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The Oncologist, Vol. 10, No. 8, 565-578, September 2005; doi:10.1634/theoncologist.10-8-565
© 2005 AlphaMed Press

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Development of Farnesyl Transferase Inhibitors: A Review

Natalie M.G.M. Appelsa, Jos H. Beijnena,b,c, Jan H.M. Schellensb,c

a Department of Pharmacy & Pharmacology, Slotervaart Hospital/The Netherlands Cancer Institute, Amsterdam, The Netherlands; b Antoni van Leeuwenhoek Hospital/The Netherlands Cancer Institute, Amsterdam, The Netherlands; c Division of Drug Toxicology, Department of Biomedical Analysis, Faculty of Pharmaceutical Sciences, Utrecht University, Utrecht, The Netherlands

Correspondence: Jan H.M. Schellens, M.D., Ph.D., Department of Medical Oncology, Antoni van Leeuwenhoek Hospital/The Nether-lands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands. Telephone: 31-0-20-512-2569; Fax: 31-0-20-512-2572; e-mail: j.schellens{at}nki.nl


   LEARNING OBJECTIVES
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 Learning objectives
Abstract
 Introduction
 Conclusions and future...
 Disclosure of potential...
 References
 
After completing this course, the reader will be able to:

  1. Describe the potential mechanisms by which farnesyl transferases inhibit tumor growth.
  2. Explain possible mechanisms by which tumor cells may develop resistance to this class of agents.
  3. Discuss the scientific requirements for developing targeted cancer treatments that will actually be useful in patients.

Access and take the CME test online and receive 1 hour of AMA PRA category 1 credit at CME.TheOncologist.com


   ABSTRACT
Top
 Learning objectives
 Abstract
Introduction
 Conclusions and future...
 Disclosure of potential...
 References
 
Farnesyl transferase inhibitors are a new class of biologically active anticancer drugs. The exact mechanism of action of this class of agents is, however, currently unknown. The drugs inhibit farnesylation of a wide range of target proteins, including Ras. It is thought that these agents block Ras activation through inhibition of the enzyme farnesyl transferase, ultimately resulting in cell growth arrest. In preclinical models, the farnesyl transferase inhibitors showed great potency against tumor cells; yet in clinical studies, their activity was far less than anticipated. Reasons for this disappointing clinical outcome might be found in the drug-development process. In this paper, we outline an algorithm that is potentially useful for the development of biologically active anticancer drugs. The development of farnesyl transferase inhibitors, from discovery to clinical trials, is reviewed on the basis of this algorithm. We found that two important steps of this algorithm were underestimated. First, understanding of the molecular biology of the defective pathway has mainly been focused on H-Ras activation, whereas activation of K-Ras or other farnesylated proteins is probably more important in tumorigenesis. Inhibition of farnesylation is possibly not sufficient, because geranylgeranylation might activate K-Ras and suppress the effect of farnesyl transferase inhibitors. Furthermore, a well-defined proof of concept in preclinical and clinical studies has not been achieved. Integrating the proposed algorithm in future studies of newly developed biologically active anti-cancer drugs might increase the rate of success of these compounds in patients.

Key Words. Farnesyl transferase inhibitors • Drug development • Oncogenes • Targeted therapy • Signal transduction


   INTRODUCTION
Top
 Learning objectives
 Abstract
 Introduction
Conclusions and future...
 Disclosure of potential...
 References
 
Mutations of the ras gene are early events in the development of cancer. The Ras proteins play a pivotal role in the transduction of cell growth–stimulating signals, and mutation of the ras gene leads to constant activation of the protein, ultimately resulting in uncontrolled cell proliferation. The high prevalence of mutated ras genes, found in 30% of all human cancers, makes this pathway an attractive target for anticancer drug development.

A promising way of interfering with Ras function seemed to be the inhibition of farnesyl transferase, the enzyme coupling a 15-carbon isoprenyl group to Ras proteins, by farnesyl transferase inhibitors (FTIs). By inhibition of Ras farnesylation, a blockade of the signal transduction pathway is accomplished with cessation of cell growth [1–3]. Thus, it was predicted that FTIs would be effective therapeutic agents in the treatment of cancer.

More than a decade later, at least six FTIs are being, or have been, tested in clinical trials, including BMS-214662 (Bristol-Myers Squibb, Princeton, NJ, http://www.bms.com), L778123 (Merck & Co., Inc., Whitehouse Station, NJ, http://www.merck.com), tipifarnib (experimental name, R115777; ZarnestraTM; Ortho Biotech Products, L.P., Bridgewater, NJ, http://www.orthobiotech.com), lonafarnib (experimental name, SCH66336; SarasarTM; Schering-Plough Corporation, Kenilworth, NJ, http://www.sch-plough.com), FTI-277 (Calbiochem, EMD Biosciences, San Diego, http://www.emdbiosciences.com), and L744832 (Biomol International L.P., Plymouth Meeting, PA, http://www.biomol.com) [4, 5]. The results of these trials, however, led to a number of questions. First, the promising results in preclinical models were not confirmed in the clinic. Unexpectedly, tumors containing non-mutated Ras were also sensitive to FTIs. Furthermore, it is questioned whether, in dose-finding studies of biochemical modulators like FTIs, the drug target or its biochemical effect would be a better pharmacodynamic end point than the classic study end point of clinical toxicity.

This review attempts to summarize the current knowledge on the mechanism of action and clinical activity of FTIs. Our aim was to find explanations for the observations in clinical trials of FTIs and to define uncertainties in current study design. To this end, we used an algorithm that is potentially useful for the development of biologically targeted drugs [6].

