Dataset Information

The homodimer of prostate-specific membrane antigen is a functional target for cancer therapy.

ABSTRACT: Prostate-specific membrane antigen (PSMA) is a type 2 integral membrane glycoprotein that serves as an attractive target for cancer immunotherapy by virtue of its abundant and restricted expression on the surface of prostate carcinomas and the neovasculature of most other solid tumors. However, relatively little is known about the molecular structure of this target. Here, we report that PSMA is expressed on tumor cells as a noncovalent homodimer. A truncated PSMA protein, lacking transmembrane and cytoplasmic domains, also formed homodimers, indicating that the extracellular domain is sufficient for dimerization. PSMA dimers but not monomers displayed a native conformation and possessed high-level carboxypeptidase activity. A unique dimer-specific epitope was identified by using one of a panel of novel mAbs. When used to immunize animals, dimer but not monomer elicited antibodies that efficiently recognized PSMA-expressing tumor cells. These findings on PSMA structure and biology may have important implications for active and passive immunotherapy of prostate and other cancers.

SUBMITTER: Schulke N

PROVIDER: S-EPMC240662 | biostudies-literature | 2003 Oct

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

The homodimer of prostate-specific membrane antigen is a functional target for cancer therapy.

Schülke Norbert N Varlamova Olga A OA Donovan Gerald P GP Ma Dangshe D Gardner Jason P JP Morrissey Donna M DM Arrigale Robert R RR Zhan Cenchen C Chodera Amy J AJ Surowitz Kenneth G KG Maddon Paul J PJ Heston Warren D W WD Olson William C WC

Proceedings of the National Academy of Sciences of the United States of America 20031001 22

Prostate-specific membrane antigen (PSMA) is a type 2 integral membrane glycoprotein that serves as an attractive target for cancer immunotherapy by virtue of its abundant and restricted expression on the surface of prostate carcinomas and the neovasculature of most other solid tumors. However, relatively little is known about the molecular structure of this target. Here, we report that PSMA is expressed on tumor cells as a noncovalent homodimer. A truncated PSMA protein, lacking transmembrane a ...[more]

PMID: 14583590

Similar Datasets

Project description:Auger radiopharmaceutical therapy is a promising strategy for micrometastatic disease given high linear energy transfer and short range in tissues, potentially limiting normal tissue toxicities. We previously demonstrated anti-tumor efficacy of a small-molecule Auger electron emitter targeting the prostate-specific membrane antigen (PSMA), 2-[3-[1-carboxy-5-(4-[125I]iodo-benzoylamino)-pentyl]-ureido]-pentanedioic acid), or 125I-DCIBzL, in a mouse xenograft model. Here, we investigated the therapeutic efficacy, long-term toxicity, and biodistribution of 125I-DCIBzL in a micrometastatic model of prostate cancer (PC). Methods: To test the therapeutic efficacy of 125I-DCIBzL in micrometastatic PC, we used a murine model of human metastatic PC in which PSMA+ PC3-ML cells expressing firefly luciferase were injected intravenously in NSG mice to form micrometastatic deposits. One week later, 0, 0.37, 1.85, 3.7, 18.5, 37, or 111 MBq of 125I-DCIBzL was administered (intravenously). Metastatic tumor burden was assessed using bioluminescence imaging (BLI). Long-term toxicity was evaluated via serial weights and urinalysis of non-tumor-bearing mice over a 12-month period, as well as final necropsy. Results: In the micrometastatic PC model, activities of 18.5 MBq 125I-DCIBzL and above significantly delayed development of detectable metastatic disease by BLI and prolonged survival in mice. Gross metastases were detectable in control mice and those treated with 0.37-3.7 MBq 125I-DCIBzL at a median of 2 weeks post-treatment, versus 4 weeks for those treated with 18.5-111 MBq 125I-DCIBzL (P<0.0001 by log-rank test). Similarly, treatment with ≥18.5 MBq 125I-DCIBzL yielded a median survival of 11 weeks, compared with 6 weeks for control mice (P<0.0001). At 12 months, there was no appreciable toxicity via weight, urinalysis, or necropsy evaluation in mice treated with any activity of 125I-DCIBzL, which represents markedly less toxicity than the analogous PSMA-targeted α-particle emitter. Macro-to-microscale dosimetry modeling demonstrated lower absorbed dose in renal cell nuclei versus tumor cell nuclei due to lower levels of drug uptake and cellular internalization in combination with the short range of Auger emissions. Conclusion: PSMA-targeted radiopharmaceutical therapy with the Auger emitter 125I-DCIBzL significantly delayed development of detectable metastatic disease and improved survival in a micrometastatic model of PC, with no long-term toxicities noted at 12 months, suggesting a favorable therapeutic ratio for treatment of micrometastatic PC.

