation of several targetable factors, including CDK1/2, Akt, and PLK1, demonstrating the potential therapeutic relevance of 17q22 loss in mCRPC.ConclusionsCopy number loss is common in enzalutamide-resistant tumors. Focal deletion of chromosome 17q22 defines a previously unappreciated molecular subset of enzalutamide-resistant mCRPC associated with poor clinical outcome.
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- 2020
61. The DNA methylation landscape of advanced prostate cancer
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Zhao, Shuang G, Chen, William S, Li, Haolong, Foye, Adam, Zhang, Meng, Sjöström, Martin, Aggarwal, Rahul, Playdle, Denise, Liao, Arnold, Alumkal, Joshi J, Das, Rajdeep, Chou, Jonathan, Hua, Junjie T, Barnard, Travis J, Bailey, Adina M, Chow, Eric D, Perry, Marc D, Dang, Ha X, Yang, Rendong, Moussavi-Baygi, Ruhollah, Zhang, Li, Alshalalfa, Mohammed, Laura Chang, S, Houlahan, Kathleen E, Shiah, Yu-Jia, Beer, Tomasz M, Thomas, George, Chi, Kim N, Gleave, Martin, Zoubeidi, Amina, Reiter, Robert E, Rettig, Matthew B, Witte, Owen, Yvonne Kim, M, Fong, Lawrence, Spratt, Daniel E, Morgan, Todd M, Bose, Rohit, Huang, Franklin W, Li, Hui, Chesner, Lisa, Shenoy, Tanushree, Goodarzi, Hani, Asangani, Irfan A, Sandhu, Shahneen, Lang, Joshua M, Mahajan, Nupam P, Lara, Primo N, Evans, Christopher P, Febbo, Phillip, Batzoglou, Serafim, Knudsen, Karen E, He, Housheng H, Huang, Jiaoti, Zwart, Wilbert, Costello, Joseph F, Luo, Jianhua, Tomlins, Scott A, Wyatt, Alexander W, Dehm, Scott M, Ashworth, Alan, Gilbert, Luke A, Boutros, Paul C, Farh, Kyle, Chinnaiyan, Arul M, Maher, Christopher A, Small, Eric J, Quigley, David A, and Feng, Felix Y
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Biological Sciences ,Bioinformatics and Computational Biology ,Genetics ,Cancer ,Prostate Cancer ,Human Genome ,Urologic Diseases ,Cancer Genomics ,Biotechnology ,2.1 Biological and endogenous factors ,Aged ,Aged ,80 and over ,Carcinogenesis ,DNA Methylation ,Epigenomics ,Gene Expression Regulation ,Neoplastic ,Genome ,Humans ,Male ,Middle Aged ,Mutation ,Prospective Studies ,Prostatic Neoplasms ,Sequence Analysis ,DNA ,Exome Sequencing ,Whole Genome Sequencing ,Medical and Health Sciences ,Developmental Biology ,Agricultural biotechnology ,Bioinformatics and computational biology - Abstract
Although DNA methylation is a key regulator of gene expression, the comprehensive methylation landscape of metastatic cancer has never been defined. Through whole-genome bisulfite sequencing paired with deep whole-genome and transcriptome sequencing of 100 castration-resistant prostate metastases, we discovered alterations affecting driver genes that were detectable only with integrated whole-genome approaches. Notably, we observed that 22% of tumors exhibited a novel epigenomic subtype associated with hypermethylation and somatic mutations in TET2, DNMT3B, IDH1 and BRAF. We also identified intergenic regions where methylation is associated with RNA expression of the oncogenic driver genes AR, MYC and ERG. Finally, we showed that differential methylation during progression preferentially occurs at somatic mutational hotspots and putative regulatory regions. This study is a large integrated study of whole-genome, whole-methylome and whole-transcriptome sequencing in metastatic cancer that provides a comprehensive overview of the important regulatory role of methylation in metastatic castration-resistant prostate cancer.
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- 2020
62. A Novel Radioligand Reveals Tissue Specific Pharmacological Modulation of Glucocorticoid Receptor Expression with Positron Emission Tomography
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Huang, Yangjie, Zhao, Ning, Wang, Yung-hua, Truillet, Charles, Wei, Junnian, Blecha, Joseph E, VanBrocklin, Henry F, Seo, Youngho, Sayeed, Mohd, Feldman, Brian J, Aggarwal, Rahul, Behr, Spencer C, Shao, Hao, Wilson, David M, Villanueva-Meyer, Javier E, Gestwicki, Jason E, and Evans, Michael J
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Biological Sciences ,Chemical Sciences ,Biomedical Imaging ,Animals ,Dexamethasone ,Fluorine Radioisotopes ,Gene Expression ,Glucocorticoids ,Male ,Mice ,Mice ,Inbred C57BL ,Mice ,Knockout ,Positron-Emission Tomography ,Quinolines ,Receptors ,Glucocorticoid ,Organic Chemistry ,Biological sciences ,Chemical sciences - Abstract
The complexity of glucocorticoid receptor (GR) signaling cannot be measured with direct tissue analysis in living subjects, which has stifled our understanding of GR's role in human physiology or disease and impeded the development of selective GR modulators. Herein, we report 18F-5-(4-fluorobenzyl)-10-methoxy-2,2,4-trimethyl-2,5-dihydro-1H-chromeno[3,4-f]quinoline (18F-YJH08), a radioligand that enables noninvasive measurements of tissue autonomous GR expression levels in vivo with positron emission tomography (PET). YJH08 potently binds GR (Ki ∼ 0.4 nM) with ∼100-fold selectivity compared to nuclear hormone receptors in the same subfamily. 18F-YJH08 was prepared via Cu(OTf)2(py)4-mediated radiofluorination of an arylboronic acid pinacol ester with ∼12% decay corrected radiochemical yield from the starting 18F-fluoride ion. We applied treatment with the tissue-wide GR agonist dexamethasone and adrenalectomy and generated an adipocyte specific GR knockout mouse to show that 18F-YJH08 specifically binds GR in normal mouse tissues, including those for which aberrant GR expression is thought to drive severe diseases (e.g., brain, adipose tissue, kidneys). Remarkably, 18F-YJH08 PET also revealed that JG231, a potent and bioavailable HSP70 inhibitor, selectively degrades GR only in the adipose tissue of mice, a finding that foreshadows how GR targeted PET might be integrated into drug discovery to screen for selective GR modulation at the tissue level, beyond the historical screening that was performed at the transcriptional level. In summary, 18F-YJH08 enables a quantitative assessment of GR expression levels in real time among multiple tissues simultaneously, and this technology is a first step toward unraveling the daunting complexity of GR signaling and rationally engineering tissue specific therapeutic modulators in vivo.
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- 2020
63. Transcriptional profiling identifies an androgen receptor activity-low, stemness program associated with enzalutamide resistance
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Alumkal, Joshi J, Sun, Duanchen, Lu, Eric, Beer, Tomasz M, Thomas, George V, Latour, Emile, Aggarwal, Rahul, Cetnar, Jeremy, Ryan, Charles J, Tabatabaei, Shaadi, Bailey, Shawna, Turina, Claire B, Quigley, David A, Guan, Xiangnan, Foye, Adam, Youngren, Jack F, Urrutia, Joshua, Huang, Jiaoti, Weinstein, Alana S, Friedl, Verena, Rettig, Matthew, Reiter, Robert E, Spratt, Daniel E, Gleave, Martin, Evans, Christopher P, Stuart, Joshua M, Chen, Yiyi, Feng, Felix Y, Small, Eric J, Witte, Owen N, and Xia, Zheng
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Urologic Diseases ,Genetics ,Prostate Cancer ,Aging ,Cancer ,Development of treatments and therapeutic interventions ,5.1 Pharmaceuticals ,Aged ,Aged ,80 and over ,Antineoplastic Agents ,Benzamides ,Drug Resistance ,Neoplasm ,Gene Expression Profiling ,Humans ,Male ,Middle Aged ,Nitriles ,Phenylthiohydantoin ,Prostate-Specific Antigen ,Prostatic Neoplasms ,Castration-Resistant ,Receptors ,Androgen ,enzalutamide ,resistance ,androgen receptor ,stemness - Abstract
The androgen receptor (AR) antagonist enzalutamide is one of the principal treatments for men with castration-resistant prostate cancer (CRPC). However, not all patients respond, and resistance mechanisms are largely unknown. We hypothesized that genomic and transcriptional features from metastatic CRPC biopsies prior to treatment would be predictive of de novo treatment resistance. To this end, we conducted a phase II trial of enzalutamide treatment (160 mg/d) in 36 men with metastatic CRPC. Thirty-four patients were evaluable for the primary end point of a prostate-specific antigen (PSA)50 response (PSA decline ≥50% at 12 wk vs. baseline). Nine patients were classified as nonresponders (PSA decline
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- 2020
64. Hyperpolarized 13C-pyruvate MRI detects real-time metabolic flux in prostate cancer metastases to bone and liver: a clinical feasibility study
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Chen, Hsin-Yu, Aggarwal, Rahul, Bok, Robert A, Ohliger, Michael A, Zhu, Zi, Lee, Philip, Gordon, Jeremy W, van Criekinge, Mark, Carvajal, Lucas, Slater, James B, Larson, Peder EZ, Small, Eric J, Kurhanewicz, John, and Vigneron, Daniel B
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Biomedical and Clinical Sciences ,Clinical Sciences ,Oncology and Carcinogenesis ,Liver Disease ,Aging ,Clinical Trials and Supportive Activities ,Biomedical Imaging ,Digestive Diseases ,Clinical Research ,Urologic Diseases ,Cancer ,Prostate Cancer ,4.4 Population screening ,Detection ,screening and diagnosis ,Aged ,Aged ,80 and over ,Antineoplastic Combined Chemotherapy Protocols ,Bone Neoplasms ,Carbon Isotopes ,Carboplatin ,Docetaxel ,Feasibility Studies ,Follow-Up Studies ,Humans ,Liver Neoplasms ,Magnetic Resonance Imaging ,Male ,Middle Aged ,Pilot Projects ,Prognosis ,Prostatic Neoplasms ,Pyruvic Acid ,Survival Rate ,Urology & Nephrology ,Clinical sciences ,Oncology and carcinogenesis - Abstract
BackgroundHyperpolarized (HP) 13C-pyruvate MRI is a stable-isotope molecular imaging modality that provides real-time assessment of the rate of metabolism through glycolytic pathways in human prostate cancer. Heretofore this imaging modality has been successfully utilized in prostate cancer only in localized disease. This pilot clinical study investigated the feasibility and imaging performance of HP 13C-pyruvate MR metabolic imaging in prostate cancer patients with metastases to the bone and/or viscera.MethodsSix patients who had metastatic castration-resistant prostate cancer were recruited. Carbon-13 MR examination were conducted on a clinical 3T MRI following injection of 250 mM hyperpolarized 13C-pyruvate, where pyruvate-to-lactate conversion rate (kPL) was calculated. Paired metastatic tumor biopsy was performed with histopathological and RNA-seq analyses.ResultsWe observed a high rate of glycolytic metabolism in prostate cancer metastases, with a mean kPL value of 0.020 ± 0.006 (s-1) and 0.026 ± 0.000 (s-1) in bone (N = 4) and liver (N = 2) metastases, respectively. Overall, high kPL showed concordance with biopsy-confirmed high-grade prostate cancer including neuroendocrine differentiation in one case. Interval decrease of kPL from 0.026 at baseline to 0.015 (s-1) was observed in a liver metastasis 2 months after the initiation of taxane plus platinum chemotherapy. RNA-seq found higher levels of the lactate dehydrogenase isoform A (Ldha,15.7 ± 0.7) expression relative to the dominant isoform of pyruvate dehydrogenase (Pdha1, 12.8 ± 0.9).ConclusionsHP 13C-pyruvate MRI can detect real-time glycolytic metabolism within prostate cancer metastases, and can measure changes in quantitative kPL values following treatment response at early time points. This first feasibility study supports future clinical studies of HP 13C-pyruvate MRI in the setting of advanced prostate cancer.