Successful Drug Development
One of the main objectives in the process of drug development is to increase its success rate. Biological insight into the mechanisms of defective molecular pathways in cancer cells has resulted in the identification of novel targets for drug development. The development process of these biologically targeted agents provides unique opportunities for successful drug development, which may not be driven by the assessment of the maximum-tolerated dose (MTD). In Table 1Go, an algorithm for the development of biologically targeted anticancer drugs is proposed, in which ten essential steps are identified [6, 7].


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  		Table 1. Algorithm for the development of biologically active drugs
 
The first step is the identification of a distinct aberration in a biological pathway. The key proteins in this biological pathway, often a receptor or an enzyme, are called the "drugable" targets. Elucidation of the protein structure helps to determine which chemical entities are likely to bind to the protein with high affinity. The next step is optimization of the lead compound using high-throughput screening (HTS) of combinatorial chemistry compound libraries. In principle, the compound with the highest affinity for the target protein should be tested in cell lines that are relevant for the disease. When promising activity is observed, the preclinical proof of concept studies are extended to relevant in vivo models.

Before testing the clinical activity of the drug, a clear absorption/distribution/metabolism/excretion (ADME) profile is warranted. Knowledge of in vivo metabolic and excretory pathways is useful to predict the ADME profile and pharmacokinetic parameters of the drug in humans. In the following steps, pharmacokinetic parameters are correlated with clinical efficacy or toxicity (pharmacokinetic–pharmacodynamic relation). The biochemical effect on the target protein is another important pharmacodynamic end point of biologically targeted drugs. Therefore, to find optimal biochemical doses, sensitive and selective biomarker assays are of great importance. Both the MTD as well as optimal biochemical dose studies should be undertaken to determine the recommended treatment dose. Finally, after completion of all preceding steps, clinical trials can be started to prove clinical activity.

In this review, we discuss these steps for the development of FTIs as new anticancer drugs targeting Ras activation.

Strong Molecular Epidemiology Specific for the Disease
The family of ras genes consists of three functional genes, H-ras, K-ras, and N-ras. These genes are highly homologous and encode for four 21-kDa proteins—H-Ras, the splice variants Ki4A-Ras and Ki4B-Ras, and N-Ras, respectively.

The first step in Table 1Go states that there must be a strong molecular epidemiology specific for the disease. It has been demonstrated that ras gene mutations frequently occur in various human tumor types [8]. K-ras mutations have the highest incidence, mainly in adenocarcinoma of the pancreas (90%), colon (50%), and lung (30%) [8]. The N-ras gene is predominantly mutated in myeloid leukemia (30%) [8]. Furthermore, it was found that the prevalence of K-ras mutations is a strong and independent marker of poor prognosis in non-small cell lung cancer (NSCLC) [9, 10]. K-ras mutation is also a prognostic factor in colon cancer, at least when analyzed simultaneously with p16 alterations [11]. For childhood acute lymphocytic leukemia, it has been suggested that N-ras mutation in codon 12 or 13 could serve as an independent factor for an increased risk of relapse [12].

In conclusion, it has been shown that there is a strong relationship between the occurrence of ras mutations and the development of specific types of cancer. Nonetheless, a ras gene alteration is alone not sufficient for malignant transformation. Tumorigenesis starts with accumulation of different molecular genetic changes. K-ras mutations have been found in the initiating stage of tumor development of among others. colorectal cancer and ovarian cancer [13, 14]. Thus, although the occurrence of a K-ras mutation might serve as a good predictive marker for prognosis, tumor development is not necessarily caused by this single genetic alteration alone. Moreover, later genetic events might affect tumor growth control. In that case, blocking of Ras activation by FTIs might have little effect on tumor growth. This could be an important pitfall in FTI development.

Elucidation of the Molecular Mechanism of the Deranged or Aberrant Pathway
Ras proteins are GTPases that play a central role in growth signal transduction pathways. Upon binding GTP, Ras transduces the signal to various effector proteins. Subsequently, it becomes inactivated through conversion of GTP to GDP by an intrinsic GTPase (Fig. 1Go). A point mutation in codon 12, 13, or 61 of the ras gene leads to insensitivity of Ras to the GTPase-activating protein (GAP) and a significantly lower GTPase activity. Thus, mutated proteins are then constitutively activated, resulting in deranged or aberrant signal transduction.



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  		Figure 1. Ras activation pathway. When GTP binds to Ras, it becomes activated. Subsequently, an intrinsic GTPase dephosphorylates GTP, resulting in inactivation of the Ras protein. Abbreviations: GAP, GTPase-activating protein; GDP, guanine-diphosphate; GEF, guanine nucleotide exchange factor; GTP, guanine-triphosphate; Pi, inorganic phosphate.

 
The pathways that are controlled by activated Ras are designed to prolong cell survival and promote cell proliferation (Fig. 2Go). The best elucidated pathway is the Raf–mitogen-activated protein/extracellular signal-related kinase kinase (Mek)–extracellular signal-related kinase (Erk) pathway [15]. Transcription factors in the nucleus are activated by Erk (or mitogen-activated protein kinase [MAPK]), leading to cellular proliferation and apoptosis. A second pathway in which Ras is involved is the phosphatidylinositol 3' kinase (PI3K)/Akt pathway, leading to increased cell survival [16]. A third effector protein of Ras is Tiam1 [17]. This protein regulates Rac, which in turn activates various proteins, including RhoB, nuclear factor kappa B (NF{kappa}B), and c-Jun N-terminal kinase (JNK). RhoB is involved in many cellular processes, including regulation of cytoskeleton actin dynamics, cell adhesion, cell transformation, cell survival and others. NF{kappa}B is a regulator of the transcription of genes for cell survival and immune responses [18]. JNK, also known as stress-activated protein kinase, plays a role in cell migration processes [19]. Ral guanine nucleotide dissociation stimulator (RalGDS) is involved in Golgi trafficking and regulation of transcription factors that control cell proliferation. Recently, it was shown in vivo that RalGDS is also required for Ras-induced tumor formation [20]. In addition to these four pathways, at least seven other signal transduction routes that are regulated by Ras are currently known and more might be discovered (Fig. 2Go).



