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Updated: May 20, 2026
A Bioluminescent and Fluorescent Orthotopic Syngeneic Murine Model of Androgen-dependent and Castration-resistant Prostate Cancer
Published on: March 6, 2018
Engineering a prostate-specific membrane antigen-activated tumor endothelial cell prodrug for cancer therapy
Samuel R Denmeade1, Annastasiah M Mhaka, D Marc Rosen
1The Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA. denmesa@jhmi.edu
Abstract:
Heterogeneous expression of drug target proteins within tumor sites is a major mechanism of resistance to anticancer therapies. We describe a strategy to selectively inhibit, within tumor sites, the function of a critical intracellular protein, the sarcoplasmic/endoplasmic reticulum calcium adenosine triphosphatase (SERCA) pump, whose proper function is required by all cell types for viability. To achieve targeted inhibition, we took advantage of the unique expression of the carboxypeptidase prostate-specific membrane antigen (PSMA) by tumor endothelial cells within the microenvironment of solid tumors. We generated a prodrug, G202, consisting of a PSMA-specific peptide coupled to an analog of the potent SERCA pump inhibitor thapsigargin. G202 produced substantial tumor regression against a panel of human cancer xenografts in vivo at doses that were minimally toxic to the host. On the basis of these data, a phase 1 dose-escalation clinical trial has been initiated with G202 in patients with advanced cancer.
Insights
Researchers developed a novel prodrug, G202, to target cancer by inhibiting the sarcoplasmic/endoplasmic reticulum calcium adenosine triphosphatase (SERCA) pump. This strategy showed significant tumor regression in preclinical models with minimal toxicity, leading to a phase 1 clinical trial.
Area of Science:
- Oncology
- Pharmacology
- Molecular Biology
Background:
- Tumor heterogeneity in drug target expression drives anticancer therapy resistance.
- The sarcoplasmic/endoplasmic reticulum calcium adenosine triphosphatase (SERCA) pump is essential for cell viability.
- Targeting intracellular proteins within tumors presents a therapeutic challenge.
Purpose of the Study:
- To develop a strategy for selective inhibition of the SERCA pump within tumor sites.
- To create a prodrug that leverages tumor-specific antigens for targeted drug delivery.
- To evaluate the efficacy and toxicity of the novel prodrug G202 in preclinical cancer models.
Main Methods:
- Generation of G202, a prodrug linking a prostate-specific membrane antigen (PSMA)-targeting peptide to a SERCA pump inhibitor (thapsigargin analog).
- In vivo testing of G202 against human cancer xenografts in mice.
- Assessment of tumor regression and host toxicity at various G202 doses.
Main Results:
- G202 demonstrated significant tumor regression across multiple human cancer xenografts.
- The prodrug exhibited minimal toxicity to the host at effective therapeutic doses.
- Preclinical efficacy supports the clinical investigation of G202.
Conclusions:
- Targeted inhibition of the SERCA pump using the PSMA-targeting prodrug G202 is a promising strategy for cancer therapy.
- G202 offers a potential approach to overcome drug resistance mediated by heterogeneous target expression.
- A phase 1 clinical trial is underway to evaluate G202 in patients with advanced cancer.
