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Journal of Clinical Oncology, Vol 26, No 3 (January 20), 2008: pp. 348-349 © 2008 American Society of Clinical Oncology. DOI: 10.1200/JCO.2007.14.3164
mTOR: The Mammalian Target of ReplicationUniversity of Chicago Cancer Research Center, Chicago, IL In Edmond Rostand's play Cyrano de Bergerac (1897), the beautiful Roxane, mistakenly believing that the love letters written by Cyrano come from the handsome Christian de Neuvillette, falls in love with the latter. It is not until the tragic end of the play that Roxane realizes she has overlooked Cyrano's talent and passion lamenting, "I have loved but one man in my life, and I have lost him twice." More than a century later, the age of targeted cancer therapy is on us with several agents either approved or demonstrating considerable promise. Molecular and biochemical engineering have allowed scientists to discover targets of interest, manufacture compounds that inhibit specific proteins or genes, and validate these effects in preclinical and clinical models. Three decades ago, a different paradigm existed because the target of a drug was often elucidated after its effect on tumors was established. Rapamycin, also called sirolimus, is an example of this latter process and, much like Roxane's Cyrano, has been unnoticed for too long. Rapamycin was initially discovered in 1975 on the island of Rapa Nui, from which it derives its name. Initially developed as an antibiotic, it was noted that rapamycin possesses antiproliferative properties, especially against lymphocytes. Thus, the agent was studied as an immunosuppressive and eventually approved for prophylaxis of renal allograft rejection. In 1991, the target of rapamycin was discovered in yeast and named target of rapamycin (TOR).1 The only known homolog in mammals was subsequently cloned and called mammalian target of rapamycin, or mTOR.2 Since then, we have learned a great deal about the mechanism by which rapamycin interacts with mTOR, the mTOR pathway itself, and the relevance of the pathway to diseases including cancer. While rapamycin was enjoying success in the organ transplantation literature its potential as an antineoplastic agent was almost abjured but not completely forgotten. In fact, pharmaceutical companies began to envision the potential for mTOR inhibitors in cancer therapy and soon initiated programs to discover new compounds that act analogously, if not identically, to rapamycin. A phase I trial administering the mTOR inhibitor deforolimus appears in the current issue of the Journal of Clinical Oncology.3 There are three rapamycin analogs in cancer clinical trials: temsirolimus, everolimus, and deforolimus. As a class of agents, they appear to have activity or efficacy in a wide range of malignancies including renal cell carcinoma (RCC), sarcoma, lymphoma, leukemia, glioblastoma, endometrial carcinoma, and neuroendocrine carcinomas. The potential to combine the agents with other inhibitors, cytotoxic chemotherapy, or radiotherapy exists and is being evaluated. Temsirolimus has recently been approved in the United States after a phase III trial demonstrated an overall survival benefit in RCC compared with interferon alone or lower doses of the combination. The report by Mita et al3 in this issue illustrates several factors that have become apparent regarding this class of agents and are worth highlighting. Notably, the maximally effective dose, as defined by response or survival extension, is likely to be significantly lower than the maximum-tolerated dose (MTD). Partial responses were noted at different dose levels ranging from 3 to 18.75 mg/d in the study by Mita et al, whereas inhibition of the pharmacodynamic marker described, phosphorylation of eukaryotic initiation factor 4E binding protein 1 (4E-BP1), was maximally observed at the lowest dose level. Indeed, the approved dose of temsirolimus is almost 10 times lower than the MTD. mTOR inhibitors have specific and relatively consistent toxicities such as hyperlipidemia, hyperglycemia, stomatitis, rash, and myelosuppression, which were all observed by Mita et al. These toxicities are rarely life threatening or serious (the rare occurrence of interstitial pneumonitis being a notable exception), and resolve with drug discontinuation. Moreover, immunosuppression does not appear to be problematic, at least when these agents are administered on an intermittent schedule. In addition, the spectrum of activity of these agents, as mentioned, includes carcinomas, sarcomas, and lymphomas with partial responses confirmed in the study by Mita et al in patients with RCC and Ewing sarcoma and a minor response in a patient with anaplastic large-cell lymphoma. Everolimus is currently being evaluated in randomized trials in patients with prostate cancer, carcinoid tumor, and pancreatic neuroendocrine tumors. Thus, it is likely that oncologists will soon have three mTOR inhibitors to choose from in treating their patients. But what ever happened to rapamycin? Didn't we already have an orally administered and US Food and Drug Administration–approved mTOR inhibitor at our disposal whose pharmacokinetics are well described, for which therapeutic drug monitoring is readily available, and which has been used in thousands of transplant patients? Unfortunately, the situation is not that simple. In organ transplant recipients, a daily dosing schedule is employed and is purposefully immunosuppressive. The oral bioavailability of the agent is low and the interpatient variability in blood levels is high. Until recently, a clinical trial administering rapamycin to cancer patients had never been conducted, although reports of activity in Kaposi's sarcoma and acute myeloid leukemia have been published.4,5 