Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Beyond PSMA: theranostic cell surface targets in metastatic prostate cancer

Prostate Cancer and Prostatic Diseases (2025)Cite this article

Subjects

Abstract

Background

Despite advancements in treatment, metastatic prostate cancer remains a lethal disease. As prostate cancer becomes resistant to standard of care treatments like androgen receptor pathway inhibitors (ARPIs) and chemotherapy, cell surface tumor antigens and receptors become increasingly heterogeneous and diverse, dependent on androgen receptor dependency with relevance for both diagnostic positron emission tomography (PET) imaging and cell surface targeting therapeutics. Our review aims to describe emerging theranostic targets and agents in cell surface imaging and therapies.

Methods

A literature search was carried out in March 2025, on Pubmed, as well as Clinicaltrials.gov to determine cell surface targets with viable trials for imaging and/or therapeutic agents. Keyword searches included “Prostate Cancer” AND “CRPC” AND “Cell Surface Targets.”

Results

Among the literature, 13 novel targets with robust supporting literature were found. Targets were subsequently divided into targets of interest in AR-positive and AR-negative (NEPC and/or double negative) mCRPC. Ongoing and completed trials for imaging and/or therapeutics leveraging these targets was described.

Conclusion

Numerous prostate cancer cell surface markers are emerging as theranostic targets. For patients ineligible for or developing progression following PSMA-targeting therapies, extending cell surface targeting therapeutics, whether they are ADCs, cellular therapies, or RPTs, is increasingly vital.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on SpringerLink
  • Instant access to the full article PDF.

USD 39.95

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: The ideal theranostic cell surface target.
Fig. 2: Cell surface targeting therapeutic modalities.
Fig. 3: Potential cell surface targets in different prostate cancer subtypes.

Similar content being viewed by others

References

  1. Sartor O, de Bono J, Chi KN, Fizazi K, Herrmann K, Rahbar K, et al. Lutetium-177-PSMA-617 for metastatic castration-resistant prostate cancer. N Engl J Med. 2021;385:1091–103.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Morris MJ, Castellano D, Herrmann K, de Bono JS, Shore ND, Chi KN, et al. 177)Lu-PSMA-617 versus a change of androgen receptor pathway inhibitor therapy for taxane-naive patients with progressive metastatic castration-resistant prostate cancer (PSMAfore): a phase 3, randomised, controlled trial. Lancet. 2024;404:1227–39.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Vlachostergios PJ, Niaz MJ, Sun M, Mosallaie SA, Thomas C, Christos PJ, et al. Prostate-specific membrane antigen uptake and survival in metastatic castration-resistant prostate cancer. Front Oncol. 2021;11:630589.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Murthy V, Allen-Auerbach M, Lam R, Owen D, Czernin J, Calais J. PSMA-negative lesion progression under (177)Lu-PSMA radioligand therapy. J Nucl Med. 2023;64:1502–3.

    Article  CAS  PubMed  Google Scholar 

  5. Guo C, Figueiredo I, Gurel B, Neeb A, Seed G, Crespo M, et al. B7-H3 as a therapeutic target in advanced prostate cancer. Eur Urol. 2023;83:224–38.

    Article  CAS  PubMed  Google Scholar 

  6. Zhang T, Agarwal A, Almquist RG, Runyambo D, Park S, Bronson E, et al. Expression of immune checkpoints on circulating tumor cells in men with metastatic prostate cancer. Biomark Res. 2021;9:14.

    Article  PubMed  PubMed Central  Google Scholar 

  7. Thang SP, Violet J, Sandhu S, Iravani A, Akhurst T, Kong G, et al. Poor outcomes for patients with metastatic castration-resistant prostate cancer with low prostate-specific membrane antigen (PSMA) expression deemed ineligible for (177)Lu-labelled PSMA radioligand therapy. Eur Urol Oncol. 2019;2:670–6.

    Article  PubMed  Google Scholar 

  8. Buteau JP, Martin AJ, Emmett L, Iravani A, Sandhu S, Joshua AM, et al. PSMA and FDG-PET as predictive and prognostic biomarkers in patients given [(177)Lu]Lu-PSMA-617 versus cabazitaxel for metastatic castration-resistant prostate cancer (TheraP): a biomarker analysis from a randomised, open-label, phase 2 trial. Lancet Oncol. 2022;23:1389–97.

