Advances in Targeted Therapies for Triple-Negative Breast Cancer

McCann, Kelly; Hurvitz, Sara A.; McAndrew, Nicholas P.

doi:10.1007/s40265-019-01155-4

Cited by 70 publications

(51 citation statements)

References 69 publications

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“…As both PDGFRβ and PD-L1 are crucial targets for TNBC treatments [31,43,44], we tested whether their co-inhibition would enhance TNBC cells killing. To this aim, we used an aptamer and a mAb that we previously validated as high a nity binders and inhibitors of PDGFRβ [31] and PD-L1 [40,45], respectively, in different tumor types including TNBC.…”

Section: Resultsmentioning

confidence: 99%

Aptamer targeted therapy potentiates immune checkpoint blockade in triple-negative breast cancer

Camorani

Passariello

Agnello

et al. 2020

Preprint

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Background: Triple-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.Methods: The 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 4T1 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 4T1 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. Results: We 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. Conclusion: Co-treatment of PDGFRβ aptamer with anti-PD-L1 mAbs is a viable strategy, thus providing for the first an evidence of the efficacy of PDGFRβ/PD-L1 co-targeting combination therapy in TNBC.

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Section: Resultsmentioning

confidence: 99%

Aptamer targeted therapy potentiates immune checkpoint blockade in triple-negative breast cancer

Camorani

Passariello

Agnello

et al. 2020

Preprint

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“…Poly-ADP-Ribose Polymerase Inhibitors (PARPi) inhibit the activity of PARP as a DNA damage sensor and consequently halt this pathway of DNA repair. Two agents from this class, namely olaparib and talazoparib, have been recently approved for advanced cases of BRCA1/2 positive BC (McCann et al, 2019).…”

Section: Poly-adp-ribose Polymerase Inhibitors (Parpi)mentioning

confidence: 99%

Toxicity and Pharmacogenomic Biomarkers in Breast Cancer Chemotherapy

2020

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Breast cancer (BC) is one of the most prevalent types of cancer worldwide with high morbidity and mortality rates. Treatment modalities include systemic therapy, in which chemotherapy is a major component in many cases. Several chemotherapeutic agents are used in combinations or as single agents with many adverse events occurring in variable frequencies. These events can be a significant barrier in completing the treatment regimens. Germline genomic variants are thought of as potential determinants in chemotherapy response and the development of side effects. Some pharmacogenomic studies were designed to explore germline variants that can be used as biomarkers for predicting developing toxicity or adverse events during chemotherapy in BC. In this review, we reassess and summarize the major findings of pharmacogenomic studies of chemotherapy toxicity during BC management. In addition, deficiencies hampering utilizing these findings and the potential targets of future research are emphasized. Main insufficiencies in toxicity pharmacogenomics studies originate from study design, sample limitations, heterogeneity of selected genes, variants, and toxicity definitions. With the advent of high throughput genotyping techniques, researchers are expected to explore the identified as well as the potential genetic biomarkers of toxicity and efficacy to improve BC management. However, to achieve this, the limitations of previous work should be evaluated and avoided to reach more conclusive and translatable evidence for personalizing BC chemotherapy.

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“…5 With the absence of specific biomarkers in TNBC cells, researchers have been looking to exploit the rich epitheliallike and mesenchymal-like cancer stem cells by targeting pathways upregulated in these cells 49 ; however, these findings are in the early discovery phase. The main categories of therapies for TNBC currently being introduced into the clinical realm, albeit with limited data, 50 include (1) poly-ADP-ribosyl polymerase (PARP) inhibitors in the metastatic setting, 51 given in combination therapy with DNA damaging alkylating chemotherapeutics (e.g., platinum) to patients with tumors lacking functional BRCA1 or BRCA2 genes (with resultant impaired ability to repair double-stranded DNA damage); (2) AKT inhibitor (ipatasertib), which has shown modest efficacy in progression-free survival 50 ; and (3) immunotherapy agents, for example, checkpoint inhibitors to programmed cell death protein 1 (PD-1) and programmed death-ligand 1 (PD-L1). PD-1 and PD-L1 bind to sites of DNA damage to target repair pathway activation.…”

Section: Tnbc: Current Treatmentmentioning

confidence: 99%

KISS1/KISS1R and Breast Cancer: Metastasis Promoter

et al. 2019

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Kisspeptins (KPs), peptide products of the kisspeptin-1 (KISS1) gene, are the endogenous ligands for the KISS1 receptor, KISS1R, which is a G protein-coupled receptor. In many human tumors, KISS1 functions as a metastasis-suppressor gene and KISS1/KISS1R signaling has antimetastatic and tumor-suppressor roles. On the contrary, emerging evidence indicates that the KP/KISS1R pathway plays detrimental roles in triple negative breast cancer (TNBC), the most difficult type of breast cancer to treat. TNBC patients initially respond to chemotherapy, but tumors acquire drug resistance and many patients relapse and die of metastases within a few years. In this review, we summarize recent developments in the understanding of the mechanisms by which KP/KISS1R signaling plays an adverse role in TNBC. This includes focusing on how KISS1R signaling regulates the cell cytoskeleton to induce tumor invadopodia formation and how KISS1R communicates with growth factor receptors such as the epidermal growth factor receptor, the receptor tyrosine kinase AXL, and transforming growth factor-β to promote cell invasion, metastasis, and drug resistance.

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Advances in Targeted Therapies for Triple-Negative Breast Cancer

Cited by 70 publications

References 69 publications

Aptamer targeted therapy potentiates immune checkpoint blockade in triple-negative breast cancer

Aptamer targeted therapy potentiates immune checkpoint blockade in triple-negative breast cancer

Toxicity and Pharmacogenomic Biomarkers in Breast Cancer Chemotherapy

KISS1/KISS1R and Breast Cancer: Metastasis Promoter

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