Phase II Study of the Efficacy and Tolerability of Two Dosing Regimens of the Farnesyl Transferase Inhibitor, R115777, in Advanced Breast Cancer

Johnston, Stephen; Hickish, Tamas; Ellis, Paul; Houston, Stephen; Kèlland, Lloyd R.; Dowsett, Mitch; Salter, Janine; Michiels, Bart; Pérez‐Ruixo, Juan José; Palmer, Peter; Howes, Angela

doi:10.1200/jco.2003.10.064

Cited by 188 publications

(125 citation statements)

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“…Tumor regression in this mouse model was associated with a reduction in MAP kinase activity and an increase in apoptosis (Norgaard et al 1999). However, Johnston et al (2003) did not find a correlation between response to the FTI, R 155777, and expression of HER-2/ neu, in patients with metastatic breast cancer.…”

Section: Effects Of Ftis Independent Of Rasmentioning

confidence: 87%

“…However, as described later, despite the initial belief that FTIs act solely through the Ras pathway, it is now apparent that they have other effects on several cellular signal transduction processes, which may be independent of Ras (Johnston & Kelland 2001). This hypothesis may explain why FTIs have activity in breast cancer models preclinically (Kelland et al 2001), and may be active clinically (Johnston et al 2003), despite the fact that breast cancers rarely have mutations of ras (Clark & Der 1995a). …”

Section: Targeted Therapies In Breast Cancermentioning

confidence: 99%

“…Secondly, FTIs have been demonstrated to inhibit growth of tumors expressing wild-type ras in vivo (Liu et al 1998, Feldkamp et al 2001. Lastly, responses have been demonstrated with the FTI, R115777, in breast cancers, which have a very low rate of ras mutations (Johnston et al 2003). The most likely explanation for these Ras-independent effects is that FTIs have effects on several other prenylated proteins involved in crucial cellular signal transduction pathways.…”

Section: Effects Of Ftis Independent Of Rasmentioning

confidence: 99%

“…However, breast cancers have been shown to have aberrant signaling though the Ras signal transduction pathway (Clark & Der 1995b), and preclinical evaluation of FTIs in breast cancer models have produced promising results (Kelland et al 2001). Following phase I trials, the FTI, RII5777, has been evaluated in patients with advanced breast cancer, with encouraging results (Johnston et al 2003).…”

Section: Introductionmentioning

confidence: 99%

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Farnesyl transferase inhibitors: the next targeted therapies for breast cancer?

O’Regan¹,

Khuri²

2004

Endocr Relat Cancer

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The ras family of proto-oncogenes are upstream mediators of several essential cellular signal transduction pathways involved in cell proliferation and survival. Point mutations of ras oncogenes result in constitutively active Ras and have been shown to be oncogenic. However, ras activation can occur in the absence of ras mutations secondary to upstream receptor activation. The first important step in Ras activation is farnesylation by farnesyl transferase, and inhibitors of this enzyme have been demonstrated to inhibit Ras signaling, and have anti-tumor effects. However, it is now clear that farnesyl transferase inhibitors (FTIs) have activity independent of Ras, most likely due to effects on prenylated proteins downstream of Ras, which explains their activity in several malignancies, including breast cancer, where ras mutations are rare. Several FTIs are in clinical development for the treatment of solid tumors. Preclinical evidence suggests that FTIs can inhibit breast cancers in vitro and in vivo, and a phase II trial of the FTI, R115777, in patients with advanced breast cancer produced encouraging results. Based on prior successful outcomes with agents targeting the estrogen and epidermal growth factor receptor pathways in breast cancer, the FTIs, used alone or more likely with other agents, may be the next exciting targeted therapy in breast cancer.

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Section: Effects Of Ftis Independent Of Rasmentioning

confidence: 87%

Section: Targeted Therapies In Breast Cancermentioning

confidence: 99%

Section: Effects Of Ftis Independent Of Rasmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Farnesyl transferase inhibitors: the next targeted therapies for breast cancer?

O’Regan¹,

Khuri²

2004

Endocr Relat Cancer

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“…Lonafarnib is synergistic with cisplatin and additive with gemcitabine in vitro, and active against breast carcinoma xenografts [31,32,42]. FTIs alone are clinically very active in breast cancer [21]: a phase II study of tipifarnib dosed continuously in 76 advanced breast cancer patients demonstrated 4 PR and 6 SD lasting >24 weeks, and when dosed for 21 out of 28 days, 5 PRs and 3 prolonged SD were noted in 35 patients [21,24]. Therefore, further exploration of lonafarnib and other FTIs with chemotherapy in breast cancer may be warranted.…”

Section: Discussionmentioning

confidence: 99%

A phase I safety, pharmacological, and biological study of the farnesyl protein transferase inhibitor, lonafarnib (SCH 663366), in combination with cisplatin and gemcitabine in patients with advanced solid tumors