    Article  CAS  PubMed  Google Scholar 

  9. Modi S, Jacot W, Yamashita T, Sohn J, Vidal M, Tokunaga E, et al. Trastuzumab Deruxtecan in Previously Treated HER2-Low Advanced Breast Cancer. N Engl J Med. 2022;387:9–20.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Powles T, Valderrama BP, Gupta S, Bedke J, Kikuchi E, Hoffman-Censits J, et al. Enfortumab Vedotin and Pembrolizumab in Untreated Advanced Urothelial Cancer. N Engl J Med. 2024;390:875–88.

    Article  CAS  PubMed  Google Scholar 

  11. Sharifi MN, Shi Y, Chrostek MR, Callahan SC, Shang T, Berg TJ, et al. Clinical cell-surface targets in metastatic and primary solid cancers. JCI Insight. 2024;9:e183674.

  12. Lee JK, Bangayan NJ, Chai T, Smith BA, Pariva TE, Yun S, et al. Systemic surfaceome profiling identifies target antigens for immune-based therapy in subtypes of advanced prostate cancer. Proc Natl Acad Sci USA. 2018;115:E4473–E82.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Antonarakis ES, Park SH, Goh JC, Shin SJ, Lee JL, Mehra N, et al. Pembrolizumab plus olaparib for patients with previously treated and biomarker-unselected metastatic castration-resistant prostate cancer: the randomized, open-label, phase III KEYLYNK-010 trial. J Clin Oncol. 2023;41:3839–50.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Brady L, Kriner M, Coleman I, Morrissey C, Roudier M, True LD, et al. Inter- and intra-tumor heterogeneity of metastatic prostate cancer determined by digital spatial gene expression profiling. Nat Commun. 2021;12:1426.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Ocana A, Amir E, Pandiella A. HER2 heterogeneity and resistance to anti-HER2 antibody-drug conjugates. Breast Cancer Res. 2020;22:15.

    Article  PubMed  PubMed Central  Google Scholar 

  16. Boyd M, Ross SC, Dorrens J, Fullerton NE, Tan KW, Zalutsky MR, et al. Radiation-induced biologic bystander effect elicited in vitro by targeted radiopharmaceuticals labeled with alpha-, beta-, and auger electron-emitting radionuclides. J Nucl Med. 2006;47:1007–15.

    CAS  PubMed  Google Scholar 

  17. Shen M, Liu S, Stoyanova T. The role of Trop2 in prostate cancer: an oncogene, biomarker, and therapeutic target. Am J Clin Exp Urol. 2021;9:73–87.

    PubMed  PubMed Central  Google Scholar 

  18. Sgouros G, Bodei L, McDevitt MR, Nedrow JR. Radiopharmaceutical therapy in cancer: clinical advances and challenges. Nat Rev Drug Discov. 2020;19:589–608.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Poty S, Francesconi LC, McDevitt MR, Morris MJ, Lewis JS. alpha-Emitters for Radiotherapy: From Basic Radiochemistry to Clinical Studies-Part 1. J Nucl Med. 2018;59:878–84.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Fu Z, Gao C, Wu T, Wang L, Li S, Zhang Y, et al. Peripheral neuropathy associated with monomethyl auristatin E-based antibody-drug conjugates. iScience. 2023;26:107778.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Buteau JP, Kostos L, Alipour R, Jackson P, McInstosh L, Emmerson B, et al. Clinical trial protocol for VIOLET: a single-center, phase I/II trial evaluation of radioligand treatment in patients with metastatic castration-resistant prostate cancer with [(161)Tb]Tb-PSMA-I&T. J Nucl Med. 2024;65:1231–8.

    Article  CAS  PubMed  Google Scholar 

  22. Gualberto A. Brentuximab Vedotin (SGN-35), an antibody-drug conjugate for the treatment of CD30-positive malignancies. Expert Opin Investig Drugs. 2012;21:205–16.

    Article  CAS  PubMed  Google Scholar 

  23. Li K, Guo J, Guo H, Zhang Q, Huang H, Zhou L, et al. Updated results from a phase I/II study of CBP-1018, a bi-ligand–drug conjugate (Bi-XDC) as late line therapy for patients with metastatic castration resistant prostate cancer (mCRPC). J Clin Oncol. 2025;43:161.

