- Email: [email protected]
Farnesyl transferase inhibitors in myeloid malignancies
Farnesyl transferase inhibitors in myeloid malignancies
Farnesyl transferase inhibitors in myeloid malignancies
dergoing rapid clinical development. This latter class of agents, and its potential role in hematologic malignancies, will be the focus of this review.
BACKGROUND Jeffrey E. Lancet1, Judith E. Karp2 1
University of Rochester, James P. Wilmot Cancer Center, 601 Elmwood Avenue,
Box 704 Rochester, NY 14642, USA 2
Johns Hopkins University, Sydney Kimmel Cancer Center, 1650 Orleans Street,
Baltimore, MD 21201, USA
Abstract Farnesyl transferase inhibitors (FTIs) are a novel class of anti-cancer agents that competitively inhibit farnesyl protein transferase (FPT), and are currently being developed and tested across a wide range of human cancers. Hematologic malignancies, particularly those of myeloid origin, are reasonable disease targets in that they likely overexpress relevant biologic targets, such as Ras, mitogen-activated protein kinase (MAPK), or AKT, that depend upon FPT activity to promote proliferation and survival. Phase I clinical trials using FTIs in acute myelogenous leukemia (AML) and other myeloid malignancies have been performed, demonstrating enzyme target inhibition, low toxicity, and promising response rates. These findings have prompted further development in phase II trials, in order to clarify the response rate and to identify the actual downstream signal transduction targets that may be modified by these agents. It is anticipated that such information will ultimately define the optimal roles of FTIs in patients with AML and other myeloid disorders, facilitate the incorporation of FTIs into current therapeutic strategies for myeloid malignancies, and provide insight into effective methods of combining FTIs with other signal transduction inhibitors. c 2003 Elsevier Science Ltd. All rights reserved. KEY WORDS: farnesyl transferase inhibitors; myeloid malignancies; Ras; signal transduction
INTRODUCTION ecent advances in the understanding of molecular mechanisms of neoplasia have driven the development of new therapeutic compounds that target molecules governing cellular proliferation, differentiation, and survival. As such, a panoply of novel pharmacologic agents has entered cancer clinical trials. Signal transduction inhibitors are among the most promising of these agents, with an ever-expanding repertoire of malignancies being tested. For example, Imatinib Mesylate (formerly known as STI-571), a relatively potent and selective inhibitor of the BCR–ABL tyrosine kinase, has met with early success in the treatment of all phases of chronic myelogenous leukemia.1–3 Other signal transduction inhibitors in clinical trials target the tyrosine kinase domain of different molecules, including receptors for epidermal growth factor (EGF), vascular endothelial growth factor (VEGF), and FLT-3. Farnesyl transferase inhibitors represent another class of signal transduction inhibitor un-
R
Farnesyl transferase inhibitors are potent and selective competitive inhibitors of intracellular farnesyl protein transferase (FPT), an enzyme that catalyzes the transfer of a farnesyl moiety to the cysteine terminal residue of a substrate protein (Fig. 1).4 A host of intracellular proteins are substrates for prenylation via FTIs, including Ras, Rho-B, Rac, and Lamin proteins.5 Of particular interest in the development of FTIs was the potential to inhibit farnesylation of Ras proteins. The Ras family of oncoproteins is a critical network of signal transduction pathways that impacts cellular proliferation, survival, and differentiation (Fig. 2).5–7 Localization of the Ras protein to the cell membrane, where it is capable of activating downstream signaling events, requires the transfer of an isoprenyl group to its C-terminal amino acid motif.4;8 Mutated ras can fail to interact appropriately with its negative regulators, thereby leading to constitutive activation in the GTP-bound form.7 Hence, the central role of Ras in intracellular signaling, in conjunction with its frequently mutated status in human malignancies, makes it an attractive therapeutic target. However, inhibiting farnesylation of other proteins, such as Rho B, may play an equally important role in the ultimate mechanism by which these agents exert their anti-neoplastic effects.9;10 FTIs have been studied extensively in pre-clinical models, both in-vitro and in-vivo.11–20 Several important observations have arisen from these preclinical studies. First of all, FTIs are able to cause morphologic reversion of ras transformed cells.4;15;19;21 Second, growth inhibitory effects can be demonstrated in malignant cells with and without ras mutations, although tumor cells that are driven by overexpression or muation of certain ras isoforms (e.g., K-ras) appear to be more resistant to the anti-proliferative effects of FTIs.11;12;16;18;20;22 Third, the mechanisms behind the anti-tumor effects appear to be heterogeneous; while these agents clearly have antiproliferative and growth inhibitory effects, evidence suggests a role for pro-apoptotic effects as well, possibly through inhibition of the PI-3K pathway.9;23 Taken together, these findings have prompted interest in pursuing FTI therapy in clinical cancer trials.
MYELOID MALIGNANCIES AS THERAPEUTIC SETTINGS FOR FTI THERAPY Hematologic malignancies represent an ideal clinical venue in which to study FTI therapy. As will be discussed below, these diseases often express molecular targets germane to FTI therapy. In addition, the pathologic tissue of interest (e.g., leukemic bone marrow) is often readily accessible by means of minimally invasive procedures. As such, the biologic effects of a therapeutic compound in malignant cells can be more easily studied than in cases of solid tumors.
c 2003 Elsevier Science Ltd. All rights reserved.
Blood Reviews (2003) 17, 123–129 doi:10.1016/S0268-960X(03)00008-0
123
Lancet and Karp
Fig. 1 Farnesylation pathway (adapted with kind permission from Lippincott, Williams, and Wilkins in Rowinsky et al.5
Fig. 2 Ras-mediated signaling pathways. Farnesylated Ras protein tranlocates to the cell membrane. In its GTP-bound form, Ras mediates diverse signaling pathways that regulate many cellular functions.
Ras-mediated signaling pathways as they relate to myeloid diseases As discussed previously, activated Ras directs many crucial intracellular signaling events. Certain molecular events pathognomonic to myeloid malignancies may depend upon Ras signaling to facilitate the ultimate transformation or leukemogenic process, thereby making Ras itself a rational target for new therapeutic agents such as FTIs. One example of how Ras plays a vital role in leukemogenesis can be demonstrated in a chronic myelogenous leukemia (CML) model, where leukemic transformation depends upon the presence of a specific oncoprotein, BCR–ABL, resulting from a translocation between chromosomes 9 and 22. In this model, investigators have shown that introduction of a dominant 124
Blood Reviews (2003) 17, 123–129
c 2003 Elsevier Science Ltd. All rights reserved.
negative (inactive) ras into BCR–ABL transfected hematopoietic or fibroblast cells results in a complete blockage of malignant transformation.24 In AML, certain receptors on myeloid progenitor cells are thought to be important in cellular signaling, via interaction with their ligands. For example, FLT-3 is a receptor that is known to play a central role in the proliferation, survival and differentiation of early murine and human hematopoietic precursor cells.25 When internal tandem duplication (ITD) of the FLT3 gene occurs, as is the case in up to 20–35% of AML cases,26–28 this receptor can induce transformation as well as growth factor-independent activation of signaling pathways, particularly Jak/Stat and MAPK.29;30 In accordance with these findings, it has also been demonstrated that transfection with a dominant-negative
Farnesyl transferase inhibitors in myeloid malignancies form of Ras inhibits colony formation in cells containing the FLT-3 ITD mutation.29 Such findings provide rationale for targeting Ras itself in myeloid malignancies. Downstream from Ras, there are a number of effector molecules and pathways that influence a variety of cellular processes thought to be important in both normal and malignant hematopoiesis (Fig. 2). One such pathway is the Raf– MEK–MAPK cascade, in which a series of phosphorylation events ultimately leads to the localization of phosphorylated MAPK to the cell nucleus, where it activates transcription factors that help to govern cellular proliferation and apoptosis.31–35 A second Ras-mediated signaling pathway of importance is the PI-3K–AKT pathway. In this effector pathway, the activated Ras protein binds and activates PI3K, a tyrosine kinase, which in turn phosphorylates AKT, a potent suppressor of apoptosis.36–38 These signaling pathways likely have significant implications in the development and propagation of malignant hematopoiesis. For instance, mutant (constitutively activated) Raf can abrogate growth factor dependency in hematopoietic cells.39 In addition, pharmacologic inhibitors of MEK function and antisense RNA to MEK can block Ras or Raf-mediated transformation and cytokinestimulated growth.40 The Ras–PI3K–AKT pathway is germane to hematopoiesis and leukemogenesis as well. For example, it has been shown that intact PI3K–AKT signaling is essential for BCR–ABL induced transformation and colony growth.41 Further evidence to support the critical role of the PI3K–AKT pathway in malignant hematopoiesis can be found in a study whereby Ras mutants incapable of activating the Raf–MEK– ERK pathway were still able to inhibit apoptosis in IL-3-dependent cell lines. This effect was blocked by Wortmannin, emphasizing the importance of the PI3K–AKT pathway in hematopoiesis.39 Data extracted from clinical AML samples also lend evidence to the relevance of Ras and its signaling pathways in this disease. One potentially important finding is that ras (particularly the N-ras isoform) is mutated in up to 48% of AML and MDS cases, although there is considerable variation in these rates amongst published series.42–47 Signaling through the MAPK pathway may also be altered in AML. To this end, it has been suggested that constitutive activation of MAPK (ERK), as determined by the presence of phosphory-
lated MAPK in AML cells at diagnosis, occurs at a high frequency in AML.48–50 Abnormal signaling through the PI-3K/ AKT pathway may also occur in AML. Some preliminary data have indicated that a majority of AML samples express phosphorylated (or activated) AKT as compared to normal control samples.51 Clinical rationale for new agents in myeloid diseases From a clinical standpoint, the myeloid malignancies, particularly AML, represent a cohort of diseases that are appropriate candidates for new, targeted therapies such as FTIs. As evidenced by many clinical trials, AML is a disease of primarily of older individuals that is associated with a very low rate of long-term survival, especially in older patients, with median survival on the order of 1 year.52 In addition, the rates of chemotherapy-associated severe toxicities, along with death, are very high in this disease. In adults over age 60, the risk of treatment-related death is on the order of 20% during the induction phase of therapy.53–56 In patients fortunate enough to achieve complete remission through chemotherapy, the remission duration is usually short, generally on the order of 1 year or less.53–56 Besides the toxicity risks, chemotherapy failure in AML is often due to the presence of multi-drug resistance phenotype, which correlates negatively with remission rate.57;58 For these reasons, new agents that may pose less toxicity, as well as novel mechanisms of antitumor activity, are necessary to improve outcomes in patients with AML. In a similar light, myelodysplastic syndromes, particularly those with a high international prognostic system score (IPSS), are associated with poor long-term prognoses.59 Other myeloid diseases such as chronic myelogenous leukemia (in accelerated or blast phase) and certain myeloproliferative disorders carry poor prognoses, and are also reasonable diseases in which to investigate new therapies.
