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Cancer Jan 2010Mammalian target of rapamycin (mTOR) inhibitors may have efficacy as an intervention for advanced malignancies. Oral ulceration (OU), reported as mucositis, has been a...
BACKGROUND
Mammalian target of rapamycin (mTOR) inhibitors may have efficacy as an intervention for advanced malignancies. Oral ulceration (OU), reported as mucositis, has been a dose-limiting toxicity for this new class of agents. An analysis of the appearance, course, and toxicity associations of mTOR inhibitor-associated stomatitis (mIAS) demonstrated that the condition is distinct from conventional mucositis (CM) and more closely resembles aphthous stomatitis.
METHODS
Safety data from 78 solid tumor patients enrolled in 2 Phase 1, multicenter trials of the mTOR inhibitor deforolimus (AP23573, MK-8669) were evaluated. Adverse events (AEs) based on National Cancer Institute Common Toxicity Criteria for National Cancer Institute Common Terminology Criteria for Adverse Events (version 3.0) criteria were coded, consolidated, and stratified according to the presence or absence and duration of concordant OU. The relation between OU and other AEs was analyzed.
RESULTS
Treatment-emergent AEs were reported in 91% of 78 study participants. OUs were reported in 66%, appeared within 5 days of deforolimus administration, and were discrete, ovoid, superficial, well demarcated, and surrounded by an erythematous halo. Their clinical appearance and distribution were similar to that of aphthous stomatitis but inconsistent with CM. Patients with OU were more likely to have nonspecific rashes and acneiform dermatitis but not gastrointestinal AEs.
CONCLUSIONS
OU associated with mTOR inhibitor therapy differed from CM. Lesions more closely resembled those of aphthous stomatitis. The lack of other gastrointestinal involvement but the presence of a higher incidence of concomitant cutaneous AEs provided additional evidence to suggest a distinction between mIAS and CM. Treatment strategies for aphthous stomatitis may be a rational approach for the prevention and control of mIAS.
Topics: Adult; Aged; Antineoplastic Agents; Clinical Trials, Phase I as Topic; Female; Humans; Intracellular Signaling Peptides and Proteins; Male; Middle Aged; Mucositis; Neoplasms; Protein Serine-Threonine Kinases; Sirolimus; Stomatitis; TOR Serine-Threonine Kinases
PubMed: 19862817
DOI: 10.1002/cncr.24696 -
Journal of Hematology & Oncology Oct 2009The mammalian target of rapamycin (mTOR) is an intracellular serine/threonine protein kinase positioned at a central point in a variety of cellular signaling cascades.... (Review)
Review
The mammalian target of rapamycin (mTOR) is an intracellular serine/threonine protein kinase positioned at a central point in a variety of cellular signaling cascades. The established involvement of mTOR activity in the cellular processes that contribute to the development and progression of cancer has identified mTOR as a major link in tumorigenesis. Consequently, inhibitors of mTOR, including temsirolimus, everolimus, and ridaforolimus (formerly deforolimus) have been developed and assessed for their safety and efficacy in patients with cancer. Temsirolimus is an intravenously administered agent approved by the US Food and Drug Administration (FDA) and the European Medicines Agency (EMEA) for the treatment of advanced renal cell carcinoma (RCC). Everolimus is an oral agent that has recently obtained US FDA and EMEA approval for the treatment of advanced RCC after failure of treatment with sunitinib or sorafenib. Ridaforolimus is not yet approved for any indication. The use of mTOR inhibitors, either alone or in combination with other anticancer agents, has the potential to provide anticancer activity in numerous tumor types. Cancer types in which these agents are under evaluation include neuroendocrine tumors, breast cancer, leukemia, lymphoma, hepatocellular carcinoma, gastric cancer, pancreatic cancer, sarcoma, endometrial cancer, and non-small-cell lung cancer. The results of ongoing clinical trials with mTOR inhibitors, as single agents and in combination regimens, will better define their activity in cancer.
Topics: Animals; Antineoplastic Agents; Cell Transformation, Neoplastic; Drug Delivery Systems; Drug Discovery; Humans; Intracellular Signaling Peptides and Proteins; Models, Biological; Neoplasms; Protein Kinase Inhibitors; Protein Serine-Threonine Kinases; TOR Serine-Threonine Kinases
PubMed: 19860903
DOI: 10.1186/1756-8722-2-45 -
Clinical Cancer Research : An Official... Feb 2009This was a phase I trial to determine the maximum tolerated dose and toxicity of deforolimus (AP23573, MK-8669), an inhibitor of mammalian target of rapamycin (mTOR)....
PURPOSE
This was a phase I trial to determine the maximum tolerated dose and toxicity of deforolimus (AP23573, MK-8669), an inhibitor of mammalian target of rapamycin (mTOR). The pharmacokinetics, pharmacodynamics, and antineoplastic effects were also studied.
EXPERIMENTAL DESIGN
Deforolimus was administered intravenously over 30 min every 7 days according to a flat dosing schedule. Dose was escalated according to an accelerated titration design. Patients remained on study until disease progression as long as they tolerated the drug without significant toxicities.
