Article

Phase II trial of tipifarnib plus neoadjuvant doxorubicin-cyclophosphamide in patients with clinical stage IIB-IIIC breast cancer

New York Cancer Consortium, including the Montefiore-Einstein Cancer Center, Montefiore Medical Center, Bronx, New York 10461, USA.
Clinical Cancer Research (Impact Factor: 8.19). 05/2009; 15(8):2942-8. DOI: 10.1158/1078-0432.CCR-08-2658
Source: PubMed

ABSTRACT Tipifarnib is a farnesyl transferase (FTase) inhibitor that has activity in metastatic breast cancer and enhances the efficacy of cytotoxic agents in preclinical models. We evaluated the biological effects of tipifarnib in primary breast cancers in vivo, whether adding tipifarnib to preoperative chemotherapy increased the pathologic complete response rate (pCR) at surgery, and determined whether biomarkers predictive of pCR could be identified.
Forty-four patients with stage IIB-IIIC breast cancer received up to four cycles of neoadjuvant doxorubicin-cyclophosphamide (AC) every 2 weeks plus tipifarnib and filgrastim followed by surgery. Enzymatic assays measuring FTase activity and Western blotting for phospho (p)-signal transducer and activator of transcription 3 (STAT3), phospho-extracellular signal-regulated kinase, p-AKT, and p27 were done in 11 patients who agreed to optional tissue biopsies before therapy and 2 hours after the final dose of tipifarnib during the first cycle, and predictive biomarkers were evaluated by immunohistochemistry in 33 patients. The trial was powered to detect an improvement in breast pCR rate of 10% or less expected for AC alone to 25% for AC-tipifarnib (alpha = 0.05, beta = 0.10).
Eleven patients had a breast pCR (25%; 95% confidence interval, 13-40%). FTase enzyme activity decreased in all patients (median, 91%; range, 24-100%) and p-STAT3 expression decreased in 7 of 9 (77%) patients. Low tumor Ki-67 expression (below the median of 60%) at baseline was significantly associated with resistance to therapy (P = 0.01).
Tipifarnib inhibits FTase activity in human breast tumors in vivo, is associated with down-regulation of p-STAT3, and enhances the breast pCR rate, thus meriting further evaluation.