    Article  Google Scholar 

  24. Cappell KM, Kochenderfer JN. Long-term outcomes following CAR T cell therapy: what we know so far. Nat Rev Clin Oncol. 2023;20:359–71.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Narayan V, Barber-Rotenberg JS, Jung IY, Lacey SF, Rech AJ, Davis MM, et al. PSMA-targeting TGFbeta-insensitive armored CAR T cells in metastatic castration-resistant prostate cancer: a phase 1 trial. Nat Med. 2022;28:724–34.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Dorff TB, Blanchard MS, Adkins LN, Luebbert L, Leggett N, Shishido SN, et al. PSCA-CAR T cell therapy in metastatic castration-resistant prostate cancer: a phase 1 trial. Nat Med. 2024;30:1636–44.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Zhang B, Yang M, Zhang W, Liu N, Wang D, Jing L, et al. Chimeric antigen receptor-based natural killer cell immunotherapy in cancer: from bench to bedside. Cell Death Dis. 2024;15:50.

    Article  PubMed  PubMed Central  Google Scholar 

  28. Paredes-Moscosso SR, Nathwani AC. 10 years of BiTE immunotherapy: an overview with a focus on pancreatic cancer. Front Oncol. 2024;14:1429330.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Bluemn EG, Coleman IM, Lucas JM, Coleman RT, Hernandez-Lopez S, Tharakan R, et al. Androgen Receptor Pathway-Independent Prostate Cancer Is Sustained through FGF Signaling. Cancer Cell. 2017;32:474–89 e6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Watson PA, Arora VK, Sawyers CL. Emerging mechanisms of resistance to androgen receptor inhibitors in prostate cancer. Nat Rev Cancer. 2015;15:701–11.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Antonarakis ES, Chandhasin C, Osbourne E, Luo J, Sadar MD, Perabo F. Targeting the N-terminal domain of the androgen receptor: a new approach for the treatment of advanced prostate cancer. Oncologist. 2016;21:1427–35.

    Article  PubMed  PubMed Central  Google Scholar 

  32. Hubert RS, Vivanco I, Chen E, Rastegar S, Leong K, Mitchell SC, et al. STEAP: a prostate-specific cell-surface antigen highly expressed in human prostate tumors. Proc Natl Acad Sci USA. 1999;96:14523–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Nolan-Stevaux O. AMG 509: A novel, humanized, half-Life extended, bispecific STEAP1 × CD3 T cell recruiting XmAb® 2+1 antibody. Cancer Res. 2020;80:DDT02–3.

    Article  Google Scholar 

  34. Ylitalo EB, Thysell E, Jernberg E, Lundholm M, Crnalic S, Egevad L, et al. Subgroups of Castration-resistant Prostate Cancer Bone Metastases Defined Through an Inverse Relationship Between Androgen Receptor Activity and Immune Response. Eur Urol. 2017;71:776–87.

    Article  PubMed  Google Scholar 

  35. Burnell SEA, Spencer-Harty S, Howarth S, Bodger O, Kynaston H, Morgan C, et al. Utilisation of the STEAP protein family in a diagnostic setting may provide a more comprehensive prognosis of prostate cancer. PLoS One. 2019;14:e0220456.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Carrasquillo JA, Fine BM, Pandit-Taskar N, Larson SM, Fleming SE, Fox JJ, et al. Imaging patients with metastatic castration-resistant prostate cancer using (89)Zr-DFO-MSTP2109A anti-STEAP1 antibody. J Nucl Med. 2019;60:1517–23.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Kelly WK, Danila DC, Lin CC, Lee JL, Matsubara N, Ward PJ, et al. Xaluritamig, a STEAP1 x CD3 XmAb 2+1 immune therapy for metastatic castration-resistant prostate cancer: results from dose exploration in a first-in-human study. Cancer Discov. 2024;14:76–89.

    Article  CAS  PubMed  Google Scholar 

  38. Miller CD, Lozada JR, Zorko NA, Elliott A, Makovec A, Radovich M, et al. Pan-cancer interrogation of B7-H3 (CD276) as an actionable therapeutic target across human malignancies. Cancer Res Commun. 2024;4:1369–79.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Roth TJ, Sheinin Y, Lohse CM, Kuntz SM, Frigola X, Inman BA, et al. B7-H3 ligand expression by prostate cancer: a novel marker of prognosis and potential target for therapy. Cancer Res. 2007;67:7893–900.

    Article  CAS  PubMed  Google Scholar 

  40. Xia L, Wu Y, Ren Y, Wang Z, Zhou N, Zhou W, et al. A whole-body imaging technique for tumor-specific diagnostics and screening of B7H3-targeted therapies. J Clin Invest. 2025;135:e186388.

