Results of a study of the oral inhibitor PTC299 on tumor VEGF synthesis.

Luke, Jason J.; Callahan, Leigh Ann; Darby, C. H.; Winkelman, J.; Barth, Juergen; Elfring, Gary L.; Ogden, Angela; Schwartz, G. K.; Gounder, Mrinal M.

doi:10.1200/jco.2011.29.15_suppl.3069

Cited by 2 publications

(3 citation statements)

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“…Studies in cancer patients at doses used in these studies demonstrated that PTC299 reduces levels of VEGF in cancer patients . Because the healthy subjects in these studies were not under physiological stress and based on the mode of activity of PTC299, as expected, we did not observe a PTC299‐induced pharmacodynamic effect on circulating VEGF.…”

Section: Discussionmentioning

confidence: 67%

“…Studies in cancer patients at doses used in these studies demonstrated that PTC299 reduces levels of VEGF in cancer patients. [13][14][15][16] Because the healthy subjects in these studies were not under physiological stress and based on the mode of activity of PTC299, as expected, we did not observe a PTC299-induced pharmacodynamic effect on circulating VEGF. The phase 1 studies in healthy volunteers reported here provide an important understanding of the safety and pharmacokinetics of PTC299 and will allow us to model dosing and predict exposures more accurately if PTC299 goes forward in nononcological indications or for specific oncological indications.…”

Section: Discussionmentioning

confidence: 99%

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Phase 1 Study of Safety, Tolerability, and Pharmacokinetics of PTC299, an Inhibitor of Stress‐Regulated Protein Translation

Weetall

Davis

Elfring

et al. 2016

Clinical Pharm in Drug Dev

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PTC299 is a novel small molecule that specifically blocks the production of protein from selected mRNAs that under certain conditions use noncanonical ribosomal translational pathways. Hypoxia, oncogenic transformation, and viral infections limit normal translation and turn on these noncanonical translation pathways that are sensitive to PTC299. Vascular endothelial cell growth factor (VEGF) is an example of a transcript that is posttranscriptionally regulated. Single doses of PTC299 (0.03 to 3 mg/kg) were administered orally to healthy volunteers in a phase 1 single ascending‐dose study. In a subsequent multiple ascending‐dose study in healthy volunteers, multiple‐dose regimens (0.3 to 1.2 mg/kg twice a day or 1.6 mg/kg 3 times a day for 7 days) were evaluated. PTC299 was well tolerated in these studies. As expected in healthy volunteers, mean plasma VEGF levels did not change. Increases in Cmax and AUC of PTC299 were dose‐proportional. The target trough plasma concentration associated with preclinical efficacy was achieved within 7 days at doses of 0.6 mg/kg twice daily and above. These data demonstrate that PTC299 is orally bioavailable and well tolerated and support clinical evaluation of PTC299 in cancer, certain viral infections, or other diseases in which deregulation of translational control is a causal factor.

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Section: Discussionmentioning

confidence: 67%

Section: Discussionmentioning

confidence: 99%

Phase 1 Study of Safety, Tolerability, and Pharmacokinetics of PTC299, an Inhibitor of Stress‐Regulated Protein Translation

Weetall

Davis

Elfring

et al. 2016

Clinical Pharm in Drug Dev

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“…A number of such non-TKI, nonYantibody-based targeted anticancer therapeutics are in early stages of development. Examples include enzastaurin, an inhibitor of protein kinase C-A (a downstream effector of VEGFR) 85 ; PTC299, a translational inhibitor of VEGF synthesis 86,87 ; and ALN-VSP, which uses lipid nanoparticle technology to target VEGF-A and kinesin spindle protein via RNA interference. 88 Although combining these with VEGF-directed therapies already in use seems intuitive, it may not prove feasible because of added toxicity.…”

Section: Other Strategies Targeting Vegfmentioning

confidence: 99%

Novel Approaches Targeting the Vascular Endothelial Growth Factor Axis in Renal Cell Carcinoma

Voss¹,

Hsieh²,

Motzer³

2013

The Cancer Journal

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In recent years, functional characterization of the von Hippel-Lindau tumor suppressor, hypoxia-induced factors, and one of their key downstream effectors, the vascular endothelial growth factor (VEGF), has revolutionized treatment of advanced renal cell carcinoma. Therapeutic strategies targeting the ligand itself (VEGF-A) or its receptor (VEGFR2) have proven successful. However, complete remissions are rare, and with time patients invariably suffer disease progression. It is understood that this is due to incomplete suppression of VEGF signaling and/or adaptive up-regulation of non-VEGF-dependent tumor-promoting stimuli. In this article, we review novel VEGF-directed agents that are being developed to address the shortcomings of current targeted drugs for the treatment of advanced renal cell carcinoma. Building on our current understanding of molecular mechanisms behind resistance, examples include next-generation multitarget tyrosine kinase inhibitors, biologics, and other compounds.

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Results of a study of the oral inhibitor PTC299 on tumor VEGF synthesis.

Cited by 2 publications

References 0 publications

Phase 1 Study of Safety, Tolerability, and Pharmacokinetics of PTC299, an Inhibitor of Stress‐Regulated Protein Translation

Phase 1 Study of Safety, Tolerability, and Pharmacokinetics of PTC299, an Inhibitor of Stress‐Regulated Protein Translation

Novel Approaches Targeting the Vascular Endothelial Growth Factor Axis in Renal Cell Carcinoma

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