Chow

Eckhardt

O’Bryant

et al. 2007

Cancer Chemother Pharmacol

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Purpose-This phase I study was conducted to evaluate the safety, tolerability, pharmacological properties and biological activity of the combination of the lonafarnib, a farnesylproteintransferase (FTPase) inhibitor, with gemcitabine and cisplatin in patients with advanced solid malignancies.Experimental design-This was a single institution study to determine the maximal tolerated dose (MTD) of escalating lonafarnib (75-125 mg po BID) with gemcitabine (750-1,000 mg/m 2 on days 1, 8, 15) and fixed cisplatin (75 mg/m 2 day 1) every 28 days. Due to dose-limiting toxicities (DLTs) of neutropenia and thrombocytopenia in initial patients, these patients were considered "heavily pretreated" and the protocol was amended to limit prior therapy and re-escalate lonafarnib © Springer-Verlag 2007 Correspondence to: Lia Gore, lia.gore@uchsc.edu. NIH Public Access Author ManuscriptCancer Chemother Pharmacol. Author manuscript; available in PMC 2010 January 29. in "less heavily pre-treated patients" on 28-day and 21-day schedules. Cycle 1 and 2 pharmacokinetics (PK), and farnesylation of the HDJ2 chaperone protein and FPTase activity were analyzed.Results-Twenty-two patients received 53 courses of therapy. Nausea, vomiting, and fatigue were frequent in all patients. Severe toxicities were observed in 91% of patients: neutropenia (41%), nausea (36%), thrombocytopenia (32%), anemia (23%) and vomiting (23%). Nine patients withdrew from the study due to toxicity. DLTs of neutropenia, febrile neutropenia, thrombocytopenia, and fatigue limited dose-escalation on the 28-day schedule. The MTD was established as lonafarnib 75 mg BID, gemcitabine 750 mg/m 2 days 1, 8, 15, and cisplatin 75 mg/m 2 in heavily pre-treated patients. The MTD in the less heavily pre-treated patients could not be established on the 28-day schedule as DLTs were observed at the lowest dose level, and dose escalation was not completed on the 21-day schedule due to early study termination by the Sponsor. No PK interactions were observed. FTPase inhibition was not observed at the MTD, however HDJ-2 gel shift was observed in one patient at the 100 mg BID lonafarnib dose. Anti-cancer activity was observed: four patients had stable disease lasting >2 cycles, one subject had a complete response, and another had a partial response, both with metastatic breast cancer. Conclusion-Lonafarnib

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Antitumor effects of low‐dose tipifarnib on the mTOR signaling pathway and reactive oxygen species production in HIF‐1α‐expressing gastric cancer cells

et al. 2021

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Farnesyltransferase inhibitors (FTIs) suppress tumor aggressiveness in several malignancies by inhibiting Ras signaling. However, treatment of cells with a low dose of the FTI tipifarnib suppresses the expression of hypoxia‐inducible factor‐1α (HIF‐1α) and results in antitumor effects without inhibiting the Ras pathway. Although we previously reported that elevated HIF‐1α expression is associated with an aggressive phenotype in gastric cancer (GC), little is known about the antitumor effects of FTIs on GC. In this study, we examined the relationship between the antitumor effects of low‐dose tipifarnib and HIF‐1α expression in GC cells. Under normoxic conditions, HIF‐1α was expressed only in MKN45 and KATOIII cells. The inhibitory effect of tipifarnib on HIF‐1α was observed in HIF‐1α‐positive cells. Low‐dose tipifarnib had antitumor effects only on HIF‐1α‐positive cells both in vitro and in vivo . Furthermore, low‐dose tipifarnib inactivated ras homolog enriched in brain (Rheb)/mammalian target of rapamycin (mTOR) signaling and decreased intracellular reactive oxygen species (ROS) levels in HIF‐1α‐positive GC cells. Our results that the antitumor effects of low‐dose tipifarnib are at least partially mediated through suppression of mTOR signaling and HIF‐1α expression via inhibition of Rheb farnesylation and reduction in ROS levels. These findings suggest that low‐dose tipifarnib may be capable of exerting an antitumor effect that is dependent on HIF‐1α expression in GC cells. Tipifarnib may have potential as a novel therapeutic agent for HIF‐1α‐expressing GC exhibiting an aggressive phenotype.

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Phase II Study of the Efficacy and Tolerability of Two Dosing Regimens of the Farnesyl Transferase Inhibitor, R115777, in Advanced Breast Cancer

Abstract: The farnesyl transferase inhibitor R115777 has demonstrated clinical activity in patients with metastatic breast cancer, and the ID regimen has a significantly improved therapeutic index compared with the CD regimen.

Cited by 188 publications

References 19 publications

Farnesyl transferase inhibitors: the next targeted therapies for breast cancer?

Farnesyl transferase inhibitors: the next targeted therapies for breast cancer?

A phase I safety, pharmacological, and biological study of the farnesyl protein transferase inhibitor, lonafarnib (SCH 663366), in combination with cisplatin and gemcitabine in patients with advanced solid tumors

Antitumor effects of low‐dose tipifarnib on the mTOR signaling pathway and reactive oxygen species production in HIF‐1α‐expressing gastric cancer cells

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