RAD001 (Everolimus) inhibits growth of prostate cancer in the bone and the inhibitory effects are increased by combination with docetaxel and zoledronic acid

Morgan, Todd M.; Pitts, Tiffany E.M.; Gross, Ted S.; Poliachik, Sandra L.; Vessella, Robert L.; Corey, Eva

doi:10.1002/pros.20752

Cited by 61 publications

(49 citation statements)

References 39 publications

(43 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…However, when docetaxel was used in combination with dasatinib, the dose resulted in significant decreases in PSA levels beyond those seen with the administration of dasatinib alone. We have previously seen this increased efficacy with the use of other pharmaceuticals in combination with docetaxel over either agent alone (Brubaker et al, 2006;Morgan et al, 2008). In addition, src inhibition has been reported to increase sensitivity of other advanced cancers to several already used chemotherapies and specifically to docetaxel resistance (Yezhelyev et al, 2004;Han et al, 2006).…”

Section: Discussionmentioning

confidence: 93%

“…A total of 48 animals were injected, and 4 weeks after the tumour cell injection animals that had serum PSA level 40.6 ng ml À1 (IMx Total PSA Assay) were randomised into four groups using the following design: (1) a control group receiving placebo treatment (n ¼ 8, PSA -4.376 ± 1.13 ng ml À1 (mean ± s.e.m. )); (2) a group receiving docetaxel at 5 mg kg À1 (Morgan et al, 2008; n ¼ 7, PSA -6.507±1.38 ng ml À1 ); (3) a group receiving dasatinib only at 50 mg kg À1 (n ¼ 8, PSA -6.136 ± 0.99 ng ml À1 ) and (4) a group receiving a combination of dasatinib 50 mg kg À1 and docetaxel 5 mg kg À1 (n ¼ 8, PSA -6.045±1.098 ng ml À1 ). There were no differences in enrolment PSA levels (ANOVA, P ¼ 0.5834).…”

Section: In Vivo Studiesmentioning

confidence: 99%

See 1 more Smart Citation

Dasatinib inhibits the growth of prostate cancer in bone and provides additional protection from osteolysis

et al. 2009

View full text Add to dashboard Cite

BACKGROUND: Dasatinib is a small molecule kinase inhibitor that has recently been shown to inhibit Src family kinases (SFK) and also has activity against CaP. Of importance to metastatic CaP, which frequently metastasises to bone, SFK are also vital to the regulation of bone remodelling. We sought to determine the ability of dasatinib to inhibit growth of CaP in bone. METHODS: C4-2B CaP cells were injected into tibiae of SCID mice and treated with dasatinib, alone or in combination with docetaxel. Serum prostate-specific antigen levels, bone mineral density, radiographs and histology were analysed. RESULTS: Treatment with dasatinib alone significantly lowered sacrifice serum prostate-specific antigen levels compared to control, 2.3 ± 0.4 vs 9.2 ± 2.1 (P ¼ 0.004). Combination therapy improved efficacy over dasatinib alone (P ¼ 0.010). Dasatinib increased bone mineral density in tumoured tibiae by 25% over control tumoured tibiae (Po0.001). CONCLUSION: Dasatinib inhibits growth of C4-2B cells in bone with improved efficacy when combined with docetaxel. Additionally, dasatinib inhibits osteolysis associated with CaP. These data support further study of dasatinib in clinical trials for men with CaP bone metastases.

show abstract

Section: Discussionmentioning

confidence: 93%

Section: In Vivo Studiesmentioning

confidence: 99%

Dasatinib inhibits the growth of prostate cancer in bone and provides additional protection from osteolysis

et al. 2009

View full text Add to dashboard Cite

show abstract

“…Activation of the PI3K/Akt/mTOR pathway has recently been implicated in resistance to docetaxel (Qian et al 2010), and combining PI3K/Akt/mTOR pathway inhibitors with docetaxel has demonstrated enhanced activity in a variety of preclinical models (Morgan et al 2008, Fung et al 2009, Dubrovska et al 2010, Qian et al 2010, Maira et al 2012b, Morikawa et al 2012. The enhanced efficacy of BEZ235 with docetaxel was shown to be a result of BEZ235-induced reduction of CD133C/CD44C tumor progenitor cells, and docetaxel-induced reduction of the tumor bulk, which resulted in near complete tumor regression in a mouse prostate cancer xenograft model (Dubrovska et al 2010).…”

Section: Combination With Chemotherapymentioning

confidence: 99%

Targeting the PI3K/Akt/mTOR pathway in castration-resistant prostate cancer

Bitting

Armstrong

2013

Endocrine-Related Cancer

280

243

View full text Add to dashboard Cite

The phosphatidylinositol 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) pathway is a key signaling pathway that has been linked to both tumorigenesis and resistance to therapy in prostate cancer and other solid tumors. Given the significance of the PI3K/Akt/mTOR pathway in integrating cell survival signals and the high prevalence of activating PI3K/Akt/mTOR pathway alterations in prostate cancer, inhibitors of this pathway have great potential for clinical benefit. Here, we review the role of the PI3K/Akt/mTOR pathway in prostate cancer and discuss the potential use of pathway inhibitors as single agents or in combination in the evolving treatment landscape of castration-resistant prostate cancer.

show abstract

“…In fact, in vitro and in vivo studies have demonstrated that ZA plus Everolimus (RAD001) augment the growth-blocking effect seen with either drug alone. 26,27 Clinical trials have indicated a reduced incidence of skeletalrelated events in men with hormone-refractory metastatic PC treated with ZA. 5 Hence, it has been argued that ZA may directly influence metastatic tumor spread.…”

Section: Discussionmentioning

confidence: 99%

Zoledronic acid influences growth, migration and invasive activity of prostate cancer cells in vitro

Mani

Vallo

Barth

et al. 2012

Prostate Cancer Prostatic Dis

View full text Add to dashboard Cite

BACKGROUND:The influence of the bisphosphonate zoledronic acid (ZA) on prostate cancer (PC) growth, adhesion and invasive behavior was investigated. METHODS: PC-3, DU-145 and LNCaP cells were treated with ZA, and tumor-cell growth was then investigated by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. Furthermore, tumor-cell adhesion to vascular endothelium or to immobilized extracellular matrix proteins, as well as migratory properties of the cells, was evaluated. Integrin b subtypes, integrin-dependent signaling, as well as cell-cycle regulating proteins, were analyzed by western blots. RESULTS: ZA dose-dependently reduced tumor-cell growth but did not impair tumor --endothelium and tumor --matrix interaction. However, ZA significantly inhibited tumor migration and invasive activity. Cyclin E was reduced by ZA in LNCaP and DU-145, and p21 was elevated in LNCaP cells. p27 was upregulated in all tumor cell lines, compared with the controls. ZA elevated b1-integrin in PC-3 and diminished b4-integrin in PC-3 and DU-145 cells. CONCLUSION: ZA inhibits PC growth and motility but does not influence the mechanical contact between tumor cells and the vascular wall.

show abstract

RAD001 (Everolimus) inhibits growth of prostate cancer in the bone and the inhibitory effects are increased by combination with docetaxel and zoledronic acid

Cited by 61 publications

References 39 publications

Dasatinib inhibits the growth of prostate cancer in bone and provides additional protection from osteolysis

Dasatinib inhibits the growth of prostate cancer in bone and provides additional protection from osteolysis

Targeting the PI3K/Akt/mTOR pathway in castration-resistant prostate cancer

Zoledronic acid influences growth, migration and invasive activity of prostate cancer cells in vitro

Contact Info

Product

Resources

About