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- 2020
65. Germline polymorphisms associated with impaired survival outcomes and somatic tumor alterations in advanced prostate cancer
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Chen, William S, Feng, Eric L, Aggarwal, Rahul, Foye, Adam, Beer, Tomasz M, Alumkal, Joshi J, Gleave, Martin, Chi, Kim N, Reiter, Robert E, Rettig, Matthew B, Evans, Christopher P, Small, Eric J, Sharifi, Nima, and Zhao, Shuang G
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Biotechnology ,Cancer ,Clinical Research ,Human Genome ,Genetic Testing ,Prostate Cancer ,Genetics ,Urologic Diseases ,Aetiology ,2.1 Biological and endogenous factors ,Good Health and Well Being ,Aged ,Androgen Antagonists ,Biomarkers ,Tumor ,DNA ,Neoplasm ,Follow-Up Studies ,Germ Cells ,Humans ,Male ,Polymorphism ,Genetic ,Prognosis ,Prostatic Neoplasms ,Castration-Resistant ,Retrospective Studies ,Survival Rate ,Oncology and Carcinogenesis ,Urology & Nephrology - Abstract
IntroductionGermline variants in androgen metabolism genes may influence clinical response to androgen deprivation therapy (ADT) in advanced prostate cancer. We sought to investigate the prognostic significance of germline variants in androgen metabolism genes with respect to overall survival (OS) after ADT, and to associate germline variants with tumor genomic features.MethodsGermline and somatic whole-genome sequencing (WGS) data were evaluated in a cohort of 101 men with metastatic castration-resistant prostate cancer (mCRPC). Survival analyses were performed to identify polymorphisms associated with impaired OS after primary ADT. Germline variants found to be prognostic of OS were associated with tumor somatic DNA-sequence alterations based on WGS performed on paired metastasis biopsies from the same 101 patients. Gene set enrichment analysis was performed based on tumor RNA-sequencing data to identify genomic pathways differentially expressed in patients with germline variants.ResultsA comprehensive literature review identified 17 candidate polymorphisms in nine androgen metabolism genes that have been previously shown to have an association with response to ADT in prostate cancer. Of these, the variant rs1856888 allele located 13 kb upstream of HSD3B1 was found to be significantly associated with impaired OS (P = 0.029). Variant rs1856888 was commonly co-inherited with the well-characterized HSD3B1(1245A>C) polymorphism, and there was a trend toward shorter median OS in patients with HSD3B1(1245A>C) compared with homozygous wild-type patients (P = 0.052). While HSD3B1 germline variants were not associated with common somatic tumor DNA alterations, they were associated with increased tumor expression of cell proliferation and cell cycle genes.ConclusionsThis study presents a comprehensive assessment of germline variants in androgen metabolism genes and highlights HSD3B1 polymorphisms as prognostic of OS after ADT and associated with an aggressive gene expression tumor profile in mCRPC.
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- 2020
66. Quantitative and Qualitative Improvement of Low-Count [68Ga]Citrate and [90Y]Microspheres PET Image Reconstructions Using Block Sequential Regularized Expectation Maximization Algorithm
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Seo, Youngho, Khalighi, Mohammad Mehdi, Wangerin, Kristen A, Deller, Timothy W, Wang, Yung-Hua, Jivan, Salma, Kohi, Maureen P, Aggarwal, Rahul, Flavell, Robert R, Behr, Spencer C, and Evans, Michael J
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Biomedical and Clinical Sciences ,Clinical Sciences ,Cancer ,Clinical Research ,Biomedical Imaging ,Bioengineering ,4.2 Evaluation of markers and technologies ,Detection ,screening and diagnosis ,Algorithms ,Citrates ,Gallium ,Gallium Radioisotopes ,Humans ,Image Processing ,Computer-Assisted ,Male ,Microspheres ,Phantoms ,Imaging ,Positron Emission Tomography Computed Tomography ,Prostatic Neoplasms ,Castration-Resistant ,Radiopharmaceuticals ,Signal-To-Noise Ratio ,Yttrium Radioisotopes ,Low-count PET ,[Y-90]microspheres ,[Ga-68]citrate ,PET ,MRI ,Regularized EM ,BSREM ,PET/MRI ,[68Ga]citrate ,[90Y]microspheres ,Physiology ,Nuclear Medicine & Medical Imaging ,Clinical sciences - Abstract
PurposeThere are several important positron emission tomography (PET) imaging scenarios that require imaging with very low photon statistics, for which both quantitative accuracy and visual quality should not be neglected. For example, PET imaging with the low photon statistics is closely related to active efforts to significantly reduce radiation exposure from radiopharmaceuticals. We investigated two examples of low-count PET imaging: (a) imaging [90Y]microsphere radioembolization that suffers the very small positron emission fraction of Y-90's decay processes, and (b) cancer imaging with [68Ga]citrate with uptake time of 3-4 half-lives, necessary for visualizing tumors. In particular, we investigated a type of penalized likelihood reconstruction algorithm, block sequential regularized expectation maximization (BSREM), for improving both image quality and quantitative accuracy of these low-count PET imaging cases.ProceduresThe NEMA/IEC Body phantom filled with aqueous solution of Y-90 or Ga-68 was scanned to mimic the low-count scenarios of corresponding patient data acquisitions on a time-of-flight (TOF) PET/magnetic resonance imaging system. Contrast recovery, background variation, and signal-to-noise ratio were evaluated in different sets of count densities using both conventional TOF ordered subset expectation (TOF-OSEM) and TOF-BSREM algorithms. The regularization parameter, beta, in BSREM that controls the tradeoff between image noise and resolution was evaluated to find a value for improved confidence in image interpretation. Visual quality assessment of the images obtained from patients administered with [68Ga]citrate (n = 6) was performed. We also made preliminary visual image quality assessment for one patient with [90Y]microspheres. In Y-90 imaging, the effect of 511-keV energy window selection for minimizing the number of random events was also evaluated.ResultsQuantitatively, phantom images reconstructed with TOF-BSREM showed improved contrast recovery, background variation, and signal-to-noise ratio values over images reconstructed with TOF-OSEM. Both phantom and patient studies of delayed imaging of [68Ga]citrate show that TOF-BSREM with beta = 500 gives the best tradeoff between image noise and image resolution based on visual assessment by the readers. The NEMA-IQ phantom study with [90Y]microspheres shows that the narrow energy window (460-562 keV) recovers activity concentrations in small spheres better than the regular energy window (425-650 keV) with the beta value of 2000 using the TOF-BSREM algorithm. For the images obtained from patients with [68Ga]citrate using TOF-BSREM with beta = 500, the visual analogue scale (VAS) was improved by 17 % and the Likert score was increased by 1 point on average, both in comparison to corresponding scores for images reconstructed using TOF-OSEM.ConclusionOur investigation shows that the TOF-BSREM algorithm improves the image quality and quantitative accuracy in low-count PET imaging scenarios. However, the beta value in this algorithm needed to be adjusted for each radiopharmaceutical and counting statistics at the time of scans.
