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Keywords:

  • systemic mastocytosis;
  • therapy;
  • Kit;
  • tyrosine kinase inhibitors;
  • review

Abstract

  1. Top of page
  2. Abstract
  3. Classification of SM
  4. Pathogenesis of SM
  5. Standard Therapeutic Approaches to SM
  6. Investigational Therapeutic Approaches to SM
  7. KIT Tyrosine Kinase Inhibitors
  8. Nontyrosine Kinase Kit Signaling Inhibitors
  9. Monoclonal Antibodies
  10. DISCUSSION
  11. REFERENCES

In the absence of curative options, therapy for aggressive forms of systemic mastocytosis (SM) has relied in the use of cytoreductive agents, mainly interferon-α (IFN-α) and cladribine. However, responses are transient and only occur in a subset of patients. Gain-of-function mutations at codon 816 of the KIT protooncogene lead to constitutively active Kit receptor molecules, which are central to the pathogenesis of SM. Recent advances in the understanding of the molecular underpinnings of SM have led to the development of small molecules targeting mutant Kit tyrosine kinase isoforms that significantly have widened the range of therapeutic options for patients with SM. Some of these promising agents, such as dasatinib, AMN107, and PKC412, currently are under investigation in clinical trials whereas, others are at different stages of preclinical development. In addition, monoclonal antibodies directed to neoplastic mast cell-restricted surface antigens constitute a viable option for the treatment of SM that warrants further investigation. Cancer 2006. © 2006 American Cancer Society.

Systemic mastocytosis (SM) encompasses a range of heterogeneous disorders that are characterized by overproliferation and accumulation of clonal mast cells (MCs). MCs cluster focally in the bone marrow, skeletal system, spleen, liver, and lymph nodes, although other organ systems may be involved.1, 2 The clinical manifestations of SM are related directly to tissue infiltration and to the release of chemical mediators by MCs and may include, among others, skin rash, gastrointestinal symptoms, syncope, anaphylaxis, osteoporosis, organomegaly, and/or pancytopenia.1, 2 Important advances have been made over the last decade in our understanding of the molecular pathogenesis of SM. Gain-of-function point mutations in the KIT kinase domain are present in the majority of patients with SM, resulting in ligand-independent, constitutive activation of Kit signaling, thus leading to uncontrolled MC proliferation and resistance to apoptosis.3 The most frequently encountered mutation is D816V, which maps to the tyrosine kinase domain4 and renders this KIT mutant amenable to targeted therapies. Herein, we review the therapeutic modalities currently employed in the treatment of SM with particular emphasis on small-molecule tyrosine kinase inhibitors that target the mutated Kit protein.

Classification of SM

  1. Top of page
  2. Abstract
  3. Classification of SM
  4. Pathogenesis of SM
  5. Standard Therapeutic Approaches to SM
  6. Investigational Therapeutic Approaches to SM
  7. KIT Tyrosine Kinase Inhibitors
  8. Nontyrosine Kinase Kit Signaling Inhibitors
  9. Monoclonal Antibodies
  10. DISCUSSION
  11. REFERENCES

In 2001, a new set of diagnostic criteria (Table 1) and an updated consensus classification system (Table 2) were proposed by the World Health Organization.5 In this system, SM is divided into 4 main subcategories. Indolent SM (ISM) is the most frequent form of SM, and its diagnosis requires the exclusion of signs of end-organ dysfunction (Table 3; ‘C’ findings), associated hematopoietic clonal non-MC disease (AHNMD), and MC leukemia (MCL).1, 2 Recently, a new subtype of SM, smoldering SM (SSM), has been identified.6 Patients with SSM exhibit higher MC burden than ISM and ‘B’ findings (Table 3) without significant functional impairment. Some patients with SM have an associated AHNMD, most commonly chronic myelomonocytic leukemia (CMML),7, 8 or hypereosinophilic syndrome (HES) carrying the Fip1-like-1 platelet-derived growth factor receptor α (FIPL1/PDGFRα) hybrid gene.9–11 Most patients with SM-AHNMD harbor the KIT D816V mutation,12 although this appears to be mutually exclusive with FIPL1/PDGFRα.10 Aggressive SM (ASM) is characterized by life-threatening impaired organ function from MC infiltration, and patients present with marked cytopenias, hepatosplenomegaly and ascites, osteolyses with pathologic fractures, malabsorption, and/or severe peptic ulcer disease. These patients exhibit so-called ‘C’ findings and have very high serum tryptase levels. MCL is the most aggressive form of SM, and patients with MCL present with rapidly progressive organopathy and a dense infiltration of MCs with blast-like morphology, accounting for ≥20% of the cells in bone marrow aspirates.13, 14 In the peripheral blood, MCs comprise ≥10% of circulating leukocytes, although an aleukemic variant of MCL has been described.13 Patients with MCL die of the disease within 12 months after diagnosis.

