Effects of Src kinase inhibition by saracatinib (AZD0530) on bone turnover in advanced malignancy in a Phase I study

Hannon, Rosemary A.; Finkelman, Richard D.; Clack, Glen; Iacona, Renee; Rimmer, Martin; Gossiel, Fatma; Baselga, J.; Eastell, Richard

doi:10.1016/j.bone.2011.12.017

Cited by 26 publications

(25 citation statements)

References 43 publications

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“…The reported decrease in biochemical markers of bone resorption (CTX and UNTx) is comparable with that observed in studies of bisphosphonates in postmenopausal women. A study in patients with advanced solid malignancies metastatic to bone and resistant to standard treatment demonstrated significant dose-related reductions in bone resorption markers; there was a decrease in the bone formation marker, P1NP, but not in BAP (Hannon et al 2012). Current Phase 1 trials in solid-tumor cancer patients with bone metastases will provide insights as to whether this drug will be useful in the setting of metastatic bone disease via its apparent anti-resorptive effects.…”

Section: Src Inhibitor: Saracatanibmentioning

confidence: 99%

Effects of tyrosine kinase inhibition on bone metabolism: untargeted consequences of targeted therapies

Alemán¹,

Farooki²,

Girotra³

2014

Endocrine-Related Cancer

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Tyrosine kinase inhibitors (TKIs) are at the forefront of molecular-targeted therapies for cancer. With the advent of imatinib for the treatment of chronic myelogenous leukemia, a new wave of small-molecule therapeutics redefined the oncologic treatment to become chronically administered medications with tolerable side-effect profiles compared with cytotoxic agents. Effects on bone mineral metabolism were observed during early imatinib treatment, in the form of hypophosphatemia with increased urinary phosphorus excretion. This finding led to detailed investigations of off-target effects responsible for changes in bone cell maturation, activity, and impact on bone mass. Subsequently, another BCR-Abl inhibitor (dasatinib), vascular endothelial growth factor (VEGF) inhibitors (sorafenib and sunitinib) as well as rearranged during transfection (RET) inhibitors (vandetanib and cabozantinib) were developed. Inhibition of bone resorption appears to be a class effect and is likely contributed by TKI effects on the hematopoietic and mesenchymal stem cells. As long-term, prospective, clinical outcomes data accumulate on these targeted therapies, the full extent of off-target side effects on bone health will need to be considered along with the significant benefits of tyrosine kinase inhibition in oncologic treatment. Key Words" bone " calcium " metastasis " parathyroid hormone " tyrosine kinase inhibitor

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Section: Src Inhibitor: Saracatanibmentioning

confidence: 99%

Effects of tyrosine kinase inhibition on bone metabolism: untargeted consequences of targeted therapies

Alemán¹,

Farooki²,

Girotra³

2014

Endocrine-Related Cancer

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“…In support, preclinical studies have shown that both dasatinib and saracatinib affect tumor growth in bone; a likely consequence not only of the agents’ antineoplastic cell activities but also of their inhibitory effects on osteoclast-mediated bone resorption which plays a significant role in the growth and expansion of bone neoplastic lesions (de Vries, et al, 2009, Yang, et al, 2010). Furthermore, two recent clinical studies have shown that saracatinib inhibits bone resorption (Hannon, et al, 2010, Hannon, et al, 2012). …”

Section: Discussionmentioning

confidence: 99%

Src-signaling interference impairs the dissemination of blood-borne tumor cells

et al. 2012

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Although solid tumors continuously shed cells, only a very small fraction of the neoplastic cells that enter the blood stream are capable of establishing metastases. In order to be successful these cells must attach, extravasate, proliferate, and induce angiogenesis. Preclinical studies have shown that small-molecule ATP-competitive Src kinase inhibitors can effectively impair metastasis associated tumor cell functions in vitro. However, the impact of these agents on the metastatic cascade in vivo is less well understood. The present studies examined the ability of saracatinib, a dual-specific, orally available inhibitor of Src and Abl protein tyrosine kinases, to interfere with the establishment of lung metastases in mice by tumor cells introduced into the blood stream. The results demonstrated that Src inhibition most effectively interfered with the establishment of secondary tumor deposits when treatments were administered while tumor cells were in the initial phases of dissemination.

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“…Src inhibitor dasatinib that used in chronic myelogenous leukemia also inhibits osteoclastogenesis in vitro (Vandyke et al, 2009). Other src inhibitor saracatinib decreased bone resorption markers in a phase I study (Hannon et al, 2012). In two ongoing studies dasatinib (NCT00566618) and saracatinib (NCT00558272) are still investigated in treatment of bone metastasis.…”

Section: Advances In Treatment Of Bone Metastasimentioning

confidence: 99%

“…In two ongoing studies dasatinib (NCT00566618) and saracatinib (NCT00558272) are still investigated in treatment of bone metastasis. In a randomized clinical trial cathepsin K inhibitor odanacatib suppressed bone resorption markers similar to zoledronic acid after 4 weeks of treatment and well tolerated (Hannon et al, 2012). In the future antibodies that block PTHrP, TGF-β antagonists, proteasome inhibitors and many new molecules targeting vicious cycle will be discussed in treatment of bone metastasis.…”

Section: Advances In Treatment Of Bone Metastasimentioning

confidence: 99%

Medical Treatment of Breast Cancer Bone Metastasis: From Bisphosphonates to Targeted Drugs

Erdoğan

Çiçin²

2014

Asian Pacific Journal of Cancer Prevention

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Breast cancer bone metastasis causing severe morbidity is commonly encountered in daily clinical practice. It causes pain, pathologic fractures, spinal cord and other nerve compression syndromes and life threatening hypercalcemia. Breast cancer metastasizes to bone through complicated steps in which numerous molecules play roles. Metastatic cells disrupt normal bone turnover and create a vicious cycle to which treatment efforts should be directed. Bisphosphonates have been used safely for more than two decades. As a group they delay time to first skeletal related event and reduce pain, but do not prevent development of bone metastasis in patients with no bone metastasis, and also do not prolong survival. The receptor activator for nuclear factor kB ligand inhibitor denosumab delays time to first skeletal related event and reduces the skeletal morbidity rate. Radionuclides are another treatment option for bone pain. New targeted therapies and radionuclides are still under investigation. In this review we will focus on mechanisms of bone metastasis and its medical treatment in breast cancer patients.

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Effects of Src kinase inhibition by saracatinib (AZD0530) on bone turnover in advanced malignancy in a Phase I study

Cited by 26 publications

References 43 publications

Effects of tyrosine kinase inhibition on bone metabolism: untargeted consequences of targeted therapies

Effects of tyrosine kinase inhibition on bone metabolism: untargeted consequences of targeted therapies

Src-signaling interference impairs the dissemination of blood-borne tumor cells

Medical Treatment of Breast Cancer Bone Metastasis: From Bisphosphonates to Targeted Drugs

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