CLINICAL TRIALS USING FTIS IN MALIGNANT MYELOID DISORDERS Given the plethora of clinical and preclinical data to support the use of FTIs in myeloid malignancies, a large number of clinical trials have been undertaken in this arena (Table 1).
Table 1 Clinical trials of farnesyl transferase inhibitors in myeloid malignancies Disease
FTI agent
Phase
Refractory, relapsed, or high-risk acute leukemias MDS Refractory advanced hematologic malignancies Pediatric refractory leukemias MPDs Refractory/Relapsed AML Previously untreated high-risk AML, MDS
R115777 R115777 R115777 R115777 R15777 R115777 R115777
I I I I I/II II II
CML MDS Refractory/relapsed AML, MDS
R115777 R115777 BMS-214662
II II I
Institution University of Maryland, University of Rochester MD Anderson University of Chicago NCI Stanford University, University of Rochester Int’l University of Rochester, University of Maryland, Stanford University, Mayo Clinic MD Anderson MD Anderson MD Anderson
c 2003 Elsevier Science Ltd. All rights reserved.
Blood Reviews (2003) 17, 123–129
125
Lancet and Karp Karp and Lancet, et al. recently reported the first completed phase I study of FTI therapy in hematologic malignancies.60 This trial was performed in a wide range of patients with poor-risk acute leukemias, utilizing the farnesyl transferase inhibitor R115777 (ZARNESTRA), administered orally for 21 days, for up to four full cycles. Reliable inhibition of farnesyl transferase activity occurred at or above the 300 mg BID dosing level, and dose-limiting toxicity, manifested as a readily reversible central neurotoxicity, was observed at the 1200 mg BID dosing level. Significantly, there was a dosedependent increase in drug concentration within the bone marrow, at higher levels than was observed in the peripheral blood. Clinical responses were observed in 10 of 34 patients, including two complete responses. Interestingly, responses occurred across the entire range of dosing levels (100–900 mg BID), challenging both the validity of the assays and the notion that a specific degree of enzyme inhibition is necessary to achieve clinical response. Responses also occurred independently of ras mutational status, as none of the 34 leukemic samples demonstrated an N-Ras mutation. Since FTIs may interfere with Ras-mediated signaling, measurement of Ras-mediated signaling intermediates, such as MAPK, could be useful in predicting response to R115777. In this study, a selected number of leukemic samples were analyzed for the presence of phosphorylated MAPK (via Western blot analysis), an important signaling intermediate of cellular proliferation within the Ras family of signaling. We observed eight patients in whom the leukemic marrow demonstrated phospho-MAPK at baseline, four of whom achieved clinical response. In the 14 patients with no evidence of baseline phospho-MAPK expression, only two responses were noted. While this observation clearly needs confirmation, it highlights the fact that measurement of MAPK and other easily measurable signaling intermediates may provide insight into downstream drug targets. Preliminary results from a large, multi-center phase II study of FTI R115777 in refractory or relapsed AML have also been recently reported.61 This trial utilized a 600 mg BIDdosing schema for 21 days every 4 weeks. At the time of the report, 17 of 50 evaluable patients (14%) with relapsed disease experienced a reduction in bone marrow blasts to <5%, while 31 of 50 (62%) had P50% decrease in bone marrow blasts from baseline. Rash and hyperbilirubinemia were among the most frequent adverse events. In addition to the endpoint of clinical response, microarray-based pharmacogenomic analysis is being performed, exploring the cellular signaling pathways that may be modulated by FTI therapy. To this end, preliminary data obtained from leukemic samples in this trial demonstrate that genes regulating apoptotic, MAPK, and TGFb pathways are modulated by treatment with R115777.62 We are currently conducting a phase II trial of R115777 in previously untreated patients with poor-risk AML and MDS, the preliminary results of which are recently reported.63 To date, we have observed responses in 10 of 30 (33%) evaluable patients, most of whom were elderly (median age 74). Notably, eight of these 10 responses were deemed complete responses. While expected grade 3 or 4 hematologic toxicity has occurred in a majority of patients, severe non-hematologic toxicity has been less common. Another interesting 126
Blood Reviews (2003) 17, 123–129
c 2003 Elsevier Science Ltd. All rights reserved.
preliminary finding is that all four patients with baseline trisomy 8 abnormality in leukemic bone marrow have experienced response to R115777. Additional non-clinical endpoints being studied at baseline and during therapy include measurement of MAPK and AKT activation, inhibition of farnesylation, and mutational status of ras and FLT3. Results of FTI therapy in other myeloid malignancies is also being reported. Kurzrock et al. 64;65 have recently reported preliminary results of phase I and II clinical trials utilizing R115777 in myelodysplastic syndromes. In the phase I study, the DLT was fatigue, occurring at 900 mg BID. An objective response rate (partial response or hematologic improvement) was detected in 33%. The phase II trial, which enrolled patients with either relapsed MDS or poor-risk previously untreated disease (over age 60), demonstrated complete responses in 2 of 16 patients. Also notable was the fact that dose reduction from 600 to 300 mg BID was frequently necessary for reasons including myelosuppression, fatigue, and cerebellar symptoms. As in the phase I trial in refractory and relapsed leukemias, there was no correlation between response and baseline Ras mutational status. Myeloproliferative diseases are also being studied for responsiveness to FTI therapy. Preliminary results of a phase II trial of FTI R115777 in CML, multiple myeloma, and myeloproliferative disorders were recently reported.66 In the CML subset, 6 of 10 patients with chronic phase disease experienced partial or complete responses, while 1 of 5 patients with accelerated disease experienced complete response. Minor cytogenetic responses were also observed in some patients. Patients with myelofibrosis experienced significant reduction in spleen size. Consistent with other studies, common grade P3 toxicities included myelosuppression, skin rash, peripheral neuropathy, and liver toxicity. Gotlib et al.67 have also reported preliminary results of a phase I/II trial in myeloproliferative diseases, including CML, myelofibrosis, and chronic myelomonocytic leukemia. At the time of this report, two of eight evaluable patients had experienced complete WBC responses. Severe anemia or thrombocytopenia occurred in four patients. This study also demonstrated biologic activity, with dose-related suppression of bone marrow CFU-GMs and inhibition of farnesylation of the surrogate marker, heat shock protein HDJ-2. Although R115777 is the most developed FTI in hematologic malignancy trials, other FTIs are also being studied in this context. A phase I trial using FTI BMS-214662, another potent and selective inhibitor of FPT, is also being performed.68 Preliminary results of this trial have shown a >50% reduction in bone marrow blasts in 5 of 22 patients. Dose limiting toxicity had not yet been reached at the time of the preliminary report.
IMPLICATIONS FOR FTI THERAPY IN MYELOID MALIGNANCIES As a new class of agents with a unique mechanism of action, farnesyl transferase inhibitors clearly have an emerging role in cancer therapy. By interfering with intracellular signaling, these agents likely inhibit leukemic cell growth and survival differently than traditional chemotherapeutic drugs. This
Farnesyl transferase inhibitors in myeloid malignancies concept is relevant to the treatment of AML and other myeloid malignancies, in which there are often drug resistance mechanisms at play that limit the efficacy of chemotherapy, and in which considerations about severe toxicities limit the ultimate benefit of cytotoxic therapy for a large proportion of patients. Although the overall role with FTI therapy in myeloid malignancies continues to emerge, some important conclusions can be reasonably made, based on the experience to date. First of all, many myeloid diseases are dependent, at least in part, by signaling processes that may be targeted directly or indirectly by FTIs. Secondly, these agents have clinical activity across a wide range of myeloid diseases, including AML, MDS, CML, and myeloproliferative diseases. The activity of FTIs in CML is of particular interest, as new invitro data have emerged, suggesting that the FTI SCH66336 potentiates apoptosis in STI-resistant cells.69 Finally, most toxicity data that have emerged to this point highlight a relative paucity of severe adverse effects directly attributable to these agents. These characteristics, in toto, are important because they point out the feasibility of eventually combining FTIs with other agents such as chemotherapy as well as highlight the potential of these agents for use over an extended period, longer than would be possible for traditional cytotoxic agents. The rapid development of FTIs and the observations pertaining to their activity in myeloid malignancies have created both challenges and opportunities. A primary challenge will be to gain a better understanding as to the precise mechanisms by which these agents exert their antineoplastic effects, across different disease subgroups. These insights will be important for many reasons. For example, knowledge about specific signaling targets that are inhibited by FTIs may eventually allow investigators to tailor such therapy to patients whose disease characteristics exhibit overexpression of these targets and to combine FTIs with other signal transduction inhibitors that block different pathways. In addition, understanding the specific tumor cellÕs response (e.g., apoptosis vs. cell cycle arrest) to the FTI will allow for the rational design of trials that incorporate traditional chemotherapy or other signal transduction modifiers to act synergistically with FTIs. For these reasons, it is critical that clinical researchers incorporate correlative studies into their trials to answer such questions. Newer techniques such as DNA microarray profiling and proteomics will permit broader investigation into families of targets that may be preferentially expressed in various disease categories. While new targeted therapies such as FTIs offer great promise, it is important to recognize that they will likely have limited roles as single agents in aggressive or refractory malignancies, which are often driven by multiple genetic lesions and diverse, non-overlapping signals. In accordance with this observation, novel approaches to the use of FTIs in myeloid malignancies are being developed. In AML, for example, we are investigating R115777 as frontline therapy in older patients with newly diagnosed AML and high-risk MDS and as consolidation (post-remission) therapy in AML patients of any age whose disease exhibits poor risk features. Both of these disease settings afford the opportunity to study the antineoplastic effect of FTIs at times when multiple genetic lesions or massive leukemic burden is less than in the refractory or
relapsed state. As such, the antineoplastic effect may be easier to identify and to study, and the feasibility of extendedduration therapy may be undertaken. Other clinical trials being planned in the setting of AML and MDS include phase I studies combining FTI with induction chemotherapy and studies that will examine the use of ‘‘upfront’’ FTI therapy, followed by standard cytotoxic chemotherapy. In CML blast phase, a phase I trial utilizing R115777 in combination with STI571 is being conducted. With the advent of other novel agents that interfere with signal transduction, such as FLT-3 inhibitors, proteasome inhibitors, and MAPK pathway inhibitors, it seems certain that further novel trials of such agents in combination with FTIs will take place in the near future.
Correspondence to: Jeffrey E. Lancet, MD, University of Rochester, James P. Wilmot Cancer Center, 601 Elmwood Avenue, Box 704, Rochester, NY 14642, USA. Tel.: +585-275-4099; Fax: +585-273-1042; E-mail: [email protected]
References 1. Druker BJ, Sawyers CL, Kantarjian H, Resta DJ, Reese SF, Ford JM et al. Activity of a specific inhibitor of the BCR–ABL tyrosine kinase in the blast crisis of chronic myeloid leukemia and acute lymphoblastic leukemia with the Philadelphia chromosome. N Engl J Med 2001; 344: 1038–1042. 2. Druker BJ, Talpaz M, Resta DJ, Peng B, Buchdunger E, Ford JM et al. Efficacy and safety of a specific inhibitor of the BCR–ABL tyrosine kinase in chronic myeloid leukemia. N Engl J Med 2001; 344: 1031–1037. 3. Talpaz M, Silver RT, Druker BJ, Goldman JM, Gambacorti-Passerini C, Guilhot F et al. Imatinib induces durable hematologic and cytogenetic responses in patients with accelerated phase chronic myeloid leukemia: results of a phase 2 study. Blood 2002; 99: 1928–1937. 4. End DW. Farnesyl protein transferase inhibitors and other therapies targeting the Ras signal transduction pathway. Invest New Drugs 1999; 17: 241–258. 5. Rowinsky EK, Windle JJ, Von Hoff DD. Ras protein farnesyltransferase: a strategic target for anticancer therapeutic development. J Clin Oncol 1999; 17: 3631–3652. 6. Boguski MS, McCormick F. Proteins regulating Ras and its relatives. Nature 1993; 366: 643–654. 7. Lowy DR, Willumsen BM. Function and regulation of ras. Annu Rev Biochem 1993; 62: 851–891. 8. Khosravi-Far R, Cox AD, Kato K, Der CJ. Protein prenylation: key to ras function and cancer intervention? Cell Growth Differ 1992; 3: 461–469. 9. Prendergast GC. Farnesyltransferase inhibitors: antineoplastic mechanism and clinical prospects. Curr Opin Cell Biol 2000; 12: 166–173. 10. Du W, Lebowitz PF, Prendergast GC. Cell growth inhibition by farnesyltransferase inhibitors is mediated by gain of geranylgeranylated RhoB. Mol Cell Biol 1999; 19: 1831–1840. 11. End DW, Smets G, Todd AV, Applegate TL, Fuery CJ, Angibaud P et al. Characterization of the antitumor effects of the selective
c 2003 Elsevier Science Ltd. All rights reserved.
Blood Reviews (2003) 17, 123–129
127
Lancet and Karp
12.
13.
14.
15.
16.
17.
18.
19.
20.
21.
22.
23.
24.
25.
26.
27.
128
farnesyl protein transferase inhibitor R115777 in vivo and in vitro. Cancer Res 2001; 61: 131–137. James G, Goldstein JL, Brown MS. Resistance of K-RasBV12 proteins to farnesyltransferase inhibitors in Rat1 cells. Proc Natl Acad Sci USA 1996; 93: 4454–4458. James GL, Goldstein JL, Brown MS, Rawson TE, Somers TC, McDowell RS et al. Benzodiazepine peptidomimetics: potent inhibitors of Ras farnesylation in animal cells. Science 1993; 260: 1937–1942. Kohl NE, Wilson FR, Mosser SD, Giuliani E, deSolms SJ, Conner MW et al. Protein farnesyltransferase inhibitors block the growth of ras-dependent tumors in nude mice. Proc Natl Acad Sci USA 1994; 91: 9141–9145. Kohl NE, Mosser SD, deSolms SJ, Giuliani EA, Pompliano DL, Graham SL et al. Selective inhibition of ras-dependent transformation by a farnesyltransferase inhibitor. Science 1993; 260: 1934–1937. Liu M, Bryant MS, Chen J, Lee S, Yaremko B, Lipari P et al. Antitumor activity of SCH 66336, an orally bioavailable tricyclic inhibitor of farnesyl protein transferase, in human tumor xenograft models and wap-ras transgenic mice. Cancer Res 1998; 58: 4947–4956. Mahgoub N, Taylor BR, Gratiot M, Kohl NE, Gibbs JB, Jacks T et al. In vitro and in vivo effects of a farnesyltransferase inhibitor on Nf1-deficient hematopoietic cells. Blood 1999; 94: 2469–2476. Nagasu T, Yoshimatsu K, Rowell C, Lewis MD, Garcia AM. Inhibition of human tumor xenograft growth by treatment with the farnesyl transferase inhibitor B956. Cancer Res 1995; 55: 5310–5314. Prendergast GC, Davide JP, deSolms SJ, Giuliani EA, Graham SL, Gibbs JB et al. Farnesyltransferase inhibition causes morphological reversion of ras-transformed cells by a complex mechanism that involves regulation of the actin cytoskeleton. Mol Cell Biol 1994; 14: 4193–4202. Sepp-Lorenzino L, Ma Z, Rands E, Kohl NE, Gibbs JB, Oliff A et al. A peptidomimetic inhibitor of farnesyl:protein transferase blocks the anchorage-dependent and -independent growth of human tumor cell lines. Cancer Res 1995; 55: 5302–5309. Kohl NE, Omer CA, Conner MW, Anthony NJ, Davide JP, deSolms SJ et al. Inhibition of farnesyltransferase induces regression of mammary and salivary carcinomas in ras transgenic mice. Nat Med 1995; 1: 792–797. Whyte DB, Kirschemeier P, Hockenberry TN, Nunez-Oliva I, James L, Catino JJ et al. K- and N-Ras are geranylgeranylated in cells treated with farnesyl protein transferase inhibitors. J Biol Chem 1997; 272: 14459–14464. Du W, Liu A, Prendergast GC. Activation of the PI3ÕK–AKT pathway masks the proapoptotic effects of farnesyltransferase inhibitors. Cancer Res 1999; 59: 4208–4212. Sawyers CL, McLaughlin J, Witte ON. Genetic requirement for Ras in the transformation of fibroblasts and hematopoietic cells by the Bcr-Abl oncogene. J Exp Med 1995; 181: 307–313. Shurin MR, Esche C, Lotze MT. FLT3: receptor and ligand. Biology and potential clinical application. Cytokine Growth Factor Rev 1998; 9: 37–48. Schnittger S, Schoch C, Dugas M, Kern W, Staib P, Wuchter C et al. Analysis of FLT3 length mutations in 1003 patients with acute myeloid leukemia: correlation to cytogenetics, FAB subtype, and prognosis in AMLCG study and usefulness as a marker for the detection of minimal residual disease. Blood 2002; 100: 59–66. Thiede C, Steudel C, Mohr B, Schaich M, Schakel U, Platzbecker U et al. Analysis of FLT3-activating mutations in 979 patients with acute
Blood Reviews (2003) 17, 123–129
c 2003 Elsevier Science Ltd. All rights reserved.
28.
29.
30.
31. 32.
33. 34.
35.
36. 37.
38.
39.
40.
41.
42.
43.
44.