  41. de Bono J, Helissey C, Fizazi K, Maroto Rey JP, Roubaud G, Antonarakis ES, et al. TAMARACK: randomized phase II trial of the B7-H3 targeting antibody drug conjugate (ADC) vobramitamab duocarmazine (vobra duo) in metastatic castration-resistant prostate cancer (mCRPC). Ann Oncol. 2024;35:S996–S7.

    Article  Google Scholar 

  42. Patel M, Dai T, Koyoma T, Falchook GS, Friedman CF, Piha-Paul SA, et al. Ifinatamab deruxtecan (I-DXd; DS-7300) in patients with advanced solid tumors: Updated clinical and biomarker results from a phase I/II study. Ann Oncol. 2023;34:S481–S2.

    Article  Google Scholar 

  43. Wang X, Singh, J, Kobayashi, M, Maejima, T, Wada, N, Nishimura, M, et al. Evaluation of immunomodulatory effects of ifinatamab deruxtecan (I-DXd) in the IDeate-Pantumor01 phase 1/2 study in patients with advanced solid tumors. J Immunotherapy Cancer. 2024;12.

  44. Shenderov E, De Marzo AM, Lotan TL, Wang H, Chan S, Lim SJ, et al. Neoadjuvant enoblituzumab in localized prostate cancer: a single-arm, phase 2 trial. Nat Med. 2023;29:888–97.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Hekim C, Leinonen J, Narvanen A, Koistinen H, Zhu L, Koivunen E, et al. Novel peptide inhibitors of human kallikrein 2. J Biol Chem. 2006;281:12555–60.

    Article  CAS  PubMed  Google Scholar 

  46. Shen F, Kelly WK, Pandit-Thaskar N, McDevitt T, Smith R, Menard K, et al. Preclinical characterization of human Kallikrein 2 (hK2) as a novel target for the treatment of prostate cancer. J Clin Oncol. 2024;42:202.

    Article  Google Scholar 

  47. Pandit-Taskar N, O’Donoghue JA, Chetty D, Max S, Wanik D, Ilovich O, et al. A phase 0 study to assess the biodistribution and pharmacokinetics of a radiolabeled antibody targeting human kallikrein 2 in participants with metastatic castration-resistant prostate cancer. J Nucl Med. 2024;65:1051–6.

    Article  PubMed  PubMed Central  Google Scholar 

  48. Morris M, Wong JYC, Nordquist L, Zelig Szmulewitz R, Agarwal N, Attiyehm EF, et al. A phase 1 study of JNJ-69086420 (JNJ-6420), an actinium-225 (225Ac) -labeled antibody targeting human kallikrein 2 (hK2), for metastatic castration-resistant prostate cancer (mCRPC). Jou. Rna Clin Oncol. 2024;42:5010.

    Google Scholar 

  49. Stein MN, Vinceneux A, Robbrecht D, Doger B, Autio KA, Schweizer MT, et al. Pasritamig, a first-in-class, bispecific T-cell engager targeting human kallikrein 2, in metastatic castration-resistant prostate cancer: a phase I study. J Clin Oncol. 2025;43:2515–26.

    Article  PubMed  Google Scholar 

  50. Saeki N, Gu J, Yoshida T, Wu X. Prostate stem cell antigen: a Jekyll and Hyde molecule? Clin Cancer Res. 2010;16:3533–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Gu Z, Thomas G, Yamashiro J, Shintaku IP, Dorey F, Raitano A, et al. Prostate stem cell antigen (PSCA) expression increases with high gleason score, advanced stage and bone metastasis in prostate cancer. Oncogene. 2000;19:1288–96.

    Article  CAS  PubMed  Google Scholar 

  52. Stein MN, Dumbrava EE, Teply BA, Gergis US, Guiterrez ME, Reshef R, et al. PSCA-targeted BPX-601 CAR T cells with pharmacological activation by rimiducid in metastatic pancreatic and prostate cancer: a phase 1 dose escalation trial. Nat Commun. 2024;15:10743.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Xie J, Molck C, Paquet-Fifield S, Butler L, Australian Prostate Cancer B, Sloan E, et al. High expression of TROP2 characterizes different cell subpopulations in androgen-sensitive and androgen-independent prostate cancer cells. Oncotarget. 2016;7:44492–504.