Table 1. World Health Organization Diagnostic Criteria for Systemic Mastocytosis*
  • *

    A diagnosis of systemic mastocytosis requires the fulfillment of either 1 major criteria and 1 minor criterion or 3 minor criteria.

Major criteria
 1. Multifocal, dense infiltrates of mast cells (≥15 mast cells in aggregates) in bone marrow biopsy sections and/or in other extracutaneous organ(s)
Minor criteria
 1. Greater than 25% mast cells in bone marrow or other extracutaneous organ(s) show an atypical morphology (typically spindle-shaped)
 2. c-kit Mutation at codon 816 is present in extracutaneous tissues
 3. Mast cells in bone marrow coexpress CD117 and either CD2, CD25, or both (by flow cytometry)
 4. Serum tryptase persistently is ≥20 ng/mL (not accounted for in patients with an associated, clonal, hematologic, nonmast cell disorder)
Table 2. World Health Organization Classification of Systemic Mastocytosis
SM variantCharacteristics
  1. SM indicates systematic mastocytosis; MC, mast cell; MPD, myeloproliferative disorder; HES, hypereosinophilic syndrome; MDS, myelodysplastic syndrome.

Indolent SMIncludes smoldering systemic mastocytosis and isolated bone marrow mastocytosis
SM with associated hematologic, non-MC-lineage disorderCommonly associated with an MPD (including HES) or MDS; occasionally seen accompanying acute leukemia
Aggressive SMFindings of end-organ dysfunction because of MC infiltration
MC leukemia≥10% MCs in peripheral blood (if <10%, aleukemic variant of MC leukemia), ≥20% MCs in bone marrow smears
Table 3. B Findings and C Findings in Systemic Mastocytosis
  1. MCs indicates mast cells.

B findings: Indication of high MC burden and expansion of the genetic defect into various myeloid lineages
 1) Infiltration grade of MCs in bone marrow >30% on histology and serum total tryptase levels <200 ng/mL
 2) Hypercellular bone marrow with loss of fat cells, discrete signs of dysmyelopoiesis without substantial cytopenias, or World Health Organization criteria for myelodysplastic syndrome or myeloproliferative disorder
 3) Organomegaly: Palpable hepatomegaly, splenomegaly, or lymphadenopathy (>2 cm on computed tomography or ultrasound) without impaired organ function
C findings: Indication of impaired organ function because of MC infiltration (confirmed by biopsy in most patients)
 1) Cytopenia(s): Absolute neutrophil count <1000/μL, or hemoglobin <10 g/dL, or platelets < 100.000/μL
 2) Hepatomegaly with ascites and impaired liver function
 3) Palpable splenomegaly with hypersplenism
 4) Malabsorption with hypoalbuminemia and weight loss
 5) Skeletal lesions: large osteolyses or/and severe osteoporosis causing pathologic fractures
 6) Life-threatening organomegaly in other organ systems that definitively is caused by an infiltration of the tissue by neoplastic MCs

Pathogenesis of SM

  1. Top of page
  2. Abstract
  3. Classification of SM
  4. Pathogenesis of SM
  5. Standard Therapeutic Approaches to SM
  6. Investigational Therapeutic Approaches to SM
  7. KIT Tyrosine Kinase Inhibitors
  8. Nontyrosine Kinase Kit Signaling Inhibitors
  9. Monoclonal Antibodies
  10. DISCUSSION
  11. REFERENCES

