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Phase I study of S-trans, trans-farnesylthiosalicylic acid (salirasib), a novel oral RAS inhibitor in patients with refractory hematologic malignancies.

ABSTRACT: Rat sarcoma (RAS)/rapidly accelerated fibrosarcoma (RAF)/mitogen-activated protein kinase activation (mutational or nonmutational) is a key pathway for survival and proliferative advantage of leukemic cells. Salirasib (Concordia Pharmaceuticals) is an oral RAS inhibitor that causes dislocation of RAS by competing directly with farnesylated RAS in binding to its putative membrane-binding proteins. Salirasib does not inhibit farnesyl transferase enzyme.We report on a phase I study of Salirasib in patients with relapsed/refractory hematologic malignancies. Salirasib was administered orally twice daily on days 1 to 21 of a 28-day cycle in a "3+3" dose escalation design.Seventeen patients with relapsed/refractory leukemia were treated for a median of 4 cycles (range, 1-29). Three patients each were enrolled at a dose level of 100, 200, 400, 600, and 800 mg twice daily and 2 patients at a dose level of 900 mg twice daily. No dose-limiting toxicities were encountered. Grade 1/2 diarrhea was the only frequent nonhematologic toxicity observed in 14 of 17 (82%) patients and was resolved with oral antidiarrheal agents. Eight (47%) patients (4 with myelodysplastic syndrome, 2 with acute myeloid leukemia, 1 with chronic myelomonocytic leukemia, and 1 with chronic myeloid leukemia) had hematological improvement; 1 in 3 lineages, 1 in 2 lineages, and 6 in 1 lineage. None of the patients achieved complete remission. The responses lasted for a median of 10 weeks (range, 5-115). The study was discontinued because of financial constraints.Salirasib was well tolerated and showed modest activity in relapsed/refractory hematological malignancies. The safety profile of Salirasib and its hematological malignancy relevant target makes it a potential drug to be used in combination therapy.

SUBMITTER: Badar T

PROVIDER: S-EPMC4509631 | biostudies-literature | 2015 Jul

REPOSITORIES: biostudies-literature

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Phase I study of S-trans, trans-farnesylthiosalicylic acid (salirasib), a novel oral RAS inhibitor in patients with refractory hematologic malignancies.

Badar Talha T Cortes Jorge E JE Ravandi Farhad F O'Brien Susan S Verstovsek Srdan S Garcia-Manero Guillermo G Kantarjian Hagop H Borthakur Gautam G

Clinical lymphoma, myeloma & leukemia 20150219 7

<h4>Background</h4>Rat sarcoma (RAS)/rapidly accelerated fibrosarcoma (RAF)/mitogen-activated protein kinase activation (mutational or nonmutational) is a key pathway for survival and proliferative advantage of leukemic cells. Salirasib (Concordia Pharmaceuticals) is an oral RAS inhibitor that causes dislocation of RAS by competing directly with farnesylated RAS in binding to its putative membrane-binding proteins. Salirasib does not inhibit farnesyl transferase enzyme.<h4>Patients and methods</ ...[more]

PMID: 25795639

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Project description:Background:Alzheimer's disease (AD), a leading cause of dementia, becomes a serious health issue for individuals and society around the world. AD is a neurodegenerative disease characterized by the deposition of amyloid-? (A?) peptides and neurofibrillary tangles (NFT) and the loss of large numbers of neurons. To date, there is no effective treatment for AD, and thus, to enhance neurogenesis in the AD brain may be a therapeutic strategy. RAS signaling pathway involves in synaptic plasticity and memory formation, which is overexpressed in brains with AD. This study used A?1-42-injected mice (A?1-42-mice) as the AD model to investigate the effects of S-trans, trans-farnesylthiosalicylic acid (FTS), a synthetic Ras inhibitor, on the impairment of neurogenesis and the spatial cognitive de?cits. Materials and methods:AD model mice were manufactured through intracerebroventricular injection of A?1-42. Morris water maze (MWM) was performed to evaluate the capacity of spatial memory, and Nissl staining was applied to assess neuronal damage in the hippocampus CA1. Immunohistochemistry of 5-bromo-2-deoxyuridine (BrdU), BrdU/neuronal nuclei (NeuN), and doublecortin (DCX) were used to detect progenitor cell proliferation, maturation, and neurite growth, respectively. And the expression levels of RAS, ERK/ERK phosphorylation (p-ERK) and CREB/CREB phosphorylation (p-CREB) were detected by Western blot. Results:The results demonstrated that FTS could prevent A?1-42 to impair survival and neurite growth of newborn neurons in the hippocampal dentate gyrus (DG) in A?1-42-mice. Furthermore, behavioral indexes and morphological findings showed that FTS improved the learning and spatial memory abilities of A?1-42-mice. In addition, FTS could inhibit the levels of hippocampal p-ERK and p-CREB activated by A?, which is the underlying molecular mechanism. Conclusion:In conclusion, these findings suggest that FTS as a RAS inhibitor could be a potential therapeutic agent for the treatment of AD.

Dataset Information

Phase I study of S-trans, trans-farnesylthiosalicylic acid (salirasib), a novel oral RAS inhibitor in patients with refractory hematologic malignancies.

Publications

Phase I study of S-trans, trans-farnesylthiosalicylic acid (salirasib), a novel oral RAS inhibitor in patients with refractory hematologic malignancies.

Similar Datasets

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