45.
myelogenous leukemia: association with FAB subtypes and identification of subgroups with poor prognosis. Blood 2002; 99: 4326–4335. Stirewalt DL, Kopecky KJ, Meshinchi S, Appelbaum FR, Slovak ML, Willman CL et al. FLT3, RAS, and TP53 mutations in elderly patients with acute myeloid leukemia. Blood 2001; 97: 3589–3595. Mizuki M, Fenski R, Halfter H, Matsumura I, Schmidt R, Muller C et al. Flt3 mutations from patients with acute myeloid leukemia induce transformation of 32D cells mediated by the Ras and STAT5 pathways. Blood 2000; 96: 3907–3914. Hayakawa F, Towatari M, Kiyoi H, Tanimoto M, Kitamura T, Saito H et al. Tandem-duplicated Flt3 constitutively activates STAT5 and MAP kinase and introduces autonomous cell growth in IL-3-dependent cell lines. Oncogene 2000; 19: 624–631. Davis RJ. Transcriptional regulation by MAP kinases. Mol Reprod Dev 1995; 42: 459–467. Dent P, Haser W, Haystead TA, Vincent LA, Roberts TM, Sturgill TW. Activation of mitogen-activated protein kinase kinase by v-Raf in NIH 3T3 cells and in vitro. Science 1992; 257: 1404–1407. Kyriakis JM, App H, Zhang XF, Banerjee P, Brautigan DL, Rapp UR et al. Raf-1 activates MAP kinase-kinase. Nature 1992; 358: 417–421. Robbins DJ, Zhen E, Owaki H, Vanderbilt CA, Ebert D, Geppert TD et al. Regulation and properties of extracellular signal-regulated protein kinases 1 and 2 in vitro. J Biol Chem 1993; 268: 5097–5106. Xing J, Ginty DD, Greenberg ME. Coupling of the RAS–MAPK pathway to gene activation by RSK2, a growth factor-regulated CREB kinase. Science 1996; 273: 959–963. Downward J. Mechanisms and consequences of activation of protein kinase B/Akt. Curr Opin Cell Biol 1998; 10: 262–267. Duronio V, Scheid MP, Ettinger S. Downstream signalling events regulated by phosphatidylinositol 3-kinase activity. Cell Signal 1998; 10: 233–239. Marte BM, Downward J. PKB/Akt: connecting phosphoinositide 3-kinase to cell survival and beyond. Trends Biochem Sci 1997; 22: 355–358. Kinoshita T, Shirouzu M, Kamiya A, Hashimoto K, Shigeyuki Y, Miyajima A. Raf/MAPK and rapamycin-sensitive pathways mediate the anti-apoptotic function of p21 Ras in IL-3-dependent hematopoietic cells. Oncogene 1997; 15: 619–627. Alessi DR, Cuenda A, Cohen P, Dudley DT, Saltiel AR. PD 098059 is a specific inhibitor of the activation of mitogen-activated protein kinase kinase in vitro and in vivo. J Biol Chem 1995; 270: 27489–27494. Skorski T, Bellacosa A, Nieborowska-Skorska M, Majewski M, Martinez R, Choi JK et al. Transformation of hematopoietic cells by BCR/ABL requires activation of a PI-3k/Akt dependent pathway. EMBO J 1997; 16: 6151–6161. Kiyoi H, Naoe T, Nakano Y, Yokota T, Minami S, Miyawaki S et al. Prognostic implication of FLT3 and N-RAS gene mutations in acute myeloid leukemia. Blood 1999; 93: 3074–3080. Lee YY, Kim WS, Bang YJ, Jung CW, Park S, Yoon WJ et al. Analysis of mutations of neurofibromatosis type1 gene and N-ras gene in acute myelogenous leukemia. Stem Cells 1995; 13: 556–563. Neubauer A, Dodge RK, George SL, Davey FR, Silver RT, Schiffer CA et al. Prognostic importance of mutations in the ras proto-oncogenes in de novo acute myeloid leukemia. Blood 1994; 83: 1603–1611. Padua RA, Guinn BA, al-Sabah AI, Smith M, Taylor C, Pettersson T et al. RAS, FMS, and p53 mutations and poor clinical outcome in myelodysplasias: a 10 year follow-up. Leukemia 1998; 12: 887–892.
Farnesyl transferase inhibitors in myeloid malignancies 46. Paquette RL, Landaw EM, Pierre RV, Kahan J, Lubbert M, Lazcano O et al. N-ras mutations are associated with poor prognosis and increased risk of leukemia in myelodysplastic syndrome. Blood 1993; 82: 590–599. 47. Radich JP, Kopecky KJ, Willman CL, Weick J, Head D, Appelbaum F et al. N-ras mutations in adult de novo acute myelogenous leukemia: prevalence and clinical significance. Blood 1990; 76: 801–807. 48. Kim SC, Hahn JS, Min YH, Yoo NC, Ko YW, Lee WJ. Constitutive activation of extracellular signal-regulated kinase in human acute leukemias: combined role of activation of MEK, hyperexpression of extracellular signal-regulated kinase, and downregulation of a phosphatase, PAC1. Blood 1999; 93: 3893–3899. 49. Kornblau SM, Milella M, Ball G, Qui YH, Ruvolo P, Estrov Z et al. ERK2 and Phospho-ERK2 are prognostic for survival in AML and complement the prognostic impact of Bax and BCL-2. Blood 2001; 98: 716a, Abstract. 50. Towatari M, Iida H, Iwata H, Hamaguchi M, Saito H. Constitutive activation of mitogen-activated protein kinase pathway in acute leukemia cells. Leukemia 1997; 11: 479–484. 51. Lancet JE, Ryan CP, Abboud CN, Rosell KE, Lu C, Karp JE et al. Differences in the expression of signal transduction molecules between normal and leukemic bone marrow. Blood 2002; 98: 111a, Abstract. 52. Lancet JE, Willman CL, Bennett JM. Acute myelogenous leukemia and aging: clinical interactions. Hematol Oncol Clin North Am 2000; 14: 251–267. 53. Lowenberg B, Suciu S, Archimbaud E, Ossenkoppele G, Verhoef GE, Vellenga E et al. Use of recombinant GM-CSF during and after remission induction chemotherapy in patients aged 61 years and older with acute myeloid leukemia: final report of AML-11, a phase III randomized study of the Leukemia Cooperative Group of European Organisation for the Research and Treatment of Cancer and the Dutch Belgian Hemato-Oncology Cooperative Group. Blood 1997; 90: 2952–2961. 54. Godwin JE, Kopecky KJ, Head DR, Willman CL, Leith CP, Hynes HE et al. A double-blind placebo-controlled trial of granulocyte colonystimulating factor in elderly patients with previously untreated acute myeloid leukemia: a Southwest oncology group study (9031). Blood 1998; 91: 3607–3615. 55. Dombret H, Chastang C, Fenaux P, Reiffers J, Bordessoule D, Bouabdallah R et al. A controlled study of recombinant human granulocyte colony-stimulating factor in elderly patients after treatment for acute myelogenous leukemia. AML Cooperative Study Group. N Engl J Med 1995; 332: 1678–1683. 56. Feldman EJ, Seiter K, Damon L, Linker C, Rugo H, Ries C et al. A randomized trial of high- vs standard-dose mitoxantrone with cytarabine in elderly patients with acute myeloid leukemia. Leukemia 1997; 11: 485–489. 57. Leith CP, Kopecky KJ, Chen IM, Eijdems L, Slovak ML, McConnell TS et al. Frequency and clinical significance of the expression of the multidrug resistance proteins MDR1/P-glycoprotein, MRP1, and LRP
58.
59.
60.
61.
62.
63.
64.
65.
66.
67.
68.
69.
in acute myeloid leukemia: a Southwest Oncology Group Study. Blood 1999; 94: 1086–1099. Leith CP, Kopecky KJ, Godwin J, McConnell T, Slovak ML, Chen IM et al. Acute myeloid leukemia in the elderly: assessment of multidrug resistance (MDR1) and cytogenetics distinguishes biologic subgroups with remarkably distinct responses to standard chemotherapy. A Southwest Oncology Group study. Blood 1997; 89: 3323–3329. Greenberg P, Cox C, LeBeau MM, Fenaux P, Morel P, Sanz G et al. International scoring system for evaluating prognosis in myelodysplastic syndromes. Blood 1997; 89: 2079–2088. Karp JE, Lancet JE, Kaufmann SH, End DW, Wright JJ, Bol K et al. Clinical and biologic activity of the farnesyltransferase inhibitor R115777 in adults with refractory and relapsed acute leukemias: a phase I clinical-correlative trial. Blood 2001; 97: 3361– 3369. Harousseau J-L, Stone R, Thomas X, Lancet J, Arani R, Thibault A et al. Interim results from a phase II study of R115777 (ZARNESTRA) in patients with refractory and relapsed acute myelogenous leukemia. Progr/Proc Am Soc Clin Oncol 2002; 21: 265a, Abstract. Raponi M, Belly R, Atkins D, Thibault A, Rackoff W, Rybak ME et al. Pharmacogenomic analysis reveals signaling pathways modulated by R115777 (Zarnestra) in acute myeloid leukemia. Prog/Proc Am Soc Clin Oncol 2002; 21: 265a, Abstract. Lancet JE, Karp JE, Gotlib J, Kaufmann SH, Gojo I, Greenberg PL et al. Zarnestra (R115777) in previously untreated poor-risk AML and MDS: preliminary results of a phase II trial. Blood 2002; 100: 560a. Kurzrock R, Sebti Sm, Kantarjian HM, Wright J, Cortes JE, Thomas DA et al. Phase I study of a farnesyl transferase inhibitor, R115777, in patients with myelodysplastic syndromes. Blood 2001; 98: 623a, Abstract. Kurzrock R, Cortes J, Rybak ME, Thibault A, Faderl S, Estey E et al. Phase II study of R115777, a farnesyltransferase inhibitor, in myelodysplastic syndrome. Blood 2001; 98: 848a, Abstract. Thomas D, Cortes J, O’Brien SM, Garcia Manero G, Kurzrock R, Giles FJ et al. R115777, a farnesyl transferase inhibitor (FTI), has significant anti-leukemia activity in patients with chronic myeloid leukemia (CML). Blood 2001; 98: 727a, Abstract. Gotlib J, Dugan K, Katamneni U, Sridhar K, Wright J, Thibault A et al. Phase I/II study of farnesyltransferase inhibitor R115777 (Zarnestra) in patients with myeloproliferative disorders (MPDs): preliminary results. J Clin Oncol 2002; 21: 4a, Abstract. Cortes J, Kurzrock R, O’Brien SM, Thomas D, Faderl S, GarciaManero G et al. Phase I study of a farnesyl transferase inhibitor (FTI), BMS-214662, in patients with refractory or relapsed acute leukemias. Blood 2002; 98: 594a, Abstract. Hoover RR, Mahon FX, Melo JV, Daley GQ. Overcoming STI571 resistance with the farnesyl transferase inhibitor SCH66336. Blood 2002; 100: 1068–1071.
c 2003 Elsevier Science Ltd. All rights reserved.