Project description:Purpose:Stereotactic ablative radiation therapy (SABR) for oligometastatic prostate cancer (OMPC) may improve clinical outcomes, but current challenges in intrafraction tracking of multiple small targets limits treatment accuracy. A biology-guided radiation therapy (BgRT) delivery system incorporating positron emission tomography (PET) detectors is being developed to use radiotracer uptake as a biologic fiducial for intrafraction tumor tracking to improve geometric accuracy. This study simulates prostate-specific membrane antigen (PSMA)-directed BgRT using a cohort from our phase II randomized trial of SABR in men with recurrent hormone sensitive OMPC and compares dose distributions to clinical SABR (CSABR). Methods and Materials:A research treatment planning system (RTPS) was used to replan 15 patients imaged with PSMA-targeted 18F-DCFPyL PET/computed tomography and previously treated with CSABR using conventional linear accelerators (linacs). The RTPS models a prototype ring-mounted linac incorporating PET and kilo-voltage computed tomography imaging subsystems and can be used to optimize BgRT plans, as well as research SABR (RSABR) plans, which use the prototype linac without radiotracer guidance. CSABR, RSABR, and BgRT plans were compared in terms of maximum planning target volume (PTV) dose (Dmax), mean dose to proximal organs at risk (DOAR), conformity index, as well as voxel-wise correlation of dose with PET specific uptake values to investigate possible dose-painting effects. Results:RSABR and BgRT plans resulted in mean ± standard deviation increases in Dmax of 4 ± 11% (P = .21) and 18 ± 15% (P < .001) and reductions in DOAR of -20 ± 19% (P <.001) and -10 ± 19% (P = .02) compared with CSABR. Similar target coverage was maintained with conformity indices of 0.81 ± 0.04 (P < .001) and 0.72 ± 0.08 (P = .44) for RSABR and BgRT compared with 0.74 ± 0.08 for CSABR. Dose and log (specific uptake values) had Pearson correlation coefficients of 0.10 (CSABR), 0.16 (RSABR), and 0.31 (BgRT). Conclusions:BgRT plans provided similar PTV coverage and conformity compared with CSABR while incorporating underlying PET activity. These results demonstrate feasibility of BgRT optimization enabling online PSMA-targeted, PET-based tracked dose delivery for OMPC.

Project description:Abstract Background Radioligand therapy (RLT) with 177lutetium (Lu)-labelled prostate-specific membrane antigen (PSMA) ligands has been increasingly used in recent years for therapy of metastatic castrate-resistant prostate cancer (mCRPC). Studies have revealed that 177Lu-PSMA ligand therapy is well tolerated and appears to cause fewer adverse effects than current standard of care third-line treatments. Notably, since 177Lu-PSMA agents are predominantly excreted by kidneys, there are concerns relating to their potential nephrotoxicity and renal outcomes. Although many recent studies have focused on mostly nephrotoxic adverse reactions at up to 3-month follow-up, assessment of renal outcomes after 177Lu-PSMA RLT in longer term follow-up is lacking. The aim of this study was to assess the influence of 177Lu-PSMA RLT on renal function in patients treated for mCRPC at >3?months post-therapy. Methods In this retrospective cohort study, we assessed 195 men with progressive mCRPC who had received therapy with 177Lu-PSMA as second- or third-line after standard therapeutic interventions. Patients underwent investigations with 68Ga-PSMA-ligand positron emission tomography/computed tomography scan to confirm PSMA-expressing mCRPC. Eligible patients were required to have estimated glomerular filtration rate (eGFR) >30?mL/min/1.73 m2, an Eastern Cooperative Oncology Group performance status score <3, no severe liver injury (as characterized by liver function tests) and no significant bone marrow dysfunction. Enrolled patients received two to five cycles of intravenous 177Lu-PSMA I&T or 177Lu-PSMA-617, at 6- to 10-week intervals. Renal outcomes were assessed according to Kidney Disease: Improving Global Outcomes guidelines as incidence of acute kidney injury (AKI), acute kidney disease (AKD) or chronic kidney disease (CKD). All assessments and tests were undertaken between therapy cycles and at follow-up of at least 3?months. Results Of 195 assessed men with mCRPC, 110 patients aged [mean ± SD (range)] 70?±?8 (53–92) years were recruited into this study with median follow-up of 8 (interquartile range 5–12, minimum 3, maximum 29) months and mean baseline eGFR 81?±?13?mL/min/1.73 m2. Pre-existing CKD was identified in 12% of patients. None of the patients experienced an AKI during RLT. Two AKD and three CKD G3a cases were identified. Analysis of possible impact of prior CKD and major risk factors (hypertension, diabetes, history of AKI) on incidence of AKD or CKD demonstrated relative risk 4.2 [95% confidence interval (CI) 1.23–14.29] and 1.91 (95% CI 1.14–3.12), respectively. However, Fisher’s exact test did not reveal statistical significance of the impact of both conditions. Conclusions Current Lu-PSMA RLT protocols appear to carry a mild nephrotoxic risk with the rate of about 4.5%. Prior CKD is potentially the most significant risk factor of post-RLT renal dysfunction.

Dataset Information

The homodimer of prostate-specific membrane antigen is a functional target for cancer therapy.

Publications

The homodimer of prostate-specific membrane antigen is a functional target for cancer therapy.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets