Sagopilone Inhibits Breast Cancer Bone Metastasis and Bone Destruction Due to Simultaneous Inhibition of Both Tumor Growth and Bone Resorption
Anne Strube1,2, Jens Hoffmann1, Elizaveta Stepina1, Peter Hauff1, Ulrich Klar1 and Sanna-Maria Käkönen1
Authors' Affiliations: 1 Global Drug Discovery, Bayer Schering Pharma AG and 2 Department of Biology, Chemistry and Pharmacy, Free University Berlin, Berlin, Germany
Requests for reprints: Sanna-Maria Käkönen, Therapeutic Research Group Oncology, Bayer Schering Pharma AG, Berlin D-13342, Germany. Phone: 49-170-226-8869; Fax: 49-30-468-97925; E-mail:
sanna.kaekoenen@bayerhealthcare.com.
Purpose: Bone metastases have a considerable impact on quality of life in patients with breast and other cancers. Tumors produce osteoclast-activating factors, whereas bone resorption promotes the growth of tumor cells, thus leading to a "vicious cycle" of bone metastasis. Sagopilone, a novel, fully synthetic epothilone, inhibits the growth of breast cancer cells in vitro and in vivo, and here we report its activity in the MDA-MB-231(SA) breast cancer bone metastasis mouse model.
Experimental Design: The potency of sagopilone was determined in treatment models simulating the adjuvant (preventive) and metastatic (therapeutic) settings in the clinic.
Results: We showed that sagopilone inhibited tumor burden and bone destruction, in addition to reducing tumor-induced cachexia and paraplegia. The reduction in osteolytic lesions, tumor growth in bone, and weight loss was statistically significant in the preventive model compared with the vehicle group. In the therapeutic model, sagopilone treatment significantly lowered the number of activated osteoclasts and significantly reduced the osteolytic lesion area, bone volume loss, and bone resorption compared with vehicle treatment while simultaneously inhibiting tumor burden. An in vitro assay confirmed that sagopilone inhibited osteoclast activation without cytotoxic effects, whereas paclitaxel resulted in lower inhibition and high levels of cytotoxicity.
Conclusions: Sagopilone seems to inhibit the vicious cycle at both the tumor growth and bone resorption stages, suggesting the possibility for substantial benefit in the treatment ofpatients with breast cancer at risk from bone metastases or with bone lesions already present. Phase II clinical trials with sagopilone in patients with breast cancer are ongoing.
Sagopilone crosses the blood-brain barrier in vivo to inhibit brain tumor growth and metastases.
Hoffmann J, Fichtner I, Lemm M, Lienau P, Hess-Stumpp H, Rotgeri A, Hofmann B, Klar U.
Bayer Schering Pharma AG, TRG Oncology, Berlin, Germany.
jens.hoffmann@bayerhealthcare.com
The aim of this study was to determine the efficacy of sagopilone (ZK-EPO), a novel epothilone, compared with other anticancer agents in orthotopic models of human primary and secondary brain tumors. Autoradiography and pharmacokinetic analyses were performed on rats and mice to determine passage across the blood-brain barrier and organ distribution of sagopilone. Mice bearing intracerebral human tumors (U373 or U87 glioblastoma, MDA-MB-435 melanoma, or patient-derived non-small-cell lung cancer [NSCLC]) were treated with sagopilone 5-10 mg/kg, paclitaxel 8-12.5 mg/kg (or temozolomide, 100 mg/kg) or control (vehicle only). Tumor volume was measured to assess antitumor activity. Sagopilone crossed the blood-brain barrier in both rat and mouse models, leading to therapeutically relevant concentrations in the brain with a long half-life. Sagopilone exhibited significant antitumor activity in both the U373 and U87 models of human glioblastoma, while paclitaxel showed a limited effect in the U373 model. Sagopilone significantly inhibited the growth of tumors from CNS metastasis models (MDA-MB-435 melanoma and patient-derived Lu7187 and Lu7466 NSCLC) implanted in the brains of nude mice, in contrast to paclitaxel or temozolomide. Sagopilone has free access to the brain. Sagopilone demonstrated significant antitumor activity in orthotopic models of both glioblastoma and CNS metastases compared with paclitaxel or temozolomide, underlining the value of further research evaluating sagopilone in the treatment of brain tumors. Sagopilone is currently being investigated in a broad phase II clinical trial program, including patients with glioblastoma, NSCLC, breast cancer, and melanoma.
