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A Bioluminescent and Fluorescent Orthotopic Syngeneic Murine Model of Androgen-dependent and Castration-resistant Prostate Cancer
Published on: March 6, 2018
Prostatic Acid Phosphatase (PAP) Antibodies to Treat Castration-Resistant Prostate Cancer
Alexander Kirschenbaum1, Pamela Cheung2, Shen Yao2
1Department of Urology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
Abstract:
Prostate cancer (PCa) is the most common cancer and the second leading cause of cancer death in American men. Most patients with metastatic disease respond initially to androgen deprivation therapy (ADT) but almost inevitably progress to castration-resistant prostate cancer (CRPC). Identification of markers and drivers of Metastatic CRPC (mCRPC) that (a) represent a progenitor-type cancer cell population, (b) persist in castration-resistant disease, (c) are actionable targets expressed on the cell surface, and (d) are induced by hypoxia is required to facilitate the development of novel targeted therapies. We identified prostatic acid phosphatase (PAP), particularly the transmembrane form (TMPAP), as one such potential target. PAP is both a phosphatase and a 5'ectonucleotidase that generates adenosine. PAP is a human tumor marker first described in 1936 and is still used as an important prognostic marker for advanced metastatic prostate cancer. Our group recently reported that the transmembrane form of the protein (TMPAP) is expressed in CRPC and can serve as a potential therapeutic target. We identified a lead human anti-TMPAP antibody clone 3D8 (3D8-Ab). 3D8-ADCs (Antibody Drug Conjugates) and 3D8-Ab were tested for their ability to reduce tumor size/volume in a xenograft model. The human PAP-expressing PCa cell line VCaP, originally derived from a vertebral metastasis from a patient with CRPC, was inoculated subcutaneously into SCID mice. Treatment with either 3D8-Ab or 3D8-ADC significantly reduced tumor size and increased animal survival. These data indicate that targeting PAP with monoclonal antibodies either alone or conjugated to toxins has the potential to treat CRPC.
Insights
Targeting prostatic acid phosphatase (PAP) with antibody therapies shows promise for treating advanced prostate cancer. Monoclonal antibodies and antibody-drug conjugates targeting transmembrane PAP (TMPAP) significantly reduced tumor size and improved survival in preclinical models.
Area of Science:
- Oncology
- Cancer Therapeutics
- Molecular Biology
Background:
- Prostate cancer (PCa) is a leading cause of cancer death in men, with metastatic disease often progressing to castration-resistant prostate cancer (CRPC) despite androgen deprivation therapy (ADT).
- Effective treatments for metastatic CRPC (mCRPC) are limited, necessitating the identification of novel therapeutic targets expressed on cancer cells.
- Prostatic acid phosphatase (PAP), particularly its transmembrane form (TMPAP), is a potential target identified as being expressed in CRPC.
Purpose of the Study:
- To identify and validate actionable cell surface targets for novel therapies against metastatic castration-resistant prostate cancer (mCRPC).
- To evaluate the therapeutic potential of targeting transmembrane prostatic acid phosphatase (TMPAP) using a human anti-TMPAP monoclonal antibody (3D8-Ab) and antibody-drug conjugates (3D8-ADCs).
Main Methods:
- Development of a human anti-TMPAP monoclonal antibody (3D8-Ab).
- Evaluation of 3D8-Ab and 3D8-ADCs in a xenograft mouse model using human PCa cell line VCaP.
- Assessment of tumor size, volume, and animal survival following treatment.
Main Results:
- Treatment with either 3D8-Ab or 3D8-ADCs significantly reduced tumor size and volume in the xenograft model.
- Both antibody-based therapies led to increased survival rates in the treated animals.
- These findings validate TMPAP as a viable therapeutic target in CRPC models.
Conclusions:
- Targeting TMPAP with monoclonal antibodies, alone or conjugated to toxins, represents a promising therapeutic strategy for CRPC.
- The anti-TMPAP antibody 3D8 and its conjugates demonstrate significant anti-tumor activity in preclinical models.
- Further development of PAP-targeted therapies could offer new treatment options for patients with advanced prostate cancer.
