[18F]-FDHT PET/CT as a tool for imaging androgen receptor expression in high-grade glioma

Abstract

Background Glioblastoma (GBM) is associated with poor overall survival. Recently, we showed that androgen receptor (AR) protein is overexpressed in 56% of GBM specimens and AR antagonists induced dose-dependent death in several GBM cell lines and significantly reduced tumor growth and prolonged the lifespan of mice implanted with human GBM. 16β-18F-fluoro-5α-dihydrotestosterone ([18F]-FDHT) is a PET tracer used to detect AR expression in prostate and breast cancers. This study was aimed at exploring the ability of [18F]-FDHT-PET to detect AR expression in high-grade gliomas. Methods Twelve patients with suspected high-grade glioma underwent a regular workup and additional dynamic and static [ 18 F]-FDHT-PET/CT. Visual and quantitative analyses of [ 18 F]-FDHT kinetics in the tumor and normal brain were performed. Mean and maximum (max) standardized uptake values (SUVs) were determined in selected volumes of interest. The patients had surgery or biopsy after PET/CT. AR protein was analyzed in the tumor samples by western blot. Fold change in AR expression was calculated by densitometry analysis. Correlation between imaging and AR protein samples was determined. Results In six of the 12 patients, [ 18 F]-FDHT uptake was significantly higher in the tumor than in the normal brain. These patients also had increased AR protein expression within the tumor. Pearson correlation coefficient analysis for the tumor-to-control normal brain uptake ratio in terms of SUVmean versus AR protein expression, was positive and significant (R = 0.84; p = 0.002). Conclusion [ 18 F]-FDHT-PET/CT could identify increased AR expression in high-grade glioma.

Androgen Receptor Expression in the Various Regions of Resected Glioblastoma Multiforme Tumors and in an In Vitro Model

“…Our observations of different levels of AR protein expression in different GBM tumor structures indirectly confirm the results of the study by Orevi et al [ 31 ]. In their work, the authors used imaging to identify AR-positive gliomas.…”

“…However, this may be due to different post-transcriptional processes in these structures. This assumption is supported by the observation of Zalcman et al [ 22 ] and Orevi et al [ 31 ], who found no correlation between AR mRNA and AR protein expressions.…”

Androgen Receptor Expression in the Various Regions of Resected Glioblastoma Multiforme Tumors and in an In Vitro Model

“…Our observations of different levels of AR protein expression in different GBM tumor structures indirectly confirm the results of the study by Orevi et al [ 31 ]. In their work, the authors used imaging to identify AR-positive gliomas.…”

“…However, this may be due to different post-transcriptional processes in these structures. This assumption is supported by the observation of Zalcman et al [ 22 ] and Orevi et al [ 31 ], who found no correlation between AR mRNA and AR protein expressions.…”

Androgen Receptor Imaging in the Management of Hormone-Dependent Cancers with Emphasis on Prostate Cancer

“…The tumor-to-normal brain SUVmean uptake ratio correlated positively with the AR protein expression, and this correlation was statistically significant (Pearson's correlation coefficient r = 0.84; p < 0.002) [52]. Orevi et al, also presented two patients imaged using [ 18 F]FDHT; one patient had a high glioma-associated tumor uptake and another patient with gliomatosis cerebri did not show any tumor uptake [52]. The dynamic imaging could confirm these differences with the time-activity curves of the SUVmax corresponding to the surgically extirpated areas and normal brain [52].…”

“…Orevi et al, also presented two patients imaged using [ 18 F]FDHT; one patient had a high glioma-associated tumor uptake and another patient with gliomatosis cerebri did not show any tumor uptake [52]. The dynamic imaging could confirm these differences with the time-activity curves of the SUVmax corresponding to the surgically extirpated areas and normal brain [52].…”

Intracranial Assessment of Androgen Receptor Antagonists in Mice Bearing Human Glioblastoma Implants

“…The clinical translation of our research findings into a PET/CT-guided human clinical trial is a significant step forward, aligning with the vision of precision medicine. The utilization of the fluoro-5α dihydrotestosterone tracer for identifying high AR expression in glioblastoma tumors, as pioneered by Orevi et al [ 4 ], is a notable advancement. The work of Orevi et al highlights the feasibility of certifying patients for AR antagonist therapy based on the presence of AR protein in their tumors, thereby opening doors for personalized treatment approaches.…”

Androgen Receptor Expression in the Various Regions of Resected Glioblastoma Multiforme Tumors and in an In Vitro Model

“…Our observations of different levels of AR protein expression in different GBM tumor structures indirectly confirm the results of the study by Orevi et al [ 31 ]. In their work, the authors used imaging to identify AR-positive gliomas.…”

“…However, this may be due to different post-transcriptional processes in these structures. This assumption is supported by the observation of Zalcman et al [ 22 ] and Orevi et al [ 31 ], who found no correlation between AR mRNA and AR protein expressions.…”

Androgen Receptor Imaging in the Management of Hormone-Dependent Cancers with Emphasis on Prostate Cancer

“…The tumor-to-normal brain SUVmean uptake ratio correlated positively with the AR protein expression, and this correlation was statistically significant (Pearson's correlation coefficient r = 0.84; p < 0.002) [52]. Orevi et al, also presented two patients imaged using [ 18 F]FDHT; one patient had a high glioma-associated tumor uptake and another patient with gliomatosis cerebri did not show any tumor uptake [52]. The dynamic imaging could confirm these differences with the time-activity curves of the SUVmax corresponding to the surgically extirpated areas and normal brain [52].…”

“…Orevi et al, also presented two patients imaged using [ 18 F]FDHT; one patient had a high glioma-associated tumor uptake and another patient with gliomatosis cerebri did not show any tumor uptake [52]. The dynamic imaging could confirm these differences with the time-activity curves of the SUVmax corresponding to the surgically extirpated areas and normal brain [52].…”

Intracranial Assessment of Androgen Receptor Antagonists in Mice Bearing Human Glioblastoma Implants

“…The clinical translation of our research findings into a PET/CT-guided human clinical trial is a significant step forward, aligning with the vision of precision medicine. The utilization of the fluoro-5α dihydrotestosterone tracer for identifying high AR expression in glioblastoma tumors, as pioneered by Orevi et al [ 4 ], is a notable advancement. The work of Orevi et al highlights the feasibility of certifying patients for AR antagonist therapy based on the presence of AR protein in their tumors, thereby opening doors for personalized treatment approaches.…”

Androgen Receptor Expression in the Various Regions of Resected Glioblastoma Multiforme Tumors and in an In Vitro Model

“…Our observations of different levels of AR protein expression in different GBM tumor structures indirectly confirm the results of the study by Orevi et al [ 31 ]. In their work, the authors used imaging to identify AR-positive gliomas.…”

“…However, this may be due to different post-transcriptional processes in these structures. This assumption is supported by the observation of Zalcman et al [ 22 ] and Orevi et al [ 31 ], who found no correlation between AR mRNA and AR protein expressions.…”

Androgen Receptor Imaging in the Management of Hormone-Dependent Cancers with Emphasis on Prostate Cancer

“…The tumor-to-normal brain SUVmean uptake ratio correlated positively with the AR protein expression, and this correlation was statistically significant (Pearson's correlation coefficient r = 0.84; p < 0.002) [52]. Orevi et al, also presented two patients imaged using [ 18 F]FDHT; one patient had a high glioma-associated tumor uptake and another patient with gliomatosis cerebri did not show any tumor uptake [52]. The dynamic imaging could confirm these differences with the time-activity curves of the SUVmax corresponding to the surgically extirpated areas and normal brain [52].…”

“…Orevi et al, also presented two patients imaged using [ 18 F]FDHT; one patient had a high glioma-associated tumor uptake and another patient with gliomatosis cerebri did not show any tumor uptake [52]. The dynamic imaging could confirm these differences with the time-activity curves of the SUVmax corresponding to the surgically extirpated areas and normal brain [52].…”

Intracranial Assessment of Androgen Receptor Antagonists in Mice Bearing Human Glioblastoma Implants

“…The clinical translation of our research findings into a PET/CT-guided human clinical trial is a significant step forward, aligning with the vision of precision medicine. The utilization of the fluoro-5α dihydrotestosterone tracer for identifying high AR expression in glioblastoma tumors, as pioneered by Orevi et al [ 4 ], is a notable advancement. The work of Orevi et al highlights the feasibility of certifying patients for AR antagonist therapy based on the presence of AR protein in their tumors, thereby opening doors for personalized treatment approaches.…”