Phase I Trial and Pharmacokinetic Study of the Farnesyltransferase Inhibitor Tipifarnib in Children With Refractory Solid Tumors or Neurofibromatosis Type I and Plexiform Neurofibromas

Widemann, Brigitte C.; Salzer, Wanda L.; Arceci, Robert J.; Blaney, Susan M.; Fox, Elizabeth; End, David W.; Gillespie, Andrea; Whitcomb, Patricia; Palumbo, Joseph S.; Pitney, Aaron; Jayaprakash, Nalini; Zannikos, Peter; Balis, Frank M.

doi:10.1200/jco.2005.03.8638

Cited by 133 publications

(90 citation statements)

References 23 publications

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“…Currently two such orally administered FTIs are in phase III clinical trials for cancer, motivated originally by the observation that the oncoprotein Ras is farnesylated. Although their efficacy in human clinical cancer trials has been somewhat disappointing, both FTIs have proven to be remarkably well tolerated (24).…”

Section: Discussionmentioning

confidence: 99%

A farnesyltransferase inhibitor prevents both the onset and late progression of cardiovascular disease in a progeria mouse model

Capell

Olive

Erdos

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

185

151

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The authors note that the description of the dosing of farnesyltransferase inhibitor (FTI) tipifarnib was incorrect. The article states that the drug was delivered in mg/kg of mouse total body weight. However, the actual study design was based on the concentration of the FTI drug in the diet (mg of FTI mixed in 1 kg of transgenic mouse dough). This dosing protocol was based on prior pharmacokinetic data, and the biomarker data included in the paper shows the desired drug effects were achieved. This error does not affect the conclusions of the article.www.pnas.org/cgi

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Section: Discussionmentioning

confidence: 99%

A farnesyltransferase inhibitor prevents both the onset and late progression of cardiovascular disease in a progeria mouse model

Capell

Olive

Erdos

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

185

151

View full text Add to dashboard Cite

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“…Furthermore, RAStargeted therapeutic approaches, such as S-trans, trans-farnesylthiosalicylic acid, have provided limited efficacy in clinical studies of NF1 (8,40). This implies that understanding the full complexity of neurofibromin function in MPNSTs requires insights into all Nf1-associated biologic processes not only those dependent on RAS-MEK-ERK signaling but also those independent of that pathway.…”

Section: Discussionmentioning

confidence: 99%

RAS/MEK–Independent Gene Expression Reveals BMP2-Related Malignant Phenotypes in the Nf1-Deficient MPNST

Sun

Haddad

Kraniak

et al. 2013

Molecular Cancer Research

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Malignant peripheral nerve sheath tumor (MPNST) is a type of soft tissue sarcoma that occurs in carriers of germline mutations in Nf1 gene as well as sporadically. Neurofibromin, encoded by the Nf1 gene, functions as a GTPase-activating protein (GAP) whose mutation leads to activation of wt-RAS and mitogen-activated protein kinase (MAPK) signaling in neurofibromatosis type I (NF1) patients' tumors. However, therapeutic targeting of RAS and MAPK have had limited success in this disease. In this study, we modulated NRAS, mitogen-activated protein/extracellular signal-regulated kinase (MEK)1/2, and neurofibromin levels in MPNST cells and determined gene expression changes to evaluate the regulation of signaling pathways in MPNST cells. Gene expression changes due to neurofibromin modulation but independent of NRAS and MEK1/2 regulation in MPNST cells indicated bone morphogenetic protein 2 (Bmp2) signaling as a key pathway. The BMP2-SMAD1/5/8 pathway was activated in NF1-associated MPNST cells and inhibition of BMP2 signaling by LDN-193189 or short hairpin RNA (shRNA) to BMP2 decreased the motility and invasion of NF1-associated MPNST cells. The pathway-specific gene changes provide a greater understanding of the complex role of neurofibromin in MPNST pathology and novel targets for drug discovery. Mol Cancer Res; 11(6); 616-27. Ó2013 AACR.

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“…This heterogeneity will need to be considered when selecting effective drugs for NF1-associated cancer treatment. This is well illustrated by the poor clinical response of NF1-associated peripheral nerve sheath tumors to farnesyltransferase inhibitors that inhibit Ras (Widemann et al, 2006), as these drugs preferentially inhibit H-Ras, rather than K-Ras (Prendergast and Rane, 2001).…”

Section: Susceptible Cell Typementioning

confidence: 99%

The ecology of brain tumors: lessons learned from neurofibromatosis-1

Pong

Gutmann

2010

Oncogene

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Traditionally, cancer studies have primarily focused on mutations that activate growth or survival pathways in susceptible pre-neoplastic/neoplastic cells. However, recent research has revealed a critical role for nonneoplastic cells within the tumor microenvironment in the process of cancer formation and progression. In addition, the existence of regional and developmental variations in susceptible cell types and supportive microenvironments support a model of tumorigenesis in which the dynamic symbiotic relationship between neoplastic and non-neoplastic cell types dictate where and when cancers form and grow. In this review, we highlight advances in neurofibromatosis type 1 (NF1) genetically engineered mouse brain tumor (glioma) modeling to reveal how cellular and molecular heterogeneity in both the pre-neoplastic/ neoplastic and non-neoplastic cellular compartments contribute to gliomagenesis and glioma growth.

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Phase I Trial and Pharmacokinetic Study of the Farnesyltransferase Inhibitor Tipifarnib in Children With Refractory Solid Tumors or Neurofibromatosis Type I and Plexiform Neurofibromas

Cited by 133 publications

References 23 publications

A farnesyltransferase inhibitor prevents both the onset and late progression of cardiovascular disease in a progeria mouse model

A farnesyltransferase inhibitor prevents both the onset and late progression of cardiovascular disease in a progeria mouse model

RAS/MEK–Independent Gene Expression Reveals BMP2-Related Malignant Phenotypes in the Nf1-Deficient MPNST

The ecology of brain tumors: lessons learned from neurofibromatosis-1

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