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SNMMI 2024: Non-PSMA Targets for Prostate Cancer Radiopharmaceutical Therapies

(UroToday.com) The Society of Nuclear Medicine & Molecular Imaging (SNMMI) 2024 Annual Meeting held in Toronto, ON between June 8th and June 11th, 2024 was host to a prostate cancer novel approaches and combination therapies session. Dr. Hossein Jadvar discussed non-PSMA targets for prostate cancer radiopharmaceutical therapies, including:

  • GRPR – Gastrin Releasing Peptide Receptor
  • FAP – Fibroblast Activation Protein (FAP)
  • PSCA – Prostate Stem Cell Antigen (PSCA)
  • CD46 – Cluster of Differentiation 46
  • DLL3 – Delta-like Ligand 3
  • GPC3 – Glypican-3
  • hK2 – Human Kallikrein 2
  • STEAP1 – Six-transmembrane Epithelial Antigen of Prostate-1
  • TROP-2 – Transmembrane GlycoproteinTrophoblast Cell Surface Antigen-2
  • TK – Thymidine Kinase
  • VCN – Vicrostatin

Gastrin Releasing Peptide (GRP) is a mammalian counterpart of amphibian bombesin (BBN; natural 14-AA peptide). Its receptors include:

  • BB1 (neuromedin-BR)
  • BB2 (GRPr)
  • BB3 (orphan)
  • BB4 (amphibian)

GRP-r is expressed at only very low levels in normal prostate glands but is increased in 45–100% of human prostate cancers. Patients with mCRPC + neuroendocrine differentiation (present in 30–100% of mCRPC cases) have tumors with high GRP, activation of GRPr, and stimulation of proliferation. There is increasing interest in the use of nonradioactive, cytotoxic and radioactive GRP analogues that target GRP-r-expressing cancers. Nonradioactive GRP-r antagonists can inhibit the growth of androgen-dependent and -independent prostate cancer xenografts. However, the radioactive GRP analogues have shown the most promising antitumor results. 177Lu-labelled GRP-r antagonist (177Lu-RM2) at high doses was able to induce a complete remission in six out of 10 mice with PC-3 xenografts.1,2

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In 2013, Roivainen and colleagues published the first-in-human study investigating the safety, tolerability, metabolism, pharmacokinetics, biodistribution, and radiation dosimetry of the 68Ga-bombesin antagonist 68Ga-DOTA-4-amino-1-carboxymethylpiperidine-d-Phe-Gln-Trp-Ala-Val-Gly-His-Sta-Leu-NH2 (BAY 86-7548). Five healthy men underwent dynamic whole-body PET/CT after an intravenous injection of BAY 86-7548 (138 ± 5 MBq). Three radioactive plasma metabolites were detected. The proportion of unchanged BAY 86-7548 decreased from 92% ± 9% at 1 min after injection to 19% ± 2% at 65 min. The organs with the highest absorbed doses were the urinary bladder wall (0.62 mSv/MBq) and the pancreas (0.51 mSv/MBq). The mean effective dose was 0.051 mSv/MBq. BAY 86-7548 was well tolerated by all subjects. The investigators concluded that intravenously injected BAY 86-7548 is safe, and rapid metabolism is demonstrated. A 150-MBq injection of BAY 86-7548 results in an effective dose of 7.7 mSv, which could be reduced to 5.7 mSv with frequent bladder voids.3

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As previously noted, 68Ga-RM2 is a synthetic bombesin receptor antagonist that targets the gastrin-releasing peptide receptor. In 2018, Minamimoto et al. published the results of a study of  68Ga-RM2 in patients with biochemical recurrence and negative findings on conventional imaging (n=32). The observed 68Ga-RM2 PET detection rate was 72%. 68Ga-RM2 PET identified recurrent prostate cancer in 23 of the 32 participants, whereas the simultaneous MRI scan identified recurrent disease in 11 of the 32 patients. The investigators concluded that 68Ga-RM2 PET can be used for assessment of GRPr expression in patients with biochemical recurrence. High uptake in multiple areas compatible with cancer lesions suggests that 68Ga-RM2 is a promising PET radiopharmaceutical for localization of disease in patients with biochemical recurrence and negative findings on conventional imaging.4

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To date, however, it appears that 68Ga-PSMA-11 still outperforms 68Ga-RM2 PET/MRI scans in the biochemically recurrent setting. As demonstrated in the figure below, 68Ga-PSMA-11 PET/CT was able to detect lymph node and seminal vesicle disease in a patient with no abnormal 68Ga-RM2 PET/MRI uptake.5 Better understanding of these two modalities and how they contrast/complement each other requires further investigation.

