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PMID: 18361409 Published · ppublish English Journal Article Research Support, N.I.H., Extramural

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

The Prostate ·Vol. 68 ·No. 8 ·2008-06-01 ·Pages 861-71

Morgan TM, Pitts TE, Gross TS, Poliachik SL, Vessella RL, Corey E

Abstract

mTOR activity is increased in advanced prostate cancer (CaP) as a result of a high rate of PTEN mutations. RAD001 (Everolimus) is a new orally available mTOR inhibitor. The objective of our study was to evaluate the effects of RAD001 on the growth of CaP in the bone, both alone and in combination with docetaxel and zoledronic acid. C4-2 CaP cells were injected into tibiae of mice and the animals were treated with RAD001, docetaxel, and zoledronic acid alone or in combination. Histomorphometrical analysis, serum PSA measurements, bone mineral density (BMD), and microCT were used to determine the effects of treatment on tumor and bone. All three agents alone decreased tumor volume, and RAD001 and docetaxel also decreased levels of serum PSA by 68% and 65%, respectively (both P < 0.01). Combinations of the agents were more effective in decreasing tumor volume than single agents. Three-drug treatment showed the greatest effect: 64% inhibition versus control (P < 0.01). Treatment with RAD001 interfered with the weight loss associated with growth of this tumor in the bone (non-RAD001 groups: 4.0% decrease in body weight, P = 0.0014; RAD001 groups: increase of 3.6% in body weight, P = 0.0037). RAD001 inhibited growth of C4-2 cells in bone, an effect augmented by addition of docetaxel and zoledronic acid. Moreover RAD001 had a significant impact on maintenance of body weight. RAD001 may hold promise for its effects on both metastatic CaP and the important syndrome of tumor cachexia.

MeSH Terms
Animals Antineoplastic Combined Chemotherapy Protocols/therapeutic use Body Weight/drug effects Bone Neoplasms/diagnostic imaging,drug therapy,secondary Cell Line, Tumor Cell Proliferation/drug effects Diphosphonates/administration & dosage Docetaxel Everolimus Humans Imidazoles/administration & dosage Male Mice Prostatic Neoplasms/drug therapy,enzymology,pathology Protein Kinase Inhibitors/administration & dosage,therapeutic use Protein Kinases/metabolism Sirolimus/administration & dosage,analogs & derivatives,therapeutic use TOR Serine-Threonine Kinases Taxoids/administration & dosage Tomography, X-Ray Computed Zoledronic Acid
Chemicals
Diphosphonates Imidazoles Protein Kinase Inhibitors Taxoids Docetaxel Zoledronic Acid Everolimus Protein Kinases MTOR protein, human mTOR protein, mouse TOR Serine-Threonine Kinases Sirolimus
Authors & Affiliations
6 authors, click to expand affiliations / ORCID
Morgan Todd M
Department of Urology, University of Washington School of Medicine, Seattle, Washington 98195, USA.
Pitts Tiffany E M
Gross Ted S
Poliachik Sandra L
Vessella Robert L
Corey Eva
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Article Info
Journal
The Prostate
Abbr.
Prostate
ISSN
0270-4137
DOI
10.1002/pros.20752
Published
2008-06-01
Pages
861-71
Language
English
Region
United States
NLM ID
8101368
PMCID
PMC3162313
Subset
IM
Grants
NCI NIH HHS · P50 CA097186 · United States
NCI NIH HHS · P50 CA097186-06 · United States
External Links
PubMed source DOI: 10.1002/pros.20752 PMC Full Text View journal details
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