The role of antiresorptive therapies in improving patient care in early and metastatic breast cancer

Candelaria-Quintana, Dulcinea; Dayao, Zoneddy; Royce, Melanie

doi:10.1007/s10549-011-1800-z

Cited by 7 publications

(5 citation statements)

References 73 publications

(89 reference statements)

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“…However, they are not effective in destroying the established bone metastases and do not improve patients' survival. 9 Therefore, the development of novel therapies to treat bone metastases of breast cancer is an unmet need in medicine.…”

Section: Introductionmentioning

confidence: 99%

Systemic Delivery of an Oncolytic Adenovirus Expressing Decorin for the Treatment of Breast Cancer Bone Metastases

Yang

Neill

et al. 2015

Human Gene Therapy

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The development of novel therapies for breast cancer bone metastasis is a major unmet medical need. Toward that end, we have constructed an oncolytic adenovirus, Ad.dcn, and a nonreplicating adenovirus, Ad(E1-).dcn, both containing the human decorin gene. Our in vitro studies showed that Ad.dcn produced high levels of viral replication and the decorin protein in the breast tumor cells. Ad(E1-).dcn-mediated decorin expression in MDA-MB-231 cells downregulated the expression of Met, β-catenin, and vascular endothelial growth factor A, all of which are recognized decorin targets and play pivotal roles in the progression of breast tumor growth and metastasis. Adenoviral-mediated decorin expression inhibited cell migration and induced mitochondrial autophagy in MDA-MB-231 cells. Mice bearing MDA-MB-231-luc skeletal metastases were systemically administered with the viral vectors, and skeletal tumor growth was monitored over time. The results of bioluminescence imaging and X-ray radiography indicated that Ad.dcn and Ad(E1-).dcn significantly inhibited the progression of bone metastases. At the terminal time point, histomorphometric analysis, micro-computed tomography, and bone destruction biomarkers showed that Ad.dcn and Ad(E1-).dcn reduced tumor burden and inhibited bone destruction. A nonreplicating adenovirus Ad(E1-).luc expressing the luciferase 2 gene had no significant effect on inhibiting bone metastases, and in several assays, Ad.dcn and Ad(E1-).dcn were better than Ad.luc, a replicating virus expressing the luciferase 2 gene. Our data suggest that adenoviral replication coupled with decorin expression could produce effective antitumor responses in a MDA-MB-231 bone metastasis model of breast cancer. Thus, Ad.dcn could potentially be developed as a candidate gene therapy vector for treating breast cancer bone metastases.

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Section: Introductionmentioning

confidence: 99%

Systemic Delivery of an Oncolytic Adenovirus Expressing Decorin for the Treatment of Breast Cancer Bone Metastases

Yang

Neill

et al. 2015

Human Gene Therapy

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“…Therefore, to facilitate an adequate medical decision making, we here review the adverse event profile of the 2 classes of bone antiresorptive agents in advanced breast cancer [9,12,16,17,18]. In the adjuvant therapy setting of early-stage breast cancer patients, the incidence of similar side effects appears to be lower due to reduced doses and frequencies of osteoclast inhibitors administered [19]. …”

Section: Introductionmentioning

confidence: 99%

Side Effects of Bone-Targeted Therapies in Advanced Breast Cancer

Domschke

Schuetz²

2014

Breast Care

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In up to 75% of cases, advanced breast cancer patients eventually develop bone metastases with often debilitating skeletal-related events (SREs). Osteoclast inhibitors are commonly used as therapeutic mainstay with clinical studies showing superiority of denosumab over bisphosphonates (e.g., zoledronate) for the prevention of SREs. The present review discusses the adverse event profile of these agents, and addresses the prevention and management of untoward side effects. Adverse events associated with osteoclast inhibitors comprise osteonecrosis of the jaw and hypocalcemia. Hypocalcemia is more common with denosumab, particularly in severe renal dysfunction. During therapy, the appropriate prevention of these adverse events includes close attention to dental health, avoidance of invasive dental procedures, supplementation with calcium and vitamin D unless patients are hypercalcemic, and regular monitoring of relevant serum values. Relating to the risk of nephrotoxicity, bisphosphonates but not denosumab have been incriminated. Therefore, serum creatinine levels should be checked prior to each dose of zoledronate, and in severe renal dysfunction (creatinine clearance < 30 ml/min) zoledronate is contraindicated anyway. Acute-phase reactions are particularly linked to bisphosphonates. Consequently, if these adverse events predominate, switching to denosumab is recommended.

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“…Although the two types of drugs - bisphosphonates, and denosumab, an antibody against RANKL - can inhibit bone resorption, their ability to cure bone metastases remains to be established. 3 Thus, development of novel therapies to treat breast cancer bone metastasis is a major unmet need in medicine.…”

Section: Introductionmentioning

confidence: 99%

Intravenous administration of adenoviruses targeting transforming growth factor beta signaling inhibits established bone metastases in 4T1 mouse mammary tumor model in an immunocompetent syngeneic host

Zhang

Gupta

et al. 2012

Cancer Gene Ther

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We have examined the effect of adenoviruses expressing soluble transforming growth factor receptorII-Fc (sTGFβRIIFc) in a 4T1 mouse mammary tumor bone metastasis model using syngeneic BALB/c mice. Infection of 4T1 cells with a non-replicating adenovirus, Ad(E1-).sTβRFc, or with two oncolytic adenoviruses, Ad.sTβRFc and TAd.sTβRFc, expressing sTGFβRIIFc (the human TERT promoter drives viral replication in TAd.sTβRFc) produced sTGFβRIIFc protein. Oncolytic adenoviruses produced viral replication and induced cytotoxicity in 4T1 cells. 4T1 cells were resistant to the cytotoxic effects of TGFβ-1 (up to 10 ng/ml). However, TGFβ-1 induced the phosphorylation of SMAD2 and SMAD3, which were inhibited by co-incubation with sTGFβRIIFc protein. TGFβ-1 also induced IL-11, a well-known osteolytic factor. Intracardiac injection of 4T1-luc2 cells produced bone metastases by day 4. Intravenous injection of Ad.sTβRFc (on days 5 and 7) followed by bioluminescence imaging (BLI) of mice on days 7, 11 and 14 in tumor bearing mice indicated inhibition of bone metastasis progression (p<0.05). X-ray radiography of mice on day 14 showed a significant reduction of the lesion size by Ad.sTβRFc (p<0.01) and TAd.sTβRFc (p<0.05). Replication-deficient virus Ad(E1-).sTβRFc expressing sTGFβRIIFc showed some inhibition of bone metastasis, while Ad(E1-).Null was not effective in inhibiting bone metastases. Thus, systemic administration of Ad.sTβRFc and TAd.sTβRFc can inhibit bone metastasis in the 4T1 mouse mammary tumor model, and can be developed as potential anti-tumor agents for breast cancer.

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The role of antiresorptive therapies in improving patient care in early and metastatic breast cancer

Cited by 7 publications

References 73 publications

Systemic Delivery of an Oncolytic Adenovirus Expressing Decorin for the Treatment of Breast Cancer Bone Metastases

Systemic Delivery of an Oncolytic Adenovirus Expressing Decorin for the Treatment of Breast Cancer Bone Metastases

Side Effects of Bone-Targeted Therapies in Advanced Breast Cancer

Intravenous administration of adenoviruses targeting transforming growth factor beta signaling inhibits established bone metastases in 4T1 mouse mammary tumor model in an immunocompetent syngeneic host

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