Blood Reviews (2003) 17, 123–129
129
Farnesyl transferase inhibitors in myeloid malignancies
dergoing rapid clinical development. This latter class of agents, and its potential role in hematologic malignancies, will be the focus of this review.
BACKGROUND Jeffrey E. Lancet1, Judith E. Karp2 1
University of Rochester, James P. Wilmot Cancer Center, 601 Elmwood Avenue,
Box 704 Rochester, NY 14642, USA 2
Johns Hopkins University, Sydney Kimmel Cancer Center, 1650 Orleans Street,
Baltimore, MD 21201, USA
Abstract Farnesyl transferase inhibitors (FTIs) are a novel class of anti-cancer agents that competitively inhibit farnesyl protein transferase (FPT), and are currently being developed and tested across a wide range of human cancers. Hematologic malignancies, particularly those of myeloid origin, are reasonable disease targets in that they likely overexpress relevant biologic targets, such as Ras, mitogen-activated protein kinase (MAPK), or AKT, that depend upon FPT activity to promote proliferation and survival. Phase I clinical trials using FTIs in acute myelogenous leukemia (AML) and other myeloid malignancies have been performed, demonstrating enzyme target inhibition, low toxicity, and promising response rates. These findings have prompted further development in phase II trials, in order to clarify the response rate and to identify the actual downstream signal transduction targets that may be modified by these agents. It is anticipated that such information will ultimately define the optimal roles of FTIs in patients with AML and other myeloid disorders, facilitate the incorporation of FTIs into current therapeutic strategies for myeloid malignancies, and provide insight into effective methods of combining FTIs with other signal transduction inhibitors. c 2003 Elsevier Science Ltd. All rights reserved. KEY WORDS: farnesyl transferase inhibitors; myeloid malignancies; Ras; signal transduction
INTRODUCTION ecent advances in the understanding of molecular mechanisms of neoplasia have driven the development of new therapeutic compounds that target molecules governing cellular proliferation, differentiation, and survival. As such, a panoply of novel pharmacologic agents has entered cancer clinical trials. Signal transduction inhibitors are among the most promising of these agents, with an ever-expanding repertoire of malignancies being tested. For example, Imatinib Mesylate (formerly known as STI-571), a relatively potent and selective inhibitor of the BCR–ABL tyrosine kinase, has met with early success in the treatment of all phases of chronic myelogenous leukemia.1–3 Other signal transduction inhibitors in clinical trials target the tyrosine kinase domain of different molecules, including receptors for epidermal growth factor (EGF), vascular endothelial growth factor (VEGF), and FLT-3. Farnesyl transferase inhibitors represent another class of signal transduction inhibitor un-
R
Farnesyl transferase inhibitors are potent and selective competitive inhibitors of intracellular farnesyl protein transferase (FPT), an enzyme that catalyzes the transfer of a farnesyl moiety to the cysteine terminal residue of a substrate protein (Fig. 1).4 A host of intracellular proteins are substrates for prenylation via FTIs, including Ras, Rho-B, Rac, and Lamin proteins.5 Of particular interest in the development of FTIs was the potential to inhibit farnesylation of Ras proteins. The Ras family of oncoproteins is a critical network of signal transduction pathways that impacts cellular proliferation, survival, and differentiation (Fig. 2).5–7 Localization of the Ras protein to the cell membrane, where it is capable of activating downstream signaling events, requires the transfer of an isoprenyl group to its C-terminal amino acid motif.4;8 Mutated ras can fail to interact appropriately with its negative regulators, thereby leading to constitutive activation in the GTP-bound form.7 Hence, the central role of Ras in intracellular signaling, in conjunction with its frequently mutated status in human malignancies, makes it an attractive therapeutic target. However, inhibiting farnesylation of other proteins, such as Rho B, may play an equally important role in the ultimate mechanism by which these agents exert their anti-neoplastic effects.9;10 FTIs have been studied extensively in pre-clinical models, both in-vitro and in-vivo.11–20 Several important observations have arisen from these preclinical studies. First of all, FTIs are able to cause morphologic reversion of ras transformed cells.4;15;19;21 Second, growth inhibitory effects can be demonstrated in malignant cells with and without ras mutations, although tumor cells that are driven by overexpression or muation of certain ras isoforms (e.g., K-ras) appear to be more resistant to the anti-proliferative effects of FTIs.11;12;16;18;20;22 Third, the mechanisms behind the anti-tumor effects appear to be heterogeneous; while these agents clearly have antiproliferative and growth inhibitory effects, evidence suggests a role for pro-apoptotic effects as well, possibly through inhibition of the PI-3K pathway.9;23 Taken together, these findings have prompted interest in pursuing FTI therapy in clinical cancer trials.
MYELOID MALIGNANCIES AS THERAPEUTIC SETTINGS FOR FTI THERAPY Hematologic malignancies represent an ideal clinical venue in which to study FTI therapy. As will be discussed below, these diseases often express molecular targets germane to FTI therapy. In addition, the pathologic tissue of interest (e.g., leukemic bone marrow) is often readily accessible by means of minimally invasive procedures. As such, the biologic effects of a therapeutic compound in malignant cells can be more easily studied than in cases of solid tumors.
c 2003 Elsevier Science Ltd. All rights reserved.
Blood Reviews (2003) 17, 123–129 doi:10.1016/S0268-960X(03)00008-0
123
Lancet and Karp
Fig. 1 Farnesylation pathway (adapted with kind permission from Lippincott, Williams, and Wilkins in Rowinsky et al.5
Fig. 2 Ras-mediated signaling pathways. Farnesylated Ras protein tranlocates to the cell membrane. In its GTP-bound form, Ras mediates diverse signaling pathways that regulate many cellular functions.
Ras-mediated signaling pathways as they relate to myeloid diseases As discussed previously, activated Ras directs many crucial intracellular signaling events. Certain molecular events pathognomonic to myeloid malignancies may depend upon Ras signaling to facilitate the ultimate transformation or leukemogenic process, thereby making Ras itself a rational target for new therapeutic agents such as FTIs. One example of how Ras plays a vital role in leukemogenesis can be demonstrated in a chronic myelogenous leukemia (CML) model, where leukemic transformation depends upon the presence of a specific oncoprotein, BCR–ABL, resulting from a translocation between chromosomes 9 and 22. In this model, investigators have shown that introduction of a dominant 124
Blood Reviews (2003) 17, 123–129
c 2003 Elsevier Science Ltd. All rights reserved.
negative (inactive) ras into BCR–ABL transfected hematopoietic or fibroblast cells results in a complete blockage of malignant transformation.24 In AML, certain receptors on myeloid progenitor cells are thought to be important in cellular signaling, via interaction with their ligands. For example, FLT-3 is a receptor that is known to play a central role in the proliferation, survival and differentiation of early murine and human hematopoietic precursor cells.25 When internal tandem duplication (ITD) of the FLT3 gene occurs, as is the case in up to 20–35% of AML cases,26–28 this receptor can induce transformation as well as growth factor-independent activation of signaling pathways, particularly Jak/Stat and MAPK.29;30 In accordance with these findings, it has also been demonstrated that transfection with a dominant-negative
Farnesyl transferase inhibitors in myeloid malignancies form of Ras inhibits colony formation in cells containing the FLT-3 ITD mutation.29 Such findings provide rationale for targeting Ras itself in myeloid malignancies. Downstream from Ras, there are a number of effector molecules and pathways that influence a variety of cellular processes thought to be important in both normal and malignant hematopoiesis (Fig. 2). One such pathway is the Raf– MEK–MAPK cascade, in which a series of phosphorylation events ultimately leads to the localization of phosphorylated MAPK to the cell nucleus, where it activates transcription factors that help to govern cellular proliferation and apoptosis.31–35 A second Ras-mediated signaling pathway of importance is the PI-3K–AKT pathway. In this effector pathway, the activated Ras protein binds and activates PI3K, a tyrosine kinase, which in turn phosphorylates AKT, a potent suppressor of apoptosis.36–38 These signaling pathways likely have significant implications in the development and propagation of malignant hematopoiesis. For instance, mutant (constitutively activated) Raf can abrogate growth factor dependency in hematopoietic cells.39 In addition, pharmacologic inhibitors of MEK function and antisense RNA to MEK can block Ras or Raf-mediated transformation and cytokinestimulated growth.40 The Ras–PI3K–AKT pathway is germane to hematopoiesis and leukemogenesis as well. For example, it has been shown that intact PI3K–AKT signaling is essential for BCR–ABL induced transformation and colony growth.41 Further evidence to support the critical role of the PI3K–AKT pathway in malignant hematopoiesis can be found in a study whereby Ras mutants incapable of activating the Raf–MEK– ERK pathway were still able to inhibit apoptosis in IL-3-dependent cell lines. This effect was blocked by Wortmannin, emphasizing the importance of the PI3K–AKT pathway in hematopoiesis.39 Data extracted from clinical AML samples also lend evidence to the relevance of Ras and its signaling pathways in this disease. One potentially important finding is that ras (particularly the N-ras isoform) is mutated in up to 48% of AML and MDS cases, although there is considerable variation in these rates amongst published series.42–47 Signaling through the MAPK pathway may also be altered in AML. To this end, it has been suggested that constitutive activation of MAPK (ERK), as determined by the presence of phosphory-
lated MAPK in AML cells at diagnosis, occurs at a high frequency in AML.48–50 Abnormal signaling through the PI-3K/ AKT pathway may also occur in AML. Some preliminary data have indicated that a majority of AML samples express phosphorylated (or activated) AKT as compared to normal control samples.51 Clinical rationale for new agents in myeloid diseases From a clinical standpoint, the myeloid malignancies, particularly AML, represent a cohort of diseases that are appropriate candidates for new, targeted therapies such as FTIs. As evidenced by many clinical trials, AML is a disease of primarily of older individuals that is associated with a very low rate of long-term survival, especially in older patients, with median survival on the order of 1 year.52 In addition, the rates of chemotherapy-associated severe toxicities, along with death, are very high in this disease. In adults over age 60, the risk of treatment-related death is on the order of 20% during the induction phase of therapy.53–56 In patients fortunate enough to achieve complete remission through chemotherapy, the remission duration is usually short, generally on the order of 1 year or less.53–56 Besides the toxicity risks, chemotherapy failure in AML is often due to the presence of multi-drug resistance phenotype, which correlates negatively with remission rate.57;58 For these reasons, new agents that may pose less toxicity, as well as novel mechanisms of antitumor activity, are necessary to improve outcomes in patients with AML. In a similar light, myelodysplastic syndromes, particularly those with a high international prognostic system score (IPSS), are associated with poor long-term prognoses.59 Other myeloid diseases such as chronic myelogenous leukemia (in accelerated or blast phase) and certain myeloproliferative disorders carry poor prognoses, and are also reasonable diseases in which to investigate new therapies.