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  		Figure 2. Ras-mediated signal transduction pathways. Currently, at least 11 downstream effectors of Ras are known. These effector proteins bind preferentially to the activated form of Ras, and all of them interact with a region in the so-called effector domains of Ras. Activation of the effectors leads to different cellular responses, such as transcription regulation, cell survival processes, and Golgi trafficking. The signaling pathways are tightly regulated in normal cells, but they become aberrant in tumor cells. Abbreviations: AF6, afadin; BAD, Bcl2 antagonist of cell death; Erk, extracellular signal-regulated kinase; GAP, GTPase-activating protein; IMP, impedes mitogenic signal propagation; JNK, c-Jun N-terminal kinase; Mek, mitogen-activated protein/extracellular signal-regulated kinase kinase; MEKK, Mitogen-activated protein kinase kinase kinase; NF{kappa}B, nuclear factor kappa B; Nore1, Ras effector-like protein; PI3K, phosphatidylinositol 3' kinase; PIP3, phosphatidylinositol 3,4,5-tris-phosphate; PKC, protein kinase C; PLC{varepsilon}, lysophosphatidic acid acyl-transferase-epsilon; RalGDS, Ral guanine nucleotide dissociation stimulator; Rin1, Ras and Rab interactor 1; SEK, stress/extracellular-regulated kinase.

 
Substantial knowledge about the molecular biology of Ras and its downstream pathways has been obtained during the past decades. However, some facts have been neglected during the development of FTIs. For instance, RhoB, an important downstream effector of Ras, is also farnesylated as well as geranylgeranylated. This implies that administration of an FTI will also affect the function of this protein. It has been shown that treatment of rat fibroblasts with L744832 indeed leads to higher geranylgeranylated RhoB levels [21]. The influence of FTIs on the function of RhoB has been discussed extensively in the literature. The Prendergast group has shown that an increase of geranylgeranylated RhoB (GG-RhoB) leads to induction of apoptosis and proposed that not Ras but RhoB is the real drug target of FTIs [22, 23]. However, Chen et al. showed that in human tumor cell lines farnesylated RhoB (F-RhoB) and GG-RhoB are equally potent at inhibiting cell growth, indicating that an effect on cell proliferation after administration of an FTI cannot be attributed to changing F-RhoB and/or GG-RhoB levels [24].

A second important observation that was made after the start of the development of FTIs has been described by Jiang et al. [25]. They found that administration of an FTI to human cancer cells induces apoptosis through inhibition of the PI3K/Akt2 cascade, but that neither Ras nor RhoB, but an as-yet-unknown short-lived farnesylated protein, mediates this inhibition [25].

Thus, although the Ras pathways have been investigated intensively, the complex biology and contribution of other main proteins to the cellular pharmacology of FTIs have probably not been sufficiently elucidated during the preclinical and clinical development of these anti-cancer drugs.

Identification and Crystal Structure Determination of a "Drugable" Target: FTase
To become functionally active, the Ras protein has to undergo several post-translational modifications (Fig. 3Go). The first step in this process is the farnesylation of the cysteine in the so-called CAAX box at the C-terminal end (C, cysteine; A, any aliphatic amino acid; X, typically serine or methionine). Subsequently, the AAX amino acids are cleaved off by Ras-converting enzyme I, and then the farnesylated cysteine is carboxymethylated by isoprenylcysteine carboxyl methyltransferase [26]. Upon palmitoylation (H-Ras, N-Ras, and Ki4A-Ras) or through the presence of a polybasicdomain (Ki4B-Ras), the protein is anchored in the cell membrane [27]. When a GTP binds to Ras, it becomes activated. Farnesylation of the C-terminal cysteine by the enzyme farnesyl transferase (FTase) is thus essential for Ras function, and therefore, FTase could be an attractive target for intervention.



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  		Figure 3. Post-translational modification of Ras proteins. After translation in the ribosomes, Ras is farnesylated in the cytosol. The farnesylated protein is translocated to the endoplasmic reticulum. The second and third post-translational steps involve proteolysis and carboxymethylation, respectively. Finally, Ras is palmitoylated and transported to the plasma membrane. Abbreviations: ER, endoplasmic reticulum; FTase, farnesyltransferase; Icmt, isoprenylcysteine carboxyl methyltransferase; Rce1, Ras-converting enzyme 1; PTase, palmitoyltransferase.

 
FTase has two binding sites; one has a recognition site for farnesyl pyrophosphate and the other for the CA1A2X box of the protein. Long et al. [28] revealed the crystal structure of human FTase and predicted that of the CAAX cognate tetrapeptides, only peptides with valine or isoleucine on the A2 position are farnesylated.

Clarification of the crystal structure also showed that mutation of amino acid 12 results in replacement of the glycine, which leads to steric interference in the hydrolysis of GTP. The glutamine at position 61 plays an important role in the catalysis of the GTPase reaction. Consequently, mutations at these positions lead to impaired activity of the enzyme [29].

Based on these findings, peptidomimetic inhibitors of FTase have been designed. Yet both K-Ras and N-Ras can also be geranylgeranylated as an alternative way of pre-nylation [30]. The potential of cross-prenylation suggests that geranylgeranyl transferase I (GGTase-I) could restore the function of these Ras proteins if FTase is inhibited. Indeed, it was recently found that protein farnesylation is not required for lung tumorigenesis in a K-Ras–dependent mouse model [31]. However, it is not clear whether the function of farnesylated Ras is the same as that of geranylgeranylated Ras. Possibly, both FTase and GGTase-I should have been assigned as "drugable" targets.

