Prostate-Specific Membrane Antigen (PSMA) Targeted Bio-orthogonal Therapy for Metastatic Prostate Cancer
Abstract
Prostate cancer (PCa) is the second most frequently occurring cancer in men after lung cancer, and approximately 900,000 new cases of PCa are detected each year. Initial treatment for localized disease is typically a combination of surgery and/or radiation therapy. Recurrent, locally advanced, or metastatic PCa, is treated by hormone deprivation therapy using luteinizing hormone-releasing hormone (LHRH) agonists or orchiectomy. Unfortunately, PCa invariably becomes androgen-independent, and, at this stage, is called castration-resistant prostate cancer (CRPCa). Metastatic CRPCa, which primarily manifests as bone metastases, is a lethal disease, as chemotherapy typically does not provide high efficacy and is complicated by side effects. Typical survival benefits of therapy are currently only 3 to 5 months and the death rate is more than 250,000 patients per year. Chemotherapy alone is of little benefit in this setting, and novel targeted treatments that can overcome the castration resistance are being developed. Several attempts to target an important biomarker of aggressive prostate cancer, PSMA (prostate-specific membrane antigen expressed on the surface of aggressive cancer cells), resulted in the development of so-called "antibody-drug conjugates" (ADC). These novel therapeutics can deliver the drug specifically to cancer cells and spare the rest of the body from the toxic effects of therapy. Unfortunately, the biology of ADC distribution and clearance in the body rendered them highly toxic and the development status of new ADC for prostate cancer therapy is currently uncertain. In this application, we propose to develop and validate a novel, two-component, targeted therapeutic system that will provide a safe and precise way to deliver toxic anticancer drugs directly to tumor cells and minimize toxic effects for patients. This goal will be achieved by highly specific delivery of pretargeting agents to the PSMA-positive prostate cancer, thus limiting the circulation time of potentially toxic drug carriers, and by using a new ligation chemistry that does not interfere with any known biological functions. The new therapy has two components that will be administered within a specific interval of 12 to 24 hours. The first component will selectively label PSMA-positive prostate cancer cells, and the second component will deliver highly toxic anticancer drugs only to cells prelabeled with the first component. Both components of the delivery system can be noninvasively imaged to enable the selection of tumors/patients based on their PSMA status, and to optimize timing of administration. For instance, patients who do not show efficient binding and accumulation of the first pretargeting component can be spared from administration of the second cytotoxic drug carrier component. The new therapeutic strategy will be initially tested in prostate cancer cells, which we will follow with in vivo studies using mouse models of human metastatic prostate cancer. Although currently the proposed research is limited to preclinical prostate cancer models, using non-toxic and biocompatible components, such as humanized antibody, human albumin carriers, and bioorthogonal click chemistry, will enable rapid transition to translational studies in humans. We envision that, if successful, this treatment strategy can be used to treat advanced and metastatic PSMA-positive prostate cancer.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 31, 2017
- Source ID
- W81XWH1610595
Entities
People
- Dmitri Artemov
Organizations
- Johns Hopkins University
- United States Army