Prostate Specific Membrane Antigen as Biomarker and Therapeutic Target for Prostate Cancer

Wolf, Philipp

doi:10.5772/26951

Cited by 6 publications

(8 citation statements)

References 86 publications

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“…The clinical success of immunotherapeutic approaches in prostate cancer has been limited to date, although a number of prostate lineage-specific antigens, such as prostate-specific membrane antigen (PSMA, also known as FOLH1), offer potential therapeutic targets. The biology of PSMA and its relevance as a tumorspecific antigen for mCRPC has been reviewed extensively (7)(8)(9). PSMA has been used as a target for the development of diagnostics (10) and for therapeutic mAbs (11)(12)(13)(14).…”

Section: Introductionmentioning

confidence: 99%

MOR209/ES414, a Novel Bispecific Antibody Targeting PSMA for the Treatment of Metastatic Castration-Resistant Prostate Cancer

Hernández-Hoyos

Sewell

Bader

et al. 2016

Molecular Cancer Therapeutics

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Treatment of metastatic, castration-resistant prostate cancer (mCRPC) remains a highly unmet medical need and current therapies ultimately result in disease progression. Immunotherapy is a rapidly growing approach for treatment of cancer but has shown limited success to date in the treatment of mCRPC. We have developed a novel humanized bispecific antibody, MOR209/ES414, built on the ADAPTIR (modular protein technology) platform, to redirect T-cell cytotoxicity toward prostate cancer cells by specifically targeting T cells through CD3e to prostate cancer cells expressing PSMA (prostate-specific membrane antigen). In vitro cross-linking of T cells with PSMAexpressing tumor cells by MOR209/ES414 triggered potent targetdependent tumor lysis and induction of target-dependent T-cell activation and proliferation. This activity occurred at low picomolar concentrations of MOR209/ES414 and was effective at low T-effector to tumor target cell ratios. In addition, cytotoxic activity was equivalent over a wide range of PSMA expression on target cells, suggesting that as few as 3,700 PSMA receptors per cell are sufficient for tumor lysis. In addition to high sensitivity and in vitro activity, MOR209/ES414 induced limited production of cytokines compared with other bispecific antibody formats. Pharmacokinetic analysis of MOR209/ES414 demonstrated a serum elimination half-life in NOD/SCID g (NSG) mice of 4 days. Administration of MOR209/ES414 in murine xenograft models of human prostate cancer significantly inhibited tumor growth, prolonged survival, and decreased serum prostate-specific antigen levels only in the presence of adoptively transferred human T cells. On the basis of these preclinical findings, MOR209/ES414 warrants further investigation as a potential therapeutic for the treatment of CRPC. Mol Cancer Ther; 15(9); 2155-65. Ó2016 AACR.

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Section: Introductionmentioning

confidence: 99%

MOR209/ES414, a Novel Bispecific Antibody Targeting PSMA for the Treatment of Metastatic Castration-Resistant Prostate Cancer

Hernández-Hoyos

Sewell

Bader

et al. 2016

Molecular Cancer Therapeutics

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“…Furthermore, PSMA expression was observed to decrease in the prostate cancer cell line, LNCap, when incubated with androgen dihydrotestosterone and, conversely, cells grown in androgen-stripped media displayed increased PSMA expression [34]. It is clear that increased expression and enzymatic activity of PSMA in aggressive tumors are telling of a selective advantage bestowed by PSMA upon tumor cells and this contributes to prostate carcinogenesis [35].…”

Section: Clinical Relevance Of Psmamentioning

confidence: 98%

“…Clinical trials with 99m Tc-labeled J591 established detection of primary prostate cancer, as well as prostate bed recurrence and distant metastases, again, including metastasis to bone [30,47]. Several other developed monoclonal antibodies (3/A12, 3/E7 and 3/F11) bind to different epitopes of PSMA [35]. A study using 64 Cu-3/A12 for PET imaging of prostate cancer xenograft showed a good tumor-to-background ratio [44].…”

Section: Psma As a Biomarkermentioning

confidence: 99%

The Clinical and Therapeutic Uses of MDM2 and PSMA and Their Potential Interaction in Aggressive Cancers

2015

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Prostate-specific membrane antigen (PSMA) overexpression is observed in the neovasculature of solid tumors, but not in the vasculature of normal tissues. Increased PSMA expression is positively associated with tumor stage and grade, although its function in cancer remains unclear. Mouse double minute 2 (MDM2) is a negative regulator of the p53 tumor suppressor and is reported to regulate VEGF expression and angiogenesis. Both proteins have been considered as biomarkers and therapeutic targets for advanced solid tumors. Our work and a recent microarray-based gene profiling study suggest there could be signaling interplay between MDM2 and PSMA. We herein review the mechanisms underlining the outgrowth of tumors associated with PSMA and MDM2, their potential interaction and how this may be applied to anticancer therapeutics.

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“…29,30 In normal prostate, PSMA is generally present as a soluble protein in cytoplasm; however, during cancer progression, cells begin to express more PSMA as an insoluble membrane form, resulting in high PSMA expression in high-grade and metastatic PCa and making it a promising target for imaging and therapy. 21,29,[31][32][33] Little information is available regarding the mechanisms controlling the expression of this gene; however, PSMA loss of expression seems to be connected with cancer progression from androgen-dependent to the androgen-independent stage. This can be exemplarily observed in the metastatic cell lines PC-3 and LNCaP.…”

Section: Molecular Targeting Of Pca and Tumor Modelsmentioning

confidence: 99%

Bispecific radioligands targeting prostate‐specific membrane antigen and gastrin‐releasing peptide receptors on the surface of prostate cancer cells

Liolios

Sachpekidis

Schäfer

et al. 2019

Labelled Comp Radiopharmac

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Metastases of prostate cancer usually show highly heterogeneous or partly lost prostate-specific membrane antigen (PSMA) expression. In order to image and treat both PSMA positive and negative tissues, the extension of PSMA tracer specificity to other receptors, also highly expressed on the surface of prostate cancer cells, has been suggested. Prostate cancer cells usually express both PSMA and gastrin-releasing peptide (GRP) receptors; thus, bispecific heterodimeric molecules, addressing both targets at the same time, may significantly improve prostate cancer imaging and therapy. This article summarizes preclinical data regarding low-molecular weight molecules targeting PSMA and GRP receptors.

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Prostate Specific Membrane Antigen as Biomarker and Therapeutic Target for Prostate Cancer

Cited by 6 publications

References 86 publications

MOR209/ES414, a Novel Bispecific Antibody Targeting PSMA for the Treatment of Metastatic Castration-Resistant Prostate Cancer

MOR209/ES414, a Novel Bispecific Antibody Targeting PSMA for the Treatment of Metastatic Castration-Resistant Prostate Cancer

The Clinical and Therapeutic Uses of MDM2 and PSMA and Their Potential Interaction in Aggressive Cancers

Bispecific radioligands targeting prostate‐specific membrane antigen and gastrin‐releasing peptide receptors on the surface of prostate cancer cells

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