ABSTRACT
Treatment paradigms for patients with upper tract urothelial carcinoma (UTUC) are typically extrapolated from studies of bladder cancer despite their distinct clinical and molecular characteristics. The advancement of UTUC research is hampered by the lack of disease-specific models. Here, we report the establishment of patient derived xenograft (PDX) and cell line models that reflect the genomic and biological heterogeneity of the human disease. Models demonstrate high genomic concordance with the corresponding patient tumors, with invasive tumors more likely to successfully engraft. Treatment of PDX models with chemotherapy recapitulates responses observed in patients. Analysis of a HER2 S310F-mutant PDX suggests that an antibody drug conjugate targeting HER2 would have superior efficacy versus selective HER2 kinase inhibitors. In sum, the biological and phenotypic concordance between patient and PDXs suggest that these models could facilitate studies of intrinsic and acquired resistance and the development of personalized medicine strategies for UTUC patients.
Subject(s)
Carcinoma, Transitional Cell/genetics , Carcinoma, Transitional Cell/pathology , Gene Expression Regulation, Neoplastic , Urinary Bladder Neoplasms/genetics , Urinary Bladder Neoplasms/pathology , Urothelium/pathology , Aged , Animals , Antibodies, Monoclonal, Humanized/pharmacology , Antineoplastic Agents/pharmacology , Biopsy , Camptothecin/analogs & derivatives , Camptothecin/pharmacology , Female , Gene Expression Profiling , Genetic Variation , High-Throughput Nucleotide Sequencing , Humans , Immunoconjugates/pharmacology , Interleukin Receptor Common gamma Subunit/genetics , Male , Mice , Mice, Inbred NOD , Mice, SCID , Middle Aged , Mutation , Neoplasm Metastasis , Neoplasm Transplantation , Phenotype , Precision Medicine , Prospective Studies , Quinolines/pharmacology , Retrospective Studies , Sequence Analysis, RNA , TrastuzumabABSTRACT
18F-fluorodihydrotestosterone (18F-FDHT) PET/CT potentially provides a noninvasive method for assessment of androgen receptor expression in patients with metastatic castration-resistant prostate cancer (mCRPC). The objective of this study was to assess simplified methods for quantifying 18F-FDHT uptake in mCRPC patients and to assess effects of tumor perfusion on these 18F-FDHT uptake metrics. Methods: Seventeen mCRPC patients were included in this prospective observational multicenter study. Test and retest 30-min dynamic 18F-FDHT PET/CT scans with venous blood sampling were performed in 14 patients. In addition, arterial blood sampling and dynamic 15O-H2O scans were obtained in a subset of 6 patients. Several simplified methods were assessed: Patlak plots; SUV normalized to body weight (SUVBW), lean body mass (SUVLBM), whole blood (SUVWB), parent plasma activity concentration (SUVPP), area under the parent plasma curve (SUVAUC,PP), and area under the whole-blood input curve (SUVAUC,WB); and SUVBW corrected for sex hormone-binding globulin levels (SUVSHBG). Results were correlated with parameters derived from full pharmacokinetic 18F-FDHT and 15O-H2O. Finally, the repeatability of individual quantitative uptake metrics was assessed. Results: Eighty-seven 18F-FDHT-avid lesions were evaluated. 18F-FDHT uptake was best described by an irreversible 2-tissue-compartment model. Replacing the continuous metabolite-corrected arterial plasma input function with an image-derived input function in combination with venous sample data provided similar Ki results (R2 = 0.98). Patlak Ki and SUVAUC,PP showed an excellent correlation (R2 > 0.9). SUVBW showed a moderate correlation to Ki (R2 = 0.70, presumably due to fast 18F-FDHT metabolism. When calculating SUVSHBG, correlation to Ki improved (R2 = 0.88). The repeatability of full kinetic modeling parameters was inferior to that of simplified methods (repeatability coefficients > 36% vs. < 28%, respectively). 18F-FDHT uptake showed minimal blood flow dependency. Conclusion:18F-FDHT kinetics in mCRPC patients are best described by an irreversible 2-tissue-compartment model with blood volume parameter. SUVAUC,PP showed a near-perfect correlation with the irreversible 2-tissue-compartment model analysis and can be used for accurate quantification of 18F-FDHT uptake in whole-body PET/CT scans. In addition, SUVSHBG could potentially be used as an even simpler method to quantify 18F-FDHT uptake when less complex scanning protocols and accuracy are required.
Subject(s)
Dihydrotestosterone/analogs & derivatives , Fluorine Radioisotopes/pharmacokinetics , Positron Emission Tomography Computed Tomography , Prostatic Neoplasms, Castration-Resistant/diagnostic imaging , Aged , Aged, 80 and over , Body Weight , Dihydrotestosterone/pharmacokinetics , Humans , Image Processing, Computer-Assisted , Kinetics , Male , Middle Aged , Neoplasm Metastasis , Prospective Studies , Radiopharmaceuticals/pharmacokinetics , Reproducibility of ResultsABSTRACT
The unprecedented progress in the treatment of metastatic castration-resistant prostate cancer is only beginning to be realized in patients with noncastrate disease. This slow progress in part reflects the use of trial objectives focused on time-to-event end points, such as time to metastasis and overall survival, which require long follow-up durations and large sample sizes, and has been further delayed by the use of approved therapies that are effective at the time of progression. Our central hypotheses are that progress can be accelerated, and that outcomes can be improved by shifting trial objectives to response measures occurring early that solely reflect the effects of the treatment. To test these hypotheses, a continuously enrolling multi-arm, multi-stage randomized trial design, analogous to that used in the STAMPEDE trial, has been developed. Eligibility is focused on patients with incurable disease or those with a high risk of death with any form of monotherapy alone. The primary objective is to eliminate all disease using a multimodality treatment strategy. End points include pathological complete response and an undetectable level of serum prostate-specific antigen, with recovery of serum testosterone levels. Both are binary, objective, and provide an early, quantitative indication of efficacy.
Subject(s)
Androgen Antagonists/therapeutic use , Drug Development , Prostatic Neoplasms/drug therapy , Humans , Male , Neoplasm Metastasis , Progression-Free Survival , Prostate-Specific Antigen/blood , Prostatic Neoplasms/blood , Prostatic Neoplasms/epidemiology , Randomized Controlled Trials as TopicABSTRACT
This corrects the article DOI: 10.1038/nrclinonc.2017.160.