Identification and Optimization of a Lead Molecule: FTIs
After the discovery that Ras proteins have to be farnesylated to become functionally active, many efforts were undertaken to interfere in this activation step. Several inhibitors of the target enzyme FTase were developed following rational design strategies [32], as well as on screening of combinatorial libraries [33].

Currently known FTIs can be divided into three categories based on their mechanism of action: compounds competitive with farnesylpyrophosphate, compounds competitive with CAAX, and bisubstrate analogues that combine features of both [5]. The second class of compounds in particular has shown promising results. This group can be divided into two subclasses comprising peptidomimetic and nonpeptidomimetic agents, respectively. Examples of the latter compounds are tipifarnib and lonafarnib, both identified by screening large libraries of chemical entities and not related to an FTase substrate (Fig. 4Go). These FTIs were shown to be potent in many in vitro and in vivo tumor models. These agents are currently undergoing testing in various phase I, phase II, and phase III studies.



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  		Figure 4. Chemical structures of farnesyl transferase inhibitors currently in clinical trials: tipifarnib (A), lonafarnib (B), BMS-214662 (C), and L778123 (D).

 
With regard to our proposed algorithm, this step has been completed well. The lead compound was optimized to obtain the lowest 50% inhibitory concentration (IC50) in an FTase inhibition assay using H-Ras or K-Ras as the substrate [34, 35]. Further optimization steps focused on maximal inhibition of Ras farnesylation and cell growth in vitro. Thus, not only the activity of the FTase itself, but also its effect on farnesylated proteins was tested.

Preclinical In Vitro and In Vivo Proof of Concept
In preclinical experiments, FTIs have shown significant potency as anticancer drugs. IC50 values in the low nanomolar range were found for both H-Ras and K-Ras substrates [34, 36]. In addition to this, a large panel of cancer cell lines was highly sensitive to FTIs [36, 37]. Especially in H-Ras–mutated cancer cells, transformation is often completely inhibited after administration of an FTI. On the other hand, the expression of mutated N-Ras or K-Ras frequently leads to increased cell survival. In contrast to H-Ras, both N-Ras and K-Ras proteins can alternatively be geranylgeranylated, thereby having an escape mechanism to the inhibition of Ras activation. Remarkably, several cell lines bearing no ras mutation also appeared sensitive to FTIs [37]. Thus, the sensitivity of a cell line to an FTI seems not to be dependent on ras mutational status only. Nevertheless, many investigations during the development of FTIs were aimed exclusively at the inhibition of Ras functioning, considering Ras as the main target of FTIs.

In an attempt to unravel the mechanism of tumor growth inhibition by FTIs, Ashar et al. [38] showed that a mutation in p53 can influence sensitivity to FTIs as well. They hypothesized that at least two different pathways (one being p53-independent) are responsible for the pharmacological action of FTIs [38].

In vivo models can provide further hints of activity of newly developed drugs. Xenograft models with tumors harboring different ras mutations or no mutation at all could successfully be treated with FTIs [36, 39, 40]. Mice which were injected with cells from human melanoma and human lung, colon, prostate, pancreas, or bladder tumors, respectively, were investigated. Most FTIs had cytostatic activities, only BMS-21466 was mainly cytotoxic due to its additional potent apoptotic activity. Sun et al. [41] showed that, although tumors with a K-ras mutation regressed after treatment with an FTI, the prenylation of K-Ras was not inhibited. This observation could indicate that farnesylated proteins other than K-Ras may be targets of FTIs. Another option is that inhibition of K-Ras farnesylation leads to increased geranylgeranylated K-Ras levels, which might alter the function of K-Ras.

In contrast to a xenograft model, transgenic mouse models with spontaneous tumor occurrence and intact host immunity are available. These characteristics make this mouse model interesting for preclinical testing of new drugs like FTIs. Transgenic mice that had developed mammary or salivary tumors containing an H-ras mutation could successfully be treated with 20-mg/kg lonafarnib, resulting in complete regression of the tumor [39]. In mammary tumors of transgenic mice with N-ras and K-ras4B mutations, inhibition of tumor growth was achieved after administration of the FTI L744832 [42, 43]. Analysis of the tumors with western blotting techniques revealed that Ras prenylation was hardly blocked. Probably, the protein becomes geranylgeranylated when farnesylation is inhibited.

A third preclinical in vivo model in which FTIs have been tested is mice with chemically induced lung tumors [44, 45]. In these mice, almost every tumor contained a K-ras mutation. Treatment with FTI-276 or tipifarnib inhibited tumor growth significantly.

Mijimolle and coworkers chose a genetic approach to investigate the antitumor effects of inhibition of FTase by generating constitutive and conditional knockout mice for the ß-subunit of FTase [31]. In that model, it was seen that the presence of FTase was critical for tumor progression during chemical skin carcinogenesis. However, conversion of cells from normal to malignant did not require farnesylated proteins. Also, adult homeostasis was not hampered by the absence of FTase. These observations suggest that FTIs could be used as chemopreventive agents and support the safe use of FTIs in humans.

The observed good efficacy of FTIs against various tumors in preclinical models stimulated the start of clinical trials. However, a clear explanation for the biological mechanism of FTIs was lacking, because the mechanism of tumor growth arrest has not been determined. This might have been a pitfall in the development from preclinical to clinical investigations. Because molecular pathways may be different in the test animals used in preclinical models from those in humans, it is of importance to know exactly which pathways are targeted by a newly developed anticancer compound. With that information, a better prediction of the clinical activity of the drug might be made.

ADME Studies
Tipifarnib and lonafarnib have both entered phase III clinical studies and are considered to be the two most promising oral FTIs. In the development of both compounds, effort was undertaken to increase oral bioavailability and metabolic stability. Maximal plasma concentrations are reached at 2–4 hours after administration for tipifarnib and at 6–8 hours for lonafarnib [46, 47].

