ABSTRACT
In addition to dysregulated JAK/STAT signaling, activation of the AKT/mTOR pathway occurs in myelofibrosis, a myeloproliferative neoplasm with no approved therapies. We conducted a phase 1/2 study with everolimus, an mTOR inhibitor, in 39 high- or intermediate-risk primary or postpolycythemia vera/postessential thrombocythemia myelofibrosis subjects. Responses were evaluated in 30 patients of phase 2. No dose-limiting toxicity was observed in phase 1 up to 10 mg/d. When this dose was used in phase 2, grade ≥ 3 toxicities were infrequent; the commonest toxicity was grade 1-2 stomatitis. Rapid and sustained splenomegaly reduction of > 50% and > 30% occurred in 20% and 44% of subjects, respectively. A total of 69% and 80% experienced complete resolution of systemic symptoms and pruritus. Response in leukocytosis, anemia, and thrombocytosis occurred in 15%-25%. Clinical responses were not associated with reduced JAK2V617F burden, circulating CD34(+) cells, or cytokine levels, whereas CCDN1 mRNA and phospho-p70S6K level, known targets of mTOR, and WT1 mRNA were identified as possible biomarkers associated with response. Response rate was 60% when European Network for Myelofibrosis criteria were used (8 major, 7 moderate, 3 minor responses) or 23% when IWG-MRT criteria (1 partial response, 6 clinical improvements) were used. These results provide proof-of-concept that targeting mTOR pathway in myelofibrosis may be clinically relevant.
Subject(s)
Primary Myelofibrosis/drug therapy , Protein Kinase Inhibitors/therapeutic use , Sirolimus/analogs & derivatives , TOR Serine-Threonine Kinases/antagonists & inhibitors , Adult , Aged , Cyclin D1/genetics , Everolimus , Female , Humans , Janus Kinase 2/genetics , Male , Middle Aged , Mutation , Polycythemia Vera/complications , Primary Myelofibrosis/enzymology , Primary Myelofibrosis/etiology , Protein Kinase Inhibitors/administration & dosage , Protein Kinase Inhibitors/adverse effects , RNA, Messenger/genetics , RNA, Messenger/metabolism , Receptors, Thrombopoietin/genetics , Signal Transduction/drug effects , Sirolimus/administration & dosage , Sirolimus/adverse effects , Sirolimus/therapeutic use , Thrombocythemia, Essential/complications , Treatment Outcome , WT1 Proteins/geneticsABSTRACT
Although imatinib may be effective in hypereosinophilic syndromes, the exact response kinetics are not known. Imatinib was administered at 100-400 mg/d each week in a 12-week response-oriented schedule, targeting a complete clinical and haematological remission (CR). CR was achieved in 11/23 patients (6/6 with FIP1L1-PDGRFA rearrangement and 5/17 without, P = 0.006), most after 2 weeks of 100 mg/d imatinib. The maximum imatinib dose had no effect in early unresponsive patients. Low-dose, short-course imatinib may represent a rational choice for identifying responsive cases, both within and outside the pre-defined FIP1L1 rearrangement subset.
Subject(s)
Hypereosinophilic Syndrome/drug therapy , Piperazines/administration & dosage , Pyrimidines/administration & dosage , Adult , Aged , Benzamides , Dose-Response Relationship, Drug , Drug Administration Schedule , Eosinophils/pathology , Female , Gene Rearrangement , Humans , Hypereosinophilic Syndrome/genetics , Imatinib Mesylate , Leukocyte Count , Male , Middle Aged , Oncogene Proteins, Fusion/genetics , Piperazines/therapeutic use , Pyrimidines/therapeutic use , Receptor, Platelet-Derived Growth Factor alpha/genetics , Treatment Outcome , Young Adult , mRNA Cleavage and Polyadenylation Factors/geneticsABSTRACT
Tuberous Sclerosis Complex (TSC) is a tumor suppressor gene disorder with mutations of TSC1/TSC2 genes. This leads to the development of hamartomas that most frequently affect central nervous system, kidney, and skin. Angiomyolipomas are abdominal masses made up of muscle vessels and adipose tissues that grow mostly in proximity to kidneys and liver. Bleeding and kidney failure are the major justification for surgery. This study shows that angiomyolipoma-derived human smooth muscle TSC2-/- cells express the apoptosis inhibitor protein survivin when exposed to IGF-1. Survivin expression is also triggered whenever culture conditions perturb normal TSC2-/- cell function, such as the omission of EGF from the growth medium, the supplementation of anti-EGFR, blockade of PI3K and ERK, or inhibition of mTOR. Interestingly, single or simultaneous inhibition of PI3K by LY294002 and ERK by PD98059 does not prevent IGF-1-mediated survivin expression. Apoptogenic Smac/DIABLO, which is constitutively expressed by TSC2-/- A+ cells, is down-regulated by IGF-1 even in the presence of LY294002 and PD98059. These cells release IGF-1 by means of a negative feedback-regulated mechanism that is overrun when they are exposed to antibodies to IGF-1R, which increases the released amount by more than 400%. The autocrine release of IGF-1 may therefore be a powerful mechanism of survival of the tightly packed cells in the thick-walled vessels of TSC angiomyolipoma and in lymphangioleiomyomatosis (LAM) nodules. Future experimental therapies for TSC and LAM may result from the targeted inhibition of survivin, which may enhance sensitivity to TSC2 therapy.
Subject(s)
Angiomyolipoma/pathology , Gene Expression , Inhibitor of Apoptosis Proteins/metabolism , Tuberous Sclerosis/pathology , Tumor Suppressor Proteins/metabolism , Adult , Angiomyolipoma/genetics , Cells, Cultured , Feedback, Physiological , Female , Humans , Immunohistochemistry , Insulin-Like Growth Factor I/metabolism , Insulin-Like Growth Factor I/pharmacology , Muscle, Smooth/cytology , Muscle, Smooth/metabolism , Tuberous Sclerosis/genetics , Tuberous Sclerosis Complex 2 Protein , Tumor Suppressor Proteins/geneticsABSTRACT
Insulin-like growth factor-I receptor (IGF-IR) is often overexpressed in malignant tumors, and is involved in the establishment and maintenance of malignant phenotypes. Tyrosine kinase receptor endocytosis is commonly triggered by ligand binding and occurs via clathrin-coated vescicles that transfer the receptor to the lysosome system for degradation. Our study aims at the evaluation of the mechanisms involved in IGF-IR downregulation in neoplastic (Npl) and non-neoplastic (non-Npl) cells. Exposure to insulin-like growth factor-I (IGF-I) of human lung adenocarcinoma cell lines (A549 and H1299) triggers IGF-IR ubiquitination and internalization processes that require energy and are preceded by the phosphorylation of receptor tyrosines. Differently from other plasma membrane substrates of the ubiquitin system, IGF-IR is degraded mostly by the proteasome in these tumor cell lines. The degradation is inhibited by lactacystin and unaffected by lysosomal inhibitors such as bafilomycin A1 and NH(4)Cl. IGF-IR is processed in a similar manner also in fresh specimens of human lung tumors, while it requires active lysosomal functions in non-Npl human lung tissues. These results suggest that the degradation routes of ubiquitinated IGF-IR diverge in normal and Npl cells, and further support the involvement of IGF-IR signaling in cancer. Such a different route for IGF-IR processing might take place sometime during development, since both proteasome and lysosome pathways are active in fetal lung human fibroblasts, IMR90 cells.