Phase I Study of the Farnesyltransferase Inhibitor Lonafarnib with Paclitaxel in Solid Tumors

Khuri, Fadlo R.; Glisson, Bonnie S.; Kim, Edward S.; Statkevich, Paul; Thall, Peter F.; Meyers, Michael L.; Herbst, Roy S.; Munden, Reginald F.; Tendler, Craig; Zhu, Yali; Bangert, S; Thompson, Elizabeth; Lu, Charles; Wang, Xue Mei; Shin, Dong M.; Kies, Merrill S.; Papadimitrakopoulou, Vassiliki A.; Fossella, Frank V.; Kirschmeier, Paul T.; Bishop, W. Robert; Hong, Waun Ki

doi:10.1158/1078-0432.ccr-03-0412

Cited by 76 publications

(58 citation statements)

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“…Overall, FTIs have been shown to have mild toxicities, but also modest activity with the exception of acute myeloid leukemia (AML). 31,32 SCH-66336 (lonafarnib) was one of the first FTIs to undergo clinical testing, with early hints of activity in a number of different tumor types 33,34 as well as the demonstration of improved responses when combined with cytotoxic agents. 33 A subsequent confirmatory phase 3 trial failed to demonstrate a benefit for the combination among a group of unselected patients with lung cancer.…”

Section: Discussionmentioning

confidence: 99%

“…31,32 SCH-66336 (lonafarnib) was one of the first FTIs to undergo clinical testing, with early hints of activity in a number of different tumor types 33,34 as well as the demonstration of improved responses when combined with cytotoxic agents. 33 A subsequent confirmatory phase 3 trial failed to demonstrate a benefit for the combination among a group of unselected patients with lung cancer. 35 Lonafarnib was tested in conjuction with the tyrosine kinase inhibitor inatinib and was noted to enhance imatinib-induced apoptosis of imatinibsensitive and imatinib-resistant cell lines and primary human chronic myeloid leukemia (CML) cells, independent of the presence of an activated ras oncogene.…”

Section: Discussionmentioning

confidence: 99%

“…We did not test doses higher than 5 M because there were no clinical data suggesting that level could be clinically achieved. 33 The combination effect is associated with rapid and early caspase activation to a greater extent than is seen with either agent alone, and concomitant to the rapid induction of cell death, is a rapid reduction in p-AKT expression both in cell lines and primary human tumor cells. This reduction is noted as early as 15 hours after exposure and is seen to a much greater extent in combination therapy than with either agent given alone.…”

Section: Discussionmentioning

confidence: 99%

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The combination of the farnesyl transferase inhibitor lonafarnib and the proteasome inhibitor bortezomib induces synergistic apoptosis in human myeloma cells that is associated with down-regulation of p-AKT

David

Sun

Waller

et al. 2005

Blood

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The identification of signaling pathways critical to myeloma growth and progression has yielded an array of novel agents with clinical activity. Multiple myeloma (MM) growth is IL-6 dependent, and IL-6 is secreted in an autocrine/paracrine fashion with signaling via the Ras/Raf/mitogen-activated protein kinase (MAPK) pathway. We hypothesized that combining a Ras pathway inhibitor (lonafarnib, SCH66336) with a proteasome inhibitor

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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The combination of the farnesyl transferase inhibitor lonafarnib and the proteasome inhibitor bortezomib induces synergistic apoptosis in human myeloma cells that is associated with down-regulation of p-AKT

David

Sun

Waller

et al. 2005

Blood

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“…Combining FTIs with other chemotherapeutic agents has produced some promising results. In combination with paclitaxel, lonafarnib showed clinical activity in people with non-small cell lung cancer 98 . Although FTIs have clinical activities, the effects seem to be largely independent of the inhibition of Ras protein; no correlations with Ras mutation status or with Ras inhibition have been observed.…”

Section: Ftis Have Ras-independent Clinical Activitiesmentioning

confidence: 99%

Therapeutic intervention based on protein prenylation and associated modifications

et al. 2006

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In eukaryotic cells, a specific set of proteins are modified by C-terminal attachment of 15-carbon farnesyl groups or 20-carbon geranylgeranyl groups that function both as anchors for fixing proteins to membranes and as molecular handles for facilitating binding of these lipidated proteins to other proteins. Additional modification of these prenylated proteins includes C-terminal proteolysis and methylation, and attachment of a 16-carbon palmitoyl group; these modifications augment membrane anchoring and alter the dynamics of movement of proteins between different cellular membrane compartments. The enzymes in the protein prenylation pathway have been isolated and characterized. Blocking protein prenylation is proving to be therapeutically useful for the treatment of certain cancers, infection by protozoan parasites and the rare genetic disease Hutchinson-Gilford progeria syndrome.Isoprenoids are lipids made of five-carbon blocks, and they constitute one of the main classes of natural products. A subset of isoprenoids called prenyl groups are found on a variety of biological substances, including proteins. Prenylated proteins and peptides are found in most (if not all) eukaryotes. They arise from the post-translational attachment of 15-carbon farnesyl or 20-carbon geranylgeranyl groups to the C-terminal segment of proteins. Protein prenyl groups not only are hydrophobic elements that bind proteins to membranes, but, at least in some cases, they also function as molecular handles that bind to hydrophobic grooves on the surface of soluble protein factors; these factors then remove the prenylated protein from the membrane in a regulated manner. NIH Public Access Author ManuscriptNat Chem Biol. Author manuscript; available in PMC 2010 June 28. Published in final edited form as:Nat Chem Biol. 2006 October ; 2(10): 518-528. doi:10.1038/nchembio818. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author ManuscriptProtein prenylation has been vigorously studied over the past ~15 years because it is found on several signaling proteins (including heterotrimeric G proteins) that connect cell surface receptors to intracellular effectors, and also on Ras proteins, one of the most common oncoproteins found in human tumors. Ras proteins serve as molecular switches at cellular membranes to control propagation of growth signals from cell surface receptors to nuclear transcription factors. Because Ras mutations are important in many human cancers, there has been extensive focus on Ras prenylation. Discovery of protein prenyl groups and structural varietiesThe first reports of prenylated proteins and peptides described the secreted pheromone peptides from jelly fungi 1,2 , whose structure resembles that of the well-known a-factor mating pheromone from baker's yeast (Saccharomyces cerevisiae), which contains a cysteine methylester farnesylated at the C terminus 3 . In the 1980s, studies on the timing of cholesterol biosynthesis with respect to the cell cycle in human cells led to the discovery that a compound deriv...

