Targeted therapy of metastatic breast cancer

Abstract

Breast cancer is a heterogeneous disease characterised by a dysregulation of multiple pathways related to cell differentiation, cell cycle control, apoptosis, angiogenesis and development of metastasis. Acting against these pathways provides therapeutic targets for new targeted biologic therapies, which, in the future, might constitute a key for fighting cancer. The development of molecular technology in recent years has allowed a further comprehension of these mutations and dysregulated pathways leading to oncogenesis. New targeted biologic therapies will block essential functions of cancer cells and tumour stroma. A growing number of therapy options, alone or in combination with background treatments (chemotherapy, hormone therapy, radiotherapy), will allow oncologists a better adaptation of treatment to patients and disease characteristics. Examples of approved targeted agents in breast cancer include agents targeting the human epidermal growth factor receptor 2 (HER2), such as trastuzumab, lapatinib and the anti-VEGF bevacizumab. In addition, there are other therapy classes under evaluation, including novel antiEGFR or antiHER2 therapies; agents fighting other tyrosine kinases, including the Src and the insulinlike growth factor receptor; agents interfering critically relevant pathways, such as PI3K/AKT/mTOR inhibitors; and agents promoting apoptosis, such as PARP inhibitors (for particular breast cancer subtypes, such as basal-like, or breast cancer with BRCA mutations) and others. The better selectivity against malignant cells of these therapies, when compared to conventional chemotherapy, gives, a priori, at least two advantages to biologic treatments: fewer side effects and a more individualised treatment of cancer depending on the tumour's molecular characteristics. The ability to identify patients' subgroups and response predicting factors will be crucial in obtaining the greatest benefit with minimal toxicity levels. Unsolved questions remain, such as appropriate patient selection based on the expression of the therapeutic target in the tumour, the study of the efficacy of the drug in not so extensively pretreated populations and with a greater chance of response, the use of new pharmacodynamic models to help to define new response predicting factors for a specific new biologic therapy, the combined and rational use of different biologic therapies having different molecular targets and fighting the same target through a complementary mechanism of action that might improve clinical efficacy.

The Emerging Role of QSOX1 in Cancer

“…Other examples of targeted enzyme therapy for cancer include the mammalian target of rapamycin inhibitors for breast and renal cell cancers (everolimus, temsirolimus) (2,55), the tyrosine kinase inhibitor regorafenib for colorectal cancer (33), and aromatase inhibitors, which decrease the production of estrogen and are used to treat estrogen receptor (ER)-positive breast cancer (61). Examples of monoclonal antibodies used to target a specific protein include bevacizumab, which targets vascular endothelial growth factor (VEGF), cetuximab and panitumumab, which bind epidermal growth factor receptor (EGFR) (colorectal cancer) (83), and trastuzamab, which targets human EGFR-2 and is used in HER-2 positive breast cancer (75).…”

Modulating autophagy: a strategy for cancer therapy

“…Randomized phase III trials have already demonstrated significant clinical benefits of treatment with single-agent temsirolimus in advanced renal cell carcinoma and relapsed and/or refractory mantle cell lymphoma[91]–[93]. Phase I and II trials have also been carried out in other malignancies, such as glioblastoma[94], breast cancer[95], endometrial cancer[93], non-Hodgkin lymphomas[92], and multiple myeloma[93].…”

17β-Estradiol Augments 18F-FDG Uptake and Glycolysis of T47D Breast Cancer Cells via Membrane-Initiated Rapid PI3K–Akt Activation

“…Although tamoxifen did not directly simulate 18 F-FDG uptake in our in vitro experiments, the usefulness of metabolic flare seen on 18 F-FDG PET for indicating responsive tumors (7-9)-which may require tamoxifen action in an in vivo environment-is not invalidated. More recently, novel targeted agents that involve or directly target the PI3K-Akt pathway are emerging for the treatment of breast cancer (34). The success of such targeted therapies requires biomarkers of tumor response to guide individualized treatment decisions.…”