PMID: 18780814 [PubMed - indexed for MEDLINE]
ZK-EPO
ZK-EPO is a fully synthetic epothilone that was reportedly designed to overcome multidrug resistance [58]. In a phase I study, this epothilone analog was given as a 30-minute i.v. infusion once every 3 weeks; the starting dose was 0.6 mg/m2. Dose-limiting grade 3 peripheral neuropathy and grade 3 ataxia occurred at the 16-mg/m2 dose (one patient) and the 29-mg/m2 dose (one patient), respectively. Confirmed PRs were observed in patients with taxane-pretreated breast cancer and prolonged SD was seen in patients with non-small cell lung cancer, cholangiocarcinoma, head and neck cancer uveal, melanoma, and adrenal carcinoma.
ZK-EPO is being evaluated in patients with metastatic breast cancer as a single agent and in combination with carboplatin in patients with platinum-sensitive, recurrent ovarian cancer. The combination of ZK-EPO and prednisone as first-line chemotherapy in patients with metastatic androgen-independent prostate cancer will be evaluated in a phase II trial.
2.3 Sagopilone TOP
Sagopilone is a fully-synthetic epothilone (figure 1) that has been designed specifically to overcome multidrug resistance. It is currently undergoing development in patients with MBC as a single agent.[33] Confirmed partial responses have so far been observed in two taxane-pretreated breast cancer patients involved in a phase I study, including one patient with taxane-resistant disease.[31] These patients were part of a broader study initiated to determine the maximum tolerated dose and dose-limiting toxicity of sagopilone. The study was ongoing when results were reported in 2005. At the time, it had enrolled 47 patients who had been given doses ranging from 0.6 to 29 mg/m2 as a 30-minute intravenous infusion once every 3 weeks. The two breast cancer patients whose tumours responded to treatment received doses of 12 and 16 mg/m2, respectively. An additional 13 patients with various advanced solid tumours achieved stable disease lasting between 3 and >16 months. The maximum tolerated dose had not been reached at the time of reporting and only two patients had experienced dose-limiting toxicities (grade 3 peripheral neuropathy at 16 mg/m2 and grade 3 ataxia at 29 mg/m2). The most common adverse events overall were grade 1-2 peripheral sensory neuropathy (34% of patients) and nausea (17%).
Improved Cellular Pharmacokinetics and Pharmacodynamics Underlie the Wide Anticancer Activity of Sagopilone
Jens Hoffmann1, Ilio Vitale4,5,6, Bernd Buchmann1, Lorenzo Galluzzi4,5,6, Wolfgang Schwede1, Laura Senovilla4,5,6, Werner Skuballa1, Sonia Vivet4,5,6,Rosemarie B. Lichtner1, José M. Vicencio4,5,6, Theocharis Panaretakis4,5,6, Gerhard Siemeister1, Hermann Lage2, Lisa Nanty4,5,6, Stefanie Hammer1, Kevin Mittelstaedt1,Sebastian Winsel1,3, Julia Eschenbrenner1,3, Maria Castedo4,5,6, Carine Demarche1, Ulrich Klar1 and Guido Kroemer4,5,6
1 Bayer Schering Pharma AG, TRG Oncology; 2 Charité, Institute of Pathology, Humboldt University; and 3 Institute for Chemistry and Biochemistry, Freie Universität, Berlin, Germany; 4 Institut National de la Sante et de la Recherche Medicale, U848; 5 Institut Gustave Roussy; and 6 Université Paris-Sud 11, Villejuif, France
Requests for reprints: Jens Hoffmann, Bayer Schering Pharma AG, TRG Oncology, Müllerstrasse, 172-178, G-13342 Berlin, Germany. Phone: 49-30-468-17611; Fax: 49-30-468-97611; E-mail:jens.hoffmann@bayerhealthcare.com or Guido Kroemer, Institut National de la Sante et de la Recherche Medicale, U848, Institut Gustave Roussy, Pavillon de Recherche 139 rue Camille-Desmoulins, F-94805 Villejuif, France. Phone: 33-1-4211-6046; Fax: 33-1-4211-6047; E-mail:
kroemer@igr.fr.