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- 2020
67. Dramatic response to combination pembrolizumab and radiation in metastatic castration resistant prostate cancer
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Han, Harry J, Li, Yun Rose, Roach, Mack, and Aggarwal, Rahul
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Biomedical and Clinical Sciences ,Clinical Sciences ,Oncology and Carcinogenesis ,Immunology ,Cancer ,Prostate Cancer ,Urologic Diseases ,Development of treatments and therapeutic interventions ,Evaluation of treatments and therapeutic interventions ,5.1 Pharmaceuticals ,6.1 Pharmaceuticals ,anti-PD-1 ,immune checkpoint inhibitors ,immunotherapy ,mismatch repair ,radiation therapy ,Oncology and carcinogenesis - Abstract
Immune checkpoint inhibitors targeting PD-1 and PD-L1 have demonstrated anti-tumor activity in several advanced solid malignancies. In previously treated metastatic castration resistant prostate cancer (mCRPC), a small subset of patients have a therapeutic response to checkpoint inhibition. Those who do respond to anti-PD-1/PD-L1 therapy have a marked, durable response to treatment, suggesting some derive long-term benefit from immune checkpoint blockade. In other cancers, one strategy to increase the efficacy of immune checkpoint blockade is to combine it with a pro-immune stimulatory agent, such as radiation. Here we present a case of a patient with heavily treated mCRPC who had a significant tumor response to concurrent pembrolizumab and radiation therapy to the primary prostatic mass. We review the growing evidence supporting the use of this combination therapy in other cancers and its potential benefit and safety in mCRPC. Our report highlights a potential therapeutic approach that should be further investigated in previously treated mCRPC.
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- 2020
68. MEK-ERK signaling is a therapeutic target in metastatic castration resistant prostate cancer
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Nickols, Nicholas G, Nazarian, Ramin, Zhao, Shuang G, Tan, Victor, Uzunangelov, Vladislav, Xia, Zheng, Baertsch, Robert, Neeman, Elad, Gao, Allen C, Thomas, George V, Howard, Lauren, De Hoedt, Amanda M, Stuart, Josh, Goldstein, Theodore, Chi, Kim, Gleave, Martin E, Graff, Julie N, Beer, Tomasz M, Drake, Justin M, Evans, Christopher P, Aggarwal, Rahul, Foye, Adam, Feng, Felix Y, Small, Eric J, Aronson, William J, Freedland, Stephen J, Witte, Owen N, Huang, Jiaoti, Alumkal, Joshi J, Reiter, Robert E, and Rettig, Matthew B
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Biomedical and Clinical Sciences ,Clinical Sciences ,Oncology and Carcinogenesis ,Prostate Cancer ,Cancer ,Urologic Diseases ,Genetics ,Development of treatments and therapeutic interventions ,5.1 Pharmaceuticals ,Aged ,Antineoplastic Agents ,Biopsy ,Disease-Free Survival ,Gene Amplification ,Gene Expression Regulation ,Neoplastic ,Humans ,MAP Kinase Signaling System ,Male ,Middle Aged ,Mitogen-Activated Protein Kinase 3 ,Molecular Targeted Therapy ,Phosphorylation ,Prospective Studies ,Prostate ,Prostatic Neoplasms ,Castration-Resistant ,Protein Kinase Inhibitors ,Pyridones ,Pyrimidinones ,RNA-Seq ,Urology & Nephrology ,Clinical sciences ,Oncology and carcinogenesis - Abstract
BackgroundMetastatic castration resistant prostate cancer (mCRPC) is incurable and progression after drugs that target the androgen receptor-signaling axis is inevitable. Thus, there is an urgent need to develop more effective treatments beyond hormonal manipulation. We sought to identify activated kinases in mCRPC as therapeutic targets for existing, approved agents, with the goal of identifying candidate drugs for rapid translation into proof of concept Phase II trials in mCRPC.MethodsTo identify evidence of activation of druggable kinases in these patients, we compared mRNA expression from metastatic biopsies of patients with mCRPC (n = 101) to mRNA expression in localized prostate from TCGA and used this analysis to infer differential kinase activity. In addition, we assessed the differential phosphorylation levels for key MAPK pathway kinases between mCRPC and localized prostate cancers.ResultsTranscriptomic profiling of 101 patients with mCRPC as compared to patients with localized prostate cancer identified evidence of hyperactive ERK1, and whole genome sequencing revealed frequent amplifications of members of the MAPK pathway in 32% of this cohort. Next, we confirmed elevated levels of phosphorylated ERK1/2 in castration resistant prostate cancer as compared to untreated primary prostate cancer. We observed that the presence of detectable phosphorylated ERK1/2 in the primary tumor is associated with biochemical failure after radical prostatectomy independent of clinicopathologic features. ERK1 is the immediate downstream target of MEK1/2, which is druggable with trametinib, an approved therapeutic for melanoma. Trametinib elicited a profound biochemical and clinical response in a patient who had failed multiple prior treatments for mCRPC.ConclusionsWe conclude that pharmacologic targeting of the MEK/ERK pathway may be a viable treatment strategy for patients with refractory metastatic prostate cancer. An ongoing Phase II trial tests this hypothesis.
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- 2019
69. Genomic Drivers of Poor Prognosis and Enzalutamide Resistance in Metastatic Castration-resistant Prostate Cancer
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Chen, William S, Aggarwal, Rahul, Zhang, Li, Zhao, Shuang G, Thomas, George V, Beer, Tomasz M, Quigley, David A, Foye, Adam, Playdle, Denise, Huang, Jiaoti, Lloyd, Paul, Lu, Eric, Sun, Duanchen, Guan, Xiangnan, Rettig, Matthew, Gleave, Martin, Evans, Christopher P, Youngren, Jack, True, Lawrence, Lara, Primo, Kothari, Vishal, Xia, Zheng, Chi, Kim N, Reiter, Robert E, Maher, Christopher A, Feng, Felix Y, Small, Eric J, Alumkal, Joshi J, and Team, on behalf of the West Coast Prostate Cancer Dream
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Biotechnology ,Clinical Research ,Urologic Diseases ,Prostate Cancer ,Rare Diseases ,Genetics ,Cancer ,Human Genome ,Detection ,screening and diagnosis ,2.1 Biological and endogenous factors ,4.1 Discovery and preclinical testing of markers and technologies ,Aetiology ,Good Health and Well Being ,Aged ,Antineoplastic Agents ,Benzamides ,Biomarkers ,Tumor ,Drug Resistance ,Neoplasm ,Humans ,Male ,Middle Aged ,Neoplasm Metastasis ,Neoplasm Staging ,Nitriles ,Outcome Assessment ,Health Care ,Phenylthiohydantoin ,Predictive Value of Tests ,Prognosis ,Prostate ,Prostate-Specific Antigen ,Prostatic Neoplasms ,Castration-Resistant ,Whole Genome Sequencing ,Advanced prostate cancer ,Castration-resistant ,Clinical outcomes ,Enzalutamide ,Genomics ,Metastatic prostate cancer ,Prognostic factors ,West Coast Prostate Cancer Dream Team ,Clinical Sciences ,Urology & Nephrology - Abstract
BackgroundMetastatic castration-resistant prostate cancer (mCRPC) is the lethal form of the disease. Several recent studies have identified genomic alterations in mCRPC, but the clinical implications of these genomic alterations have not been fully elucidated.ObjectiveTo use whole-genome sequencing (WGS) to assess the association between key driver gene alterations and overall survival (OS), and to use whole-transcriptome RNA sequencing to identify genomic drivers of enzalutamide resistance.Design, setting, and participantsWe performed survival analyses and gene set enrichment analysis (GSEA) on WGS and RNA sequencing results for a cohort of 101 mCRPC patients.Outcome measurements and statistical analysisOS was the clinical endpoint for all univariate and multivariable survival analyses. Candidate drivers of enzalutamide resistance were identified in an unbiased manner, and mutations of the top candidate were further assessed for enrichment among enzalutamide-resistant patients using Fisher's exact test.Results and limitationsHarboring two DNA alterations in RB1 was independently predictive of poor OS (median 14.1 vs 42.0mo; p=0.007) for men with mCRPC. GSEA identified the Wnt/β-catenin pathway as the top differentially modulated pathway among enzalutamide-resistant patients. Furthermore, β-catenin mutations were exclusive to enzalutamide-resistant patients (p=0.01) and independently predictive of poor OS (median 13.6 vs 41.7mo; p=0.025).ConclusionsThe presence of two RB1 DNA alterations identified in our WGS analysis was independently associated with poor OS among men with mCRPC. The Wnt/β-catenin pathway plays an important role in enzalutamide resistance, with differential pathway expression and enrichment of β-catenin mutations in enzalutamide-resistant patients. Moreover, β-catenin mutations were predictive of poor OS in our cohort.Patient summaryWe observed a correlation between genomic findings for biopsy samples from metastases from men with metastatic castration-resistant prostate cancer (mCRPC) and clinical outcomes. This work sheds new light on clinically relevant genomic alterations in mCRPC and provides a roadmap for the development of new personalized treatment regimens in mCRPC.
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- 2019
70. Deep whole-genome ctDNA chronology of treatment-resistant prostate cancer
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Herberts, Cameron, Annala, Matti, Sipola, Joonatan, Ng, Sarah W. S., Chen, Xinyi E., Nurminen, Anssi, Korhonen, Olga V., Munzur, Aslı D., Beja, Kevin, Schönlau, Elena, Bernales, Cecily Q., Ritch, Elie, Bacon, Jack V. W., Lack, Nathan A., Nykter, Matti, Aggarwal, Rahul, Small, Eric J., Gleave, Martin E., Quigley, David A., Feng, Felix Y., Chi, Kim N., and Wyatt, Alexander W.
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- 2022
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71. Correlating survival outcomes in patients with advanced prostate cancer with novel hyperpolarized 13C MRI metabolic imaging biomarkers.
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Chen, Hsin-Yu, primary, de Kouchkovsky, Ivan, additional, Bok, Robert A., additional, Ohliger, Michael A., additional, Wang, Zhen J., additional, Gebrezgiabhier, Daniel, additional, Nickles, Tanner, additional, Carvajal, Lucas E., additional, Gordon, Jeremy W., additional, Larson, Peder E.Z., additional, Kurhanewicz, John, additional, Aggarwal, Rahul Raj, additional, and Vigneron, Daniel B., additional
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- 2024
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72. Informed decision-making about germline testing among Veterans with advanced prostate cancer (APC): A mixed-methods study.
