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SUNITINIB: THE MULTI-TARGETED APPROACH

by Selleckchem | Mar 13 2012

SUNITINIB: A Multikinase Inhibitor

Sunitinib is an oral, small molecule of the protein kinase subfamily called Tyrosine Kinase’s (TKI’s). Tyrosine kinases functions by the phosphorylation of a target protein utilizing ATP as its source. Phosphorylation of the target protein simulates either “on” or “off” in terms of activity. Unregulated activities of tyrosine kinases have been linked to many cancer types, leading researchers to develop strategies to inhibit specific Tyrosine kinase activity. TKI’s began to to be developed and tested pre-clinically in the late 1990’s and early 2000, several have reached fast track approval status due to the success of early trials. Sunitinib is one of the currently approved drugs and is approved for renal cell carcinoma (RCC) and imatinib-resistant gastrointestinal stromal tumor (GIST) as early as 2006. Sunitinib is the only TKI that has been approved for two different indications.

Sunitinib: Properties and Availability

Sunitinib suppliers market it under the brand name of Sutent and its development is controlled in tandem by Pfizer pharmaceutical company, although its original name was Su11248. To buy Sunitinib – the free base is widely commercially available at research grade and Sunitinib price for a 10 mg vial range from $50 to 200 depending on supplier. The Sunitinib malate salt is also commercially available at research grade and is significantly cheaper than the free base with prices ranging from $90 – 120 for a 1 g vial. Clinically Sunitinib cost is noted as being one of the highest costing drugs of its type, prompting criticized from medical associations. Initially US and UK insurance companies rejected Student as a treatment due to the excessive costs, however, with a price restructuring and public complaints Student is available on the UK healthcare program. In the US the financial burden for Student remains with the patient.

Sunitinib structure is described as Butanedioic acid, hydroxy-, (2S)-, but like most tyrosine kinase inhibitors Sunitinib solubility in water and ethanol is extremely poor; however Sunitinib can be dissolved in DMSO up to 40 mg/ml. When stored at -20^oC, Sunitinib stability for the free base is for 2 years, no details are given on stability in solution although some reference is given to the fact that Sunitinib is light sensitive.

Sunitinib IC50 against VEGFR, PDGFR, KIT, FTL3 tyrosine kinase inhibition is ~ 7 nM, 61 nM, 10 nM and 50 nM respectively.

Sunitinib Preclinical investigation

Suntinib is reported extensively in literature with regard to its antitumor and antiangiogenic properties. Sunitinib has been tested against a wide range of cancer types with varying success. Sunitinib has been established as being active against platelet-derived growth factor receptor (PDGFR)[1], vascular endothelial growth factor receptor (VEGFR) [2], KIT [1] and FLT3 [3]. Sunitinib VEGFR kinase inhibitor has been demonstrates to active against breast cancer models in an early animal study [4] and in models of small cell lung cancer where significant tumor responses were observed [1]. Sunitinib Kit kinase inhibitor was studied in a variety of hematological cancers with mixed results. It was suggested that Sunitinib PDGFR kinase inhibitor would only be useful in the subset of the population that contained a mutation in the tyrosine kinase, additionally it was observed that combination with rapamycin enhanced sunitinibs activity in this population subset. [5] Sunitinib FLT3 kinase inhibitor demonstrates consistently activity against mutated tyrosine kinase. In response to this Sunitinib was tested against Gastrointestinal stromal tumors (GIST) which are mutated in the c-KIT gene. Significant inhibition of tumor growth was observed prompting the initiation of phase 1 trials. [6-9]

Sunitinib: Clinical Status

Sunitinib clinical trials have been conducted at phase 1 / 2 levels and are currently in phase 3 for a variety of conditions. Phase 1 trails established the Sunitinib mechanism of action as the simultaneous inhibition of multiple kinases. [10-15] In general, initial work with GIST and RCC patients demonstrate a significant advantage over traditional treatments leading to Sunitinib being approved for clinical use against GIST and RCC [7]. Sunitinib lung cancer activity was evalutated in a phase 2 trial with NSCLC patients and extensive SCLC patients, the general conclusions was that as a single agent Sunitinib had a low response in these tumor types (>2%) but in combination treatments Sunitinib appears to be a good maintenance therapy post treatment [16-22]. Sunitinib breast cancer activity has also been investigated but the results were disappointing with response rates of singl agent Sunitinib being lower than traditional chemotherapy.[23-25]. Much remains to be determined about the activity of this molecule in regards to chemotherapy but it has shown significant promise in many area’s and combinations of traditional treatment and TKI’s continue to be explored.

References

1. Abrams TJ, Lee LB et al. SU11248 inhibits KIT and platelet-derived growth factor receptor beta in preclinical models of human small cell lung cancer. Mol Cancer Ther 2003; 2(5):471-478.

2. Mendel DB, Laird AD et al. In vivo antitumor activity of SU11248, a novel tyrosine kinase inhibitor targeting vascular endothelial growth factor and platelet-derived growth factor receptors: determination of a pharmacokinetic/pharmacodynamic relationship. Clin Cancer Res 2003; 9(1):327-337.

