18F-DCFPyL (PSMA) PET as a radiotherapy response assessment tool in metastatic prostate cancer

Aruz Mesci; Elham Ahmadi; Amr Ali; Mohammad Gouran-Savadkoohi; Evangelia Evelyn Tsakiridis; Olga-Demetra Biziotis; Tom Chow; Anil Kapoor; Monalisa Sur; Gregory R Steinberg; Stanley Liu; Katherine Zukotynski; Theodoros Tsakiridis

doi:10.1016/j.ctro.2023.100583

¹⁸F-DCFPyL (PSMA) PET as a radiotherapy response assessment tool in metastatic prostate cancer

Clin Transl Radiat Oncol. 2023 Jan 18:39:100583. doi: 10.1016/j.ctro.2023.100583. eCollection 2023 Mar.

Authors

Aruz Mesci^{1

2}, Elham Ahmadi^{2

3}, Amr Ali^{2

3}, Mohammad Gouran-Savadkoohi^{1

2}, Evangelia Evelyn Tsakiridis^{4

3}, Olga-Demetra Biziotis^{2

3}, Tom Chow⁵, Anil Kapoor⁶, Monalisa Sur⁷, Gregory R Steinberg^{4

3}, Stanley Liu⁸, Katherine Zukotynski⁹, Theodoros Tsakiridis^{1

2

3}

Affiliations

¹ Radiation Oncology, Juravinski Cancer Centre, Hamilton Health Sciences, Ontario, Canada.
² Dept. of Oncology, McMaster University, Hamilton, Ontario, Canada.
³ Centre for Metabolism, Obesity and Diabetes Research, McMaster University, Hamilton, Ontario, Canada.
⁴ Dept. of Medicine, McMaster University, Hamilton, Ontario, Canada.
⁵ Physics, Juravinski Cancer Centre, Hamilton Health Sciences, Ontario, Canada.
⁶ Division of Urology, McMaster University and St. Joseph's Hospital, Hamilton, Ontario, Canada.
⁷ Dept. of Pathology, McMaster University, Hamilton, Ontario, Canada.
⁸ Radiation Oncology, Odette Cancer Centre, Sunnybrook Health Sciences Centre, University of Toronto, Toronto, Ontario, Canada.
⁹ Dept. of Radiology, McMaster University, Hamilton, Ontario, Canada.

Abstract

Background: Prostate Specific Membrane Antigen (PSMA) - positron emission tomography (PET) guides metastasis-directed radiotherapy (MDRT) in prostate cancer (PrCa). However, its value as a treatment response assessment tool after MDRT remains unclear. Importantly, there is limited understanding of the potential of radiotherapy (RT) to alter PSMA gene (folate hydrolase 1; FOLH1) expression.

Methodology: We reviewed a series of 11 men with oligo-metastatic PrCa (25 metastasis sites) treated with MDRT before re-staging with ¹⁸F-DCFPyL (PSMA) PET upon secondary recurrence. Acute effects of RT on PSMA protein and mRNA levels were examined with qPCR and immunoblotting in human wild-type androgen-sensitive (LNCap), castrate-resistant (22RV1) and castrate-resistant neuroendocrine (PC3 and DU145) PrCa cell lines. Xenograft tumors were analyzed with immunohistochemistry. Further, we examined PSMA expression in untreated and irradiated radio-resistant (RR) 22RV1 (22RV1-RR) and DU145 (DU145-RR) cells and xenografts selected for survival after high-dose RT.

Results: The majority of MDRT-treated lesions showed lack of PSMA-PET/CT avidity, suggesting treatment response even after low biological effective dose (BED) MDRT. We observed similar high degree of heterogeneity of PSMA expression in both human specimens and in xenograft tumors. PSMA was highly expressed in LNCap and 22RV1 cells and tumors but not in the neuroendocrine PC3 and DU145 models. Single fraction RT caused detectable reduction in PSMA protein but not in mRNA levels in LNCap cells and did not significantly alter PSMA protein or mRNA levels in tissue culture or xenografts of the other cell lines. However, radio-resistant 22RV1-RR cells and tumors demonstrated marked decrease of PSMA transcript and protein expression over their parental counterparts.

Conclusions: PSMA-PET may be a promising tool to assess RT response in oligo-metastatic PrCa. However, future systematic investigation of this concept should recognize the high degree of heterogeneity of PSMA expression within prostate tumors and the risk for loss of PSMA expression in tumor surviving curative courses of RT.

Keywords: ADT, Androgen Deprivation Therapy; AMACR, Alpha-Methylacyl-CoA Racemase; ARAT, Androgen Receptor Axis-Targeted; BED, Biological Effective Dose; CRPC, Castration Resistant Prostate Cancer; FOLH1 expression; FOLH1, Folate Hydrolase 1; H&E, Hematoxylin and Eosin; H-Score, Histologic Score; HSPC, Hormone Sensitive Prostate Cancer; IHC, Immunohistochemistry; Immunohistochemistry; LHRH, Luteinizing Hormone Releasing Hormone; MDRT, Metastasis Directed Radiotherapy; NH, Hormone Naïve; P-H3, Phosphorylated Histone-H3; PET, Positron Emission Tomography; PSA, Prostate Specific Antigen; PSMA, Prostate Specific Membrane Antigen; PSMA-PET; PrCa, Prostate Cancer; RP, Radical Prostatectomy; RT, Radiation Therapy; Radio-resistance; Rec, Recurrence; SUV, Standardized Uptake Value; Tumor heterogeneity; mCRPC, Metastatic Castration Resistant Prostate Cancer; mRNA, Messenger Ribonucleic Acid; qPCR; qPCR, Quantitative Polymerase Chain Reaction.