Targeted Prodrug Approaches for Hormone Refractory Prostate Cancer

Abstract

Due to the propensity of relapse and resistance with prolonged androgen deprivation therapy (ADT), there is a growing interest in developing non-hormonal therapeutic approaches as alternative treatment modalities for hormone refractory prostate cancer (HRPC). Although the standard treatment for HRPC consists of a combination of ADT with taxanes and anthracyclines, the clinical use of chemotherapeutics is limited by systemic toxicity stemming from nondiscriminatory drug exposure to normal tissues. In order to improve the tumor selectivity of chemotherapeutics, various targeted prodrug approaches have been explored. Antibody-directed enzyme prodrug therapy (ADEPT) and gene-directed enzyme prodrug therapy (GDEPT) strategies leverage tumor-specific antigens and transcription factors for the specific delivery of cytotoxic anticancer agents using various prodrug-activating enzymes. In prostate cancer, overexpression of tumor-specific proteases such as prostate-specific antigen (PSA) and prostate-specific membrane antigen (PSMA) is being exploited for selective activation of anticancer prodrugs designed to be activated through proteolysis by these prostate cancer-specific enzymes. PSMA- and PSA-activated prodrugs typically comprise an engineered high-specificity protease peptide substrate coupled to a potent cytotoxic agent via a linker for rapid release of cytotoxic species in the vicinity of prostate cancer cells following proteolytic cleavage. Over the past two decades, various such prodrugs have been developed and they were effective at inhibiting prostate tumor growth in rodent models; several of these prodrug approaches have been advanced to clinical trials and may be developed into effective therapies for HRPC.

MAOA-a novel decision maker of apoptosis and autophagy in hormone refractory neuroendocrine prostate cancer cells

“…However, over time a significant population of patients loses responsiveness to ADT and develops hormone-refractory prostate cancer (HRPC)4. Due to the improvement of healthcare, patients now live long enough to develop HRPC and in spite of aggressive treatments, the mortality rate of HRPC is always high5. One important feature of HRPC is its association with neuroendocrine differentiation (NED)67.…”

Thapsigargin, Origin, Chemistry, Structure-Activity Relationships and Prodrug Development

“…A few attempts to develop prodrug based on the substrate specificity of PSA have been made [46]. In this case advantage of the ability of PSA to cleave on the C-site of Gln was taken to construct a number of peptides terminating with Gln.…”

“…PSMA is a carboxypeptidase, which cleaves poly--glutamoyl peptide bonds in glutamated folates and thereby enables uptake of folate [46,48]. PSMA is expressed in the prostate but in spite of the name PSMA is overexpressed in neovasculature in a number of tumors including hepatocellular carcinoma, mesothelioma, ovarian cancer, renal cancer, bladder cancer, renal cancer and breast cancer [48].…”

Improving the Specificity of the Prostate‐Specific Antigen Substrate Glutaryl‐Hyp‐Ala‐Ser‐Chg‐Gln as a Promoiety

“…While alternative treatment modalities involving platinum compounds, radiopharmaceuticals and monoclonal antibodies have been explored recently , the clinical use of chemotherapeutics such as docetaxel, mitoxantrone, and doxorubicin is limited by systemic toxicity stemming from non‐discriminatory drug exposure to normal tissues . To mitigate this issue, one of the approaches developed to improve the selectivity of chemotherapy toward tumor cells involves the targeted prodrug strategy . Secretion of active prostate‐specific antigen (PSA) in the tumor microenvironment can be exploited for targeted activation of peptide prodrugs in cancer cells .…”

“…To mitigate this issue, one of the approaches developed to improve the selectivity of chemotherapy toward tumor cells involves the targeted prodrug strategy . Secretion of active prostate‐specific antigen (PSA) in the tumor microenvironment can be exploited for targeted activation of peptide prodrugs in cancer cells . PSA is a serine protease with chymotrypsin‐like activity and is predominantly expressed in the prostate although present in other normal and tumor tissues at low concentrations .…”