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

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

Gordana Maric et al. Onco Targets Ther. 2013.

Abstract

Molecularly targeted therapies are rapidly growing with respect to their clinical development and impact on cancer treatment due to their highly selective anti-tumor action. However, many aggressive cancers such as triple-negative breast cancer (TNBC) currently lack well-defined therapeutic targets against which such agents can be developed. The identification of tumor-associated antigens and the generation of antibody drug-conjugates represent an emerging area of intense interest and growth in the field of cancer therapeutics. Glycoprotein non-metastatic b (GPNMB) has recently been identified as a gene that is over-expressed in numerous cancers, including TNBC, and often correlates with the metastatic phenotype. In breast cancer, GPNMB expression in the tumor epithelium is associated with a reduction in disease-free and overall survival. Based on these findings, glembatumumab vedotin (CDX-011), an antibody-drug conjugate that selectively targets GPNMB, is currently being investigated in clinical trials for patients with metastatic breast cancer and unresectable melanoma. This review discusses the physiological and potential pathological roles of GPNMB in normal and cancer tissues, respectively, and details the clinical advances and challenges in targeting GPNMB-expressing malignancies.

Keywords: CDX-011; GPNMB; antibody-drug conjugates; breast cancer; osteoactivin.

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Figures

Figure 1

Figure 1

A schematic representation of GPNMB indicating the domains and motifs contributing to GPNMB function. Notes: The symbols (filled circles) located above the extracellular domain of GPNMB represent glycosylation sites. The RGD sequence comprises an integrin binding domain, where R = Arginine, G = Glycine, D = Aspartic acid. The YxxI sequence constitutes a hemITAM motif, where Y = tyrosine, x = any amino acid, I = isoleucine. The di-leucine motif is a lysosomal/endosomal targeting motif of the D/ExxxLL type, where D = Aspartic acid, E = Glutamic acid, x = any amino acid, L = leucine. Abbreviations: GPNMB, glycoprotein non-metastatic b; hemiTAM, immunoreceptor tyrosine-based activation motif; PKD, polycystic kidney disease; RGD, integrin-binding.

Figure 2

Figure 2

Potential mechanisms through which GPNMB promotes malignant cellular phenotypes within cancer cells. Notes: GPNMB may act cell autonomously (green panel) to induce intracellular signaling, which can influence the expression of multiple targets, including matrix metalloproteinases and cytokines, and enhance the invasiveness of tumor cells. GPNMB may also be important in regulating interactions between tumor cells and cells within the tumor microenvironment (blue panels). It can act as a cell/cell adhesion molecule by engaging integrins expressed on cells in the tumor microenvironment, such as endothelial cells. GPNMB-mediated interactions with syndecan-4 expressed on T cells can block the proliferation and activation of these cells, leading to an immunosuppressive environment favoring tumor growth. Finally, GPNMB may function in a paracrine fashion due to shedding of its extracellular domain, or through its release from cells in the form of microvesicles, leading to endothelial cell recruitment. All of these potential functions of GPNMB can promote tumor growth, invasion, and metastasis in a variety of cancer cells. Abbreviations: ECD, extracellular domain; GPNMB, glycoprotein non-metastatic b.

Figure 3

Figure 3

Therapeutic strategies employing anti-GPNMB antibody-drug conjugates (ADCs). Notes: in normal cells, GPNMB is preferentially localized within endosomal/lysosomal compartments, which is not accessible to anti-GPNMB ADCs. In many cancers, including breast, melanoma, and brain cancers, the levels of GPNMB expression increases and a greater proportion is localized on the cell surface. These GPNMB-expressing cancer cells are more susceptible to killing by anti-GPNMB ADCs (CDX-011, F6v-PE38). Evidence suggests that coupling kinase inhibitors (serine/threonine and tyrosine kinase inhibitors), which increase GPNMB expression, may enhance the efficacy of tumor cell killing by anti-GPNMB ADCs. Likewise, inhibiting GPNMB shedding could also lead to greater GPNMB surface expression and more targets for anti-GPNMB ADCs. Thus, GPNMB represents an attractive target due to low surface expression in normal cells and its increased expression in cancer cells, which leads to better tumor cell killing with anti-GPNMB ADCs. Combination therapies have the potential to achieve benefit from enhanced efficacy of the anti-GPNMB ADCs and effects of the coupled inhibitors (kinase inhibitors), but there is the potential risk that those tumor cells not killed by combination treatment may adopt increasing malignant phenotypes due to elevated GPNMB expression. Abbreviations: ADC, antibody-drug conjugate; CDX-011, glembatumumab vedotin; GPNMB, glycoprotein non-metastatic b.

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