The absolute bioavailability of tipifarnib has been estimated to be 34% ± 10% [48]. A mass balance study showed extensive metabolism [49]. In urine, tipifarnib is mainly present as its glucuronide, whereas in fecal extracts loss of the methyl-imidazole group represents the major metabolic pathway. Overall, approximately 15% of tipifarnib and its metabolites are excreted in urine, whereas approximately 80% is excreted in feces [49]. To our knowledge, additional ADME data from studies in humans using lonafarnib, or other FTIs, have not been hitherto reported.

Based on the available literature, it is difficult to draw conclusions about the execution of this drug-development phase. The contradictory tumor responses in in vivo models and clinical studies could result from different distributions and metabolisms of FTIs in animals and in humans. Therefore, it is of great importance to compare parameters like plasma clearance, bioavailability, and metabolic pathways from test animals in which a tumor response was observed with those parameters from humans. Singh and others have made a start in this direction by comparing pharmacokinetic and metabolic data of L778123 in rats and dogs [50]. A striking difference in oral bioavailability was found (45% in rats versus 100% in dogs). Also, the metabolism of L778123 displayed species differences in rats compared with dogs. This observation underlines the importance of comparing in vivo and clinical ADME data during the development of biologically targeted anticancer agents.

Assessment of Biomarker Assays for Clinical Research
Biochemical modulators like FTIs represent a new class of anticancer drugs. In classic phase I trials with investigational anticancer drugs, the agents are administered to patients starting with a very low dose based on mouse toxicology data. Next, dose escalation is performed to find the highest dose that a patient can reasonably tolerate. Clinical toxicity is thus the pharmacodynamic study end point. In oncology, the belief persists that one can expect the highest antitumor activity of a drug when administered at the highest dose that a patient can tolerate. However, it can be questioned whether this also holds for the new anticancer drugs that are classified as biochemical modulators, like FTIs. Administration of a higher dose than necessary to block the biochemical pathway of interest might not lead to a better antitumor activity but exposes patient unnecessarily to unwanted side effects. In dose-finding studies of biochemical modulators, the drug target or its biochemical effect might be a better pharmacodynamic end point than toxicity.

Ideally, to determine the biochemical effect of a biologically active drug, the effect on its target is analyzed in the tumor. However, the tumor is often not accessible for biopsy, and surrogate tissue samples like white blood cells or buccal mucosa cells are taken for analysis. It is not always possible to measure the direct target of the drug in surrogate tissues, because it either is not present in these cell types or is present at too low concentrations. In this case, other proteins that are also affected by the drug are chosen for analysis. The activation levels of these proteins are measured and are intended to substitute for the relevant clinical effect of the drug. These biological effects on target proteins are called surrogate end points.

Ras activation can be considered as a surrogate end point in FTI intervention. However, activation of Ras in surrogate tissues is difficult to analyze with the currently available techniques (see below). Because more than 30 proteins are known to be farnesylated, many possible surrogate end points are available to monitor the biochemical activities of FTIs in clinical trials.

Ras
The most interesting target to investigate the biological effect of FTIs is Ras farnesylation. Ras proteins are, in principle, present in all human cells. However, the levels of the four isoforms vary widely per cell type.

In human tumor cells grown in culture, the levels of unprenylated and prenylated Ras were a valuable marker for FTase inhibition [36, 51]. However, in clinical trials, unprenylated Ras could not be detected in peripheral blood mononuclear cells (PBMCs) after administration of an FTI [52, 53]. Although PBMCs are of interest for monitoring pharmacodynamic effects, they are poor surrogate tissues for Ras farnesylation studies due to the lack of turnover.

FTase Activity
The direct target of FTIs is the enzyme FTase. Although inhibition of this enzyme is the most direct evidence that FTIs are functionally active in human cells, most pharmacodynamic studies focus on detection of farnesylation of its substrates like HDJ-2 or prelamin A [54]. Determination of FTase activity is possible by measuring the amount of ex vivo added radioactive farnesyl pyrophosphate that is bound to a peptide derived from lamin B or K-Ras in a scintillation proximity assay or filter binding assay. It was shown that administration of tipifarnib to patients with pancreatic cancer inhibits FTase activity in PBMCs by 35%–50% [55]. No evidence of antitumor activity was found, however. In patients with advanced multiple myeloma, FTase was inhibited by 40%–60% [56]. Again, inhibition could not be related to tumor response. Similar inhibition values were observed in phase I trials with i.v.-administered BMS-214662 [57, 58]. There was no correlation between the levels of FTase activity and clinical response. The lack of correlation between the amount of FTase inhibition and the level of tumor response in these studies might be explained by the fact that other resistance mechanisms protect the tumor from cell growth inhibition. Also, it might be that FTase activity in PBMCs is not a good surrogate end point for growth inhibition of tumor tissue. Furthermore, the degree of inhibition of FTase could be too low to induce tumor regression. In two studies with patients suffering from hematologic cancer, FTase activity was determined in bone marrow cells. Treatment with tipifarnib resulted in potent FTase inhibition of 70%–90%. Although higher FTase inhibition levels were observed in bone marrow cells than in PBMC samples, again there was no correlation with clinical response [56, 59]. This could, again, indicate that other reactive mechanisms of protection of tumor cells play a pronounced role in the observed clinical effect of FTIs.

Interestingly, the degree of baseline FTase activity levels in colon cancer correlates with the presence of K-ras mutation, tumor location, and histological differentiation [60]. These observations suggest that not only the constitutive activity of the mutated Ras protein, but also upregulation of the Ras-activating enzyme could play a role in uncontrolled cell growth processes.