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Kwon, Daniel H, primary, McPhaul, Marissa, additional, Sumra, Saffanat, additional, Ursem, Carling Jade, additional, Walker, Evan Justin, additional, Scheuner, Maren Theresa, additional, Wang, Sunny, additional, Aggarwal, Rahul Raj, additional, Huang, Franklin W., additional, and Belkora, Jeffrey, additional
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- 2024
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73. Health-related quality of life (HRQOL) results from PRESTO (AFT-19), a phase 3 randomized trial of intensification of androgen blockade in patients with high-risk biochemically relapsed castration sensitive prostate cancer.
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Chen, Ronald C., primary, Mazza, Gina L., additional, Fruth, Briant, additional, Xiao, Han, additional, Picus, Joel, additional, Taplin, Mary Ellen, additional, Dorff, Tanya B., additional, Appleman, Leonard Joseph, additional, Weckstein, Douglas Jay, additional, Patnaik, Akash, additional, Bryce, Alan Haruo, additional, Shevrin, Daniel, additional, Mohler, James L., additional, Anderson, Daniel M., additional, Rao, Arpit, additional, Tan, Alan, additional, Ryan, Charles J., additional, Eggener, Scott, additional, Morris, Michael J., additional, and Aggarwal, Rahul Raj, additional
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- 2024
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74. Development of a machine learning model to predict overall survival results from randomized clinical trials of patients with metastatic prostate cancer.
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Sabbagh, Ali, primary, Quigley, David Alan, additional, Lillis, Nicholas, additional, Zhang, Li, additional, Friesner, Isabel D, additional, Bailey, Adina, additional, Aggarwal, Rahul Raj, additional, Chappidi, Meera Reddy, additional, Singhal, Hari, additional, Zhang, Ke, additional, Greshock, Joel, additional, Li, Jinhui, additional, Yu, Margaret K., additional, Small, Eric J., additional, and Hong, Julian C., additional
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- 2024
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75. A phase 1b dose escalation study of FOR46, a novel antibody-drug conjugate targeting a tumor-specific epitope of CD46, in combination with enzalutamide (Enza) in patients with metastatic castration resistant prostate cancer (mCRPC).
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Shakhnazaryan, Nonna, primary, Curry, Nathan, additional, Rastogi, Medini, additional, Avins, Daniel, additional, Pandey, Shrina, additional, de Kouchkovsky, Ivan, additional, Kwon, Daniel, additional, Desai, Arpita, additional, Fitzgerald, Kelly N., additional, Bose, Rohit, additional, Chou, Jonathan, additional, Friedlander, Terence W., additional, Koshkin, Vadim S, additional, Fong, Lawrence, additional, Aslam, Maya, additional, Siddiqua, Khadija, additional, Small, Eric J., additional, Liu, Bin, additional, Flavell, Robert R., additional, and Aggarwal, Rahul Raj, additional
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- 2024
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76. Phase 1b study of tarlatamab in de novo or treatment-emergent neuroendocrine prostate cancer (NEPC).
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Aggarwal, Rahul Raj, primary, Rottey, Sylvie, additional, Bernard-Tessier, Alice, additional, Mellado-Gonzalez, Begoña, additional, Kosaka, Takeo, additional, Stadler, Walter Michael, additional, Sandhu, Shahneen, additional, Yu, Brian, additional, Shaw, Crystal, additional, Ju, Chia-Hsin, additional, Thompson, Corbin, additional, and Aparicio, Ana, additional
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- 2024
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77. Assessing Response to PSMA Radiopharmaceutical Therapies with Single SPECT Imaging at 24 Hours After Injection
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Yadav, Surekha, primary, Jiang, Fei, additional, Kurkowska, Sara, additional, Saelee, Rachelle, additional, Morley, Amanda, additional, Feng, Felix, additional, Aggarwal, Rahul, additional, Lawhn-Heath, Courtney, additional, Uribe, Carlos, additional, and Hope, Thomas A., additional
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- 2024
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78. Prevalence of Cardiovascular-Kidney-Metabolic Syndrome Stages in US Adults, 2011-2020
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Aggarwal, Rahul, primary, Ostrominski, John W., additional, and Vaduganathan, Muthiah, additional
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- 2024
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79. Phase I Study of CTT1057, an 18F-Labeled Imaging Agent with Phosphoramidate Core Targeting Prostate-Specific Membrane Antigen in Prostate Cancer
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Behr, Spencer C, Aggarwal, Rahul, VanBrocklin, Henry F, Flavell, Robert R, Gao, Kenneth, Small, Eric J, Blecha, Joseph, Jivan, Salma, Hope, Thomas A, Simko, Jeffry P, Kurhanewicz, John, Noworolski, Susan M, Korn, Natalie J, De Los Santos, Romelyn, Cooperberg, Matthew R, Carroll, Peter R, Nguyen, Hao G, Greene, Kirsten L, Langton-Webster, Beatrice, Berkman, Clifford E, and Seo, Youngho
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Biomedical and Clinical Sciences ,Clinical Sciences ,Oncology and Carcinogenesis ,Clinical Research ,Biomedical Imaging ,Bioengineering ,Prostate Cancer ,Urologic Diseases ,Cancer ,Aged ,Amides ,Antigens ,Surface ,Cohort Studies ,Fluorine Radioisotopes ,Glutamate Carboxypeptidase II ,Humans ,Isotope Labeling ,Male ,Middle Aged ,Phosphoric Acids ,Positron-Emission Tomography ,Prospective Studies ,Prostatic Neoplasms ,Safety ,Tissue Distribution ,Whole Body Imaging ,prostate cancer ,PSMA ,PET ,dosimetry ,CTT1057 ,Nuclear Medicine & Medical Imaging ,Clinical sciences - Abstract
Agents targeting prostate-specific membrane antigen (PSMA) comprise a rapidly emerging class of radiopharmaceuticals for diagnostic imaging of prostate cancer. Unlike most other PSMA agents with a urea backbone, CTT1057 is based on a phosphoramidate scaffold that irreversibly binds to PSMA. We conducted a first-in-humans phase I study of CTT1057 in patients with localized and metastatic prostate cancer. Methods: Two patient cohorts were recruited. Cohort A patients had biopsy-proven localized prostate cancer preceding radical prostatectomy, and cohort B patients had metastatic castration-resistant prostate cancer. Cohort A patients were imaged at multiple time points after intravenous injection with 362 ± 8 MBq of CTT1057 to evaluate the kinetics of CTT1057 and estimate radiation dose profiles. Mean organ-absorbed doses and effective doses were calculated. CTT1057 uptake in the prostate gland and regional lymph nodes was correlated with pathology, PSMA staining, and the results of conventional imaging. In cohort B, patients were imaged 60-120 min after injection of CTT1057. PET images were assessed for overall image quality, and areas of abnormal uptake were contrasted with conventional imaging. Results: In cohort A (n = 5), the average total effective dose was 0.023 mSv/MBq. The kidneys exhibited the highest absorbed dose, 0.067 mGy/MBq. The absorbed dose of the salivary glands was 0.015 mGy/MBq. For cohort B (n = 15), CTT1057 PET detected 97 metastatic lesions, and 44 of 56 bone metastases detected on CTT1057 PET (78.5%) were also detectable on bone scanning. Eight of 32 lymph nodes positive on CTT1057 PET (25%) were enlarged by size criteria on CT. Conclusion: CTT1057 is a promising novel phosphoramidate PSMA-targeting 18F-labeled PET radiopharmaceutical that demonstrates similar biodistribution to urea-based PSMA-targeted agents, with lower exposure to the kidneys and salivary glands. Metastatic lesions are detected with higher sensitivity on CTT1057 imaging than on conventional imaging. Further prospective studies with CTT1057 are warranted to elucidate its role in cancer imaging.
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- 2019
80. Whole-Genome and Transcriptional Analysis of Treatment-Emergent Small-Cell Neuroendocrine Prostate Cancer Demonstrates Intraclass Heterogeneity
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Aggarwal, Rahul R, Quigley, David A, Huang, Jiaoti, Zhang, Li, Beer, Tomasz M, Rettig, Matthew B, Reiter, Rob E, Gleave, Martin E, Thomas, George V, Foye, Adam, Playdle, Denise, Lloyd, Paul, Chi, Kim N, Evans, Christopher P, Lara, Primo N, Feng, Felix Y, Alumkal, Joshi J, and Small, Eric J
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Biological Sciences ,Biomedical and Clinical Sciences ,Genetics ,Clinical Sciences ,Oncology and Carcinogenesis ,Human Genome ,Prostate Cancer ,Urologic Diseases ,Cancer ,Rare Diseases ,Adenocarcinoma ,Biomarkers ,Tumor ,Biopsy ,Genome-Wide Association Study ,Humans ,Male ,Neuroendocrine Tumors ,Prostatic Neoplasms ,Castration-Resistant ,Receptors ,Androgen ,Transcription ,Genetic ,Developmental Biology ,Oncology & Carcinogenesis ,Biochemistry and cell biology ,Oncology and carcinogenesis - Abstract
Therapeutic resistance in metastatic castration-resistant prostate cancer (mCRPC) can be accompanied by treatment-emergent small-cell neuroendocrine carcinoma (t-SCNC), a morphologically distinct subtype. We performed integrative whole-genome and -transcriptome analysis of mCRPC tumor biopsies including paired biopsies after progression, and multiple samples from the same individual. t-SCNC was significantly less likely to have amplification of AR or an intergenic AR-enhancer locus, and demonstrated lower expression of AR and its downstream transcriptional targets. Genomic and transcriptional hallmarks of t-SCNC included biallelic loss of RB1, elevated expression levels of CDKN2A and E2F1, and loss of expression of the AR and AR-responsive genes including TMPRSS2 and NKX3-1. We identified three tumors that converted from adenocarcinoma to t-SCNC and demonstrate spatial and temporal intrapatient heterogeneity of metastatic tumors harboring adenocarcinoma, t-SCNC, or mixed expression phenotypes, with implications for treatment strategies in which dual targeting of adenocarcinoma and t-SCNC phenotypes may be necessary. IMPLICATIONS: The t-SCNC phenotype is characterized by lack of AR enhancer gain and loss of RB1 function, and demonstrates both interindividual and intraindividual heterogeneity.Visual Overview: http://mcr.aacrjournals.org/content/molcanres/17/6/1235/F1.large.jpg.