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In 2021, Baratto et al. published the results of a 50-patient study comparing 68Ga-RM2 PET/MRI to 68Ga-PSMA11 PET/CT (n = 23) or 18F-DCFPyL PET/CT (n = 27) in the biochemically recurrent setting. RM2 PET was positive in 35 and negative in 15 of the 50 patients. PSMA PET was positive in 37 and negative in 13 of the 50 patients. Both scans detected 70 lesions in 32 patients. Forty-three lesions in 18 patients were identified only on one scan: 68Ga-RM2 detected seven more lesions in four patients, while PSMA detected 36 more lesions in 13 patients. The authors concluded that 68Ga-RM2 is a valuable radiopharmaceutical even when compared with the more widely used 68Ga-PSMA11/18F-DCFPyL in the evaluation of biochemically recurrent prostate cancer.6

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More recently in 2024, Fernandez et al. published the results of a study evaluating the expression of GRPr and PSMA in a cohort of 17 mCRPC patients, who were referred for radioligand therapy and underwent 68Ga-PSMA-11 and 68Ga-RM2 PET/CT imaging 8.8 ± 8.6 days apart, to compare the biodistribution of each tracer. 68Ga-PSMA-11 demonstrated significantly higher uptake in tumor lesions in bone, lymph nodes, prostate, and soft tissues and detected 23% more lesions compared to 68Ga-RM2. In 4/17 patients (23.5%), the biodistribution of both tracers was comparable. These results suggest that PSMA expression in mCRPC patients was higher compared to GRPr.7

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The next biologic target discussed by Dr. Jadvar was Fibroblast Activation Protein (FAP).

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FAP inhibitor–based molecular imaging has shown encouraging results in cancer diagnosis, making them innovative targets for FAP inhibitor–based radionuclide therapies. Cancer-associated fibroblasts (CAFs) are a critical and abundant component of the tumor microenvironment. These are involved in tumor progression, including tumorigenesis, neoangiogenesis, metastasis, immunosuppression, and drug resistance. Activated CAFs have fibroblast activation protein (FAP) a receptors, which are imaged using several small FAP inhibitors (FAPIs). Several preclinical and clinical studies have investigated the role of FAPI-based radionuclide therapy in various malignancies. Preliminary results have shown safety in all studies and efficacy to a variable extent.8

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In 2019, the results of a dosimetry estimate for 68Ga-FAPI-2 and 68Ga-FAPI-4 PET/CT were published and compared to those from an 18F-FDG-PET/CT. Tumor-to-background contrast ratios were equal to or even better than those of 18F-FDG with these novel tracers.9

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The FAP-targeted antibody imaging probe, [89Zr]Zr-B12 IgG, was evaluated by PET/CT imaging in preclinical prostate cancer models. Analysis of patient data documented FAP overexpression in metastatic disease across tumor subtypes. PET imaging with [89Zr]Zr-B12 IgG demonstrated high tumor uptake and long-term retention of the probe in the preclinical models examined. FAP-positive stroma tumor uptake of [89Zr]Zr-B12 IgG was 5-fold higher than the isotype control with mean %ID/cc of 34.13 ± 1.99 versus 6.12 ± 2.03 (n = 3/group; P = 0.0006) at 72 hours. Ex vivo biodistribution corroborated these results documenting rapid blood clearance by 24 hours and high tumor uptake of [89Zr]Zr-B12 IgG by 72 hours. The study investigators concluded that FAP is a promising target for imaging the prostate cancer tumor microenvironment. Validation of [89Zr]Zr-B12 IgG as a selective imaging probe for FAP-expressing tumors presents a new approach for noninvasive PET/CT imaging of mCRPC.10

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Whereas Ga-PSMA mainly accumulates in castrate-sensitive and resistant prostate cancer (but not neuroendocrine disease), there is high accumulation of Ga-FAPI-04 targeting fibroblasts across the various subtypes of prostate cancer. This supports the use of FAPI-molecular theranostics across the prostate cancer disease spectrum.

Jadvar11.png

A promising tracer in this space is [68Ga]Ga-FAPI-PSMA, which is prepared by radiolabeling conjugated DOTA-FAPI-PSMA with the short half-life radionuclide 68Ga. This allows for the dual targeting of both PSMA and FAPs, potentially augmenting the diagnostic and theranostic potential of this tracer.11

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Additional emerging anti-FAP targeted agents include 68Ga-FAP-2286 (diagnostic tracer), 177Lu-FAP-2286 (radioligand therapy), and 90Y-FAPI-45 (radioligand therapy).

