PSMA – Shielding » Johns Hopkins Drug Discovery
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PSMA – Shielding

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Prostate Specific Membrane Antigen

Molecular radiotherapy targeted to the cell surface metalloenzyme prostate-specific membrane antigen (PSMA) has emerged as a promising treatment approach for metastatic castration-resistant prostate cancer (mCRPC). Multiple small molecule PSMA ligands have been conjugated to positron or beta/alpha-emitting radionuclides, and are in development for prostate cancer imaging or treatment (1-4). Several PSMA-targeted radiotherapeutics have shown significant efficacy in late stage mCRPC patients under compassionate care, but high specific uptake into salivary glands and kidneys results in dose-limiting xerostomia and potential for nephrotoxicity (5). JHDD has discovered novel small molecule PSMA ligands that preferentially distribute to non-tumor tissues including the salivary glands and kidneys, acting as a shield that can selectively block radiotherapeutic uptake into healthy organs but not metastases, thereby mitigating radiotoxicity while preserving efficacy. These compounds have the potential to improve the tolerability and therapeutic index of PSMA-targeted radiotherapy, and to enable earlier, higher dose administration of this promising treatment to mCRPC patients.

References

    1. Fendler WP, Rahbar K, Herrmann K, Kratochwil C, Eiber M. “(177)Lu-PSMA Radioligand Therapy for Prostate Cancer.” Journal of Nuclear Medicine: official publication, Society of Nuclear Medicine. 2017;58(8):1196-200 – PubMed PMID: 28663195
    2. Kratochwil C, Bruchertseifer F, Rathke H, Hohenfellner M, Giesel FL, Haberkorn U, Morgenstern A. “Targeted Alpha Therapy of mCRPC with (225)Actinium-PSMA-617: Swimmer-Plot analysis suggests efficacy regarding duration of tumor-control.” Journal of Nuclear Medicine: official publication, Society of Nuclear Medicine. 2018 – PubMed PMID: 29326358
    3. Virgolini I, Decristoforo C, Haug A, Fanti S, Uprimny C. “Current Status of Theranostics in Prostate Cancer.” European Journal of Nuclear Medicine and Molecular Imaging. 2017 – PubMed PMID: 29282518
    4. von Eyben FE, Roviello G, Kiljunen T, Uprimny C, Virgolini I, Kairemo K, Joensuu T. “Third-line treatment and (177)Lu-PSMA radioligand therapy of metastatic castration-resistant prostate cancer: a systematic review.” European Journal of Nuclear Medicine and Molecular Imaging. 2017 – PubMed PMID: 29247284
    5. Rathke H, Giesel FL, Flechsig P, Kopka K, Mier W, Hohenfellner M, Haberkorn U, Kratochwil C. “Repeated Lu-177-PSMA-617 radioligand therapy using treatment activities up to 9.3 GBq.” Journal of Nuclear Medicine: official publication, Society of Nuclear Medicine. 2017 – PubMed PMID: 28798031