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- 2019
81. Translation of Carbon‐13 EPI for hyperpolarized MR molecular imaging of prostate and brain cancer patients
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Gordon, Jeremy W, Chen, Hsin‐Yu, Autry, Adam, Park, Ilwoo, Van Criekinge, Mark, Mammoli, Daniele, Milshteyn, Eugene, Bok, Robert, Xu, Duan, Li, Yan, Aggarwal, Rahul, Chang, Susan, Slater, James B, Ferrone, Marcus, Nelson, Sarah, Kurhanewicz, John, Larson, Peder EZ, and Vigneron, Daniel B
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Engineering ,Biomedical Engineering ,Urologic Diseases ,Clinical Research ,Bioengineering ,Aging ,Neurosciences ,Biomedical Imaging ,Prostate Cancer ,Cancer ,Artifacts ,Bicarbonates ,Brain ,Brain Neoplasms ,Calibration ,Carbon Isotopes ,Carbon-13 Magnetic Resonance Spectroscopy ,Echo-Planar Imaging ,Humans ,Image Enhancement ,Image Processing ,Computer-Assisted ,Lactic Acid ,Male ,Molecular Imaging ,Phantoms ,Imaging ,Prostate ,Prostatic Neoplasms ,Pyruvic Acid ,Signal-To-Noise Ratio ,DNP ,EPI ,hyperpolarization ,oncology ,pyruvate ,Nuclear Medicine & Medical Imaging ,Biomedical engineering - Abstract
PurposeTo develop and translate a metabolite-specific imaging sequence using a symmetric echo planar readout for clinical hyperpolarized (HP) Carbon-13 (13 C) applications.MethodsInitial data were acquired from patients with prostate cancer (N = 3) and high-grade brain tumors (N = 3) on a 3T scanner. Samples of [1-13 C]pyruvate were polarized for at least 2 h using a 5T SPINlab system operating at 0.8 K. Following injection of the HP substrate, pyruvate, lactate, and bicarbonate (for brain studies) were sequentially excited with a singleband spectral-spatial RF pulse and signal was rapidly encoded with a single-shot echo planar readout on a slice-by-slice basis. Data were acquired dynamically with a temporal resolution of 2 s for prostate studies and 3 s for brain studies.ResultsHigh pyruvate signal was seen throughout the prostate and brain, with conversion to lactate being shown across studies, whereas bicarbonate production was also detected in the brain. No Nyquist ghost artifacts or obvious geometric distortion from the echo planar readout were observed. The average error in center frequency was 1.2 ± 17.0 and 4.5 ± 1.4 Hz for prostate and brain studies, respectively, below the threshold for spatial shift because of bulk off-resonance.ConclusionThis study demonstrated the feasibility of symmetric EPI to acquire HP 13 C metabolite maps in a clinical setting. As an advance over prior single-slice dynamic or single time point volumetric spectroscopic imaging approaches, this metabolite-specific EPI acquisition provided robust whole-organ coverage for brain and prostate studies while retaining high SNR, spatial resolution, and dynamic temporal resolution.
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- 2019
82. Coil combination methods for multi-channel hyperpolarized 13C imaging data from human studies
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Zhu, Zihan, Zhu, Xucheng, Ohliger, Michael A, Tang, Shuyu, Cao, Peng, Carvajal, Lucas, Autry, Adam W, Li, Yan, Kurhanewicz, John, Chang, Susan, Aggarwal, Rahul, Munster, Pamela, Xu, Duan, Larson, Peder EZ, Vigneron, Daniel B, and Gordon, Jeremy W
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Physical Sciences ,Biomedical Imaging ,Algorithms ,Breast Neoplasms ,Carbon Isotopes ,Computer Simulation ,Electromagnetic Fields ,Female ,Humans ,Image Processing ,Computer-Assisted ,Magnetic Resonance Imaging ,Molecular Imaging ,Neoplasms ,Phantoms ,Imaging ,Pyruvic Acid ,Reproducibility of Results ,Signal-To-Noise Ratio ,Coil combination ,C-13 ,Hyperpolarized ,Pyruvate ,DNP ,(13)C ,Engineering ,Biophysics ,Physical sciences - Abstract
Effective coil combination methods for human hyperpolarized 13C spectroscopy multi-channel data had been relatively unexplored. This study implemented and tested several coil combination methods, including (1) the sum-of-squares (SOS), (2) singular value decomposition (SVD), (3) Roemer method by using reference peak area as a sensitivity map (RefPeak), and (4) Roemer method by using ESPIRiT-derived sensitivity map (ESPIRiT). These methods were evaluated by numerical simulation, thermal phantom experiments, and human cancer patient studies. Overall, the SVD, RefPeak, and ESPIRiT methods demonstrated better accuracy and robustness than the SOS method. Extracting complex pyruvate signal provides an easy and excellent approximation of the coil sensitivity map while maintaining valuable phase information of the coil-combined data.
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- 2019
83. Spatio-Temporally Constrained Reconstruction for Hyperpolarized Carbon-13 MRI Using Kinetic Models
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Maidens, John, Gordon, Jeremy W, Chen, Hsin-Yu, Park, Ilwoo, Van Criekinge, Mark, Milshteyn, Eugene, Bok, Robert, Aggarwal, Rahul, Ferrone, Marcus, Slater, James B, Kurhanewicz, John, Vigneron, Daniel B, Arcak, Murat, and Larson, Peder EZ
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Bioengineering ,Biomedical Imaging ,Detection ,screening and diagnosis ,4.1 Discovery and preclinical testing of markers and technologies ,Algorithms ,Animals ,Carbon Isotopes ,Humans ,Image Processing ,Computer-Assisted ,Kidney ,Magnetic Resonance Imaging ,Male ,Molecular Imaging ,Prostate ,Prostatic Neoplasms ,Rats ,Rats ,Sprague-Dawley ,Signal-To-Noise Ratio ,Parameter estimation ,linear systems ,inverse problems ,optimization ,magnetic resonance imaging ,carbon ,molecular imaging ,Information and Computing Sciences ,Engineering ,Nuclear Medicine & Medical Imaging - Abstract
We present a method of generating spatial maps of kinetic parameters from dynamic sequences of images collected in hyperpolarized carbon-13 magnetic resonance imaging (MRI) experiments. The technique exploits spatial correlations in the dynamic traces via regularization in the space of parameter maps. Similar techniques have proven successful in other dynamic imaging problems, such as dynamic contrast enhanced MRI. In this paper, we apply these techniques for the first time to hyperpolarized MRI problems, which are particularly challenging due to limited signal-to-noise ratio (SNR). We formulate the reconstruction as an optimization problem and present an efficient iterative algorithm for solving it based on the alternation direction method of multipliers. We demonstrate that this technique improves the qualitative appearance of parameter maps estimated from low SNR dynamic image sequences, first in simulation then on a number of data sets collected in vivo. The improvement this method provides is particularly pronounced at low SNR levels.
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- 2018
84. Technique development of 3D dynamic CS‐EPSI for hyperpolarized 13C pyruvate MR molecular imaging of human prostate cancer
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Chen, Hsin‐Yu, Larson, Peder EZ, Gordon, Jeremy W, Bok, Robert A, Ferrone, Marcus, van Criekinge, Mark, Carvajal, Lucas, Cao, Peng, Pauly, John M, Kerr, Adam B, Park, Ilwoo, Slater, James B, Nelson, Sarah J, Munster, Pamela N, Aggarwal, Rahul, Kurhanewicz, John, and Vigneron, Daniel B
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Engineering ,Biomedical Engineering ,Biomedical Imaging ,Digestive Diseases ,Bioengineering ,Urologic Diseases ,Prostate Cancer ,Cancer ,Aged ,Animals ,Echo-Planar Imaging ,Humans ,Imaging ,Three-Dimensional ,Male ,Mice ,Phantoms ,Imaging ,Prostate ,Prostatic Neoplasms ,Pyruvic Acid ,Rats ,human prostate cancer ,hyperpolarized C-13 pyruvate ,3D dynamic imaging ,Nuclear Medicine & Medical Imaging ,Biomedical engineering - Abstract
PurposeThe purpose of this study was to develop a new 3D dynamic carbon-13 compressed sensing echoplanar spectroscopic imaging (EPSI) MR sequence and test it in phantoms, animal models, and then in prostate cancer patients to image the metabolic conversion of hyperpolarized [1-13 C]pyruvate to [1-13 C]lactate with whole gland coverage at high spatial and temporal resolution.MethodsA 3D dynamic compressed sensing (CS)-EPSI sequence with spectral-spatial excitation was designed to meet the required spatial coverage, time and spatial resolution, and RF limitations of the 3T MR scanner for its clinical translation for prostate cancer patient imaging. After phantom testing, animal studies were performed in rats and transgenic mice with prostate cancers. For patient studies, a GE SPINlab polarizer (GE Healthcare, Waukesha, WI) was used to produce hyperpolarized sterile GMP [1-13 C]pyruvate. 3D dynamic 13 C CS-EPSI data were acquired starting 5 s after injection throughout the gland with a spatial resolution of 0.5 cm3 , 18 time frames, 2-s temporal resolution, and 36 s total acquisition time.ResultsThrough preclinical testing, the 3D CS-EPSI sequence developed in this project was shown to provide the desired spectral, temporal, and spatial 5D HP 13 C MR data. In human studies, the 3D dynamic HP CS-EPSI approach provided first-ever simultaneously volumetric and dynamic images of the LDH-catalyzed conversion of [1-13 C]pyruvate to [1-13 C]lactate in a biopsy-proven prostate cancer patient with full gland coverage.ConclusionThe results demonstrate the feasibility to characterize prostate cancer metabolism in animals, and now patients using this new 3D dynamic HP MR technique to measure kPL , the kinetic rate constant of [1-13 C]pyruvate to [1-13 C]lactate conversion.
