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Triple-negative breast cancer and the potential for targeted therapy.

ABSTRACT: Breast cancer is composed of several well-recognized subtypes including estrogen receptor, progesterone receptor and HER2 triple-negative breast cancer (TNBC). Without available targeted therapy options, standard of care for TNBC remains chemotherapy. It is of interest to note that TNBC tumors generally have better responses to chemotherapy compared with other subtypes. However, patients without complete response account for approximately 80% of TNBC. Mounting evidence suggests significant heterogeneity within the TNBC subtype, and studies have focused on genetic targets with high rates of altered expression. Recent studies suggest clear possibilities for benefits from targeted therapy in TNBC. In this review, we summarize studies of targeted therapy, including within mouse models, and discuss their applications in the development of combinatorial treatments to treat TNBC.

SUBMITTER: Jhan JR

PROVIDER: S-EPMC5694022 | biostudies-literature | 2017 Nov

REPOSITORIES: biostudies-literature

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Triple-negative breast cancer and the potential for targeted therapy.

Jhan Jing-Ru JR Andrechek Eran R ER

Pharmacogenomics 20171102 17

Breast cancer is composed of several well-recognized subtypes including estrogen receptor, progesterone receptor and HER2 triple-negative breast cancer (TNBC). Without available targeted therapy options, standard of care for TNBC remains chemotherapy. It is of interest to note that TNBC tumors generally have better responses to chemotherapy compared with other subtypes. However, patients without complete response account for approximately 80% of TNBC. Mounting evidence suggests significant heter ...[more]

PMID: 29095114

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Project description:BackgroundTriple-negative breast cancer (TNBC) is a uniquely aggressive cancer with high rates of relapse due to resistance to chemotherapy. TNBC expresses higher levels of programmed cell death-ligand 1 (PD-L1) compared to other breast cancers, providing the rationale for the recently approved immunotherapy with anti-PD-L1 monoclonal antibodies (mAbs). A huge effort is dedicated to identify actionable biomarkers allowing for combination therapies with immune-checkpoint blockade. Platelet-derived growth factor receptor β (PDGFRβ) is highly expressed in invasive TNBC, both on tumor cells and tumor microenvironment. We recently proved that tumor growth and lung metastases are impaired in mouse models of human TNBC by a high efficacious PDGFRβ aptamer. Hence, we aimed at investigating the effectiveness of a novel combination treatment with the PDGFRβ aptamer and anti-PD-L1 mAbs in TNBC.MethodsThe targeting ability of the anti-human PDGFRβ aptamer toward the murine receptor was verified by streptavidin-biotin assays and confocal microscopy, and its inhibitory function by transwell migration assays. The anti-proliferative effects of the PDGFRβ aptamer/anti-PD-L1 mAbs combination was assessed in human MDA-MB-231 and murine 4 T1 TNBC cells, both grown as monolayer or co-cultured with lymphocytes. Tumor cell lysis and cytokines secretion by lymphocytes were analyzed by LDH quantification and ELISA, respectively. Orthotopic 4 T1 xenografts in syngeneic mice were used for dissecting the effect of aptamer/mAb combination on tumor growth, metastasis and lymphocytes infiltration. Ex vivo analyses through immunohistochemistry, RT-qPCR and immunoblotting were performed.ResultsWe show that the PDGFRβ aptamer potentiates the anti-proliferative activity of anti-PD-L1 mAbs on both human and murine TNBC cells, according to its human/mouse cross-reactivity. Further, by binding to activated human and mouse lymphocytes, the aptamer enhances the anti-PD-L1 mAb-induced cytotoxicity of lymphocytes against tumor cells. Importantly, the aptamer heightens the antibody efficacy in inhibiting tumor growth and lung metastases in mice. It acts on both tumor cells, inhibiting Akt and ERK1/2 signaling pathways, and immune populations, increasing intratumoral CD8 + T cells and reducing FOXP3 + Treg cells.ConclusionCo-treatment of PDGFRβ aptamer with anti-PD-L1 mAbs is a viable strategy, thus providing for the first time an evidence of the efficacy of PDGFRβ/PD-L1 co-targeting combination therapy in TNBC.

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Triple-negative breast cancer and the potential for targeted therapy.

Publications

Triple-negative breast cancer and the potential for targeted therapy.

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