Ras•GTP
To measure the activation state of Ras through quantification of the amount of GTP bound to Ras (Ras•GTP), a luciferase-based enzymatic assay has been developed [61]. Feldkamp et al. [62] showed that with this assay a regression model could be built to determine the efficacy of lonafarnib in astrocytomas. When isotype-specific Ras•GTP levels were combined, the IC50 could be predicted with high accuracy. High levels of K- or N-Ras•GTP in in vitro cells and xenograft models resulted in resistance against FTIs, whereas high H-Ras•GTP levels caused superior drug efficacy [62].

Activated Ras can also be quantified by immunoprecipitation with the Ras-binding domain of Raf-1 [63]. Addition of lonafarnib to leukemic BCR/ABL-BaF3 cells significantly reduced the amount of K-Ras bound to Raf-1 [64]. This implies that, although K-Ras can also be geranylgeranylated, association of K-Ras with its effector molecule, Raf-1, is effectively inhibited by FTIs. Resistance to FTI treatment of cell lines harboring a K-Ras mutation might be caused by activation of downstream effectors other than Raf-1 by geranylgeranylated K-Ras.

Analysis of Ras•GTP levels in tumor tissue or PBMCs in clinical trials with FTIs has not been described, as far as we know.

ras Mutation
Surprisingly, few investigations have been directed to explore relationships between ras mutational status and antitumor activity in clinical trials. In preclinical research, it was shown that mutation in the ras gene is not a prerequisite for activity of FTIs. Cell lines harboring no ras mutation or a mutation in the H-ras gene were most susceptible to FTI treatment [36, 37]. Crul et al. [46] performed a phase I study with tipifarnib in 28 patients with advanced cancer. ras mutational status was determined in 15 patients, of which five had a K-ras mutation. None of the latter patients responded to the therapy with tipifarnib. This finding agrees with the preclinical observations that tumor cells that express mutated K-Ras are often resistant to FTI treatment. Furthermore, it was observed that clinical responses in patients with hematological malignancies were unrelated to ras mutational status [56, 59, 65–67]. In these studies, most responders did not have a ras mutation. These findings, as well as preclinical results, indicate, against the expectation, that the antitumor activity of FTIs may not be dependent on the presence of a ras mutation.

HDJ-2/DNA-J
The 44-kDa protein HDJ-2 (or DNA-J) is a member of the heat shock protein (HSP)40 family and functions as a chaperone protein to promote protein transport and folding both by binding to unfolded polypeptides and by regulating the activity of HSP70 [68]. Administration of FTIs can upregulate HSP70, leading to enhanced apoptosis [69].

In a comparison of potential biomarkers for FTI inhibition, HDJ-2 was shown to be a very suitable marker in both cycling and noncycling cells [54]. In several clinical trials, a correlation between inhibition of HDJ-2 farnesylation in PBMCs or bone marrow cells and antitumor effect was examined [53, 55, 56, 59, 70–72]. Although in almost all samples inhibition of HDJ-2 farnesylation was shown (maximal 70%), there was no correlation between the percentage of inhibition and antitumor activity. One study reported a significant correlation between the levels of unfarnesylated HDJ-2 in bone marrow samples and clinical activity in patients with hematological malignancies [73]. However, only a limited number of patients in that trial (n = 3) had evidence of clinical response. Further investigations in a larger patient population are therefore warranted. In conclusion, these results indicate that the farnesylation level of this protein might be a good biomarker for FTase activity but cannot be used as a surrogate end point for the clinical antitumor activity of FTIs.

Lamins
Lamin A is a protein involved in the regulation of the nuclear structure that is farnesylated during maturation [74]. Adjei et al. [75] developed a histochemical assay to detect prelamin A, the unprocessed precursor of lamin A, in buccal mucosa cells. Inhibition of FTase results in the appearance of prelamin A. The dose of the administered FTI correlated well with the percentage of inhibition. However, no correlation was found between the amount of prelamin A and tumor response upon treatment with an FTI [47, 70, 76, 77].

Like lamin A, lamin B plays an important role in the organization of the nuclear envelope and the lamina, and is farnesylated to become functionally active. A Western blot assay was developed to detect both unfarnesylated and farnesylated lamin B in tumor cells in tissue culture. However, in PBMCs immunoreactivity was too low [52]. Therefore, lamin B farnesylation is not a suitable biomarker.

PxF
PxF is a farnesylated protein of 33 kDa that is located on the outer side of peroxisomes [78]. Its function has not been unraveled yet, but it probably plays a role in the process of peroxisomal biogenesis or assembly. In cultured cells, addition of an FTI resulted in the appearance of unprocessed PxF. However, in the PBMCs of patients receiving an FTI, no inhibition of PxF farnesylation could be detected [75].

RhoB
The role of RhoB in tumorigenesis was investigated extensively during the past several years. The Rho GTPase family affects various cellular processes like proliferation, apoptosis, actin formation, adhesion, and motility. At first, RhoA was widely investigated, but it later became clear that RhoB also may play an important role in FTI response. Recent evidence suggests that it acts as a tumor suppressor protein [21, 24, 79]. In head and neck carcinoma, RhoB levels decreased significantly with tumor stage, sustaining the hypothesis that the presence of RhoB is critical for tumor growth inhibition [80].

No correlation has been found between the prenylation levels of RhoB and tumor regression in clinical trials [52]. However, with current Western blotting techniques, it is not possible to distinguish between farnesylated RhoB and geranylgeranylated RhoB, making it difficult to determine the real biochemical effect of FTIs on the prenylation status of RhoB.