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- 2018
85. Investigation of analysis methods for hyperpolarized 13C‐pyruvate metabolic MRI in prostate cancer patients
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Larson, Peder EZ, Chen, Hsin‐Yu, Gordon, Jeremy W, Korn, Natalie, Maidens, John, Arcak, Murat, Tang, Shuyu, Criekinge, Mark, Carvajal, Lucas, Mammoli, Daniele, Bok, Robert, Aggarwal, Rahul, Ferrone, Marcus, Slater, James B, Nelson, Sarah J, Kurhanewicz, John, and Vigneron, Daniel B
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Prostate Cancer ,Urologic Diseases ,Bioengineering ,Biomedical Imaging ,Cancer ,Area Under Curve ,Carbon Isotopes ,Computer Simulation ,Humans ,Magnetic Resonance Imaging ,Male ,Middle Aged ,Prostatic Neoplasms ,Pyruvic Acid ,hyperpolarized MRI ,kinetic modeling ,metabolic imaging ,prostate cancer ,13C-pyruvate ,Medicinal and Biomolecular Chemistry ,Biomedical Engineering ,Clinical Sciences ,Nuclear Medicine & Medical Imaging - Abstract
MRI using hyperpolarized (HP) carbon-13 pyruvate is being investigated in clinical trials to provide non-invasive measurements of metabolism for cancer and cardiac imaging. In this project, we applied HP [1-13 C]pyruvate dynamic MRI in prostate cancer to measure the conversion from pyruvate to lactate, which is expected to increase in aggressive cancers. The goal of this work was to develop and test analysis methods for improved quantification of this metabolic conversion. In this work, we compared specialized kinetic modeling methods to estimate the pyruvate-to-lactate conversion rate, kPL , as well as the lactate-to-pyruvate area-under-curve (AUC) ratio. The kinetic modeling included an "inputless" method requiring no assumptions regarding the input function, as well as a method incorporating bolus characteristics in the fitting. These were first evaluated with simulated data designed to match human prostate data, where we examined the expected sensitivity of metabolism quantification to variations in kPL , signal-to-noise ratio (SNR), bolus characteristics, relaxation rates, and B1 variability. They were then applied to 17 prostate cancer patient datasets. The simulations indicated that the inputless method with fixed relaxation rates provided high expected accuracy with no sensitivity to bolus characteristics. The AUC ratio showed an undesired strong sensitivity to bolus variations. Fitting the input function as well did not improve accuracy over the inputless method. In vivo results showed qualitatively accurate kPL maps with inputless fitting. The AUC ratio was sensitive to bolus delivery variations. Fitting with the input function showed high variability in parameter maps. Overall, we found the inputless kPL fitting method to be a simple, robust approach for quantification of metabolic conversion following HP [1-13 C]pyruvate injection in human prostate cancer studies. This study also provided initial ranges of HP [1-13 C]pyruvate parameters (SNR, kPL , bolus characteristics) in the human prostate.
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- 2018
86. Addressing authorship dilemmas in scholarly publications: a solution-oriented study.
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Aggarwal, Rahul
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POWER (Social sciences) , *AUTHORSHIP collaboration , *AUTHORSHIP , *HIGHER education , *DECISION making - Abstract
In scholarly publications, determining authorship- and the order of authors’ names- has become increasingly challenging. This is partly due to the evolving landscape of multidisciplinary teams, which can involve numerous contributors. Relying solely on descriptive and consensus-based qualitative approaches can lead to uncertainty. The dilemma also extends to cases where a valid contributor may simply receive an acknowledgement for his or her contribution, rather than being listed as a joint author. Trusting authors to adhere to moral standards when deciding authorship and acknowledgments can result in conflicts that are difficult for readers to navigate. This poses accountability challenges, especially when dealing with a substantial number of authors. This study proposes a simplified and transparent quantitative approach to address these concerns. The methodology is based on two key parameters: first, the evaluation of the time invested by each contributor in the publication; and, second, the normalized assessment of the value of their time. Through a contribution analysis utilizing these parameters, a predetermined threshold is established to define authorship. Contributors falling below this threshold can be recognized in some other way, for example, in acknowledgments for their valuable input. While the approach proposed may be more applicable in some disciplines and higher education systems than others, it does offer a quantitative foundation to support qualitative discussions among potential authors, helping them reach a consensus on authorship and authorship order without conflict. This method seeks to prevent injustices and ensure that all contributors have a voice, regardless of their power and influence. [ABSTRACT FROM AUTHOR]
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- 2024
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87. Generalizability of the Spectrum of Kidney Risk in the FINEARTS-HF Trial to U.S. Adults With Heart Failure.
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OSTROMINSKI, JOHN W., AGGARWAL, RAHUL, CLAGGETT, BRIAN L., KULAC, IAN J., DESAI, AKSHAY S., JHUND, PARDEEP S., LAM, CAROLYN S.P., PITT, BERTRAM, SENNI, MICHELE, SHAH, SANJIV J., VOORS, ADRIAAN A., ZANNAD, FAIEZ, LAY-FLURRIE, JAMES, VISWANATHAN, PRABHAKAR, MCMURRAY, JOHN J.V., SOLOMON, SCOTT D., and VADUGANATHAN, MUTHIAH
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- 2024
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88. The Role of Bee Products in Cosmetic and Skincare Industry: Current Trends and Future Prospects.
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Gupta, Garima, Rawat, Divyanshi, and Aggarwal, Rahul
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- 2024
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89. Abdominal Aortic Aneurysm-Attributed Mortality in the United States.
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Zuin, Marco, Aggarwal, Rahul, Bikdeli, Behnood, Kirksey, Lee, Hussain, Mohamad A., Bilato, Marco J., Bilato, Claudio, and Piazza, Gregory
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AORTA , *MORTALITY , *ABDOMINAL aortic aneurysms - Published
- 2024
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90. 68Ga-FAP-2286 PET of Solid Tumors: Biodistribution, Dosimetry, and Comparison with 18F-FDG.
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Kline, Brad, Yadav, Surekha, Youngho Seo, Ippisch, Robin Cumming, Castillo, Jessa, Aggarwal, Rahul R., Kelley, Robin Kate, Behr, Spencer C., Flavell, Robert R., Lawhn-Heath, Courtney, Melisko, Michelle, Rugo, Hope S., Wang, Victoria, Yom, Sue S., Ha, Patrick, Fei Jiang, and Hope, Thomas A.
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- 2024
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91. Initial Experience with 68Ga-FAP-2286 PET Imaging in Patients with Urothelial Cancer.
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Koshkin, Vadim S., Kumar, Vipul, Kline, Brad, Escobar, Domenique, Aslam, Maya, Cooperberg, Matthew R., Aggarwal, Rahul R., de Kouchkovsky, Ivan, Chou, Jonathan, Meng, Maxwell V., Friedlander, Terence, Porten, Sima, and Hope, Thomas A.
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- 2024
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92. The Emerging Role of Next-Generation Imaging in Prostate Cancer
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Murthy, Vishnu, Aggarwal, Rahul, and Koo, Phillip J.
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- 2022
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93. Targeting CD46 for both adenocarcinoma and neuroendocrine prostate cancer.
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Su, Yang, Liu, Yue, Behrens, Christopher R, Bidlingmaier, Scott, Lee, Nam-Kyung, Aggarwal, Rahul, Sherbenou, Daniel W, Burlingame, Alma L, Hann, Byron C, Simko, Jeffry P, Premasekharan, Gayatri, Paris, Pamela L, Shuman, Marc A, Seo, Youngho, Small, Eric J, and Liu, Bin
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Prostate ,Cell Line ,Tumor ,Animals ,Macaca fascicularis ,Humans ,Neuroendocrine Tumors ,Adenocarcinoma ,Prostatic Neoplasms ,Benzamides ,Nitriles ,Phenylthiohydantoin ,Androstenes ,Recombinant Fusion Proteins ,Antineoplastic Agents ,Antibodies ,Monoclonal ,Antibodies ,Neoplasm ,Antigens ,Neoplasm ,Therapeutics ,Xenograft Model Antitumor Assays ,Signal Transduction ,Antibody Affinity ,Female ,Male ,Tumor Microenvironment ,Membrane Cofactor Protein ,Oncology ,Prostate cancer ,Cancer ,Rare Diseases ,Prostate Cancer ,Biotechnology ,Urologic Diseases ,5.1 Pharmaceuticals ,Development of treatments and therapeutic interventions - Abstract
Although initially responsive to androgen signaling inhibitors (ASIs), metastatic castration-resistant prostate cancer (mCRPC) inevitably develops and is incurable. In addition to adenocarcinoma (adeno), neuroendocrine prostate cancer (NEPC) emerges to confer ASI resistance. We have previously combined laser capture microdissection and phage antibody display library selection on human cancer specimens and identified novel internalizing antibodies binding to tumor cells residing in their tissue microenvironment. We identified the target antigen for one of these antibodies as CD46, a multifunctional protein that is best known for negatively regulating the innate immune system. CD46 is overexpressed in primary tumor tissue and CRPC (localized and metastatic; adeno and NEPC), but expressed at low levels on normal tissues except for placental trophoblasts and prostate epithelium. Abiraterone- and enzalutamide-treated mCRPC cells upregulate cell surface CD46 expression. Genomic analysis showed that the CD46 gene is gained in 45% abiraterone-resistant mCRPC patients. We conjugated a tubulin inhibitor to our macropinocytosing anti-CD46 antibody and showed that the resulting antibody-drug conjugate (ADC) potently and selectively kills both adeno and NEPC cell lines in vitro (sub-nM EC50) but not normal cells. CD46 ADC regressed and eliminated an mCRPC cell line xenograft in vivo in both subcutaneous and intrafemoral models. Exploratory toxicology studies of the CD46 ADC in non-human primates demonstrated an acceptable safety profile. Thus, CD46 is an excellent target for antibody-based therapy development, which has potential to be applicable to both adenocarcinoma and neuroendocrine types of mCRPC that are resistant to current treatment.