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- 2 -Fact SheetBayer Schering Pharma Development ProjectsBusiness Unit: OncologyDevelopment candidate sagopilone (ZK-EPO) – Potential for a newoption to treat solid tumorsPotential for a wide therapeutic windowPromising in multi-resistant tumorsStatus: June 2007At a glanceName of the activesubstanceSagopilone (ZK-EPO)Type of substanceFully syntheticepothilone(low molecular weightactive substance)Project descriptionThe novel anti-cancer agent sagopilone (ZK-EPO) iscurrently being tested in an extensive program of clinicalPhase II studies in various oncological indications. Thefully synthetic epothilone should show improved efficacyand safety in comparison with commonly usedchemotherapeutics and is designed to also retain itsefficacy within the cells of tumors with multiple resistance.Preliminary data from one of the current studies werepublished in June 2007. The Phase II study confirmedantitumor responses in patients with platinum-resistantovarian cancer. The drug was well tolerated with peripheralneuropathy being the most common side effect observed.The medical backgroundDespite numerous treatment options, the therapy of cancerstill represents an enormous challenge for medicine. OneTargeted IndicationOvarian cancerBreast cancerLung cancerProstate cancer
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- 2 -- 3 -Administration formInfusionMode of actionStabilisation ofmicrotubules thusresulting in inhibition ofcell division, whichshould lead to cell deaththerapeutic approach consists of interrupting the cell cycleand thus stopping cell division. Two quite different groupsof substances show a similar mechanism in this respct: thetaxanes (originally isolated from the Pacific yew, Taxusbrevifolia) and the epothilones (originally isolated from thebacterium Solangium cellulosum). They stabilize elementsof the cytoskeleton, the microtubules, and thus inhibit celldivision. In contrast to taxanes, epothilones may have theability to bypass some of the resistance mechanisms oftumor cells. This resistance prevents the long-term successof cancer therapy in many patients.Sagopilone is the first fully synthetic epothilone in clinicaldevelopment that may be able to fight not only tumors thatare still responsive to chemotherapy but also tumors withmultiple resistance, and achieve a betterefficacy/tolerability ratio. Sagopilone is a stabilizer ofmicrotubules that is rapidly taken up into the cell andinhibits the division of cancer cells. Moreover, sagopiloneis not recognized by the so-called efflux pumps, throughwhich other drugs are transported out of the cell. Thebypassing of this mechanism represents an importantapproach in the development of cancer therapies.SagopiloneSagopilone is a novel epothilone, the molecular structure ofwhich was designed specifically to provide advantagesover other microtubule stabilizers such as taxanes and otherepothilones. The goal in the development of this substancewas to combine high binding efficacy with a well toleratedside-effect profile. In specific studies, sagopilone showedsignificant efficacy in many in vitro and in vivo tumormodels. The research included tumors that arechemotherapeutically naive as well as tumors with multipleresistance that no longer respond to taxanes oranthracyclines. In additon, the water solubility ofsagopilone is better than that of the taxanes and does notrequire the solvent Cremophor, and this may prevent theStatusWide-rangingprogram of currentPhase II studies invarious oncologicalindicationsFirst Phase III studiesplanned for 2008
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- 3 -- 4 -occurrence of side effects.Program of studies with sagopiloneCurrently, an extensive program of Phase II studies is beingconducted with sagopilone in Europe and North America.In the clinical studies, the novel epothilone is being testedin various oncological indications. These include ovarianand breast cancer as well as prostate cancer and varioustypes of lung cancer.The clinical studies serve to provide proof of efficacy anddetermine the response rates of the listed types of cancer tosagopilone. The individual studies cover a wide spectrum:the potential of sagopilone is being tested in monotherapyand in combined therapy, and the use of the activesubstance is being investigated both as a first-line therapyand as a treatment option in patients who have alreadyreceived therapy
Quite a few of the 14 articles on it are pay-to-view. Mostly those which
have Bayer employee as one of the authors. Perhaps you can use the email address above one or both of the Bayer employees,
jens.hoffmann@bayerhealthcare.com or
sanna.kaekoenen@bayerhealthcare.com, or
of the academic Guido Kroemer,
kroemer@igr.fr and see if either or both will provide you with the article and/or any information on where the Phase II clinical trials are occuring--I could only determine there were some for bc and there were some in No. America
Good luck!
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