Kit is a 145-kDa transmembrane Class III receptor tyrosine kinase that is characterized structurally by 5 extracellular immunoglobulin-like repeats and a split tyrosine kinase domain.15 Kit-dependent cell types include MCs, hematopoietic stem cells, germ cells, melanocytes, and interstitial cells of Cajal, among others.16 Kit is required for human MC growth, differentiation, and functional activation.6 Cross-linking between 1 soluble stem cell factor (SCF) molecule and the extracellular immunoglobulin-like domains of 2 Kit molecules, induces homodimerization of Kit and autophosphorylation at the Y568 and Y570 tyrosine residues of the juxtamembrane domain.17 These residues act as docking sites for SH2-containing signal-transduction molecules, such as Janus kinase (Jak)/signal transducer and activators of transcription (STAT), Src kinases, mitogen-activated protein (MAP) kinases, and phosphatidylinositol-3 (PI3) kinase.17 Gain-of-function point mutations in the KIT kinase domain, such as D816V, result in ligand-independent, constitutive activation of Kit signaling, leading to uncontrolled MC proliferation and resistance to apoptosis.3 This somatic mutation is identified in >80% of patients with SM18–20 and involves the substitution of an aspartic residue at codon 816 of the KIT activation loop with a valine residue, leading to SCF-independent Kit autophosphorylation. Although the KIT D816V mutation occurs in a pluripotential hematopoietic progenitor cell and is detectable in monocytes and B cells, the disease remains confined to MC.21, 22 However, KIT D816V alone probably is not sufficient to exert a proliferation-enhancing oncogene effect in SM, because this mutation also is present in a self-limited form to MCL.23 Hence, secondary genetic lesions probably are required to promote uncontrolled proliferation of MCs in aggressive forms of SM. Additional chromosomal defects and genetic polymorphisms have been detected in patients with SM, particularly in those with SM-AHNMD.24–27 A subset of the latter presents with an associated HES, which, in many patients, is associated with the FIP1L1-PDGFRα hybrid gene.11, 24, 28, 29

Standard Therapeutic Approaches to SM

  1. Top of page
  2. Abstract
  3. Classification of SM
  4. Pathogenesis of SM
  5. Standard Therapeutic Approaches to SM
  6. Investigational Therapeutic Approaches to SM
  7. KIT Tyrosine Kinase Inhibitors
  8. Nontyrosine Kinase Kit Signaling Inhibitors
  9. Monoclonal Antibodies
  10. DISCUSSION
  11. REFERENCES

Historically, SM therapy has been empirical and contingent upon clinical aggressiveness at presentation. The prognosis for patients with ISM usually is good, and these patients benefit from MC modulators, such as histamine antagonists and MC stabilizers.30 Cytoreductive biologic agents, such as interferon α (IFN-α), are indicated in patients with severe osteoporosis or when symptomatic therapy fails to improve quality of life. Patients with SSM present with ‘B’ findings (Table 3), have an uncertain prognosis, and also may benefit from biologic cytoreductive therapy with IFN-α. Therapy for patients with SM-AHNMD usually is tailored toward either the MC component or the AHNMD component, depending on the severity of their disease. In most patients, the treatment of the latter usually takes precedence and should follow standard guidelines for a given hematologic disease. When the SM component is more prominent clinically, therapy with IFN-α (with or without the addition of corticosteroids) or chemotherapy with cladribine may be beneficial. Patients with ASM have poor quality of life and shorted life expectancy; therefore, they are treated with cytoreductive therapy (IFN-α with or without corticosteroids, or cladribine); in addition, some patients may benefit from hematopoietic stem cell transplantation. Patients with MCL traditionally have been treated with chemotherapy regimens similar to those employed in patients with acute myeloid leukemia (AML).31 Although these modalities can render significant MC reduction and symptom control in some patients, responses are transient, and the prognosis remains unchanged.32–34

Investigational Therapeutic Approaches to SM

  1. Top of page
  2. Abstract
  3. Classification of SM
  4. Pathogenesis of SM
  5. Standard Therapeutic Approaches to SM
  6. Investigational Therapeutic Approaches to SM
  7. KIT Tyrosine Kinase Inhibitors
  8. Nontyrosine Kinase Kit Signaling Inhibitors
  9. Monoclonal Antibodies
  10. DISCUSSION
  11. REFERENCES

The discovery of activating point mutations near the activation loop of the Kit tyrosine kinase domain has driven recent investigative efforts to identify suitable drugs that would inhibit this target. The therapeutic potential of target-specific small molecules in SM currently is being evaluated in clinical trials. Other features of malignant MCs are being investigated as potential therapeutic targets, including aberrant expression of CD25 and high activity of nuclear factor κB (NF-κB). In this review, we focus on novel therapeutic approaches to the treatment of SM; more traditional therapies, such as IFN-α35 and cladribine,2, 36 recently have been reviewed elsewhere.

KIT Tyrosine Kinase Inhibitors

  1. Top of page
  2. Abstract
  3. Classification of SM
  4. Pathogenesis of SM
  5. Standard Therapeutic Approaches to SM
  6. Investigational Therapeutic Approaches to SM
  7. KIT Tyrosine Kinase Inhibitors
  8. Nontyrosine Kinase Kit Signaling Inhibitors
  9. Monoclonal Antibodies
  10. DISCUSSION
  11. REFERENCES

Greater than 80% of patients with SM carry the Kit tyrosine kinase domain D816V mutant.18–20 Other KIT mutants that involve the kinase,37–40 as well as the transmembrane41, 42 and juxtamembrane domains,43, 44 have been described in sporadic cases of SM. Several small molecules have been developed to target Kit mutants, and some have entered clinical trials for patients with SM (Table 4).

