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RAD001 – THE mTOR INHIBITOR

by Selleckchem | May 29 2012

RAD001:
The mTOR protein which is also known as Rapamycin’s mammalian target protein is famous threonine or serine protein kinase enzyme. This kinase plays several significant roles including cellular survival, cell division, migration of cells and also in regulating a good numbers of transcriptional events linked to a huge number of signaling cascades such as aging. There are several research reports mentioning the involvement of abrupt mTOR pathway in cancer and tumorigenesis, due to this fact this pathway has become a target for the cure of large number of cancers [1]. Different mTOR inhibitors has been generated and tested, amongst these inhibitors RAD001 mTOR inhibitor is orally bio-available chemical [2]. This is developed by Novartis and is recognized under the name, Everolimus. RAD001 can be purchased easily from RAD001 supplier. According to the RAD001 structure it contains 40-O-(2-hydroxyethyl) but it is a derivative of this compound in order to enhance its pharmacokinetics. For appropriate inhibition of mTOR pathway RAD IC50 is about 1nM. The RAD001 solubility can be gained in ethnol and water as well where as a 100mg/ml solution can be gained in DMSO. If someone wants to purchase RAD001 on can pay RAD001 price of 50$ and get a vial of 5mg. One main property of this compound is its action on mTOR1 pathway rather than mTOR2 pathway as it does not affect.

RAD001 MODE OF ACTION:
mTOR pathway takes part in more than one functions of cellular signaling, therefore the RAD001 based treatment avenues finding was not a surprising topic. It is reported that this inhibitor works as strong immunosuppressant in case of cardiac [3], kidney and also some other transplants where this inhibitor showed efficient apoptotic response against a good variety of cancers and tumors [4]. RAD001 is efficient as a single agent in colon cancer case [5] and also proved as potent when used with Octreotide for the treatment of neuroendocrine tumor cells [6], RAD001 is also able to inhibit the Akt-mTOR-p70S6 kinase signaling in order to stimulate cancer cells death by apoptosis. Although a small number of research reports have been suggested about the RAD001 safety and potent chemotherapy [7], many other research studies assessed its pharmacokinetics and resulted in successful clinical trials where renal cancer treatment was done [8]. Beyond the applications in the cancer treatment RAD001 is also used for eluting stents, and these stents were much safer and accurate than traditional for example Paclitaxel etc. [9-10]. In case of coronary artery diseases and ischemia it was found as RAD001 based eluting stents were more bio-absorbable due to extensive modifications in the structure of this inhibitor [11].

RAD001 CLINICAL TRIALS:
Various in-vitro models of the breast cancer cells were analyzed upon treatment with RAD001 [12] during clinical trials it was also used for cases of recurrent breast cancer [13], this was applied as a single agent or in combination with many other therapeutic agents in clinical phase II and phase I trials respectively [14-15]. It was also used as an agent of combination therapy to those patients having hormone-receptor positive condition [16]. While experiments on in-vivo models of gastric cancers when this inhibitor was used with some other drugs specific for this type of cancer RAD001generated some of the promising results [17] which prefers its used in the more advanced forms of gastric cancers [18] and these findings can lead to the phase II clinical trials specifically gastric patients [19]. In case of renal transplantation a common choice is RAD001 as an immunosuppressant [20] and it has shown better results than a standard treatment based on Azathioprine in a research study on kidney cancer patients [21]. The mTOR inhibition generated a sufficient and promising data in carcinoids treatment [22], as mentioned above RAD001 has already been used for neuroendocrine tumors treatment in clinical phase II [23] to analyze clear regression of carcinoids leading to advanced RAD001 clinical trials providing effectiveness and good safety profile [24-25].