Centromeric Proteins
The proteins centromeric protein (CENP)-E and CENP-F play an important role during mitosis. To become functionally active, both proteins have to be prenylated. Although these proteins have not been considered as biomarkers yet, the effect of FTIs on their cellular function has been explored extensively. It has been observed that FTIs induce a G2–M pause in sensitive human tumor cells. There is evidence that this phenomenon could be attributed to the inhibition of CENP farnesylation [81]. Future studies exploring the relationship between inhibition of CENP farnesylation and clinical antitumor activity are warranted. Possibly, CENP farnesylation could serve as an appropriate surrogate end point for tumor response.

Rheb
Rheb (Ras homologue enriched in brain) is a member of the Ras superfamily and is, like Ras, farnesylated to promote its localization in the plasma membrane [82]. Rheb is involved in signal transduction pathways that regulate cell growth (e.g., the mammalian target of rapamycin [mTOR]/S6 kinase pathway). In vitro, it has been shown that Rheb activity can be blocked by FTI treatment, suggesting that Rheb farnesylation may be an important surrogate end point [83]. In vivo or clinical determinations of Rheb farnesylation levels after treatment with FTIs have not been reported.

In conclusion, it can be stated that a good surrogate end point for clinical antitumor activity has not been identified. This raises the question of whether one of the described proteins is the real antitumor target of FTIs. Possibly, inhibition of the farnesylation of another not-yet-identified protein is responsible for inhibition of tumor growth. A second possibility is that inhibition of several farnesylated proteins is required for clinical antitumor activity. In that case, the prenylation state of a cluster of proteins might correlate better with clinical outcome and could be used for clinical proof of concept.

Clinical Results
To date, at least six FTIs have been, or are being, tested in clinical trials. Unfortunately, antitumor activity has been far less than anticipated. This section deals with the clinical outcome of four of the FTIs (Fig. 4Go). Trial results from the other two, L744832 and FTI-277, are not yet available in the public domain.

Tipifarnib
Tipifarnib was the first FTI tested in a clinical trial. Phase I studies showed that myelosuppression and neurotoxicity were dose-limiting toxicities. Gastrointestinal toxicities and fatigue were observed, as well [46, 52, 84].

In early phase II studies tipifarnib was given orally at a dose of 300 mg twice daily for 21 days, followed by 1 week of rest. Three phase II trials have been reported [55, 70, 85]. Patients had advanced breast cancer, metastatic pancreatic cancer, or NSCLC, respectively. In the latter two studies, no responses were observed [55, 70]. The trial in patients with advanced breast cancer showed nine partial responses and nine cases of stable disease (of at least 24 weeks’ duration) in 76 patients [85]. More recent phase II studies explored higher dosages with strict dose-reduction rules for toxicity. In one study, patients with relapsed small-cell lung cancer received 400 mg twice daily for 14 consecutive days followed by 1 week of rest, and no objective responses and only one case of stable disease were observed [86]. To date, the most promising activity of tipifarnib was reported in patients with untreated poor-risk acute myeloid leukemia or myelodysplastic syndrome(MDS), in which a 33% response rate (eight complete responses, two partial responses) was seen [87]. Patients were dosed at 600 mg twice daily for 21 days. In a second phase II trial in patients with MDS, tipifarnib showed activity in three of 27 patients, resulting in two complete remissions and one partial remission [66]. The drug was administered at a dose of 600 mg twice daily for 4 weeks, followed by 2 weeks of rest. In patients with multiple myeloma, no complete or partial response was observed [56]. However, 64% of the patients showed stabilization of disease with a median time to progression from the start of treatment of 4 months.

Treatment with tipifarnib has been compared with placebo or standard therapies in at least two phase III studies [88, 89]. No significant antitumor effect was found in patients with advanced colorectal cancer. Also, no significant increase in response rate was observed in patients with pancreatic carcinoma when gemcitabine (Gemzar®; Eli Lilly and Company, Indianapolis, http://www.lilly.com) therapy was compared with gemcitabine combined with tipifarnib.

Lonafarnib
The first phase I trial of lonafarnib started in 1997. In the following years, different administration schedules were tested to determine the MTD and the highest achievable plasma concentrations [47, 75, 90]. The main toxicity was diarrhea, but nausea, vomiting, and fatigue were also frequently observed. The recommended dose for phase II studies was 200 mg administered orally twice daily on a continuous regimen.

In a phase II study in patients with advanced urothelial cancer, tumor responses were not observed. One patient out of 14 had stable disease [91]. Also, in a second phase II study investigating the effect of lonafarnib in patients with meta-static colorectal cancer, no responses were observed. Three of 21 patients had stable disease for at least 4 months [92]. Yang and coworkers conducted a phase II study in patients with chemotherapy-refractive advanced head and neck squamous cell carcinoma. Again, no objective response was observed, but seven of the 15 patients maintained stable disease for at least three cycles of therapy [93].

BMS-214662
BMS-214662 belongs to the class of nonpeptidomimetic FTIs. The oral formulation exhibits dose-dependent gastrointestinal toxicity, which limits its oral dosing [94]. Therefore, most phase I studies focused on optimal i.v. administration. The MTD of a 1-hour infusion once every 3 weeks was 200 mg/m2, with dose-limiting toxicities consisting of nausea, vomiting, and diarrhea [95]. When the administration scheme was extended to continuous weekly i.v. administration, MTDs of 209 mg/m2 for a 1-hour infusion and 275 mg/m2 for a 24-hour infusion were reached [58]. Besides nausea, vomiting, and diarrhea, creatinine elevation, acute pancreatitis, and renal failure (only with long exposure) were also dose-limiting. Cortes and others reported an MTD of 118 mg/m2 in patients with acute leukemia or high-risk MDS [57]. BMS-214662 was administered as a 1-hour bolus once weekly. Dose-limiting toxicities were nausea, vomiting, diarrhea, hypokalemia, and cardiovascular problems. Five patients had evidence of antileukemic activity. In two not-yet-completed trials, it was reported that doses of 300 mg/m2 on a weekly x 3 every 4 weeks schedule and 102 mg/m2 on a weekly x 4 every 6 weeks schedule were well tolerated [96, 97]. In the latter schedule, two of eight patients with solid tumors had stable disease. Administration of BMS-214662 on a daily basis resulted in an MTD of 81 mg/m2. At this dose, the level of farnesyltransferase inhibition was only transient [98].