CLINICAL TRIALS USING FTIS IN MALIGNANT MYELOID DISORDERS Given the plethora of clinical and preclinical data to support the use of FTIs in myeloid malignancies, a large number of clinical trials have been undertaken in this arena (Table 1).
Table 1 Clinical trials of farnesyl transferase inhibitors in myeloid malignancies Disease
FTI agent
Phase
Refractory, relapsed, or high-risk acute leukemias MDS Refractory advanced hematologic malignancies Pediatric refractory leukemias MPDs Refractory/Relapsed AML Previously untreated high-risk AML, MDS
R115777 R115777 R115777 R115777 R15777 R115777 R115777
I I I I I/II II II
CML MDS Refractory/relapsed AML, MDS
R115777 R115777 BMS-214662
II II I
Institution University of Maryland, University of Rochester MD Anderson University of Chicago NCI Stanford University, University of Rochester Int’l University of Rochester, University of Maryland, Stanford University, Mayo Clinic MD Anderson MD Anderson MD Anderson
c 2003 Elsevier Science Ltd. All rights reserved.
Blood Reviews (2003) 17, 123–129
125
Lancet and Karp Karp and Lancet, et al. recently reported the first completed phase I study of FTI therapy in hematologic malignancies.60 This trial was performed in a wide range of patients with poor-risk acute leukemias, utilizing the farnesyl transferase inhibitor R115777 (ZARNESTRA), administered orally for 21 days, for up to four full cycles. Reliable inhibition of farnesyl transferase activity occurred at or above the 300 mg BID dosing level, and dose-limiting toxicity, manifested as a readily reversible central neurotoxicity, was observed at the 1200 mg BID dosing level. Significantly, there was a dosedependent increase in drug concentration within the bone marrow, at higher levels than was observed in the peripheral blood. Clinical responses were observed in 10 of 34 patients, including two complete responses. Interestingly, responses occurred across the entire range of dosing levels (100–900 mg BID), challenging both the validity of the assays and the notion that a specific degree of enzyme inhibition is necessary to achieve clinical response. Responses also occurred independently of ras mutational status, as none of the 34 leukemic samples demonstrated an N-Ras mutation. Since FTIs may interfere with Ras-mediated signaling, measurement of Ras-mediated signaling intermediates, such as MAPK, could be useful in predicting response to R115777. In this study, a selected number of leukemic samples were analyzed for the presence of phosphorylated MAPK (via Western blot analysis), an important signaling intermediate of cellular proliferation within the Ras family of signaling. We observed eight patients in whom the leukemic marrow demonstrated phospho-MAPK at baseline, four of whom achieved clinical response. In the 14 patients with no evidence of baseline phospho-MAPK expression, only two responses were noted. While this observation clearly needs confirmation, it highlights the fact that measurement of MAPK and other easily measurable signaling intermediates may provide insight into downstream drug targets. Preliminary results from a large, multi-center phase II study of FTI R115777 in refractory or relapsed AML have also been recently reported.61 This trial utilized a 600 mg BIDdosing schema for 21 days every 4 weeks. At the time of the report, 17 of 50 evaluable patients (14%) with relapsed disease experienced a reduction in bone marrow blasts to <5%, while 31 of 50 (62%) had P50% decrease in bone marrow blasts from baseline. Rash and hyperbilirubinemia were among the most frequent adverse events. In addition to the endpoint of clinical response, microarray-based pharmacogenomic analysis is being performed, exploring the cellular signaling pathways that may be modulated by FTI therapy. To this end, preliminary data obtained from leukemic samples in this trial demonstrate that genes regulating apoptotic, MAPK, and TGFb pathways are modulated by treatment with R115777.62 We are currently conducting a phase II trial of R115777 in previously untreated patients with poor-risk AML and MDS, the preliminary results of which are recently reported.63 To date, we have observed responses in 10 of 30 (33%) evaluable patients, most of whom were elderly (median age 74). Notably, eight of these 10 responses were deemed complete responses. While expected grade 3 or 4 hematologic toxicity has occurred in a majority of patients, severe non-hematologic toxicity has been less common. Another interesting 126
Blood Reviews (2003) 17, 123–129
c 2003 Elsevier Science Ltd. All rights reserved.
preliminary finding is that all four patients with baseline trisomy 8 abnormality in leukemic bone marrow have experienced response to R115777. Additional non-clinical endpoints being studied at baseline and during therapy include measurement of MAPK and AKT activation, inhibition of farnesylation, and mutational status of ras and FLT3. Results of FTI therapy in other myeloid malignancies is also being reported. Kurzrock et al. 64;65 have recently reported preliminary results of phase I and II clinical trials utilizing R115777 in myelodysplastic syndromes. In the phase I study, the DLT was fatigue, occurring at 900 mg BID. An objective response rate (partial response or hematologic improvement) was detected in 33%. The phase II trial, which enrolled patients with either relapsed MDS or poor-risk previously untreated disease (over age 60), demonstrated complete responses in 2 of 16 patients. Also notable was the fact that dose reduction from 600 to 300 mg BID was frequently necessary for reasons including myelosuppression, fatigue, and cerebellar symptoms. As in the phase I trial in refractory and relapsed leukemias, there was no correlation between response and baseline Ras mutational status. Myeloproliferative diseases are also being studied for responsiveness to FTI therapy. Preliminary results of a phase II trial of FTI R115777 in CML, multiple myeloma, and myeloproliferative disorders were recently reported.66 In the CML subset, 6 of 10 patients with chronic phase disease experienced partial or complete responses, while 1 of 5 patients with accelerated disease experienced complete response. Minor cytogenetic responses were also observed in some patients. Patients with myelofibrosis experienced significant reduction in spleen size. Consistent with other studies, common grade P3 toxicities included myelosuppression, skin rash, peripheral neuropathy, and liver toxicity. Gotlib et al.67 have also reported preliminary results of a phase I/II trial in myeloproliferative diseases, including CML, myelofibrosis, and chronic myelomonocytic leukemia. At the time of this report, two of eight evaluable patients had experienced complete WBC responses. Severe anemia or thrombocytopenia occurred in four patients. This study also demonstrated biologic activity, with dose-related suppression of bone marrow CFU-GMs and inhibition of farnesylation of the surrogate marker, heat shock protein HDJ-2. Although R115777 is the most developed FTI in hematologic malignancy trials, other FTIs are also being studied in this context. A phase I trial using FTI BMS-214662, another potent and selective inhibitor of FPT, is also being performed.68 Preliminary results of this trial have shown a >50% reduction in bone marrow blasts in 5 of 22 patients. Dose limiting toxicity had not yet been reached at the time of the preliminary report.
IMPLICATIONS FOR FTI THERAPY IN MYELOID MALIGNANCIES As a new class of agents with a unique mechanism of action, farnesyl transferase inhibitors clearly have an emerging role in cancer therapy. By interfering with intracellular signaling, these agents likely inhibit leukemic cell growth and survival differently than traditional chemotherapeutic drugs. This
Farnesyl transferase inhibitors in myeloid malignancies concept is relevant to the treatment of AML and other myeloid malignancies, in which there are often drug resistance mechanisms at play that limit the efficacy of chemotherapy, and in which considerations about severe toxicities limit the ultimate benefit of cytotoxic therapy for a large proportion of patients. Although the overall role with FTI therapy in myeloid malignancies continues to emerge, some important conclusions can be reasonably made, based on the experience to date. First of all, many myeloid diseases are dependent, at least in part, by signaling processes that may be targeted directly or indirectly by FTIs. Secondly, these agents have clinical activity across a wide range of myeloid diseases, including AML, MDS, CML, and myeloproliferative diseases. The activity of FTIs in CML is of particular interest, as new invitro data have emerged, suggesting that the FTI SCH66336 potentiates apoptosis in STI-resistant cells.69 Finally, most toxicity data that have emerged to this point highlight a relative paucity of severe adverse effects directly attributable to these agents. These characteristics, in toto, are important because they point out the feasibility of eventually combining FTIs with other agents such as chemotherapy as well as highlight the potential of these agents for use over an extended period, longer than would be possible for traditional cytotoxic agents. The rapid development of FTIs and the observations pertaining to their activity in myeloid malignancies have created both challenges and opportunities. A primary challenge will be to gain a better understanding as to the precise mechanisms by which these agents exert their antineoplastic effects, across different disease subgroups. These insights will be important for many reasons. For example, knowledge about specific signaling targets that are inhibited by FTIs may eventually allow investigators to tailor such therapy to patients whose disease characteristics exhibit overexpression of these targets and to combine FTIs with other signal transduction inhibitors that block different pathways. In addition, understanding the specific tumor cellÕs response (e.g., apoptosis vs. cell cycle arrest) to the FTI will allow for the rational design of trials that incorporate traditional chemotherapy or other signal transduction modifiers to act synergistically with FTIs. For these reasons, it is critical that clinical researchers incorporate correlative studies into their trials to answer such questions. Newer techniques such as DNA microarray profiling and proteomics will permit broader investigation into families of targets that may be preferentially expressed in various disease categories. While new targeted therapies such as FTIs offer great promise, it is important to recognize that they will likely have limited roles as single agents in aggressive or refractory malignancies, which are often driven by multiple genetic lesions and diverse, non-overlapping signals. In accordance with this observation, novel approaches to the use of FTIs in myeloid malignancies are being developed. In AML, for example, we are investigating R115777 as frontline therapy in older patients with newly diagnosed AML and high-risk MDS and as consolidation (post-remission) therapy in AML patients of any age whose disease exhibits poor risk features. Both of these disease settings afford the opportunity to study the antineoplastic effect of FTIs at times when multiple genetic lesions or massive leukemic burden is less than in the refractory or
relapsed state. As such, the antineoplastic effect may be easier to identify and to study, and the feasibility of extendedduration therapy may be undertaken. Other clinical trials being planned in the setting of AML and MDS include phase I studies combining FTI with induction chemotherapy and studies that will examine the use of ‘‘upfront’’ FTI therapy, followed by standard cytotoxic chemotherapy. In CML blast phase, a phase I trial utilizing R115777 in combination with STI571 is being conducted. With the advent of other novel agents that interfere with signal transduction, such as FLT-3 inhibitors, proteasome inhibitors, and MAPK pathway inhibitors, it seems certain that further novel trials of such agents in combination with FTIs will take place in the near future.