Table 4. Effect of Novel Kit Tyrosine Kinase Inhibitors on Cell Proliferation
Agent/Cell type testedKIT isoform testedCell proliferation inhibition (IC50)Clinical experience
  1. IC50 indicates 50% inhibitory concentration; Ba/F3 (Ton.Kit.wt)/(Ton.Kit.D816V), Ba/F3 cells with doxycycline-inducible expression of wild type (WT) KIT or KIT D816V; MCs, mast cells; NS, not specified; HMC, human mast cell line carrying V560G (1.1) or V560/D816V (1.2); MCL, mast cell leukemia; MDS, myelodysplastic syndrome; MPD, myeloproliferative disorder.

AMN107 (Gleixner et al., 200657)  Ongoing clinical trial
 Ba/F3 (Ton. Kit.wt)WT KIT30–300 nM 
 Ba/F3 (Ton.Kit.D816V)KIT D816V1–3 μM 
Primary bone marrow MCsKIT D816VNS 
Dasatinib (Shah et al., 200667)  Ongoing clinical trial
 HMC-1.1KIT V560G4.6 nM 
 HMC-1.2KIT D816V/V560G490 nM 
 P815KIT D814V7 nM 
 Primary bone marrow MCsKIT D816VPreferential MC toxicity, 0.1–1 μM 
PKC412 (Gleixner et al., 200657)  Transient response in 1 patient with MCL-associated MDS/MPD (Gotlib et al., 200569)
 Ba/F3 (Ton. Kit.wt)WT KIT3–30 nM 
 Ba/F3 (Ton.Kit.D816V)KIT D816V100–300 nM 
 Primary bone marrow MCsKIT D816V50 nM 
OSI-930 (Garton et al., 200472)  
 HMC-1.1KIT V560G<100 nM 
 NCI-H526WT KIT<100 nM 
 MLN518 (Corbin et al., 200474)  
 HMC-1.1KIT V560G40 nM 
 Ba/F3 D816VKIT D816V250 nM 
 P815KIT D814V600 nM 
PD180970 (Corbin et al., 200474)  
 HMC-1.1KIT V560G40 nM 
 Ba/F3 D816VKIT D816VInsensitive 
AP23464 (Corbin et al., 200474)  
 HMC-1.1KIT V560G100 nM 
 Ba/F3 KIT D816YKIT D816Y3 nM 
 Ba/F3 KIT D816VKIT D816V11 nM 
 Ba/F3 KIT D816FKIT D816F4 nM 
 P815KIT D814V20 nM 

Imatinib mesylate

Imatinib is a potent, competitive inhibitor of various protein tyrosine kinases, such as Abl,45, 46 PDGFR,46, 47 and Kit.48, 49 Imatinib has demonstrated significant activity against neoplastic MCs that exhibit wild-type Kit and the spontaneously immortalized human MCL cell line HMC-1.1, which bears the juxtamembrane point mutant Kit V560G kinase. However, imatinib failed to inhibit HMC-1.2 cells that expressed Kit D816V (50% inhibitory concentration [IC50], >10,000 nM),50, 51 probably because of allosteric clash within the activation loop caused by the structural change at residue 816, which is key for maintaining the inactive conformation needed for imatinib binding. Imatinib also failed to inhibit the significant growth of malignant MCs from patients with SM.37, 50, 51 However, a novel point mutation within the Kit transmembrane domain has been described that involves substitution of a phenylalanine residue by a cysteine at codon 522 (F522C),41 leading to ligand-independent Kit autophosphorylation. Therapy with imatinib resulted in a dramatic decrease of F522C-expressing MCs and symptomatic improvement, further underscoring the importance of the transmembrane region in Kit activation.

