The emerging role of mammalian target of rapamycin inhibitors in the treatment of sarcomas.

The mammalian target of rapamycin (mTOR) is a protein kinase that functions as a key regulator of cell growth, proliferation and differentiation, cell-cycle progression, angiogenesis, protein degradation, and apoptosis. Following activation by a number of oncogenic signals such as growth factors, energy and nutrients, mTOR stimulates several downstream effectors including the 40S ribosomal protein S6 kinase (p70s6k) and the eukaryotic initiation factor 4 E binding protein-1 (4 EBP-1), as well as a complex network of regulatory loops. Activation of the mTOR pathway plays a critical role in the development of many tumor types, including renal cell and breast carcinomas, neuroendocrine tumors, and sarcomas. Bone and soft tissue sarcomas are rare, heterogeneous tumors that are curable by local treatments if diagnosed at early stages; however advanced or metastatic sarcomas are rarely curable and very few drugs are efficacious in this setting. Several disruptions in phosphatidylinositol-3 kinase (PI3K)-Akt-mTOR signaling are associated with malignant transformation or progression in various sarcoma sub-types. The PI3K-Akt-mTOR pathway is therefore an exciting target for therapy of sarcomas, and its blockade represents an opportunity to improve outcomes in this poor-prognosis disease. Early studies with mTOR inhibitors have demonstrated promising antitumor activity in patients with metastatic sarcoma who have failed standard treatments. This article discusses the mTOR signaling pathway and summarizes the clinical experience with mTOR inhibitors in patients with advanced or metastatic sarcoma.

Clinical activity of mammalian target of rapamycin inhibitors in solid tumors.

The phosphatidylinositol 3-kinase (PI3K)-Akt-mammalian target of rapamycin (mTOR) pathway is vital for cell metabolism, growth, and proliferation. mTOR is frequently upregulated in many tumor types and hence has become an important target in cancer treatment. Sirolimus and its derivatives (rapalogs) interact with the intracellular receptor FK506 binding protein 12 (FKBP12), forming a complex with high affinity for mTOR and thus disrupting its activity. Rapalogs are being evaluated extensively in cancer patients with different formulations and schedules. Significant clinical activity has led to their approval for the treatment of kidney cancer, mantle cell lymphoma, and subependymal giant cell astrocytoma; however, despite increasing knowledge about cancer cell biology, their activity in other malignancies is unclear. Further research is needed to identify optimal dosage, administration and targeted combination as well as the subset of patients likely to respond to mTOR/PI3K inhibition. This review focuses on a discussion of the pathway, its implications in cancer biology and results of clinical trials of rapalogs alone or in combination, organizing them by common malignancy type.

Clinical outcomes and factors predicting development of venous thromboembolic complications in patients with advanced refractory cancer in a Phase I Clinic: the M. D. Anderson Cancer Center experience.

Venous thromboembolism (VTE) is common in patients with advanced cancer and may influence patient eligibility for clinical studies, quality of life, and survival. We reviewed the medical records of 220 consecutive patients seen in the Phase I Clinical Trials Program at M. D. Anderson Cancer Center to determine the frequency of VTE, associated characteristics, and clinical outcomes. Twenty-three (10.5%) patients presenting to the Phase I Clinic had a history of VTE; 26 (11.8%) patients subsequently developed VTE, with a median follow-up of 8.4 months. These included nine (39%) patients with and 17 (8.6%) without a history of VTE (P < 0.0001). The most common events were deep venous thromboses of the extremities and pulmonary emboli. The median survival of patients with and without a history of VTE was 4.7 and 10.9 months, respectively (P = 0.0002). Multivariate analysis demonstrated that a history of VTE (P < 0.0001), pancreatic cancer (P = 0.007), and platelet count >440 x 10(9)/L (P = 0.026) predicted new VTE episodes. In conclusion, this retrospective analysis demonstrated that a history or new development of VTE was noted in 40 (18%) of 220 patients seen in our Phase I Clinic. A prognostic score that can be used to predict time to development of and frequency of VTE is proposed. Am. J. Hematol. 2009. (c) 2009 Wiley-Liss, Inc.