    Article  PubMed  PubMed Central  Google Scholar 

  54. Ajkunic A, Sayar E, Roudier MP, Patel RA, Coleman IM, De Sarkar N, et al. Assessment of TROP2, CEACAM5 and DLL3 in metastatic prostate cancer: Expression landscape and molecular correlates. NPJ Precis Oncol. 2024;8:104.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Shvartsur A, Bonavida B. Trop2 and its overexpression in cancers: regulation and clinical/therapeutic implications. Genes Cancer. 2015;6:84–105.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Bardia A, Hurvitz SA, Tolaney SM, Loirat D, Punie K, Oliveira M, et al. Sacituzumab Govitecan in Metastatic Triple-Negative Breast Cancer. N Engl J Med. 2021;384:1529–41.

    Article  CAS  PubMed  Google Scholar 

  57. Powles T, Tagawa S, Vulsteke C, Gross-Goupil M, Park SH, Necchi A, et al. Sacituzumab govitecan in advanced urothelial carcinoma: TROPiCS-04, a phase III randomized trial. Ann Oncol. 2025;36:561–71.

  58. Lang J, Tagawa ST, Slovin S, Sperger SM, Schehr JL, Stahfield C, et al. Final clinical and liquid biopsy (LBx) results of phase II trial of sacituzumab govitecan (SG) in patients (Pts) with metastatic castration resistant prostate cancer (mCRPC) progressing on androgen receptor signaling inhibitors (ARSI). Ann Oncol. 2024;35:S993–S4.

    Article  Google Scholar 

  59. Tang F, Xu D, Wang S, Wong CK, Martinez-Fundichely A, Lee CJ, et al. Chromatin profiles classify castration-resistant prostate cancers suggesting therapeutic targets. Science. 2022;376:eabe1505.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Pitzen SP, Rudenick AN, Qiu Y, Zhang W, Munro SA, McCluskey BM, et al. Comparative transcriptomics reveals a mixed basal, club, and hillock epithelial cell identity in castration-resistant prostate cancer. Proc Natl Acad Sci USA. 2025;122:e2415308122.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Zaffuto E, Pompe R, Zanaty M, Bondarenko HD, Leyh-Bannurah SR, Moschini M, et al. Contemporary Incidence and Cancer Control Outcomes of Primary Neuroendocrine Prostate Cancer: A SEER Database Analysis. Clin Genitourin Cancer. 2017;15:e793–e800.

    Article  PubMed  Google Scholar 

  62. Puca L, Gavyert K, Sailer V, Conteduca V, Dardenne E, Sigouros M, et al. Delta-like protein 3 expression and therapeutic targeting in neuroendocrine prostate cancer. Sci Transl Med. 2019;11:eaav0891.

  63. Tendler S, Dunphy MP, Agee M, O’Donoghue J, Aly RG, Choudhury NJ, et al. Imaging with [(89)Zr]Zr-DFO-SC16.56 anti-DLL3 antibody in patients with high-grade neuroendocrine tumours of the lung and prostate: a phase 1/2, first-in-human trial. Lancet Oncol. 2024;25:1015–24.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Ahn MJ, Cho BC, Felip E, Korantzis I, Ohashi K, Majem M, et al. Tarlatamab for patients with previously treated small-cell lung cancer. N Engl J Med. 2023;389:2063–75.

    Article  CAS  PubMed  Google Scholar 

  65. Aggarwal R, Rottey S, Bernard-Tessier A, Mellado-Gonzalez B, Kosaka R, Stadler WM, et al. Phase 1b study of tarlatamab in de novo or treatment-emergent neuroendocrine prostate cancer (NEPC). J Clin Oncol. 2024;42:5012.

    Article  Google Scholar 

  66. Beltran H, Johnson ML, Jain P, Schenk EL, Sanborn RE, Thompson JR, et al. Updated results from a phase 1/2 study of HPN328, a tri-specific, half-life (T1/2) extended DLL3-targeting T-cell engager in patients (pts) with small cell lung cancer (SCLC) and other neuroendocrine cancers (NEC). J Clin Oncol. 2024;42:8090.

    Article  Google Scholar 

  67. Blackhall F, Jao K, Greillier L, Cho BC, Penkov K, Reguart N, et al. Efficacy and safety of rovalpituzumab tesirine compared with topotecan as second-line therapy in DLL3-high SCLC: results from the phase 3 TAHOE study. J Thorac Oncol. 2021;16:1547–58.