Obstacles exist, but they are not insurmountable. The data demonstrating the efficacy of rapamycin prodrug (temsirolimus) and analogs (everolimus and deforolimus) has garnered a great deal of interest in developing the parent compound. The National Institutes of Health have funded two phase I studies exploring different dosing regimens of rapamycin in patients with advanced malignancies, and non–federally funded phase II studies are already underway. Investigators have hypothesized that intermittent schedules can avoid immunosuppression. Pharmacokinetic variability is common to all of the mTOR inhibitors and can be addressed by drug monitoring and dose adjustment. Low bioavailability can be overcome by increasing the dose or coadministration with a modifier of rapamycin metabolism. Our group recently reported preliminary results of a phase I study administering rapamycin on a tolerable, once-weekly schedule6 that produced typical mTOR inhibitory effects as evidenced by a list of adverse events almost identical to the study by Mita et al. In an ongoing separate trial, the CYP3A inhibitory properties of grapefruit juice are being used to advantage by administering this with weekly rapamycin in an effort to safely and effectively increase blood concentrations (http://uccrc.uchicago.edu/patients/clinicaltrials.html). This research can be completed with modest funding and will lay the foundation for phase II and III trials. There is one other compelling reason to develop rapamycin for cancer patients that is far removed from biology, but is no less important. At doses currently utilized, it would cost approximately $1,000 per month to treat a patient, but the cost could decrease dramatically when the patent for rapamycin (US patent #5,100,899) expires in 2013. With patent expiration looming and the time required to garner approval for an oncology indication, it makes little financial sense for the current manufacturer to develop rapamycin for cancer therapy, especially when the patent for rapamycin use in malignant disease has already expired. Without patent protection, there is little commercial incentive for the private sector to develop the agent. However, this is a situation in which public or philanthropic intervention would yield substantial long-term savings when one compares the price of conducting clinical trials against escalating nongeneric drug costs. The age of targeted therapy has brought with it a financial burden. The price of 1 month of temsirolimus therapy at the approved dose in RCC is approximately $5,8007—exclusive of costs associated with intravenous administration—and this is remarkably not disparate from other approved targeted agents. Therapy duration for the most effective agents can be several months to years, resulting in costs to health care systems that will eventually exceed their budgets. Rapamycin will not solve this issue, but it illustrates measures that can be taken to stem the tide. Rapamycin represents an opportunity to bring an effective therapy to cancer patients that does not require its producer to "recover the cost of research and development" which ostensibly results in prices tremendously disproportionate to manufacturing costs. Thirty-two years after the discovery of rapamycin, its prodrug, temsirolimus, has been approved for renal cell carcinoma, and two other analogs are actively being studied. Much like Roxane in Cyrano de Bergerac, we are guilty of falling in love with the attractive newer agents and ignoring what should have been as plain as the nose on our face. It is time that the oncology community began paying attention to the original mTOR inhibitor, rapamycin, and to fund and conduct larger studies with this drug. We do not need another mTOR inhibitor; we just need the common sense to learn to use the one we have. AUTHOR'S DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST Although all authors completed the disclosure declaration, the following author(s) indicated a financial or other interest that is relevant to the subject matter under consideration in this article. Certain relationships marked with a "U" are those for which no compensation was received; those relationships marked with a "C" were compensated. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors. Employment or Leadership Position: None Consultant or Advisory Role: None Stock Ownership: Ezra E.W. Cohen, Pfizer Honoraria: Ezra E.W. Cohen, Genentech Research Funding: None Expert Testimony: None Other Remuneration: None REFERENCES
1. Heitman J, Movva NR, Hall MN: Targets for cell cycle arrest by the immunosuppressant rapamycin in yeast. Science 253:905-909, 1991 2. Brown EJ, Albers MW, Shin TB, et al: A mammalian protein targeted by G1-arresting rapamycin-receptor complex. Nature 369:756-758, 1994[CrossRef][Medline] 3. Mita MM, Mita AC, Chu QS, et al: Phase I trial of the novel mammalian target of rapamycin inhibitor deforolimus (AP23573; MK-8669) administered intravenously daily for 5 days every 2 weeks to patients with advanced malignancies. J Clin Oncol 26:361-367, 2008 4. Stallone G, Schena A, Infante B, et al: Sirolimus for Kaposi's sarcoma in renal-transplant recipients. N Engl J Med 352:1317-1323, 2005 5. Récher C, Beyne-Rauzy O, Demur C, et al: Antileukemic activity of rapamycin in acute myeloid leukemia. Blood 105:2527-2534, 2005 6. Ratain MJ, Napoli KL, Knightley-Moshier K, et al: A phase 1b study of oral rapamycin (sirolimus) in patients with advanced malignancies. J Clin Oncol 25:140s, 2007 (suppl; abstr 3510) 7. Drug Topics Red Book. Montvale, NJ, Thomson Healthcare, 2007
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Copyright © 2008 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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