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- 2018
94. Clinical and Genomic Characterization of Treatment-Emergent Small-Cell Neuroendocrine Prostate Cancer: A Multi-institutional Prospective Study.
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Aggarwal, Rahul, Huang, Jiaoti, Alumkal, Joshi J, Zhang, Li, Feng, Felix Y, Thomas, George V, Weinstein, Alana S, Friedl, Verena, Zhang, Can, Witte, Owen N, Lloyd, Paul, Gleave, Martin, Evans, Christopher P, Youngren, Jack, Beer, Tomasz M, Rettig, Matthew, Wong, Christopher K, True, Lawrence, Foye, Adam, Playdle, Denise, Ryan, Charles J, Lara, Primo, Chi, Kim N, Uzunangelov, Vlado, Sokolov, Artem, Newton, Yulia, Beltran, Himisha, Demichelis, Francesca, Rubin, Mark A, Stuart, Joshua M, and Small, Eric J
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Prostate Cancer ,Clinical Research ,Human Genome ,Genetics ,Cancer ,Urologic Diseases ,Detection ,screening and diagnosis ,4.2 Evaluation of markers and technologies ,Aged ,Aged ,80 and over ,Carcinoma ,Neuroendocrine ,DNA Repair ,Humans ,Male ,Middle Aged ,Prospective Studies ,Prostatic Neoplasms ,Castration-Resistant ,Clinical Sciences ,Oncology and Carcinogenesis ,Oncology & Carcinogenesis - Abstract
Purpose The prevalence and features of treatment-emergent small-cell neuroendocrine prostate cancer (t-SCNC) are not well characterized in the era of modern androgen receptor (AR)-targeting therapy. We sought to characterize the clinical and genomic features of t-SCNC in a multi-institutional prospective study. Methods Patients with progressive, metastatic castration-resistant prostate cancer (mCRPC) underwent metastatic tumor biopsy and were followed for survival. Metastatic biopsy specimens underwent independent, blinded pathology review along with RNA/DNA sequencing. Results A total of 202 consecutive patients were enrolled. One hundred forty-eight (73%) had prior disease progression on abiraterone and/or enzalutamide. The biopsy evaluable rate was 79%. The overall incidence of t-SCNC detection was 17%. AR amplification and protein expression were present in 67% and 75%, respectively, of t-SCNC biopsy specimens. t-SCNC was detected at similar proportions in bone, node, and visceral organ biopsy specimens. Genomic alterations in the DNA repair pathway were nearly mutually exclusive with t-SCNC differentiation ( P = .035). Detection of t-SCNC was associated with shortened overall survival among patients with prior AR-targeting therapy for mCRPC (hazard ratio, 2.02; 95% CI, 1.07 to 3.82). Unsupervised hierarchical clustering of the transcriptome identified a small-cell-like cluster that further enriched for adverse survival outcomes (hazard ratio, 3.00; 95% CI, 1.25 to 7.19). A t-SCNC transcriptional signature was developed and validated in multiple external data sets with > 90% accuracy. Multiple transcriptional regulators of t-SCNC were identified, including the pancreatic neuroendocrine marker PDX1. Conclusion t-SCNC is present in nearly one fifth of patients with mCRPC and is associated with shortened survival. The near-mutual exclusivity with DNA repair alterations suggests t-SCNC may be a distinct subset of mCRPC. Transcriptional profiling facilitates the identification of t-SCNC and novel therapeutic targets.
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- 2018
95. Genomic Hallmarks and Structural Variation in Metastatic Prostate Cancer.
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Quigley, David A, Dang, Ha X, Zhao, Shuang G, Lloyd, Paul, Aggarwal, Rahul, Alumkal, Joshi J, Foye, Adam, Kothari, Vishal, Perry, Marc D, Bailey, Adina M, Playdle, Denise, Barnard, Travis J, Zhang, Li, Zhang, Jin, Youngren, Jack F, Cieslik, Marcin P, Parolia, Abhijit, Beer, Tomasz M, Thomas, George, Chi, Kim N, Gleave, Martin, Lack, Nathan A, Zoubeidi, Amina, Reiter, Robert E, Rettig, Matthew B, Witte, Owen, Ryan, Charles J, Fong, Lawrence, Kim, Won, Friedlander, Terence, Chou, Jonathan, Li, Haolong, Das, Rajdeep, Li, Hui, Moussavi-Baygi, Ruhollah, Goodarzi, Hani, Gilbert, Luke A, Lara, Primo N, Evans, Christopher P, Goldstein, Theodore C, Stuart, Joshua M, Tomlins, Scott A, Spratt, Daniel E, Cheetham, R Keira, Cheng, Donavan T, Farh, Kyle, Gehring, Julian S, Hakenberg, Jörg, Liao, Arnold, Febbo, Philip G, Shon, John, Sickler, Brad, Batzoglou, Serafim, Knudsen, Karen E, He, Housheng H, Huang, Jiaoti, Wyatt, Alexander W, Dehm, Scott M, Ashworth, Alan, Chinnaiyan, Arul M, Maher, Christopher A, Small, Eric J, and Feng, Felix Y
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Humans ,Prostatic Neoplasms ,Neoplasm Metastasis ,Cyclin-Dependent Kinases ,Proto-Oncogene Proteins c-myc ,BRCA2 Protein ,Receptors ,Androgen ,Gene Expression Profiling ,Genomics ,Tandem Repeat Sequences ,Mutation ,Aged ,Aged ,80 and over ,Middle Aged ,Male ,Tumor Suppressor Protein p53 ,Genomic Structural Variation ,DNA Copy Number Variations ,Exome ,Whole Genome Sequencing ,BRCA2 ,androgen receptor ,castration resistant prostate cancer ,chromothripsis ,gene fusion ,genomics ,metastases ,structural variation ,tandem duplication ,whole-genome sequencing ,Biological Sciences ,Medical and Health Sciences ,Developmental Biology - Abstract
While mutations affecting protein-coding regions have been examined across many cancers, structural variants at the genome-wide level are still poorly defined. Through integrative deep whole-genome and -transcriptome analysis of 101 castration-resistant prostate cancer metastases (109X tumor/38X normal coverage), we identified structural variants altering critical regulators of tumorigenesis and progression not detectable by exome approaches. Notably, we observed amplification of an intergenic enhancer region 624 kb upstream of the androgen receptor (AR) in 81% of patients, correlating with increased AR expression. Tandem duplication hotspots also occur near MYC, in lncRNAs associated with post-translational MYC regulation. Classes of structural variations were linked to distinct DNA repair deficiencies, suggesting their etiology, including associations of CDK12 mutation with tandem duplications, TP53 inactivation with inverted rearrangements and chromothripsis, and BRCA2 inactivation with deletions. Together, these observations provide a comprehensive view of how structural variations affect critical regulators in metastatic prostate cancer.
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- 2018
96. A Phase II Trial of Selinexor, an Oral Selective Inhibitor of Nuclear Export Compound, in Abiraterone- and/or Enzalutamide-Refractory Metastatic Castration-Resistant Prostate Cancer.
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Wei, Xiao X, Siegel, Adam P, Aggarwal, Rahul, Lin, Amy M, Friedlander, Terence W, Fong, Lawrence, Kim, Won, Louttit, Mirela, Chang, Emily, Zhang, Li, and Ryan, Charles J
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Humans ,Hydrazines ,Triazoles ,Phenylthiohydantoin ,Androstenes ,Aged ,Middle Aged ,Male ,Prostatic Neoplasms ,Castration-Resistant ,Oncology and Carcinogenesis ,Oncology & Carcinogenesis - Abstract
Lessons learnedIn abiraterone- and/or enzalutamide-refractory metastatic castration-resistant prostate cancer (mCRPC) patients, selinexor led to prostate-specific antigen and/or radiographic responses in a subset of patients, indicating clinical activity in this indication.Despite twice-a-week dosing and maximal symptomatic management, selinexor was associated with significant anorexia, nausea, and fatigue in mCRPC patients refractory to second-generation anti-androgen therapies, limiting further clinical development in this patient population.This study highlights the challenge of primary endpoint selection for phase II studies in the post-abiraterone and/or post-enzalutamide mCRPC space.BackgroundSelinexor is a first-in-class selective inhibitor of nuclear export compound that specifically inhibits the nuclear export protein Exportin-1 (XPO-1), leading to nuclear accumulation of tumor suppressor proteins.MethodsThis phase II study evaluated the efficacy and tolerability of selinexor in patients with metastatic castration-resistant prostate cancer (mCRPC) refractory to abiraterone and/or enzalutamide.ResultsFourteen patients were enrolled. Selinexor was initially administered at 65 mg/m2 twice a week (days 1 and 3) and was subsequently reduced to 60 mg flat dose twice a week (days 1 and 3), 3 weeks on, 1 week off, to improve tolerability. The median treatment duration was 13 weeks. At a median follow-up of 4 months, two patients (14%) had ≥50% prostate-specific antigen (PSA) decline, and seven patients (50%) had any PSA decline. Of eight patients with measurable disease at baseline, two (25%) had a partial response and four (50%) had stable disease as their best radiographic response. Five patients (36%) experienced serious adverse events (SAEs; all unrelated to selinexor), and five patients (36%) experienced treatment-related grade 3-4 AEs. The most common drug-related adverse events (AEs) of any severity were anorexia, nausea, weight loss, fatigue, and thrombocytopenia. Three patients (21%) came off study for unacceptable tolerability.ConclusionSelinexor demonstrated clinical activity and poor tolerability in mCRPC patients refractory to second-line anti-androgenic agents.
