Small Molecule-Based Prodrug Targeting Prostate Specific Membrane Antigen for the Treatment of Prostate Cancer.

Xinning Wang,Joey Mangadlao,Zhipeng Dong,Lingpeng Shan,Ziying Wang,Susann Brady-Kalnay,Mark Schluchter,Gopolakrishnan Ramamurthy,Christopher Hoimes,Zhenghong Lee,Aditi Shirke,Ethan Walker,Jing Li,Shaun Stauffer,Yu Wang,Jing Wang,Dong Luo,James P Basilion,Rongcan Sun

doi:10.3390/cancers13030417

Abstract

Metastatic castration-resistant prostate cancer poses a serious clinical problem with poor outcomes and remains a deadly disease. New targeted treatment options are urgently needed. PSMA is highly expressed in prostate cancer and has been an attractive biomarker for the treatment of prostate cancer. In this study, we explored the feasibility of targeted delivery of an antimitotic drug, monomethyl auristatin E (MMAE), to tumor tissue using a small-molecule based PSMA lig-and. With the aid of Cy5.5, we found that a cleavable linker is vital for the antitumor activity of the ligand-drug conjugate and have developed a new PSMA-targeting prodrug, PSMA-1-VcMMAE. In in vitro studies, PSMA-1-VcMMAE was 48-fold more potent in killing PSMA-positive PC3pip cells than killing PSMA-negative PC3flu cells. In in vivo studies, PSMA-1-VcMMAE significantly inhibited tumor growth leading to prolonged animal survival in different animal models, including metastatic prostate cancer models. Compared to anti-PSMA antibody-MMAE conjugate (PSMA-ADC) and MMAE, PSMA-1-VcMMAE had over a 10-fold improved maximum tolerated dose, resulting in improved therapeutic index. The small molecule-drug conjugates reported here can be easily synthesized and are more cost efficient than anti-body-drug conjugates. The therapeutic profile of the PSMA-1-VcMMAE encourages further clin-ical development for the treatment of advanced prostate cancer.

Highlights

Prostate cancer is the most common malignancy and the second leading cause of cancer death in men in the United States [1]
To determine which linker would be most suitable, we synthesized Prostate specific membrane antigen (PSMA)-1-VcMMAECy5.5 with a cathepsin cleavable linker (Figure 1A) and PSMA-1-McMMAE-Cy5.5 with noncleavable linker (Figure 1B)
The results demonstrated that PSMA-1-VcMMAE-Cy5.5 can be cleaved by cathepsin, while

Summary

Introduction

Prostate cancer is the most common malignancy and the second leading cause of cancer death in men in the United States [1]. Patients with localized disease can be treated with radical prostatectomy and/or radiation therapy [2]. In randomized controlled trials, generally comparing the treatment group to mitoxantrone, the only FDA approved chemotherapy for advanced prostate cancer before docetaxel’s approval in 2004, survival benefit for all of these agents was less than four months [2]. This year mCRPC is expected to kill 33,330 patients in the United States alone [1], underscoring the need for new therapies

Methods

Results

Discussion

Conclusion