RESULTS
Forty-six patients were enrolled on the study. Common side effects included fatigue, anorexia, and mucositis. The maximum tolerated dose was 75 mg and mucositis was the dose-limiting toxicity. Similar to other mTOR inhibitors, deforolimus exhibited nonlinear pharmacokinetics and a prolonged half-life. Among 34 patients evaluable for response, 1 patient had a partial response, 21 patients had stable disease, and 12 had progressed. Percent change in tumor size was significantly associated with AUC (P=0.015). A significant association was also detected for maximum change in cholesterol within the first two cycles of therapy and change in tumor size (r=-0.38; P=0.029).
CONCLUSIONS
Deforolimus was well tolerated on the schedule tested in this trial with toxicity and pharmacokinetic profiles that were similar to that of other mTOR inhibitors. Additional phase II studies are needed to determine if deforolimus is superior to other mTOR inhibitors in terms of efficacy. The change in serum cholesterol as a potential biomarker of activity should be studied further.
Topics: Adaptor Proteins, Signal Transducing; Adult; Aged; Cell Cycle Proteins; Female; Humans; Male; Maximum Tolerated Dose; Middle Aged; Mucositis; Neoplasms; Phosphoproteins; Phosphorylation; Protein Kinases; Sirolimus; TOR Serine-Threonine Kinases
PubMed: 19228743
DOI: 10.1158/1078-0432.CCR-08-2076 -
Bulletin Du Cancer Jan 2009PI3K/AKT/mTOR is a cell signalling pathway that plays a major role in regulation of apoptosis, cell growth and cell cycle. This pathway is often disregulated in human... (Review)
Review
PI3K/AKT/mTOR is a cell signalling pathway that plays a major role in regulation of apoptosis, cell growth and cell cycle. This pathway is often disregulated in human cancers, and constitutes an interesting target for antitumor therapy. Rapamycin is an inhibitor of mTOR that has first been developed for its immunosuppressive characteristics, as a preventive treatment of graft rejection. More recently, three rapamycin analogs have been developed, resulting in interesting results in preclinical studies on cancer cell lines : temsirolimus, everolimus, and deforolimus. These molecules are being tested in clinical studies, and both temsirolimus and everolimus have demonstrated efficacy in metastatic renal cancers. In contrast, perfosin, an AKT inhibitor, did not prove to be active in clinical studies. Many ongoing studies explore next indications of these drugs, given alone or in combination with chemotherapy or with other targeted therapy. Identification of predictive factors for sensibility to treatment represents another way of research.
Topics: Antineoplastic Agents; Cell Proliferation; Clinical Trials, Phase II as Topic; Clinical Trials, Phase III as Topic; Everolimus; Humans; Phosphatidylinositol 3-Kinases; Phosphoinositide-3 Kinase Inhibitors; Protein Kinases; Proto-Oncogene Proteins c-akt; Signal Transduction; Sirolimus; TOR Serine-Threonine Kinases
PubMed: 19211363
DOI: 10.1684/bdc.2009.0807 -
The Oncologist Feb 2008The mammalian target of rapamycin (mTOR), a serine/threonine kinase, is a downstream mediator in the phosphatidylinositol 3-kinase/Akt signaling pathway, which plays a... (Review)
Review
The mammalian target of rapamycin (mTOR), a serine/threonine kinase, is a downstream mediator in the phosphatidylinositol 3-kinase/Akt signaling pathway, which plays a critical role in regulating basic cellular functions including cellular growth and proliferation. Currently, the mTOR inhibitor rapamycin and its analogues (CCI-779, RAD001, AP23573), which induce cell-cycle arrest in the G(1) phase, are being evaluated in cancer clinical trials. The mTOR inhibitors appear to be well tolerated, with skin reactions, stomatitis, myelosuppression, and metabolic abnormalities the most common toxicities seen. These adverse events are transient and reversible with interruption of dosing. Several pieces of evidence suggest a certain antitumor activity, including tumor regressions and prolonged stable disease, which has been reported among patients with a variety of malignancies, including non-small cell lung cancer (NSCLC). These promising preliminary clinical data have stimulated further research in this setting. Here, we review the basic structure of the pathway together with current results and future developments of mTOR inhibitors in the treatment of NSCLC patients.