Download full-text

Full-text

Available from: Una Hopkins, Aug 17, 2014
0 Followers
 · 
128 Views
  • Source
    • "The known farnesylated proteins include members of the Ras superfamily of GTPases (e.g., H-Ras, K-Ras, N-Ras) (Kho et al., 2004), the precursor proteins of the nuclear lamin A (Young et al., 2005; Chang et al., 2012), and members of the DnaJ chaperone proteins (Kampinga and Craig, 2010; Stark et al., 2014). Geranylgeranylated GTPases include the Rho family of proteins, treatments of pancreatic (90% K-Ras mutations), lung, and colon carcinomas (∼30% K-Ras mutations) (Lerner et al., 1997; Sparano et al., 2009). "
    [Show abstract] [Hide abstract]
    ABSTRACT: In the human body, the complex biochemical network known as the mevalonate pathway is responsible for the biosynthesis of all isoprenoids, which consists of a vast array of metabolites that are vital for proper cellular functions. Two key isoprenoids, farnesyl pyrophosphate (FPP) and geranylgeranyl pyrophosphate (GGPP) are responsible for the post-translational prenylation of small GTP-binding proteins, and serve as the biosynthetic precursors to numerous other biomolecules. The down-stream metabolite of FPP and GGPP is squalene, the precursor to steroids, bile acids, lipoproteins, and vitamin D. In the past, interest in prenyl synthase inhibitors focused mainly on the role of the FPP in lytic bone diseases. More recently pre-clinical and clinical studies have strongly implicated high levels of protein prenylation in a plethora of human diseases, including non-skeletal cancers, the progression of neurodegenerative diseases and cardiovascular diseases. In this review, we focus mainly on the potential therapeutic value of down-regulating the biosynthesis of FPP, GGPP, and squalene. We summarize the most recent drug discovery efforts and the structural data available that support the current on-going studies.
    Frontiers in Chemistry 07/2014; 2:50. DOI:10.3389/fchem.2014.00050
  • Source
    • "The drugs chosen for this study are relatively non-toxic, work by different mechanisms and can readily be utilized for a clinical trial. Atorvastatin and celecoxib are in broad clinical use and tipifarnib is a farnesyl transferase inhibitor that has been extensively tested in clinical trials (9–12). To the best of our knowledge the simultaneous targeting of Ras and COX-2 pathways in pancreatic cancer growth is novel. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Because K-Ras mutation and cyclooxygenase-2 (COX-2) overexpression are hallmarks of majority of pancreatic cancer patients, an approach to inhibit the progression and growth of pancreatic cancer using the simultaneous administration of agents that inhibit the function of both targets, should be considered. In the present study, we assessed the effects of atorvastatin (Lipitor), celecoxib (Celebrex) and tipifarnib (Zarnestra) on the growth of human pancreatic cancer. In the in vitro studies, we found that treatment of human pancreatic tumor cells with a combination of atorvastatin, celecoxib and tipifarnib had a stronger inhibitory effect on growth and a stronger stimulatory effect on apoptosis than each drug alone or for any combination of two drugs. We also found that treatment of Panc-1 cells with a combination of all three drugs strongly decreased the levels of phosphorylated Erk1/2 and Akt. In an animal model of xenograft tumors in severe combined immunodeficient (SCID) mice, we found that daily i.p. injections of a combination of atorvastatin, celecoxib and tipifarnib had a stronger inhibitory effect on the growth of the tumors in mice than each drug alone or for any combination of two drugs. The results of our study indicate that a combination of atorvastatin, celecoxib and tipifarnib may be an effective strategy for the treatment of pancreatic cancer.
    International Journal of Oncology 03/2014; 44(6). DOI:10.3892/ijo.2014.2350 · 3.03 Impact Factor
  • Source
    • "The FTI Tipifarnib (Zarnestra, R115777) has been evaluated for the treatment of myeloid malignancy, including for elderly patients with acute myelogenous leukemia (AML) [6,12]. Moreover, Tipifarnib has shown promising results in coadjutant therapies for breast cancer [13]. The FTI Lonafarnib have shown efficacy in melanoma cells that develop resistance to Sorafenib, a pan-Raf inhibitor [14]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Farnesyltransferase inhibitors (FTIs) are anticancer agents with a spectrum of activity in Ras-dependent and independent tumor cellular and xenograph models. How inhibition of protein farnesylation by FTIs results in reduced cancer cell proliferation is poorly understood due to the multiplicity of potential FTase targets. The low toxicity and oral availability of FTIs led to their introduction into clinical trials for the treatment of breast cancer, hematopoietic malignancy, advanced solid tumor and pancreatic cancer treatment, and Hutchinson-Gilford Progeria Syndrome. Although their efficacy in combinatorial therapies with conventional anticancer treatment for myeloid malignancy and solid tumors is promising, the overall results of clinical tests are far below expectations. Further exploitation of FTIs in the clinic will strongly rely on understanding how these drugs affect global cellular activity. Using FTase inhibitor I and genome-wide chemical profiling of the yeast barcoded deletion strain collection, we identified genes whose inactivation increases the antiproliferative action of this FTI peptidomimetic. The main findings were validated in a panel of cancer cell lines using FTI-277 in proliferation and biochemical assays paralleled by multiparametric image-based analyses. ABC transporter Pdr10 or p-21 activated kinase (PAK) gene deletion increases the antiproliferative action of FTase inhibitor I in yeast cells. Consistent with this, enhanced inhibition of cell proliferation by combining group I PAK inhibition, using IPA3, with FTI-277 was observed in melanoma (A375MM), lung (A549) and colon (HT29), but not in epithelial (HeLa) or breast (MCF7), cancer cell lines. Both HeLa and A375MM cells show changes in the nuclear localization of group 1 PAKs in response to FTI-277, but up-regulation of PAK protein levels is observed only in HeLa cells. Our data support the view that group I PAKs are part of a pro-survival pathway activated by FTI treatment, and group I PAK inactivation potentiates the anti-proliferative action of FTIs in yeast as well as in cancer cells. These findings open new perspectives for the use of FTIs in combinatorial strategies with PAK inhibitors in melanoma, lung and colon malignancy.
    Molecular Cancer 08/2013; 12(1):88. DOI:10.1186/1476-4598-12-88 · 5.40 Impact Factor
Show more