No literature is available on phase II studies of BMS-214662.

L778123
In phase I trials, L778123 was administered by continuous i.v. for 7, 14 or 28 days [71]. Dose-limiting toxicities were thrombocytopenia and neutropenia. No objective responses were observed, although clinically relevant steady-state plasma concentrations were obtained. In all trials QTc prolongation was observed in at least one or more patients. Although this was not dose-limiting and was not recurrent when a lower dose was administered, it was decided to discontinue the development of this compound.


   CONCLUSIONS AND FUTURE DIRECTIONS
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 Learning objectives
 Abstract
 Introduction
 Conclusions and future...
Disclosure of potential...
 References
 
Despite high expectations based on preclinical observations, FTIs failed as single-agent anticancer drugs for most solid cancers but are promising in hematological malignancies. In this review, we tried to summarize the current knowledge about the drug development of FTIs and find explanations for the fact that these compounds are not as potent as expected. Taking the algorithm as proposed in Table 1Go into account, we find a few gaps in the drug development of FTIs.

First, the molecular pharmacology of FTIs has not yet been fully elucidated. Additional proteins that depend on post-translational farnesylation to become functionally active are still being discovered. At the moment, approximately 30 proteins are known to be farnesylated. However, the role of each of these proteins and their farnesylation levels in tumorigenesis have not yet been established, nor has the effect of FTI administration on their functioning. Furthermore, Lackner and others recently demonstrated that FTIs can also be potent inhibitors of GGTase-II (or Rab-GGTase) [99]. This enzyme is related to GGTase-I but has a distinct C-terminal sequence (CXC) and was therefore not expected to be a target of FTIs. It is clear that FTIs inhibit cell growth in some types of cancer; nevertheless, the real target(s) still have to be determined.

Second, both N- and K-Ras proteins are not only farnesylated but also geranylgeranylated [30]. It is hypothesized that geranylgeranylation forms an escape mechanism for the inhibition by FTIs. To test this hypothesis, GGTase-I inhibitors (GGTIs) as well as dual prenyl transferase inhibitors (DPTIs) have been developed. Sun et al. [100] were the first to report tumor regression effects of a GGTI in nude mice. Subsequently, Lobell et al. [101] showed that, in pre-clinical models, it was possible to completely inhibit K-Ras proteins using high micromolar concentrations of a GGTI. However, in mouse models, these concentrations were found to be lethal after a 72-hour infusion. In a modified GGTase-I activity assay, the FTI L778123 also was shown to have good inhibitory properties against GGTase-I (IC50, 100 nM) [102]. In patients receiving L778123, nongeranylgeranylated Rap1a could be detected, indicating that GGTase-I was inhibited [53]. Unfortunately, no tumor response was observed. Recently, AstraZeneca developed a new DPTI with the experimental name AZD3409, which has IC50 values of 1 nM and 8 nM for FTase and GGTase-I, respectively [103, 104]. In in vivo models, this compound was well tolerated, showed FTase inhibition levels of 80%–90%, and showed inhibition of tumor growth of up to 60%. Phase I studies have recently been started to obtain information on tolerability in humans. Phase II and III studies are warranted to determine if inhibition of both FTase and GGTase-I indeed leads to tumor growth inhibition in cancer patients.

Third, a well-defined proof of concept of preclinical studies is missing. A good biological understanding of the tumor response that has been observed in vitro and in vivo has not been found. Also, a well-defined proof of concept of clinical studies is lacking. Despite the identification of more than 30 proteins that can be farnesylated and thus are potential biomarkers, no surrogate end point for clinical antitumor activity has been identified. This raises the question of whether the clinical studies investigating FTIs should have been designed in a way different from the former trials with classic anticancer drugs. We and others recognized that the pharmacodynamic end point in studies with biologically targeted drugs has to shift from toxicity to the biochemical effect on the target protein(s) [105, 106].

Another question is whether multigenic cancers should be treated with a single agent or with a cocktail of molecular targeted therapeutics. In the literature, the general opinion seems to be in favor of a multitargeted approach, either by development of drugs that affect multiple molecular pathways or by employing a combination of anticancer drugs [107]. In preclinical studies with FTIs, synergy has been observed with several conventional anticancer drugs, such as taxanes and platinum-containing compounds [108, 109]. Based on these findings, many trials currently focus on combining FTIs with classic chemotherapeutic drugs or radiotherapy [77, 110–112].

Thus, for future development of biologically active anti-cancer drugs, we advise that emphasis be placed on biological pharmacodynamic effects as much as on cytotoxicity. Biomarker assays developed and used in preclinical studies should also be used in early clinical trials. The recommended dose for phase II studies should incorporate these biological data in addition to the usual pharmacokinetic data. Finally, phase II studies should be used to test whether activation levels of the biomarkers correlate with tumor regression data, to pilot predictive markers, and to assess combination regimens.


   DISCLOSURE OF POTENTIAL CONFLICTS OF INTEREST
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 Abstract
 Introduction
 Conclusions and future...
 Disclosure of potential...
References
 
The authors indicate no potential conflicts of interest.


   ACKNOWLEDGMENT
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 Abstract
 Introduction
 Conclusions and future...
 Disclosure of potential...
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This work was supported by the Dutch Cancer Society, grant NKI2003-2852.


   REFERENCES
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 Disclosure of potential...
 References
 

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Received April 4, 2005; accepted for publication June 23, 2005.




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