Topics: Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Non-Small-Cell Lung; Clinical Trials as Topic; Disease Progression; ErbB Receptors; Everolimus; Humans; Immunosuppressive Agents; Lung Neoplasms; Protein Kinases; Sirolimus; TOR Serine-Threonine Kinases; Treatment Outcome
PubMed: 18305058
DOI: 10.1634/theoncologist.2007-0171 -
Modern Pathology : An Official Journal... Mar 2008Metastatic sarcomas are commonly resistant to chemotherapy. The serine/threonine kinase, mammalian target of rapamycin (mTOR), is a protein kinase of the... (Clinical Trial)
Clinical Trial
Metastatic sarcomas are commonly resistant to chemotherapy. The serine/threonine kinase, mammalian target of rapamycin (mTOR), is a protein kinase of the phosphatidylinositol 3-kinase (PI3K)/AKT signaling pathway thought to have a key role in controlling cancer growth and thus is an important target for cancer therapy. Several inhibitors of mTOR are in clinical trials, including AP23573, which is being tested on metastatic sarcomas and other tumors. We hypothesized that a marker for the activity of mTOR, phosphorylated S6 ribosomal protein, would be predictive of clinical response to the drug, that is, high tumor expression would signify better response than low expression. This was a blinded study. Of 26 patients treated, 20 remained on study, with available paraffin blocks. Fourteen patients received AP23573 alone and six patients received AP23573 in combination with adriamycin. An antibody to the phosphorylated S6 ribosomal protein was used to stain the tumors, all high-grade sarcomas. Pretreatment biopsy or resection material was tested: the original tumor (n=6) or tumor recurrence/metastasis (n=14); either of these may have been after treatment with other agents. Staining was scored for both quantity/percentage of tumor cells and intensity. Scoring was performed without knowledge of tumor response. Staining quantity could be categorized into two natural groups: high expressors (> or =20% of tumor cells, 11 cases) and low expressors (0-10% of tumor cells, 9 cases). The high-expression group had eight stable and three progressive cases (73% stable disease); the low-expression group had three stable and six progressive cases (67% progressive disease). Chi-square analysis showed statistical significance (P< or =0.05) at this initial cutoff (10%) selected blindly. The level of phosphorylated S6 ribosomal protein expression was predictive of early tumor response to the mTOR inhibitor, suggesting that this is a promising new predictive sarcoma marker for targeted mTOR inhibitor therapy.
Topics: Adolescent; Adult; Aged; Biomarkers, Tumor; Disease Progression; Drug Resistance, Neoplasm; Female; Humans; Immunohistochemistry; Male; Middle Aged; Phosphatidylinositol 3-Kinases; Phosphorylation; Predictive Value of Tests; Protein Kinases; Ribosomal Protein S6; Sarcoma; Signal Transduction; Sirolimus; TOR Serine-Threonine Kinases; Treatment Outcome
PubMed: 18157089
DOI: 10.1038/modpathol.3800995 -
Ai Zheng = Aizheng = Chinese Journal of... Dec 2007Mammalian target of rapamycin (mTOR) is a key downstream molecule of PI3K/Akt pathway. It integrates input signals from growth factors, nutrients and energy to regulate... (Review)
Review
Mammalian target of rapamycin (mTOR) is a key downstream molecule of PI3K/Akt pathway. It integrates input signals from growth factors, nutrients and energy to regulate cell growth and proliferation via different cellular processes. Gene mutations of mTOR pathway-related proteins are very common in many carcinomas. Abnormal expression of these related proteins can result in aberrant hyperactivity of mTOR pathway. Therefore, mTOR-targeted therapy has shown promising role in the management of various cancers. This article reviewed the current status of researches on mTOR and its inhibitors in antitumor therapy.
Topics: Animals; Antineoplastic Agents; Everolimus; Humans; Neoplasms; Protein Kinase Inhibitors; Protein Kinases; Signal Transduction; Sirolimus; TOR Serine-Threonine Kinases
PubMed: 18076811
DOI: No ID Found -
The Oncologist Aug 2007Dysregulation of the mammalian target of rapamycin (mTOR) pathway has been found in many human tumors and implicated in the promotion of cancer cell growth and survival.... (Review)
Review
Dysregulation of the mammalian target of rapamycin (mTOR) pathway has been found in many human tumors and implicated in the promotion of cancer cell growth and survival. Hence, the mTOR pathway is considered an important target for anticancer drug development. Currently, the mTOR inhibitor rapamycin and its derivatives CCI-779, RAD001, and AP23573 are being evaluated in cancer clinical trials. To date, clinical results have shown good tolerability of treatment with mTOR inhibitors in most reports and varying effectiveness of mTOR inhibitors in a variety of tumors in a subset of patients. For the targeted treatment of sarcomas, AP23573 has shown promising clinical efficacy and low toxicity profiles in patients. Further studies should define the optimal dose/schedule, patient selection, and combination strategies with other biological agents, especially those targeting signaling pathways crucial for cell survival. Disclosure of potential conflicts of interest is found at the end of this article.
Topics: Clinical Trials as Topic; Everolimus; Humans; Phosphatidylinositol 3-Kinases; Protein Kinase Inhibitors; Protein Kinases; Proto-Oncogene Proteins c-akt; Sarcoma; Sirolimus; TOR Serine-Threonine Kinases
PubMed: 17766661
DOI: 10.1634/theoncologist.12-8-1007 -
Oncology (Williston Park, N.Y.) Jan 2007
Topics: Adult; Angiogenesis Inhibitors; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Bevacizumab; Dioxoles; Enzyme Inhibitors; Humans; Protein Kinases; Protein-Tyrosine Kinases; Sarcoma; Sirolimus; TOR Serine-Threonine Kinases; Tetrahydroisoquinolines; Thalidomide; Trabectedin; Vascular Endothelial Growth Factor A
PubMed: 17313160
DOI: No ID Found