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- 2018
97. Concordance of Circulating Tumor DNA and Matched Metastatic Tissue Biopsy in Prostate Cancer.
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Wyatt, Alexander W, Annala, Matti, Aggarwal, Rahul, Beja, Kevin, Feng, Felix, Youngren, Jack, Foye, Adam, Lloyd, Paul, Nykter, Matti, Beer, Tomasz M, Alumkal, Joshi J, Thomas, George V, Reiter, Robert E, Rettig, Matthew B, Evans, Christopher P, Gao, Allen C, Chi, Kim N, Small, Eric J, and Gleave, Martin E
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Genetics ,Cancer ,Human Genome ,Urologic Diseases ,Prostate Cancer ,4.1 Discovery and preclinical testing of markers and technologies ,Detection ,screening and diagnosis ,Good Health and Well Being ,Adenomatous Polyposis Coli Protein ,BRCA2 Protein ,Biomarkers ,Tumor ,Circulating Tumor DNA ,Class Ia Phosphatidylinositol 3-Kinase ,Cyclin-Dependent Kinase Inhibitor p27 ,DNA Copy Number Variations ,Humans ,Liquid Biopsy ,Male ,Mutation ,Neoplasm Metastasis ,Nuclear Proteins ,PTEN Phosphohydrolase ,Phosphatidylinositol 3-Kinases ,Prostatic Neoplasms ,Castration-Resistant ,Receptors ,Androgen ,Repressor Proteins ,Retinoblastoma Binding Proteins ,Tumor Suppressor Protein p53 ,Ubiquitin-Protein Ligases ,Wnt Signaling Pathway ,Oncology and Carcinogenesis ,Oncology & Carcinogenesis - Abstract
Real-time knowledge of the somatic genome can influence management of patients with metastatic castration-resistant prostate cancer (mCRPC). While routine metastatic tissue biopsy is challenging in mCRPC, plasma circulating tumor DNA (ctDNA) has emerged as a minimally invasive tool to sample the tumor genome. However, no systematic comparisons of matched "liquid" and "solid" biopsies have been performed that would enable ctDNA profiling to replace the need for direct tissue sampling. We performed targeted sequencing across 72 clinically relevant genes in 45 plasma cell-free DNA (cfDNA) samples collected at time of metastatic tissue biopsy. We compared ctDNA alterations with exome sequencing data generated from matched tissue and quantified the concordance of mutations and copy number alterations using the Fisher exact test and Pearson correlations. Seventy-five point six percent of cfDNA samples had a ctDNA proportion greater than 2% of total cfDNA. In these patients, all somatic mutations identified in matched metastatic tissue biopsies were concurrently present in ctDNA. Furthermore, the hierarchy of variant allele fractions for shared mutations was remarkably similar between ctDNA and tissue. Copy number profiles between matched liquid and solid biopsy were highly correlated, and individual copy number calls in clinically actionable genes were 88.9% concordant. Detected alterations included AR amplifications in 22 (64.7%) samples, SPOP mutations in three (8.8%) samples, and inactivating alterations in tumor suppressors TP53 , PTEN , RB1 , APC , CDKN1B , BRCA2 , and PIK3R1 . In several patients, ctDNA sequencing revealed robust changes not present in paired solid biopsy, including clinically relevant alterations in the AR, WNT, and PI3K pathways. Our study shows that, in the majority of patients, a ctDNA assay is sufficient to identify all driver DNA alterations present in matched metastatic tissue and supports development of DNA biomarkers to guide mCRPC patient management based on ctDNA alone.
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- 2017
98. Heterogeneous drug penetrance of veliparib and carboplatin measured in triple negative breast tumors
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Bartelink, Imke H, Prideaux, Brendan, Krings, Gregor, Wilmes, Lisa, Lee, Pei Rong Evelyn, Bo, Pan, Hann, Byron, Coppé, Jean-Philippe, Heditsian, Diane, Swigart-Brown, Lamorna, Jones, Ella F, Magnitsky, Sergey, Keizer, Ron J, de Vries, Niels, Rosing, Hilde, Pawlowska, Nela, Thomas, Scott, Dhawan, Mallika, Aggarwal, Rahul, Munster, Pamela N, Esserman, Laura J, Ruan, Weiming, Wu, Alan HB, Yee, Douglas, Dartois, Véronique, Savic, Radojka M, Wolf, Denise M, and van ’t Veer, Laura
- Subjects
Biomedical and Clinical Sciences ,Oncology and Carcinogenesis ,Breast Cancer ,Brain Disorders ,Cancer ,Clinical Research ,5.1 Pharmaceuticals ,Development of treatments and therapeutic interventions ,Animals ,Benzimidazoles ,Carboplatin ,Cell Line ,Tumor ,Female ,Humans ,Leukocytes ,Mononuclear ,Mice ,Penetrance ,Poly(ADP-ribose) Polymerase Inhibitors ,Spectrometry ,Mass ,Matrix-Assisted Laser Desorption-Ionization ,Triple Negative Breast Neoplasms ,Xenograft Model Antitumor Assays ,Drug penetration ,Spatial heterogeneity ,Pharmacokinetics ,Matrix-assisted laser desorption/ionization mass spectrometric imaging ,Poly(ADP-ribose) polymerase inhibitors ,Inductively coupled plasma-mass spectrometry ,Inductively coupled plasma–mass spectrometry ,Oncology & Carcinogenesis ,Oncology and carcinogenesis - Abstract
BackgroundPoly(ADP-ribose) polymerase inhibitors (PARPi), coupled to a DNA damaging agent is a promising approach to treating triple negative breast cancer (TNBC). However, not all patients respond; we hypothesize that non-response in some patients may be due to insufficient drug penetration. As a first step to testing this hypothesis, we quantified and visualized veliparib and carboplatin penetration in mouse xenograft TNBCs and patient blood samples.MethodsMDA-MB-231, HCC70 or MDA-MB-436 human TNBC cells were implanted in 41 beige SCID mice. Low dose (20 mg/kg) or high dose (60 mg/kg) veliparib was given three times daily for three days, with carboplatin (60 mg/kg) administered twice. In addition, blood samples were analyzed from 19 patients from a phase 1 study of carboplatin + PARPi talazoparib. Veliparib and carboplatin was quantified using liquid chromatography-mass spectrometry (LC-MS). Veliparib tissue penetration was visualized using matrix-assisted laser desorption/ionization mass spectrometric imaging (MALDI-MSI) and platinum adducts (covalent nuclear DNA-binding) were quantified using inductively coupled plasma-mass spectrometry (ICP-MS). Pharmacokinetic modeling and Pearson's correlation were used to explore associations between concentrations in plasma, tumor cells and peripheral blood mononuclear cells (PBMCs).ResultsVeliparib penetration in xenograft tumors was highly heterogeneous between and within tumors. Only 35% (CI 95% 26-44%), 74% (40-97%) and 46% (9-37%) of veliparib observed in plasma penetrated into MDA-MB-231, HCC70 and MDA-MB-436 cell-based xenografts, respectively. Within tumors, penetration heterogeneity was larger with the 60 mg/kg compared to the 20 mg/kg dose (RSD 155% versus 255%, P = 0.001). These tumor concentrations were predicted similar to clinical dosing levels, but predicted tumor concentrations were below half maximal concentration values as threshold of response. Xenograft veliparib concentrations correlated positively with platinum adduct formation (R 2 = 0.657), but no PARPi-platinum interaction was observed in patients' PBMCs. Platinum adduct formation was significantly higher in five gBRCA carriers (ratio of platinum in DNA in PBMCs/plasma 0.64% (IQR 0.60-1.16%) compared to nine non-carriers (ratio 0.29% (IQR 0.21-0.66%, P
- Published
- 2017
99. Association Between Medicare Program Type and Health Care Access, Acute Care Utilization, and Affordability Among Adults With Cardiovascular Disease
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Oseran, Andrew S., Sun, Tianyu, Aggarwal, Rahul, Kyalwazi, Ashley, Yeh, Robert W., and Wadhera, Rishi K.
- Published
- 2022
- Full Text
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100. Supplementary Table 2 from Immune Modulation with RANKL Blockade through Denosumab Treatment in Patients with Cancer
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Chang, Hewitt, primary, Marquez, Jaqueline, primary, Chen, Brandon K., primary, Kim, Daniel M., primary, Cheng, Michael L., primary, Liu, Eric V., primary, Yang, Hai, primary, Zhang, Li, primary, Sinha, Meenal, primary, Cheung, Alexander, primary, Kwek, Serena S., primary, Chow, Eric D., primary, Bridge, Mark, primary, Aggarwal, Rahul R., primary, Friedlander, Terence W., primary, Small, Eric J., primary, Anderson, Mark, primary, and Fong, Lawrence, primary
- Published
- 2024
- Full Text
- View/download PDF
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