3. O'Farrell AM, Abrams TJ et al. SU11248 is a novel FLT3 tyrosine kinase inhibitor with potent activity in vitro and in vivo. Blood 2003; 101(9):3597-3605.

4. Abrams TJ, Murray LJ et al. Preclinical evaluation of the tyrosine kinase inhibitor SU11248 as a single agent and in combination with "standard of care" therapeutic agents for the treatment of breast cancer. Mol Cancer Ther 2003; 2(10):1011-1021.

5. Ikezoe T, Nishioka C et al. The antitumor effects of sunitinib (formerly SU11248) against a variety of human hematologic malignancies: enhancement of growth inhibition via inhibition of mammalian target of rapamycin signaling. Mol Cancer Ther 2006; 5(10):2522-2530.

6. Apice G, Milano A et al. Medical treatment of gastrointestinal stromal tumors: state of the art and future perspectives. Rev Recent Clin Trials 2006; 1(1):35-42.

7. Demetri GD, van Oosterom AT et al. Efficacy and safety of sunitinib in patients with advanced gastrointestinal stromal tumour after failure of imatinib: a randomised controlled trial. Lancet 2006; 368(9544):1329-1338.

8. Ikezoe T, Yang Y et al. Effect of SU11248 on gastrointestinal stromal tumor-T1 cells: enhancement of growth inhibition via inhibition of 3-kinase/Akt/mammalian target of rapamycin signaling. Cancer Sci 2006; 97(9):945-951.

9. Joensuu H. Sunitinib for imatinib-resistant GIST. Lancet 2006; 368(9544):1303-1304.

10. O'Farrell AM, Foran JM et al. An innovative phase I clinical study demonstrates inhibition of FLT3 phosphorylation by SU11248 in acute myeloid leukemia patients. Clin Cancer Res 2003; 9(15):5465-5476.

11. Morimoto AM, Tan N et al. Gene expression profiling of human colon xenograft tumors following treatment with SU11248, a multitargeted tyrosine kinase inhibitor. Oncogene 2004; 23(8):1618-1626.

12. Fiedler W, Serve H et al. A phase 1 study of SU11248 in the treatment of patients with refractory or resistant acute myeloid leukemia (AML) or not amenable to conventional therapy for the disease. Blood 2005; 105(3):986-993.

13. Bello CL, Sherman L et al. Effect of food on the pharmacokinetics of sunitinib malate (SU11248), a multi-targeted receptor tyrosine kinase inhibitor: results from a phase I study in healthy subjects. Anticancer Drugs 2006; 17(3):353-358.

14. Faivre S, Delbaldo C et al. Safety, pharmacokinetic, and antitumor activity of SU11248, a novel oral multitarget tyrosine kinase inhibitor, in patients with cancer. J Clin Oncol 2006; 24(1):25-35.

15. Motzer RJ, Michaelson MD et al. Activity of SU11248, a multitargeted inhibitor of vascular endothelial growth factor receptor and platelet-derived growth factor receptor, in patients with metastatic renal cell carcinoma. J Clin Oncol 2006; 24(1):16-24.

16. Chow LQ, Blais N et al. A phase I dose-escalation and pharmacokinetic study of sunitinib in combination with pemetrexed in patients with advanced solid malignancies, with an expanded cohort in non-small cell lung cancer. Cancer Chemother Pharmacol 2011.

17. Novello S, Scagliotti GV et al. Phase II study of continuous daily sunitinib dosing in patients with previously treated advanced non-small cell lung cancer. Br J Cancer 2009; 101(9):1543-1548.

18. Gervais R, Hainsworth JD et al. Phase II study of sunitinib as maintenance therapy in patients with locally advanced or metastatic non-small cell lung cancer. Lung Cancer 2011; 74(3):474-480.

19. Novello S, Camps C et al. Phase II study of sunitinib in patients with non-small cell lung cancer and irradiated brain metastases. J Thorac Oncol 2011; 6(7):1260-1266.

20. Gridelli C, Maione P et al. Sorafenib and sunitinib in the treatment of advanced non-small cell lung cancer. Oncologist 2007; 12(2):191-200.

21. Reck M, Frickhofen N et al. Sunitinib in combination with gemcitabine plus cisplatin for advanced non-small cell lung cancer: a phase I dose-escalation study. Lung Cancer 2010; 70(2):180-187.

22. Ping G, Hui-Min W et al. Sunitinib in pretreated advanced non-small-cell lung carcinoma: a primary result from Asian population. Med Oncol 2011; 28(2):578-583.

23. Kozloff M, Chuang E et al. An exploratory study of sunitinib plus paclitaxel as first-line treatment for patients with advanced breast cancer. Ann Oncol 2010; 21(7):1436-1441.

24. Burstein HJ, Elias AD et al. Phase II study of sunitinib malate, an oral multitargeted tyrosine kinase inhibitor, in patients with metastatic breast cancer previously treated with an anthracycline and a taxane. J Clin Oncol 2008; 26(11):1810-1816.

25. Barrios CH, Liu MC et al. Phase III randomized trial of sunitinib versus capecitabine in patients with previously treated HER2-negative advanced breast cancer. Breast Cancer Res Treat 2010; 121(1):121-131.