REFERENCES:
1. Beevers, C.e.a., Curcumin inhibits the mammalian target of rapamycin-mediated signaling pathways in cancer cells. Int J Cancer, 2006. 119(4): p. 757-64.
2. Chapman, T.M.a.P., C.M., Everolimus is an immunosuppressant analog of rapamycin (sirolimus) and inhibits growth factor-mediated proliferation of haematopoietic and nonhaematopoietic cells. Drugs, 2004. 64: p. 861-874.
3. Eisen, H.J.e.a., Everolimus for the prevention of allograft rejection and vasculopathy in cardiac-transplant recipients. N. Engl. J. Med., 2003. 349(9): p. 847-58.
4. Faivre, S.e.a., Current development of mTOR inhibitors as anticancer agents. Nature Reviews Drug Discovery, 2006. 5: p. 671-688.
5. Homicsko, e.a., RAD001 (Everolimus) Improves the Efficacy of Replicating Adenoviruses that Target Colon Cancer. Cancer Res, 2005. 65(15): p. 6882-90.
6. Glasberg, S.G.e.a., Octreotide and the mTOR Inhibitor RAD001 (Everolimus) Block Proliferation and Interact with the Akt-mTOR-p70S6K Pathway in a Neuro-Endocrine Tumor Cell Line. Clinical Neuroendocrinology and Neuroendocrine Tumors, 2008 87(3): p. 168-181.
7. Kirchner, G.I.e.a., Clinical Pharmacokinetics of Everolimus. Clinical Pharmacokinetics, 2004. 43(2): p. 83-95.
8. Agarwala, e.a., Everolimus (RAD001) in the Treatment of Advanced Renal Cell Carcinoma. The Oncologist, 2010. 15: p. 236-245.
9. Grube, E.e.a., Six- and Twelve-Month Results From First Human Experience Using Everolimus-Eluting Stents With Bioabsorbable Polymer. Circulation, 2004 109: p. 2168-2171.
10. Stone, G.W.e.a., Comparison of an Everolimus-Eluting Stent and a Paclitaxel-Eluting Stent in Patients With Coronary Artery Disease. Journal of American Medical Asociation, 2008. 299(16): p. 1903-1913.
11. Ormiston, J.A.e.a., A bioabsorbable everolimus-eluting coronary stent system for patients with single de-novo coronary artery lesions (ABSORB): a prospective open-label trial. The Lancet, 2008. 371(9616): p. 899-907.
12. Boulay, A.e.a., Dual Inhibition of mTOR and Estrogen Receptor Signaling in vitro Induces Cell Death in Models of Breast Cancer. Clin Cancer Res, 2005(11): p. 5319.
13. Lane, H.A.e.a., Future Directions in the Treatment of Hormone-Sensitive Advanced Breast Cancer: The RAD001 (Everolimus)-Letrozole Clinical Program. Seminars in Oncology, 2006. 33(7): p. 18-25.
14. Awada, A.e.a., The oral mTOR inhibitor RAD001 (everolimus) in combination with letrozole in patients with advanced breast cancer: Results of a phase I study with pharmacokinetics. European Journal of Cancer, 2008. 44(1): p. 84-91.
15. Ellard, S.L.e.a., Randomized Phase II Study Comparing Two Schedules of Everolimus in Patients With Recurrent/Metastatic Breast Cancer: NCIC Clinical Trials Group IND.163. Journal of Clinical Oncology, 2009. 27(27): p. 4536-4541.
16. Baselga, J.e.a., Phase II Randomized Study of Neoadjuvant Everolimus Plus Letrozole Compared With Placebo Plus Letrozole in Patients With Estrogen Receptor-Positive Breast Cancer. Journal of Clinical Oncology, 2009 27(16): p. 2630-2637.
17. Cejka, D.e.a., Everolimus (RAD001) and anti-angiogenic cyclophosphamide show long-term control of gastric cancer growth in vivo. Cancer Biol Ther., 2008. 7(9): p. 1377-85.
18. Ajani, J.A.e.a., Evolving Chemotherapy for Advanced Gastric Cancer. The Oncologist, 2005. 10(3): p. 49-58.
19. Doi, T.e.a., Multicenter Phase II Study of Everolimus in Patients With Previously Treated Metastatic Gastric Cancer. Journal of Clinical Oncology, 2010. 28(11): p. 1904-1910.
20. Pascual, J.e.a., Everolimus (Certican) in renal transplantation: a review of clinical trial data, current usage, and future directions. Transplantation Reviews, 2006. 20(1): p. 1-18.
21. Snell, G.I.e.a., Everolimus Versus Azathioprine in Maintenance Lung Transplant Recipients: An International, Randomized, Double-Blind Clinical Trial. American Journal of Transplantation, 2006. 6(1): p. 169-177.
22. Dong, M.a.Y., J.C., mTOR inhibition, a potential novel approach for bronchial carcinoids. Endocr Relat Cancer, 2011. 18: p. C15-C18.
23. Yao, J.C.e.a., Efficacy of RAD001 (Everolimus) and Octreotide LAR in Advanced Low- to Intermediate-Grade Neuroendocrine Tumors: Results of a Phase II Study. Journal of Clinical Oncology, 2008. 26(26): p. 4311-4318.
24. Zatelli, M.C.e.a., Everolimus as a new potential antiproliferative agent in aggressive human bronchial carcinoids. Endocr Relat Cancer, 2010 17(719-729).
25. Capdevila, J.e.a., Control of carcinoid syndrome with Everolimus. Ann Oncol 2011. 22(1): p. 237-239.