    Article  CAS  PubMed  Google Scholar 

  68. Mansfield AS, Hong DS, Hann CL, Farago AF, Beltran H, Waqar SN, et al. A phase I/II study of rovalpituzumab tesirine in delta-like 3-expressing advanced solid tumors. NPJ Precis Oncol. 2021;5:74.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Korsen JA, Gutierrez JA, Tully KM, Carter LM, Samuels ZV, Khitrov S, et al. Delta-like ligand 3-targeted radioimmunotherapy for neuroendocrine prostate cancer. Proc Natl Acad Sci USA. 2022;119:e2203820119.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Tran TT, Tran QH, Nguyen QT, Le MT, Trinh DT, Thai KM. Identification of potential interleukin-8 inhibitors acting on the interactive site between chemokine and CXCR2 receptor: A computational approach. PLoS One. 2022;17:e0264385.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Li Y, He Y, Butler W, Xu L, Chang Y, Lei K, et al. Targeting cellular heterogeneity with CXCR2 blockade for the treatment of therapy-resistant prostate cancer. Sci Transl Med. 2019;11:eaax0428.

  72. Lu X, Horner JW, Paul E, Shang X, Troncoso P, Deng P, et al. Effective combinatorial immunotherapy for castration-resistant prostate cancer. Nature. 2017;543:728–32.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Spatz P, Chen X, Reichau K, Huber ME, Muhlig S, Matsusaka Y, et al. Development and Initial Characterization of the First (18)F-CXCR2-Targeting Radiotracer for PET Imaging of Neutrophils. J Med Chem. 2024;67:6327–43.

    Article  CAS  PubMed  Google Scholar 

  74. Su Y, Liu Y, Behrens CR, Bidlingmaier S, Lee NK, Aggarwal R, et al. Targeting CD46 for both adenocarcinoma and neuroendocrine prostate cancer. JCI Insight. 2018;3:e121497.

  75. Kunz N, Kemper C. Complementing Anticancer Therapy: Antibody-Drug Conjugates Targeting CD46 as Prostate Cancer Treatment. J Clin Oncol. 2025;43:1835–8.

    Article  CAS  PubMed  Google Scholar 

  76. Bidkar AP, Peter R, Wadhwa A, Bobba KN, Bidlingmaier S, Meher N, et al. Effective treatment of disseminated prostate cancer using CD46-targeted 225Ac therapy. Clin Cancer Res. 2025;31:2963–77.

  77. Li J, Huang T, Hua J, Wang Q, Su Y, Chen P, et al. CD46 targeted (212)Pb alpha particle radioimmunotherapy for prostate cancer treatment. J Exp Clin Cancer Res. 2023;42:61.

    Article  PubMed  PubMed Central  Google Scholar 

  78. Aggarwal R, Vuky J, VanderWeele D, Rettig M, Heath EI, Quigley D, et al. Phase I, first-in-human study of FOR46 (FG-3246), an immune-modulating antibody-drug conjugate targeting CD46, in patients with metastatic castration-resistant prostate cancer. J Clin Oncol. 2025;43:1824–34.

    Article  CAS  PubMed  Google Scholar 

  79. Shakhnazaryan N, Curry N, Rastogi M, Avins D, Pandey S, de Kouchkovsky I, et al. A phase 1b dose escalation study of FOR46, a novel antibody-drug conjugate targeting a tumor-specific epitope of CD46, in combination with enzalutamide (Enza) in patients with metastatic castration resistant prostate cancer (mCRPC). J Clin Oncol. 2024;42:5066.

    Article  Google Scholar 

  80. DeLucia DC, Cardillo TM, Ang L, Labrecque MP, Zhang A, Hopkins JE, et al. Regulation of CEACAM5 and therapeutic efficacy of an anti-CEACAM5-SN38 antibody-drug conjugate in neuroendocrine prostate cancer. Clin Cancer Res. 2021;27:759–74.

    Article  CAS  PubMed  Google Scholar 

  81. Besse B, Lo Russo G, Lena H, Nadal E, Cousin S, Kowalski D, et al. Tusamitamab ravtansine vs docetaxel in previously treated advanced nonsquamous NSCLC: results from phase 3 CARMEN-LC03 trial. J Thorac Oncol. 2024;19:S25–S6.

    Article  Google Scholar 

  82. Dotan E, Cohen SJ, Starodub AN, Lieu CH, Messersmith WA, Simpson PS, et al. phase I/II trial of labetuzumab govitecan (anti-CEACAM5/SN-38 antibody-drug conjugate) in patients with refractory or relapsing metastatic colorectal cancer. J Clin Oncol. 2017;35:3338–46.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Baek DS, Kim YJ, Vergara S, Conard A, Adams C, Calero G, et al. A highly-specific fully-human antibody and CAR-T cells targeting CD66e/CEACAM5 are cytotoxic for CD66e-expressing cancer cells in vitro and in vivo. Cancer Lett. 2022;525:97–107.