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“…When LNF is combined with other chemotherapeutic agents, enhanced antitumor activity is observed (4,6). In a phase I trial enrolling individuals with lung or aerodigestive tract cancer, a provocative clinical activity was observed when LNF was combined with paclitaxel (13). In a recent phase II trial, LNF plus paclitaxel achieved significant clinical activity with a favorable safety profile in patients with taxane-refractory/resistant metastatic nonsmall cell lung cancer (14), and these results were later supported by pre-clinical data in cell lines (15).…”

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confidence: 99%

The Farnesyltransferase Inhibitor Lonafarnib Induces CCAAT/Enhancer-binding Protein Homologous Protein-dependent Expression of Death Receptor 5, Leading to Induction of Apoptosis in Human Cancer Cells

Sun

Liu

Zou

et al. 2007

Journal of Biological Chemistry

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Pre-clinical studies have demonstrated that farnesyltransferase inhibitors (FTIs) induce growth arrest or apoptosis in various human cancer cells independently of Ras mutations. However, the underlying mechanism remains unknown. Death receptor 5 (DR5) is a pro-apoptotic protein involved in mediating the extrinsic apoptotic pathway. Its role in FTI-induced apoptosis has not been reported. In this study, we investigated the modulation of DR5 by the FTI lonafarnib and the involvement of DR5 up-regulation in FTI-induced apoptosis. Lonafarnib activated caspase-8 and its downstream caspases, whereas the caspase-8-specific inhibitor benzyloxycarbonyl-Ile-Glu(methoxy)-Thr-Asp(methoxy)-fluoromethyl ketone or small interfering RNA abrogated lonafarnib-induced apoptosis, indicating that lonafarnib induces caspase-8-dependent apoptosis. Lonafarnib up-regulated DR5 expression, increased cell-surface DR5 distribution, and enhanced tumor necrosis factor-related apoptosis-inducing ligand-induced apoptosis. Overexpression of a dominant-negative Fas-associated death domain mutant or silencing of DR5 expression using small interfering RNA attenuated lonafarnib-induced apoptosis. These results indicate a critical role of the DR5-mediated extrinsic apoptotic pathway in lonafarnib-induced apoptosis. By analyzing the DR5 promoter, we found that lonafarnib induced a CCAAT/enhancer-binding protein homologous protein (CHOP)-dependent transactivation of the DR5 promoter. Lonafarnib increased CHOP expression, whereas silencing of CHOP expression abrogated lonafarnib-induced DR5 expression. These results thus indicate that lonafarnib induces CHOP-dependent DR5 up-regulation. We conclude that CHOP-dependent DR5 up-regulation contributes to lonafarnib-induced apoptosis.Farnesyltransferase inhibitors (FTIs) 3 are a class of agents that suppress the farnesyltransferase enzyme to prevent farnesylation of certain proteins such as the Ras oncoprotein (1, 2). These agents inhibit proliferation and induce apoptosis in various cancer cell lines in culture or suppress the growth of xenografts in nude mice with limited toxicity (1, 2). In the clinic, FTIs are well tolerated and have some positive outcomes in certain settings such as hematological malignancies and breast cancer, although the response rates to FTIs alone are generally poor. When combined with other therapeutic agents or radiotherapy, FTIs exhibit some encouraging clinical responses (1, 2).Lonafarnib (LNF; also called SCH66336 and Sarasar), a nonpeptide tricyclic FTI, was one of the first FTIs to undergo clinical testing and to exhibit significant activity (3). In vitro, this agent, either alone or in combination with other therapeutic agents, inhibits the growth or induces apoptosis of several types of human cancer cells (4 -12). In animal models, LNF demonstrates potent oral activity in a wide array of human tumor xenograft models including tumors of colon, lung, pancreas, prostate, and urinary bladder origin (12). When LNF is combined with other chemotherapeutic agents, enhanced anti...

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Phase I Study of the Farnesyltransferase Inhibitor Lonafarnib with Paclitaxel in Solid Tumors

Abstract: ABSTRACT

Cited by 76 publications

References 34 publications

The combination of the farnesyl transferase inhibitor lonafarnib and the proteasome inhibitor bortezomib induces synergistic apoptosis in human myeloma cells that is associated with down-regulation of p-AKT

The combination of the farnesyl transferase inhibitor lonafarnib and the proteasome inhibitor bortezomib induces synergistic apoptosis in human myeloma cells that is associated with down-regulation of p-AKT

Therapeutic intervention based on protein prenylation and associated modifications

The Farnesyltransferase Inhibitor Lonafarnib Induces CCAAT/Enhancer-binding Protein Homologous Protein-dependent Expression of Death Receptor 5, Leading to Induction of Apoptosis in Human Cancer Cells

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