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2. Phase 1/2 trial of temsirolimus and sorafenib in the treatment of patients with recurrent glioblastoma: North Central Cancer Treatment Group Study/Alliance N0572

Author

David, Schiff, Kurt A, Jaeckle, S Keith, Anderson, Evanthia, Galanis, Caterina, Giannini, Jan C, Buckner, Phillip, Stella, Patrick J, Flynn, Bradley J, Erickson, John F, Schwerkoske, Vesna, Kaluza, Erin, Twohy, Janet, Dancey, John, Wright, Jann N, Sarkaria, Schiff D., Jaeckle K.A., Anderson S.K., Galanis E., Giannini C., Buckner J.C., Stella P., Flynn P.J., Erickson B.J., Schwerkoske J.F., Kaluza V., Twohy E., Dancey J., Wright J., and Sarkaria J.N.

Subjects
Sirolimus, Adult, Male, Antineoplastic Combined Chemotherapy Protocol, Maximum Tolerated Dose, Brain Neoplasms, Prognosi, glioblastoma, clinical trial, temsirolimu, Middle Aged, Sorafenib, Prognosis, targeted therapy, Article, Follow-Up Studie, Brain Neoplasm, Survival Rate, Antineoplastic Combined Chemotherapy Protocols, Humans, Female, Sirolimu, Neoplasm Recurrence, Local, Follow-Up Studies, Human
Abstract

BACKGROUND: Mitogen-activated protein kinase (MAPK) activation and mammalian target of rapamycin (mTOR)-dependent signaling are hallmarks of glioblastoma. In the current study, the authors conducted a phase 1/2 study of sorafenib (an inhibitor of Raf kinase and vascular endothelial growth factor receptor 2 [VEGFR-2]) and the mTOR inhibitor temsirolimus in patients with recurrent glioblastoma. METHODS: Patients with recurrent glioblastoma who developed disease progression after surgery or radiotherapy plus temozolomide and with ≤2 prior chemotherapy regimens were eligible. The phase 1 endpoint was the maximum tolerated dose (MTD), using a cohorts-of-3 design. The 2-stage phase 2 study included separate arms for VEGF inhibitor (VEGFi)–naive patients and patients who progressed after prior VEGFi. RESULTS: The MTD was sorafenib at a dose of 200 mg twice daily and temsirolimus at a dose of 20 mg weekly. In the first 41 evaluable patients who were treated at the phase 2 dose, there were 7 who were free of disease progression at 6 months (progression-free survival at 6 months [PFS6]) in the VEGFi-naive group (17.1%); this finding met the prestudy threshold of success. In the prior VEGFi group, only 4 of the first 41 evaluable patients treated at the phase 2 dose achieved PFS6 (9.8%), and this did not meet the prestudy threshold for success. The median PFS for the 2 groups was 2.6 months and 1.9 months, respectively. The median overall survival for the 2 groups was 6.3 months and 3.9 months, respectively. At least 1 adverse event of grade ≥3 was observed in 75.5% of the VEGFi-naive patients and in 73.9% of the prior VEGFi patients. CONCLUSIONS: The limited activity of sorafenib and temsirolimus at the dose and schedule used in the current study was observed with considerable toxicity of grade ≥3. Significant dose reductions that were required in this treatment combination compared with tolerated single-agent doses may have contributed to the lack of efficacy. Cancer 2018;124:1455-63. © 2018 American Cancer Society.

Published
2018

4. The cell-surface proteoglycan Dally regulates Wingless signalling in Drosophila.

Author

Tsuda M, Kamimura K, Nakato H, Archer M, Staatz W, Fox B, Humphrey M, Olson S, Futch T, Kaluza V, Siegfried E, Stam L, and Selleck SB

Subjects
Animals, Animals, Genetically Modified, Cloning, Molecular, Drosophila genetics, Epidermis embryology, Epidermis physiology, Female, Genes, Insect, Genetic Techniques, Genitalia embryology, Glycosylphosphatidylinositols chemistry, Glycosylphosphatidylinositols physiology, Heparan Sulfate Proteoglycans chemistry, Heparan Sulfate Proteoglycans physiology, Homeodomain Proteins physiology, Insect Proteins physiology, Larva chemistry, Male, Membrane Glycoproteins chemistry, Membrane Glycoproteins genetics, Mutation, Proteoglycans chemistry, Proteoglycans genetics, RNA metabolism, Transcription Factors physiology, Wnt1 Protein, Drosophila physiology, Drosophila Proteins, Membrane Glycoproteins physiology, Proteoglycans physiology, Proto-Oncogene Proteins physiology, Signal Transduction
Abstract

Wingless (Wg) is a member of the Wnt family of growth factors, secreted proteins that control proliferation and differentiation during development. Studies in Drosophila have shown that responses to Wg require cell-surface heparan sulphate, a glycosaminoglycan component of proteoglycans. These findings suggest that a cell-surface proteoglycan is a component of a Wg/Wnt receptor complex. We demonstrate here that the protein encoded by the division abnormally delayed (dally) gene is a cell-surface, heparan-sulphate-modified proteoglycan. dally partial loss-of-function mutations compromise Wg-directed events, and disruption of dally function with RNA interference produces phenotypes comparable to those found with RNA interference of wg or frizzled (fz)/Dfz2. Ectopic expression of Dally potentiates Wg signalling without altering levels of Wg and can rescue a wg partial loss-of-function mutant. We also show that dally, a regulator of Decapentaplegic (Dpp) signalling during post-embryonic development, has tissue-specific effects on Wg and Dpp signalling. Dally can therefore differentially influence signalling mediated by two growth factors, and may form a regulatory component of both Wg and Dpp receptor complexes.

Published
1999
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