Ridaforolimus is an inhibitor of mammalian target of rapamycin, an integral component of the phosphatidyl 3-kinase/AKT signaling pathway, with early evidence of activity in sarcomas. This multicenter, open-label, single-arm, phase II trial was conducted to assess the antitumor activity of ridaforolimus in patients with distinct subtypes of advanced sarcomas.
Patients with metastatic or unresectable soft tissue or bone sarcomas received ridaforolimus 12.5 mg administered as a 30-minute intravenous infusion once daily for 5 days every 2 weeks. The primary end point was clinical benefit response (CBR) rate (complete response or partial response [PR] or stable disease ≥ 16 weeks). Safety, progression-free survival (PFS), overall survival (OS), time to progression, and duration of response were also evaluated.
A total of 212 patients were treated in four separate histologic cohorts. In this heavily pretreated population, 61 patients (28.8%) achieved CBR. Median PFS was 15.3 weeks; median OS was 40 weeks. Response Evaluation Criteria in Solid Tumors (RECIST) confirmed response rate was 1.9%, with four patients achieving confirmed PR (two with osteosarcoma, one with spindle cell sarcoma, and one with malignant fibrous histiocytoma). Archival tumor protein markers analyzed were not correlated with CBR. Related adverse events were generally mild or moderate and consisted primarily of stomatitis, mucosal inflammation, mouth ulceration, rash, and fatigue.
Single-agent ridaforolimus in patients with advanced and pretreated sarcomas led to PFS results that compare favorably with historical metrics. A phase III trial based on these data will further define ridaforolimus activity in sarcomas.
"The program has been successful, leading to Phase I and II clinical trials for cixutumumab, sorafenib, and rapamycin for OS treatment. (84–86). In each case, these agents demonstrated high levels of response in the PPTP and were well-tolerated with promising anti-tumor activity in some adult and pediatric patients. "
[Show abstract][Hide abstract] ABSTRACT: Osteosarcoma (OS) is the most common non-hematologic primary tumor of bone in children and adults. High-dose cytotoxic chemotherapy and surgical resection have improved prognosis, with long-term survival for non-metastatic disease approaching 70%. However, most OS tumors are high grade and tend to rapidly develop pulmonary metastases. Despite clinical advances, patients with metastatic disease or relapse have a poor prognosis. Toward a better understanding of the molecular pathogenesis of human OS, several genetically modified OS mouse models have been developed and will be reviewed here. However, better animal models that more accurately recapitulate the natural progression of the disease are needed for the development of improved prognostic and diagnostic markers as well as targeted therapies for both primary and metastatic OS.
Frontiers in Oncology 07/2014; 4:189. DOI:10.3389/fonc.2014.00189
"These results are clearly insufficient but indicate that mTOR inhibitors have activity in sarcomas. However, neither in that trial nor in the preceding phase II study  patients affected by low grade ESS were enrolled. The term “sarcomas” encompasses more than 50 different malignancies with differing molecular biology, clinical behaviour, responsiveness to treatment, and prognosis, and there is no current evidence that inhibition of the mTOR pathway is an active therapeutic strategy in low grade ESS. "
[Show abstract][Hide abstract] ABSTRACT: . Endometrial stromal sarcomas (ESS) are a subtype of gynaecological sarcomas characterized by the overexpression of hormone receptors. Hormone treatment is widely used in ESS but primary or acquired resistance is common. The mammalian target of rapamycin (mTOR) pathway has been suggested to play a key role in the mechanisms of hormone resistance. Recent studies in breast and prostate cancer demonstrate that this resistance can be reversed with the addition of an mTOR inhibitor. This phenomenon has never been reported in ESS.
. We report the outcome of one patient with pretreated, progressing low grade metastatic ESS treated with medroxyprogesterone acetate in combination with the mTOR inhibitor sirolimus.
. Partial response was achieved following the addition of sirolimus to the hormone treatment. Response has been maintained for more than 2 years with minimal toxicity and treatment is ongoing.
. This case suggests that the resistance to the hormone manipulation in ESS can be reversed by the addition of an mTOR pathway inhibitor. This observation is highly encouraging and deserves further investigation.
Case Reports in Medicine 07/2014; 2014(22):612496. DOI:10.1155/2014/612496
"Thus, the combination of apomine and lovastatine which targets the mevalonate pathways significantly reduced tumour progression in osteosarcoma-bearing mice compared to single treatment which had no effect at the doses used . The mTOR inhibitor ridaforolimus has been studied in a phase II trial of patients with advanced bone sarcomas and this study revealed improved progression-free survival in advanced sarcomas including osteosarcoma . Moriceau et al. demonstrated recently that RAD001 (everolimus) a new oral mTOR inhibitor, inhibited osteosarcoma cell proliferation and its combination with zoledronic acid reduced tumour development in murine models of mixed osteoblastic/osteolytic or undifferentiated osteosarcoma . "
[Show abstract][Hide abstract] ABSTRACT: Osteosarcoma is the most common primary malignant bone tumour characterized by osteoid production and/or osteolytic lesions of bone. A lack of response to chemotherapeutic treatments shows the importance of exploring new therapeutic methods. Imatinib mesylate (Gleevec, Novartis Pharma), a tyrosine kinase inhibitor, was originally developed for the treatment of chronic myeloid leukemia. Several studies revealed that imatinib mesylate inhibits osteoclast differentiation through the M-CSFR pathway and activates osteoblast differentiation through PDGFR pathway, two key cells involved in the vicious cycle controlling the tumour development. The present study investigated the in vitro effects of imatinib mesylate on the proliferation, apoptosis, cell cycle, and migration ability of five osteosarcoma cell lines (human: MG-63, HOS; rat: OSRGA; mice: MOS-J, POS-1). Imatinib mesylate was also assessed as a curative and preventive treatment in two syngenic osteosarcoma models: MOS-J (mixed osteoblastic/osteolytic osteosarcoma) and POS-1 (undifferentiated osteosarcoma). Imatinib mesylate exhibited a dose-dependent anti-proliferative effect in all cell lines studied. The drug induced a G0/G1 cell cycle arrest in most cell lines, except for POS-1 and HOS cells that were blocked in the S phase. In addition, imatinib mesylate induced cell death and strongly inhibited osteosarcoma cell migration. In the MOS-J osteosarcoma model, oral administration of imatinib mesylate significantly inhibited the tumour development in both preventive and curative approaches. A phospho-receptor tyrosine kinase array kit revealed that PDGFRα, among 7 other receptors (PDFGFRβ, Axl, RYK, EGFR, EphA2 and 10, IGF1R), appears as one of the main molecular targets for imatinib mesylate. In the light of the present study and the literature, it would be particularly interesting to revisit therapeutic evaluation of imatinib mesylate in osteosarcoma according to the tyrosine-kinase receptor status of patients.
PLoS ONE 03/2014; 9(3):e90795. DOI:10.1371/journal.pone.0090795 · 3.23 Impact Factor
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