    Article  CAS  PubMed  Google Scholar 

  84. Jensen RT, Battey JF, Spindel ER, Benya RV. International Union of Pharmacology. LXVIII. Mammalian bombesin receptors: nomenclature, distribution, pharmacology, signaling, and functions in normal and disease states. Pharm Rev. 2008;60:1–42.

    Article  CAS  PubMed  Google Scholar 

  85. Ananias HJ, van den Heuvel MC, Helfrich W, de Jong IJ. Expression of the gastrin-releasing peptide receptor, the prostate stem cell antigen and the prostate-specific membrane antigen in lymph node and bone metastases of prostate cancer. Prostate. 2009;69:1101–8.

    Article  PubMed  Google Scholar 

  86. Qiao J, Grabowska MM, Forestier-Roman IS, Mirosevich J, Case TC, Chung DH, et al. Activation of GRP/GRP-R signaling contributes to castration-resistant prostate cancer progression. Oncotarget. 2016;7:61955–69.

    Article  PubMed  PubMed Central  Google Scholar 

  87. Belge Bilgin G, Bilgin C, Orscelik A, Burkett BJ, Thorpe MP, Johnson DR, et al. Detection rate of gastrin-releasing peptide receptor (GRPr) targeted tracers for positron emission tomography (PET) imaging in primary prostate cancer: a systematic review and meta-analysis. Ann Nucl Med. 2024;38:865–76.

    Article  CAS  PubMed  Google Scholar 

  88. Duan H, Moradi F, Davidzon GA, Liang T, Song H, Loening AM, et al. 68)Ga-RM2 PET-MRI versus MRI alone for evaluation of patients with biochemical recurrence of prostate cancer: a single-centre, single-arm, phase 2/3 imaging trial. Lancet Oncol. 2024;25:501–8.

    Article  CAS  PubMed  Google Scholar 

  89. Li S, Nguyen A, Counter W, John NC, De Leon J, Hruby G, et al. Utility of (64)Cu-Sarcophagine-Bombesin PET/CT in Men with Biochemically Recurrent Prostate Cancer and Negative or Equivocal Findings on (68)Ga-PSMA-11 PET/CT. J Nucl Med. 2024;65:1371–5.

    Article  CAS  PubMed  Google Scholar 

  90. Gonzalez-Rueda S, Garcia-Perez O, Luna-Gutierrez M, Ocampo-Garcia B, Santos-Cuevas C, Ramirez-Nava G, et al. Theranostic potential of the iPSMA-bombesin radioligand in patients with metastatic prostate cancer: a pilot study. Pharmaceutics. 2024;16.

  91. Butler W, Xu L, Zhou Y, Cheng Q, Hauck JS, He Y, et al. Oncofetal protein glypican-3 is a biomarker and critical regulator of function for neuroendocrine cells in prostate cancer. J Pathol. 2023;260:43–55.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Lin F, Clift, R, Salvador, K, Guest, M, Kim, D, Horton, S, et al. Novel GPC3-targeted radiopharmaceutical therapy for hepatocellular carcinoma and prostate cancer: Preclinical characterization in rodents and non-human primates. J Nuclear Med. 2024;65:241022.

  93. Madera L, Hernandez Rojas A, Colombo R, Wu A, Piscitelli CL, Urosev D, et al. ZW251, a novel glypican-3-targeting antibody drug conjugate bearing a topoisomerase 1 inhibitor payload. Cancer Res. 2023;83:2658.

    Article  Google Scholar 

  94. Kesch C, Yirga L, Dendl K, Handke A, Darr C, Krafft U, et al. High fibroblast-activation-protein expression in castration-resistant prostate cancer supports the use of FAPI-molecular theranostics. Eur J Nucl Med Mol Imaging. 2021;49:385–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Wang X, Zhang X, Zhang X, Guan L, Gao X, Xu L, et al. Design, preclinical evaluation, and first-in-human PET study of [(68)Ga]Ga-PSFA-01: a PSMA/FAP heterobivalent tracer. Eur J Nucl Med Mol Imaging. 2025;52:1166–76.

