Strategies for the discovery and development of therapies for metastatic breast cancer
Department of Breast Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA. Nature Reviews Drug Discovery
(Impact Factor: 41.91).
06/2012; 11(6):479-97. DOI: 10.1038/nrd2372
Nearly all deaths caused by solid cancers occur as a result of metastasis--the formation of secondary tumours in distant organs such as the lungs, liver, brain and bone. A major obstruction to the development of drugs with anti-metastatic efficacy is our fragmented understanding of how tumours 'evolve' and metastasize, at both the biological and genetic levels. Furthermore, although there is significant overlap in the metastatic process among different types of cancer, there are also marked differences in the propensity to metastasize, the extent of metastasis, the sites to which the tumour metastasizes, the kinetics of the process and the mechanisms involved. Here, we consider the case of breast cancer, which has some marked distinguishing features compared with other types of cancer. Considerable progress has been made in the development of preclinical models and in the identification of relevant signalling pathways and genetic regulators of metastatic breast cancer, and we discuss how these might facilitate the development of novel targeted anti-metastatic drugs.
Available from: Xiaoge Gao
- "Both intracellular and secreted galectin-3 were detectable in PC-3 cells and culture medium (Figure 4I-A). MDA-MB-231 also has high metastatic potential to bone in an intra-cardiac injection model and causes osteolytic lesions , and the cells both expressed endogenous galectin-3 and secreted it (Figure 4I-A). LNCaP and BT-549 cells were devoid of galectin-3 (Figure 4I-A) and were transfected with p3xflag-myc-cmv-25 plasmid containing the preprotrypsin leader sequence as a secretory signal peptide for secretion of expressed protein into the culture medium. "
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ABSTRACT: Patients with bone cancer metastasis suffer from unbearable pain and bone fractures due to bone remodeling. This is caused by tumor cells that disturb the bone microenvironment. Here, we have investigated the role of tumor-secreted sugar-binding protein, i.e., galectin-3, on osteoblast differentiation and report that it downregulates the expression of osteoblast differentiation markers, e.g., RUNX2, SP7, ALPL, COL1A1, IBSP, and BGLAP, of treated human fetal osteoblast (hFOB) cells. Co-culturing of hFOB cells with human breast cancer BT-549 and prostate cancer LNCaP cells harboring galectin-3 has resulted in inhibition of osteoblast differentiation by the secreted galectin-3 into culture medium. The inhibitory effect of galectin-3 was found to be through its binding to Notch1 in a sugar-dependent manner that has led to accelerated Notch1 cleavage and activation of Notch signaling. Taken together, our findings show that soluble galectin-3 in the bone microenvironment niche regulates bone remodeling through Notch signaling, suggesting a novel bone metastasis therapeutic target.
Available from: Vivek Subbiah
- "Moreover, bone pain impairs quality of life in patients with bone metastases. Strategies to target bone metastases have included bisphosphonate therapy (zoledronic acid), receptor activator of nuclear factor kappa-B ligand (RANK-L)–directed monoclonal antibody therapy (denosumab), and palliative radiation in addition to systemic therapy [1-4]. A recent major therapeutic advance was the US Food and Drug Administration (FDA) approval of radium-223 (Ra-223) dichloride (Xofigo injection, Bayer HealthCare Pharmaceuticals Inc) alpha particle therapy for the treatment of symptomatic bone metastases in patients with castration-resistant prostate cancer and no known visceral metastatic disease [3,5-8]. "
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Hormone-refractory breast cancer metastatic to bone is a clinically challenging disease associated with high morbidity, poor prognosis, and impaired quality of life owing to pain and skeletal-related events. In a preclinical study using a mouse model of breast cancer and bone metastases, Ra-223 dichloride was incorporated into bone matrix and inhibited proliferation of breast cancer cells and differentiation of osteoblasts and osteoclasts (all P values < .001) in vitro. Ra-223 dichloride also induced double-strand DNA breaks in cancer cells in vivo.
The US Food and Drug Administration recently approved radium-223 (Ra-223) dichloride (Ra-223; Xofigo injection) alpha-particle therapy for the treatment of symptomatic bone metastases in patients with castration-resistant prostate cancer. On the basis of a strong preclinical rationale, we used Ra-223 dichloride to treat bone metastases in a patient with breast cancer.
A 44-year-old white woman with metastatic breast cancer who was estrogen receptor–positive, BRCA1-negative, BRCA2-negative, PIK3CA mutation (p.His1047Arg) positive presented with diffuse bony metastases and bone pain. She had hormone refractory and chemotherapy refractory breast cancer. After Ra-223 therapy initiation her bone pain improved, with corresponding decrease in tumor markers and mixed response in 18F-FDG PET/CT and 18F-NaF bone PET/CT. The patient derived clinical benefit from therapy.
We have shown that Ra-223 dichloride can be safely administered in a patient with hormone-refractory bone metastasis from breast cancer at the US FDA–approved dose for prostate cancer. Furthermore, because the treatment did not cause any drop in hematologic parameters, it has the potential to be combined with other radiosensitizing therapies, which may include chemotherapy or targeted therapies. Given that Ra-223 dichloride is already commercially available, this case report may help future patients and provide a rationale for initiating clinical research in the use of Ra-223 dichloride to treat bone metastasis from breast cancer. A randomized clinical trial is needed to provide evidence of efficacy, safety, and good outcomes.
Available from: Jordi Martinez Serra
- "Drug discovery is still an expensive and inefficient process in cancer research.1 Despite the considerable progress that has been made in preclinical model development and therapeutic targets identification, new drugs are needed. "
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ABSTRACT: The xCELLigence system is a new technological approach that allows the real-time cell analysis of adherent tumor cells. To date, xCELLigence has not been able to monitor the growth or cytotoxicity of nonadherent cells derived from hematological malignancies. The basis of its technology relies on the use of culture plates with gold microelectrodes located in their base. We have adapted the methodology described by others to xCELLigence, based on the pre-coating of the cell culture surface with specific substrates, some of which are known to facilitate cell adhesion in the extracellular matrix. Pre-coating of the culture plates with fibronectin, compared to laminin, collagen, or gelatin, significantly induced the adhesion of most of the leukemia/lymphoma cells assayed (Jurkat, L1236, KMH2, and K562). With a fibronectin substrate, nonadherent cells deposited in a monolayer configuration, and consequently, the cell growth and viability were robustly monitored. We further demonstrate the feasibility of xCELLigence for the real-time monitoring of the cytotoxic properties of several antineoplastic agents. In order to validate this technology, the data obtained through real-time cell analysis was compared with that obtained from using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide method. This provides an excellent label-free tool for the screening of drug efficacy in nonadherent cells and discriminates optimal time points for further molecular analysis of cellular events associated with treatments, reducing both time and costs.
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