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The next biologic target discussed was Prostate Stem Cell Antigen (PSCA), which is highly overexpressed in most primary prostate carcinoma cells and in metastatic and hormone refractory tumor cells. It is expressed on the cell surface in 83–100% of local prostate cancers and 87–100% of prostate cancer bone metastases. PSCA is also overexpressed in a variety of other tumor entities including gallbladder, urinary bladder, breast, and pancreatic cancer, as well as renal cell carcinomas and gliomas. Expression of PSCA in prostate cancer increases with the Gleason Score, tumor stage, androgen-independent progression, and metastases formation in bone, lymph nodes, or liver. Like PSMA and all other tumor associated antigens, PSCA is not exclusively expressed in tumor tissues. Expression of PSCA was also detected at both the mRNA and protein level in healthy tissues.

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In 2014, Knowles et al. evaluated the immunoPET agents, (124)I- and (89)Zr-labeled anti-PSCA A11 minibodies, as PET radiotracers for prostate cancer imaging in xenograft mouse models.  Both (124)I- and (89)Zr-labeled A11 anti-PSCA minibody showed high-contrast imaging of PSCA expression in vivo. However, the (124)I-labeled A11 minibody was found to be the superior imaging agent because of lower nonspecific uptake and higher tumor-to-soft-tissue contrast. Partial-volume correction was found to be essential for robust quantification of immunoPET imaging with both (124)I- and (89)Zr-labeled A11 minibody.13

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Targeted alpha therapy with astatine-211-labeled anti-PSCA A11 minibody demonstrated antitumor efficacy in prostate cancer xenografts and bone microtumors, as illustrated below:

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Another biologic target is Cluster of Differentiation 46 (CD46). It is a multifunctional protein, which functions as a negative regulator of the innate immune system. It is overexpressed in prostate cancer, including primary tumor, castrate-resistant, and neuroendocrine differentiated. It demonstrates low expression in normal tissue (except placental trophoblast). Treatment with abiraterone or enzalutamide in the mCRPC setting upregulates CD46 expression. The CD46 gene is gained in 45% of abiraterone-resistant mCRPC. Antibody-drug conjugates targeting CD46 selectively kill both adenocarcinoma and neuroendocrine prostate cancer cells.14

In 2023, Bidkar et al. evaluated [225Ac]DOTA-YS5, a radioimmunotherapy agent based on the YS5 antibody, which targets a tumor-selective CD46 epitope. [225Ac]DOTA-YS5 suppressed the growth of cell-derived and patient-derived xenografts, including PSMA-positive and deficient models. It demonstrated promising early safety results. Future studies will assess this radiopharmaceutical in human models.15

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Another promising CD46-targeting radiopharmaceutical is 212Pb-TCMC-YS5, which allows for targeted alpha radiation delivery to CD46-expressing cells.

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Delta-like Ligand 3 (DLL3) is expressed in de novo and treatment-emergent small cell/neuroendocrine prostate cancer and is associated with worse survival outcomes. The PET agent, [89Zr]-DFO-DLL3-scFv has been developed as a radiotracer to detect DLL3-expressing prostate cancers with small cell/neuroendocrine differentiation. AMG 757 (tarlatamab) is a half-life-extended bispecific T-cell engager (BiTE) immunotherapy that redirects CD3-positive T cells to kill DLL3-expressing cells, exhibiting potent and durable antitumor activity.16

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Human Kallikrein 2 (hK2) is a prostate-specific enzyme governed by the androgen receptor pathway. 177Lu-labeled humanized IgG1 antibody, hu11B6, internalizes into prostate cancer cells by binding to the catalytic cleft of hK2.17

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Six-transmembrane Epithelial Antigen of Prostate-1 (STEAP1) is a novel 339-amino acid cell surface marker that acts as an ion channel or transporter protein and plays a potential role in cell adhesion and tumor proliferation/invasiveness, with high levels of expression in prostate cancer cells. STEAP1 has emerged as a candidate for therapeutic interventions using antibody-drug conjugates, such as 89Zr-MSTP2109A, an anti-STEAP1 internalizing antibody.18

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Vicrostatin (VCN) is a novel recombinant disintegrin that displays high binding affinity to a broad range of human integrins and offers substantial competitive biological advantages over other integrin-based antagonists. VCN has emerged as promising theranostic target, as illustrated below:

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Presented by: Hossein Jadvar, MD, PhD, MPH, MBA, MSL, FACNM, FSNMMI, Professor of Radiology, Urology, and Biomedical Engineering (Tenured), University of Southern California, Los Angeles, CA

Written by: Rashid Sayyid, MD, MSc – Society of Urologic Oncology (SUO) Clinical Fellow at The University of Toronto, @rksayyid on Twitter during the Society of Nuclear Medicine & Molecular Imaging (SNMMI) 2024 Annual Meeting held in Toronto, ON between June 8th and June 11th, 2024 

References:

  1. Dumont RA, Tamma M, Braun F et al. Targeted Radiotherapy of Prostate Cancer with a Gastrin-Releasing Peptide Receptor Antagonist Is Effective as Monotherapy and in Combination with Rapamycin. J Nucl Med 2013; 54: 762–769.
  2. Ischia J, Patel O, Bolton D, et al. Expression and function of gastrin-releasing peptide (GRP) in normal and cancerous urological tissues. BJU Int. 2014;113(S2): 40-47.
  3. Roivainen A, Kähkönen E, Luoto P, et al. Plasma Pharmacokinetics, Whole-Body Distribution, Metabolism, and Radiation Dosimetry of 68Ga Bombesin Antagonist BAY 86-7548 in Healthy Men. J Nucl Med. 2013;54(6): 867-72.
  4. Minamimoto R, Sonni I, Hancock S, et al. Prospective Evaluation of 68Ga-RM2 PET/MRI in Patients with Biochemical Recurrence of Prostate Cancer and Negative Findings on Conventional Imaging. J Nucl Med. 2018;59(5): 803-8.
  5. Minamimoto R, Hancock S, Schneider B, et al. Pilot Comparison of ⁶⁸Ga-RM2 PET and ⁶⁸Ga-PSMA-11 PET in Patients with Biochemically Recurrent Prostate Cancer. J Nucl Med. 2016;57(4): 557-62.
  6. Baratto L, Song H, Duan H, et al. PSMA- and GRPR-targeted PET: Results from 50 Patients with Biochemically Recurrent Prostate Cancer. J Nucl Med. 2021;62(11): 1545-9.
  7. Fernandez R, Soza-Ried C, Iagaru A, et al. Imaging GRPr Expression in Metastatic Castration-Resistant Prostate Cancer with [68Ga]Ga-RM2—A Head-to-Head Pilot Comparison with [68Ga]Ga-PSMA-11. Cancers (Basel). 2024;16(1): 173.
  8. Ora M, Soni N, Nazar AH, et al. Fibroblast Activation Protein Inhibitor-Based Radionuclide Therapies: Current Status and Future Directions. J Nucl Med. 2023;64(7): 1001-8.
  9. Giesel FL, Kratochwil C, Lindner T, et al. 68Ga-FAPI PET/CT: Biodistribution and Preliminary Dosimetry Estimate of 2 DOTA-Containing FAP-Targeting Agents in Patients with Various Cancers. J Nucl Med. 2019;60(3): 386-92.
  10. Hintz HM, Gallant JP, Vander Griend DJ, et al. Imaging Fibroblast Activation Protein Alpha Improves Diagnosis of Metastatic Prostate Cancer with Positron Emission Tomography. Clin Cancer Res. 2020;26(18): 4882-91.
  11. Wang P, Wang S, Liu F, et al. Preclinical Evaluation of a Fibroblast Activation Protein and a Prostate-Specific Membrane Antigen Dual-Targeted Probe for Noninvasive Prostate Cancer Imaging. Mol Pharm. 2023;20(2): 1415-25.
  12. Striese F, Neuber C, Gräßel S, et al. Preclinical Characterization of the 177Lu-Labeled Prostate Stem Cell Antigen (PSCA)-Specific Monoclonal Antibody 7F5. Int J Mol Sci. 2023;24(11): 9420.
  13. Knowles SM, Zettlitz KA, Tavare R, et al. Quantitative immunoPET of prostate cancer xenografts with 89Zr- and 124I-labeled anti-PSCA A11 minibody. J Nucl Med. 2014;55(3): 452-9.
  14. Su Y, Liu Y, Behrens CR, et al. Targeting CD46 for both adenocarcinoma and neuroendocrine prostate cancer. JCI Insight. 2018;3(17): e121497.
  15. Bidkar AP, Wang S, Bobba KN, et al. Treatment of Prostate Cancer with CD46-targeted 225Ac Alpha Particle Radioimmunotherapy. Clin Cancer Res. 2023;29(10): 1916-28.
  16. Chou J, Egusa EA, Wang S, et al. Immunotherapeutic Targeting and PET Imaging of DLL3 in Small-Cell Neuroendocrine Prostate Cancer. Cancer Res. 2023;83(2): 301-15.
  17. Timmermand OV, Elgqvist J, Beattie KA, et al. Preclinical efficacy of hK2 targeted [177Lu]hu11B6 for prostate cancer theranostics. Theranostics. 2019;9(8): 2129-42.
  18. Carrasquillo JA, Fine BM, Pandit-Taskar N, et al. Imaging Patients with Metastatic Castration-Resistant Prostate Cancer Using 89Zr-DFO-MSTP2109A Anti-STEAP1 Antibody. J Nucl Med. 2019;60(11): 1517-23.
  19. Jadvar H, Chen K, Park R, et al. Preclinical evaluation of a 64Cu-labeled disintegrin for PET imaging of prostate cancer. Amino Acids. 2019;51(10-12): 1569-75.