Correspondence to: Jeffrey E. Lancet, MD, University of Rochester, James P. Wilmot Cancer Center, 601 Elmwood Avenue, Box 704, Rochester, NY 14642, USA. Tel.: +585-275-4099; Fax: +585-273-1042; E-mail: [email protected]
References 1. Druker BJ, Sawyers CL, Kantarjian H, Resta DJ, Reese SF, Ford JM et al. Activity of a specific inhibitor of the BCR–ABL tyrosine kinase in the blast crisis of chronic myeloid leukemia and acute lymphoblastic leukemia with the Philadelphia chromosome. N Engl J Med 2001; 344: 1038–1042. 2. Druker BJ, Talpaz M, Resta DJ, Peng B, Buchdunger E, Ford JM et al. Efficacy and safety of a specific inhibitor of the BCR–ABL tyrosine kinase in chronic myeloid leukemia. N Engl J Med 2001; 344: 1031–1037. 3. Talpaz M, Silver RT, Druker BJ, Goldman JM, Gambacorti-Passerini C, Guilhot F et al. Imatinib induces durable hematologic and cytogenetic responses in patients with accelerated phase chronic myeloid leukemia: results of a phase 2 study. Blood 2002; 99: 1928–1937. 4. End DW. Farnesyl protein transferase inhibitors and other therapies targeting the Ras signal transduction pathway. Invest New Drugs 1999; 17: 241–258. 5. Rowinsky EK, Windle JJ, Von Hoff DD. Ras protein farnesyltransferase: a strategic target for anticancer therapeutic development. J Clin Oncol 1999; 17: 3631–3652. 6. Boguski MS, McCormick F. Proteins regulating Ras and its relatives. Nature 1993; 366: 643–654. 7. Lowy DR, Willumsen BM. Function and regulation of ras. Annu Rev Biochem 1993; 62: 851–891. 8. Khosravi-Far R, Cox AD, Kato K, Der CJ. Protein prenylation: key to ras function and cancer intervention? Cell Growth Differ 1992; 3: 461–469. 9. Prendergast GC. Farnesyltransferase inhibitors: antineoplastic mechanism and clinical prospects. Curr Opin Cell Biol 2000; 12: 166–173. 10. Du W, Lebowitz PF, Prendergast GC. Cell growth inhibition by farnesyltransferase inhibitors is mediated by gain of geranylgeranylated RhoB. Mol Cell Biol 1999; 19: 1831–1840. 11. End DW, Smets G, Todd AV, Applegate TL, Fuery CJ, Angibaud P et al. Characterization of the antitumor effects of the selective
c 2003 Elsevier Science Ltd. All rights reserved.
Blood Reviews (2003) 17, 123–129
127
Lancet and Karp
12.
13.
14.
15.
16.
17.
18.
19.
20.
21.
22.
23.
24.
25.
26.
27.
128
farnesyl protein transferase inhibitor R115777 in vivo and in vitro. Cancer Res 2001; 61: 131–137. James G, Goldstein JL, Brown MS. Resistance of K-RasBV12 proteins to farnesyltransferase inhibitors in Rat1 cells. Proc Natl Acad Sci USA 1996; 93: 4454–4458. James GL, Goldstein JL, Brown MS, Rawson TE, Somers TC, McDowell RS et al. Benzodiazepine peptidomimetics: potent inhibitors of Ras farnesylation in animal cells. Science 1993; 260: 1937–1942. Kohl NE, Wilson FR, Mosser SD, Giuliani E, deSolms SJ, Conner MW et al. Protein farnesyltransferase inhibitors block the growth of ras-dependent tumors in nude mice. Proc Natl Acad Sci USA 1994; 91: 9141–9145. Kohl NE, Mosser SD, deSolms SJ, Giuliani EA, Pompliano DL, Graham SL et al. Selective inhibition of ras-dependent transformation by a farnesyltransferase inhibitor. Science 1993; 260: 1934–1937. Liu M, Bryant MS, Chen J, Lee S, Yaremko B, Lipari P et al. Antitumor activity of SCH 66336, an orally bioavailable tricyclic inhibitor of farnesyl protein transferase, in human tumor xenograft models and wap-ras transgenic mice. Cancer Res 1998; 58: 4947–4956. Mahgoub N, Taylor BR, Gratiot M, Kohl NE, Gibbs JB, Jacks T et al. In vitro and in vivo effects of a farnesyltransferase inhibitor on Nf1-deficient hematopoietic cells. Blood 1999; 94: 2469–2476. Nagasu T, Yoshimatsu K, Rowell C, Lewis MD, Garcia AM. Inhibition of human tumor xenograft growth by treatment with the farnesyl transferase inhibitor B956. Cancer Res 1995; 55: 5310–5314. Prendergast GC, Davide JP, deSolms SJ, Giuliani EA, Graham SL, Gibbs JB et al. Farnesyltransferase inhibition causes morphological reversion of ras-transformed cells by a complex mechanism that involves regulation of the actin cytoskeleton. Mol Cell Biol 1994; 14: 4193–4202. Sepp-Lorenzino L, Ma Z, Rands E, Kohl NE, Gibbs JB, Oliff A et al. A peptidomimetic inhibitor of farnesyl:protein transferase blocks the anchorage-dependent and -independent growth of human tumor cell lines. Cancer Res 1995; 55: 5302–5309. Kohl NE, Omer CA, Conner MW, Anthony NJ, Davide JP, deSolms SJ et al. Inhibition of farnesyltransferase induces regression of mammary and salivary carcinomas in ras transgenic mice. Nat Med 1995; 1: 792–797. Whyte DB, Kirschemeier P, Hockenberry TN, Nunez-Oliva I, James L, Catino JJ et al. K- and N-Ras are geranylgeranylated in cells treated with farnesyl protein transferase inhibitors. J Biol Chem 1997; 272: 14459–14464. Du W, Liu A, Prendergast GC. Activation of the PI3ÕK–AKT pathway masks the proapoptotic effects of farnesyltransferase inhibitors. Cancer Res 1999; 59: 4208–4212. Sawyers CL, McLaughlin J, Witte ON. Genetic requirement for Ras in the transformation of fibroblasts and hematopoietic cells by the Bcr-Abl oncogene. J Exp Med 1995; 181: 307–313. Shurin MR, Esche C, Lotze MT. FLT3: receptor and ligand. Biology and potential clinical application. Cytokine Growth Factor Rev 1998; 9: 37–48. Schnittger S, Schoch C, Dugas M, Kern W, Staib P, Wuchter C et al. Analysis of FLT3 length mutations in 1003 patients with acute myeloid leukemia: correlation to cytogenetics, FAB subtype, and prognosis in AMLCG study and usefulness as a marker for the detection of minimal residual disease. Blood 2002; 100: 59–66. Thiede C, Steudel C, Mohr B, Schaich M, Schakel U, Platzbecker U et al. Analysis of FLT3-activating mutations in 979 patients with acute
Blood Reviews (2003) 17, 123–129
c 2003 Elsevier Science Ltd. All rights reserved.
28.
29.
30.
31. 32.
33. 34.
35.
36. 37.
38.
39.
40.
41.
42.
43.
44.
