Glycoprotein non-metastatic b (GPNMB): A metastatic mediator and emerging therapeutic target in cancer

Maric, Gordana; Rose, April A.N.; Annis, Matthew G.; Siegel, Peter M.

doi:10.2147/ott.s44906

Cited by 78 publications

(70 citation statements)

References 103 publications

(181 reference statements)

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“…It is a heavily glycosylated protein with sites for both N- and O- glycosylation [12]. GPNMB is localized on the plasma membrane as well as in subcellular locations in various cell types.…”

Section: Gpnmb Structure and Functionmentioning

confidence: 99%

Glycoprotein Non-Metastatic Melanoma Protein B (GPNMB) and Cancer: A Novel Potential Therapeutic Target

Taya

Hammes

2018

Steroids

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Glycoprotein non-metastatic melanoma protein B (GPNMB) is a transmembrane protein enriched on the cell surface of cancer cells, including melanoma, glioblastoma, and triple-negative breast cancer. There is growing evidence identifying GPNMB as a tumor-promoter; however, despite its biological and clinical significance, the molecular mechanisms engaged by GPNMB to promote tumorigenesis are not well understood. GPNMB promotes aggressive behaviors such as tumor cell proliferation, migration, and invasion. The extracellular domain of GPNMB shed from the cell surface interacts with integrins to facilitate in the recruitment of immune-suppressive and pro-angiogenic cells to the tumor microenvironment, thereby enhancing tumor migration and invasion. GPNMB also modulates receptor tyrosine kinases and integrin signaling in a cell autonomous fashion, leading to downstream kinase signaling that in turn triggers the expression and secretion of tumorigenic factors such as matrix metalloproteinases (MMPs) and cytokines. Therefore, GPNMB exerts its pro-tumorigenic role both intracellularly and in a paracrine fashion through shedding its extracellular domain. This review highlights the importance of GPNMB in cancer progression and discusses molecular mediators of GPNMB-induced tumor growth and invasion.

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“…It is a heavily glycosylated protein with sites for both N- and O- glycosylation [12]. GPNMB is localized on the plasma membrane as well as in subcellular locations in various cell types.…”

Section: Gpnmb Structure and Functionmentioning

confidence: 99%

Glycoprotein Non-Metastatic Melanoma Protein B (GPNMB) and Cancer: A Novel Potential Therapeutic Target

Taya

Hammes

2018

Steroids

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“…GPNMB is overexpressed on triple negative breast cancer, among other solid tumors[266]. A phase I/II clinical trial demonstrated that it is active in advanced melanoma[267].…”

Section: Antibodies As Targeting Vehiclesmentioning

confidence: 99%

“…A phase I/II clinical trial demonstrated that it is active in advanced melanoma[267]. Clinical data suggest that it is particularly active in triple negative breast cancer patients with high levels GPNMB expression[266]. Ongoing phase II studies will provide more information about its activity.…”

Section: Antibodies As Targeting Vehiclesmentioning

confidence: 99%

Mechanisms of action of therapeutic antibodies for cancer

Redman

Hill

Aldeghaither

et al. 2015

Molecular Immunology

144

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The therapeutic utility of antibodies and their derivatives is achieved by various means. The FDA has approved several targeted antibodies that disrupt signaling of various growth factor receptors for the treatment of a number of cancers. Rituximab, and other anti-CD20 monoclonal antibodies are active in B cell malignancies. As more experience has been gained with anti-CD20 monoclonal antibodies, the multifactorial nature of their anti-tumor mechanisms has emerged. Other targeted antibodies function to dampen inhibitory checkpoints. These checkpoint inhibitors have recently achieved dramatic results in several cancers, including melanoma. These and related antibodies continue to be investigated in the clinical and pre-clinical settings. Novel antibody structures that target two or more antigens have also made their way into clinical use. Tumor targeted antibodies can also be conjugated to chemo- or radiotherapeutic agents, or catalytic toxins, as a means to deliver toxic payloads to cancer cells. Here we provide a review of these mechanisms and a discussion of their relevance to current and future clinical applications.

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“…Glycoprotein non-metastatic b (GPNMB) is overexpressed in certain solid tumours, including triple-negative breast cancer and melanoma, and is the target for the immunoconjugate glembatumumab vedotin. 78 In a phase II study using glembatumumab vedotin, patients with metastatic, heavily pre-treated, breast cancer experienced a comparable overall survival to investigator’s choice of chemotherapy. 79 However, in the subset of patients with triple-negative breast cancer and high GPNMB expression, a statistically significant improvement in overall survival was observed with the use of glembatumumab vedotin over investigator’s choice of chemotherapy (10.0 months versus 5.5 months, P = 0.003).…”

Section: Immunoconjugate Therapeutic Entitiesmentioning

confidence: 99%

The development of immunoconjugates for targeted cancer therapy

2014

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Immunoconjugates are specific, highly effective, minimally toxic anticancer therapies that are beginning to show promise in the clinic. Immunoconjugates consist of three separate components: an antibody that binds to a cancer cell antigen with high specificity, an effector molecule that has a high capacity to kill the cancer cell, and a linker that will ensure the effector does not separate from the antibody during transit and will reliably release the effector to the cancer cell or tumour stroma. The high affinity antibody–antigen interaction allows specific and selective delivery of a range of effectors, including pharmacologic agents, radioisotopes, and toxins, to cancer cells. Some anticancer molecules are not well tolerated when administered systemically owing to unacceptable toxicity to the host. However, this limitation can be overcome through the linking of such cytotoxins to specific antibodies, which mask the toxic effects of the drug until it reaches its target. Conversely, many unconjugated antibodies are highly specific for a cancer target, but have low therapeutic potential and can be repurposed as delivery vehicles for highly potent effectors. In this Review, we summarize the successes and shortcomings of immunoconjugates, and discuss the future potential for the development of these therapies.

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Glycoprotein non-metastatic b (GPNMB): A metastatic mediator and emerging therapeutic target in cancer

Cited by 78 publications

References 103 publications

Glycoprotein Non-Metastatic Melanoma Protein B (GPNMB) and Cancer: A Novel Potential Therapeutic Target

Glycoprotein Non-Metastatic Melanoma Protein B (GPNMB) and Cancer: A Novel Potential Therapeutic Target

Mechanisms of action of therapeutic antibodies for cancer

The development of immunoconjugates for targeted cancer therapy

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