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Monitoring PSMA Responses to ADT in Prostate Cancer Patient-Derived Xenograft Mouse Models Using [18F]DCFPyL PET Imaging

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Abstract

Purpose

PSMA overexpression has been associated with aggressive prostate cancer (PCa). However, PSMA PET imaging has revealed highly variable changes in PSMA expression in response to ADT treatment ranging from increases to moderate decreases. To better understand these PSMA responses and potential relationship to progressive PCa, the PET imaging agent, [18F]DCFPyL, was used to assess changes in PSMA expression in response to ADT using genomically characterized LuCaP patient-derived xenograft mouse models (LuCaP-PDXs) which were found to be sensitive to ADT (LuCaP73 and LuCaP136;CS) or resistant (LuCaP167;CR).

Methods

[18F]DCFPyL (2-(3-{1-carboxy-5-[(6-[18F]fluoro-pyridine-3-carbonyl)-amino]-pentyl}-ureido)-pentanedioic acid) was used to assess PSMA in vitro (saturation assays) in LuCaP tumor membrane homogenates and in vivo (imaging/biodistribution) in LuCaP-PDXs. Control and ADT-treated LuCaPs were imaged before ADT (0 days) and 2-, 7-, 14-, and 21-days post-ADT from which tumor:muscle ratios (T:Ms) were determined and concurrently tumor volumes were measured (caliper). After the 21-day imaging, biodistributions and histologic/genomic (PSMA, AR) analysis were done.

Results

[18F]DCFPyL exhibited high affinity for PSMA and distinguished different levels of PSMA in LuCaP tumors. Post-ADT CS LuCaP73 and LuCaP136 tumor volumes significantly decreased at day 7 or 14 respectively vs controls, whereas the CR LuCaP167 tumor volumes were minimally changed. [18F]DCFPyL imaging T:Ms were increased 3–5-fold in treated LuCaP73 tumors vs controls, while treated LuCaP136 T:Ms remained unchanged which was confirmed by day 21 biodistribution results. For treated LuCaP167, T:Ms were decreased (~ 45 %) vs controls but due to low T:M values (<2) may not be indicative of PSMA level changes. LuCaP73 tumor PSMA histologic/genomic results were comparable to imaging/biodistribution results, whereas the results for other tumor types varied.

Conclusion

Tumor responses to ADT varied from sensitive to resistant among these LuCaP PDXs, while only the high PSMA expressing LuCaP model exhibited an increase in PSMA levels in response to ADT. These models may be useful in understanding the clinical relevance of PSMA PET responses to ADT and potentially the relationship to disease progression as it may relate to the genomic signature.

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Funding

This project was funded by National Cancer Institute, National Institutes of Health. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organization imply endorsement by the US Government.

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Authors and Affiliations

  1. Molecular Imaging Program, NCI/NIH, Center for Cancer Research, National Cancer Institute, Building 10, Room B3B406, Bethesda, MD, 20892, USA

    Jyoti Roy, Karen Wong, Anita T. Ton, Frank I. Lin, Peter L. Choyke & Elaine M. Jagoda

  2. Laboratory of Genitourinary Cancer Pathogenesis NCI/NIH, Bethesda, MD, USA

    Margaret E. White, Morgan Riba, Keith H. Jansson & Kathleen Kelly

  3. Chemistry and Synthesis Center, NHLBI/NIH, Rockville, MD, USA

    Falguni Basuli, Ana Christina L. Opina & Xiang Zhang

  4. Pathology/Histotechnology Laboratory, Leidos, Inc./Frederick National Laboratory for Cancer Research, NCI, Frederick, MD, USA

    Elijah Edmondson & Donna Butcher

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  1. Jyoti Roy
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  2. Margaret E. White
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  3. Falguni Basuli
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Contributions

JR: Data acquisition, analysis, and interpretation; draft and revise manuscript

MW: Data acquisition, analysis, and interpretation; revise manuscript

FB: Data acquisition; revise manuscript

AC: Data acquisition, analysis, and interpretation; revise manuscript

KW: Data acquisition; revise manuscript

MR: Data acquisition and analysis

ATT: Data acquisition; revise manuscript

XZ: Data acquisition, revise manuscript

KHJ: Data acquisition, revise manuscript

EE: Data acquisition, revise manuscript

DB: Data acquisition, revise manuscript

FIL: Revise manuscript

PLC: Study design, revise manuscript

KK: Study design, revise manuscript

EMJ: Study design; data acquisition, analysis, and interpretation; revise manuscript

All authors read and approved the final manuscript

Corresponding author

Correspondence to Elaine M. Jagoda.

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All animal experiments were conducted in compliance with the protocols approved by Animal Care and Use Committee of National Institutes of Health.

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Roy, J., White, M.E., Basuli, F. et al. Monitoring PSMA Responses to ADT in Prostate Cancer Patient-Derived Xenograft Mouse Models Using [18F]DCFPyL PET Imaging. Mol Imaging Biol 23, 745–755 (2021). https://doi.org/10.1007/s11307-021-01605-0

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