45.
myelogenous leukemia: association with FAB subtypes and identification of subgroups with poor prognosis. Blood 2002; 99: 4326–4335. Stirewalt DL, Kopecky KJ, Meshinchi S, Appelbaum FR, Slovak ML, Willman CL et al. FLT3, RAS, and TP53 mutations in elderly patients with acute myeloid leukemia. Blood 2001; 97: 3589–3595. Mizuki M, Fenski R, Halfter H, Matsumura I, Schmidt R, Muller C et al. Flt3 mutations from patients with acute myeloid leukemia induce transformation of 32D cells mediated by the Ras and STAT5 pathways. Blood 2000; 96: 3907–3914. Hayakawa F, Towatari M, Kiyoi H, Tanimoto M, Kitamura T, Saito H et al. Tandem-duplicated Flt3 constitutively activates STAT5 and MAP kinase and introduces autonomous cell growth in IL-3-dependent cell lines. Oncogene 2000; 19: 624–631. Davis RJ. Transcriptional regulation by MAP kinases. Mol Reprod Dev 1995; 42: 459–467. Dent P, Haser W, Haystead TA, Vincent LA, Roberts TM, Sturgill TW. Activation of mitogen-activated protein kinase kinase by v-Raf in NIH 3T3 cells and in vitro. Science 1992; 257: 1404–1407. Kyriakis JM, App H, Zhang XF, Banerjee P, Brautigan DL, Rapp UR et al. Raf-1 activates MAP kinase-kinase. Nature 1992; 358: 417–421. Robbins DJ, Zhen E, Owaki H, Vanderbilt CA, Ebert D, Geppert TD et al. Regulation and properties of extracellular signal-regulated protein kinases 1 and 2 in vitro. J Biol Chem 1993; 268: 5097–5106. Xing J, Ginty DD, Greenberg ME. Coupling of the RAS–MAPK pathway to gene activation by RSK2, a growth factor-regulated CREB kinase. Science 1996; 273: 959–963. Downward J. Mechanisms and consequences of activation of protein kinase B/Akt. Curr Opin Cell Biol 1998; 10: 262–267. Duronio V, Scheid MP, Ettinger S. Downstream signalling events regulated by phosphatidylinositol 3-kinase activity. Cell Signal 1998; 10: 233–239. Marte BM, Downward J. PKB/Akt: connecting phosphoinositide 3-kinase to cell survival and beyond. Trends Biochem Sci 1997; 22: 355–358. Kinoshita T, Shirouzu M, Kamiya A, Hashimoto K, Shigeyuki Y, Miyajima A. Raf/MAPK and rapamycin-sensitive pathways mediate the anti-apoptotic function of p21 Ras in IL-3-dependent hematopoietic cells. Oncogene 1997; 15: 619–627. Alessi DR, Cuenda A, Cohen P, Dudley DT, Saltiel AR. PD 098059 is a specific inhibitor of the activation of mitogen-activated protein kinase kinase in vitro and in vivo. J Biol Chem 1995; 270: 27489–27494. Skorski T, Bellacosa A, Nieborowska-Skorska M, Majewski M, Martinez R, Choi JK et al. Transformation of hematopoietic cells by BCR/ABL requires activation of a PI-3k/Akt dependent pathway. EMBO J 1997; 16: 6151–6161. Kiyoi H, Naoe T, Nakano Y, Yokota T, Minami S, Miyawaki S et al. Prognostic implication of FLT3 and N-RAS gene mutations in acute myeloid leukemia. Blood 1999; 93: 3074–3080. Lee YY, Kim WS, Bang YJ, Jung CW, Park S, Yoon WJ et al. Analysis of mutations of neurofibromatosis type1 gene and N-ras gene in acute myelogenous leukemia. Stem Cells 1995; 13: 556–563. Neubauer A, Dodge RK, George SL, Davey FR, Silver RT, Schiffer CA et al. Prognostic importance of mutations in the ras proto-oncogenes in de novo acute myeloid leukemia. Blood 1994; 83: 1603–1611. Padua RA, Guinn BA, al-Sabah AI, Smith M, Taylor C, Pettersson T et al. RAS, FMS, and p53 mutations and poor clinical outcome in myelodysplasias: a 10 year follow-up. Leukemia 1998; 12: 887–892.
Farnesyl transferase inhibitors in myeloid malignancies 46. Paquette RL, Landaw EM, Pierre RV, Kahan J, Lubbert M, Lazcano O et al. N-ras mutations are associated with poor prognosis and increased risk of leukemia in myelodysplastic syndrome. Blood 1993; 82: 590–599. 47. Radich JP, Kopecky KJ, Willman CL, Weick J, Head D, Appelbaum F et al. N-ras mutations in adult de novo acute myelogenous leukemia: prevalence and clinical significance. Blood 1990; 76: 801–807. 48. Kim SC, Hahn JS, Min YH, Yoo NC, Ko YW, Lee WJ. Constitutive activation of extracellular signal-regulated kinase in human acute leukemias: combined role of activation of MEK, hyperexpression of extracellular signal-regulated kinase, and downregulation of a phosphatase, PAC1. Blood 1999; 93: 3893–3899. 49. Kornblau SM, Milella M, Ball G, Qui YH, Ruvolo P, Estrov Z et al. ERK2 and Phospho-ERK2 are prognostic for survival in AML and complement the prognostic impact of Bax and BCL-2. Blood 2001; 98: 716a, Abstract. 50. Towatari M, Iida H, Iwata H, Hamaguchi M, Saito H. Constitutive activation of mitogen-activated protein kinase pathway in acute leukemia cells. Leukemia 1997; 11: 479–484. 51. Lancet JE, Ryan CP, Abboud CN, Rosell KE, Lu C, Karp JE et al. Differences in the expression of signal transduction molecules between normal and leukemic bone marrow. Blood 2002; 98: 111a, Abstract. 52. Lancet JE, Willman CL, Bennett JM. Acute myelogenous leukemia and aging: clinical interactions. Hematol Oncol Clin North Am 2000; 14: 251–267. 53. Lowenberg B, Suciu S, Archimbaud E, Ossenkoppele G, Verhoef GE, Vellenga E et al. Use of recombinant GM-CSF during and after remission induction chemotherapy in patients aged 61 years and older with acute myeloid leukemia: final report of AML-11, a phase III randomized study of the Leukemia Cooperative Group of European Organisation for the Research and Treatment of Cancer and the Dutch Belgian Hemato-Oncology Cooperative Group. Blood 1997; 90: 2952–2961. 54. Godwin JE, Kopecky KJ, Head DR, Willman CL, Leith CP, Hynes HE et al. A double-blind placebo-controlled trial of granulocyte colonystimulating factor in elderly patients with previously untreated acute myeloid leukemia: a Southwest oncology group study (9031). Blood 1998; 91: 3607–3615. 55. Dombret H, Chastang C, Fenaux P, Reiffers J, Bordessoule D, Bouabdallah R et al. A controlled study of recombinant human granulocyte colony-stimulating factor in elderly patients after treatment for acute myelogenous leukemia. AML Cooperative Study Group. N Engl J Med 1995; 332: 1678–1683. 56. Feldman EJ, Seiter K, Damon L, Linker C, Rugo H, Ries C et al. A randomized trial of high- vs standard-dose mitoxantrone with cytarabine in elderly patients with acute myeloid leukemia. Leukemia 1997; 11: 485–489. 57. Leith CP, Kopecky KJ, Chen IM, Eijdems L, Slovak ML, McConnell TS et al. Frequency and clinical significance of the expression of the multidrug resistance proteins MDR1/P-glycoprotein, MRP1, and LRP
58.
59.
60.
61.
62.
63.
64.
65.
66.
67.
68.
69.
in acute myeloid leukemia: a Southwest Oncology Group Study. Blood 1999; 94: 1086–1099. Leith CP, Kopecky KJ, Godwin J, McConnell T, Slovak ML, Chen IM et al. Acute myeloid leukemia in the elderly: assessment of multidrug resistance (MDR1) and cytogenetics distinguishes biologic subgroups with remarkably distinct responses to standard chemotherapy. A Southwest Oncology Group study. Blood 1997; 89: 3323–3329. Greenberg P, Cox C, LeBeau MM, Fenaux P, Morel P, Sanz G et al. International scoring system for evaluating prognosis in myelodysplastic syndromes. Blood 1997; 89: 2079–2088. Karp JE, Lancet JE, Kaufmann SH, End DW, Wright JJ, Bol K et al. Clinical and biologic activity of the farnesyltransferase inhibitor R115777 in adults with refractory and relapsed acute leukemias: a phase I clinical-correlative trial. Blood 2001; 97: 3361– 3369. Harousseau J-L, Stone R, Thomas X, Lancet J, Arani R, Thibault A et al. Interim results from a phase II study of R115777 (ZARNESTRA) in patients with refractory and relapsed acute myelogenous leukemia. Progr/Proc Am Soc Clin Oncol 2002; 21: 265a, Abstract. Raponi M, Belly R, Atkins D, Thibault A, Rackoff W, Rybak ME et al. Pharmacogenomic analysis reveals signaling pathways modulated by R115777 (Zarnestra) in acute myeloid leukemia. Prog/Proc Am Soc Clin Oncol 2002; 21: 265a, Abstract. Lancet JE, Karp JE, Gotlib J, Kaufmann SH, Gojo I, Greenberg PL et al. Zarnestra (R115777) in previously untreated poor-risk AML and MDS: preliminary results of a phase II trial. Blood 2002; 100: 560a. Kurzrock R, Sebti Sm, Kantarjian HM, Wright J, Cortes JE, Thomas DA et al. Phase I study of a farnesyl transferase inhibitor, R115777, in patients with myelodysplastic syndromes. Blood 2001; 98: 623a, Abstract. Kurzrock R, Cortes J, Rybak ME, Thibault A, Faderl S, Estey E et al. Phase II study of R115777, a farnesyltransferase inhibitor, in myelodysplastic syndrome. Blood 2001; 98: 848a, Abstract. Thomas D, Cortes J, O’Brien SM, Garcia Manero G, Kurzrock R, Giles FJ et al. R115777, a farnesyl transferase inhibitor (FTI), has significant anti-leukemia activity in patients with chronic myeloid leukemia (CML). Blood 2001; 98: 727a, Abstract. Gotlib J, Dugan K, Katamneni U, Sridhar K, Wright J, Thibault A et al. Phase I/II study of farnesyltransferase inhibitor R115777 (Zarnestra) in patients with myeloproliferative disorders (MPDs): preliminary results. J Clin Oncol 2002; 21: 4a, Abstract. Cortes J, Kurzrock R, O’Brien SM, Thomas D, Faderl S, GarciaManero G et al. Phase I study of a farnesyl transferase inhibitor (FTI), BMS-214662, in patients with refractory or relapsed acute leukemias. Blood 2002; 98: 594a, Abstract. Hoover RR, Mahon FX, Melo JV, Daley GQ. Overcoming STI571 resistance with the farnesyl transferase inhibitor SCH66336. Blood 2002; 100: 1068–1071.
c 2003 Elsevier Science Ltd. All rights reserved.
Blood Reviews (2003) 17, 123–129
129