    Article  CAS  PubMed  Google Scholar 

  96. Zhao N, Chopra S, Trepka K, Wang YH, Sakhamuri S, Hooshdaran N, et al. CUB domain-containing protein 1 (CDCP1) is a target for radioligand therapy in castration-resistant prostate cancer, including PSMA null disease. Clin Cancer Res. 2022;28:3066–75.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Gafita A, Rauscher I, Weber M, Hadaschik B, Wang H, Armstrong WR, et al. Novel framework for treatment response evaluation using PSMA PET/CT in patients with metastatic castration-resistant prostate cancer (RECIP 1.0): an international multicenter study. J Nucl Med. 2022;63:1651–8.

    CAS  PubMed  PubMed Central  Google Scholar 

  98. Powderly J, Cote, G, Flaherty, K, Szmulewitz, RZ, Ribas, A, Weber, J, et al. Interim results of an ongoing Phase I, dose escalation study of MGA271 (Fc-optimized humanized anti-B7-H3 monoclonal antibody) in patients with refractory B7-H3-expressing neoplasms or neoplasms whose vasculature expresses B7-H3. J Immunotherapy of Cancer. 2015;3:08.

  99. Beheshti M, Taimen P, Kemppainen J, Jambor I, Muller A, Loidl W, et al. Value of (68)Ga-labeled bombesin antagonist (RM2) in the detection of primary prostate cancer comparing with [(18)F]fluoromethylcholine PET-CT and multiparametric MRI-a phase I/II study. Eur Radio. 2023;33:472–82.

    Article  CAS  Google Scholar 

  100. Darson MF, Pacelli A, Roche P, Rittenhouse HG, Wolfert RL, Young CY, et al. Human glandular kallikrein 2 (hK2) expression in prostatic intraepithelial neoplasia and adenocarcinoma: a novel prostate cancer marker. Urology. 1997;49:857–62.

    Article  CAS  PubMed  Google Scholar 

  101. Sharma SK, Pourat J, Abdel-Atti D, Carlin SD, Piersigilli A, Bankovich AJ, et al. Noninvasive interrogation of DLL3 expression in metastatic small cell lung cancer. Cancer Res. 2017;77:3931–41.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Epstein JI, Amin MB, Beltran H, Lotan TL, Mosquera JM, Reuter VE, et al. Proposed morphologic classification of prostate cancer with neuroendocrine differentiation. Am J Surg Pathol. 2014;38:756–67.

    Article  PubMed  PubMed Central  Google Scholar 

  103. Zhou J, Fan X, Chen N, Zhou F, Dong J, Nie Y, et al. Identification of CEACAM5 as a biomarker for prewarning and prognosis in gastric cancer. J Histochem Cytochem. 2015;63:922–30.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Brennen WN, Isaacs JT, Denmeade SR. Rationale behind targeting fibroblast activation protein-expressing carcinoma-associated fibroblasts as a novel chemotherapeutic strategy. Mol Cancer Ther. 2012;11:257–66.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Duke Cancer Institute Center for Prostate and Urologic Cancer, Duke University Department of Medicine, Division of Medical Oncology, Durham, NC, USA

    Bilal Ashraf, Jane McKenzie & Andrew J. Armstrong

Authors
  1. Bilal Ashraf
    View author publications

    Search author on:PubMed Google Scholar

  2. Jane McKenzie
    View author publications

    Search author on:PubMed Google Scholar

  3. Andrew J. Armstrong
    View author publications

    Search author on:PubMed Google Scholar

Contributions

BA: Reviewed the literature, drafted multiple sections of the manuscript, and designed figures and tables. JM: Reviewed the literature, drafted multiple sections of the manuscript, and designed tables. AA: Developed the original concept and provided critical revision of the manuscript.

Corresponding author

Correspondence to Andrew J. Armstrong.

Ethics declarations

Competing interests

BA: None. Jane McKenzie: None. AA. • Research support (to Duke) from the NIH/NCI, PCF/Movember, DOD, Astellas, Pfizer, Bayer, Janssen, BMS, AstraZeneca, Merck, Pathos, Amgen, Novartis. • Consulting or advising relationships with Astellas, Pfizer, Bayer, Janssen, BMS, AstraZeneca, Merck, Forma, Celgene, Myovant, Exelixis, GoodRx, Novartis, Medscape, MJH, Z Alpha, Telix.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Ashraf, B., McKenzie, J. & Armstrong, A.J. Beyond PSMA: theranostic cell surface targets in metastatic prostate cancer. Prostate Cancer Prostatic Dis (2025). https://doi.org/10.1038/s41391-025-01037-9

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Version of record:

  • DOI: https://doi.org/10.1038/s41391-025-01037-9

Search

Advanced search

Quick links