From 20% to 40% of patients with SM present with bone marrow and/or peripheral blood eosinophilia,52 and clonality can be demonstrated in a significant proportion of them.53 Up to 50% of these patients express the imatinib-sensitive FIP1L1-PDGFRα oncogene that results from an interstitial deletion of chromosome 4q12, leading to the constitutive activation of the PDGFRα kinase.55 For this subset of patients, imatinib must be considered first-line therapy.11, 24 Pardanani et al. examined the associated clinicopathologic features of this mutation in a cohort of 89 patients with hypereosinophilia.11 None of 57 patients who had HES and 10 of 19 patients (56%) who had SM associated with eosinophilia carried the FIP1L1-PDGFRα oncogene. Low-dose imatinib (100 mg daily) rendered complete and durable responses in all 8 treated patients who harbored the FIP1L1-PDGFRα transcript. In contrast, only 4 of 10 treated patients (40%) patients with HES had partial responses.11 In another study, therapy with imatinib (100–400 mg per day) was administered to 12 patients with symptomatic SM.55 Three of 5 patients who had SM and eosinophilia achieved a complete clinical and hematologic response. Unfortunately, their FIP1L1- PDGFRα status was unknown. The other 2 patients failed to respond to imatinib and were the only patients who bore the KIT D816V mutation.55 Of the 7 patients who had SM without eosinophilia (all negative for the KIT D816V mutation and FIP1L1-PDGFRα status unknown), 2 patients showed a measurable response to imatinib.

In a Phase I/II trial, 10 patients with SM received imatinib 400 mg per day and prednisolone 30 mg per day for the first 2 weeks of imatinib therapy.56 Cutaneous lesions diminished in 2 of 6 patients with urticaria pigmentosa, and decreases in bone marrow MC infiltration and symptomatic improvements were observed in 60% of patients. Reductions in the size of hepatomegaly and/or splenomegaly and decreases in urinary N-methylhistamine excretion and serum tryptase levels were observed in some patients. In contrast with previous studies,11, 37, 50, 51, 55, 57 imatinib was effective in 8 of 10 patients who had the KIT D816V mutation.56 However, the use of prednisolone, which is an active therapy for SM per se, confounded the results of that study.

Based on these data, it is recommended that all patients with SM-HES be screened for the presence of the FIP1L1-PDGFRα fusion transcript.41, 58, 59 Because of anecdotal cases of cardiogenic shock in patients with SM-HES carrying the FIP1L1-PDGFRα who were treated with imatinib, the current recommendation is to administer corticosteroids daily for the first 1 or 2 weeks of imatinib therapy, particularly in patients with abnormal echocardiograms or elevated serum troponin levels.60

AMN107

AMN107 is a phenylamino-pyrimidine that is from 20-fold to 30-fold more potent than imatinib against Bcr-Abl while preserving similar activity against Kit (IC50, 60 nM) and PDGFR (IC50, 57 nM).61 The effect of AMN107 was examined on Ba/F3 cells that were transformed with murine KIT D814V, which is homologous to human KIT D816V.62 Unlike imatinib, AMN-107 effectively inhibited the growth of this cell line at concentrations of 1 μM to 2 μM and induced apoptotic cell death after 48 hours at concentrations of 2 μM to 4 μM. Similar results were obtained when Ba/F3 cells were transformed with human KIT D816V.62 Gleixner et al. observed that AMN107 strongly decreased Kit phosphorylation in HMC-1.1 cells (which express V560G) but showed only weak effects on HMC-1.2 cells (which express V560G and D816V) at a concentration of 1 μM.57 AMN107 counteracted the SCF-dependent growth of Ba/F3 cells transfected with wild-type KIT (IC50, 30–300 nM); whereas, in Ba/F3 cells that were transfected with KIT D816V, the effects of AMN107 were modest (IC50, 1–3 μM). Similarly, the apoptotic effects of AMN107 were much more pronounced on HMC-1.1 cells than on HMC-1.2 cells.57 By contrast, Verstovsek et al. reported that AMN107 was as potent as imatinib in inhibiting cellular proliferation of HMC-1.1 cells, but neither agent caused significant inhibitory effects on HMC-1.2 cells.63

Dasatinib

Dasatinib (formerly BMS-354825) is a dual Src/Abl kinase inhibitor that is 300-fold more potent against Bcr-Abl than imatinib and that also shows significant activity against wild-type Kit (IC50, 5 nM) and PDGFRβ (IC50, 28 nM).64 Dasatinib binds both the inactive and active configurations of Bcr-Abl and exhibits remarkable activity against a wide variety of Bcr-Abl mutants, except T315I.65 Dasatinib potently inhibits cell proliferation (IC50, 5–10 nM) and induces apoptosis (IC50, 14 nM) of HMC-1.1 cells.66 In contrast to imatinib,51 dasatinib inhibits Kit D816 kinase activity (IC50, 50–100 nM), although it is nearly 1 log less potent for inhibition of proliferation and induction of apoptosis (IC50, 1200 nM and 2000 nM, respectively) in HMC-1.2 cells that carry D816V. KIT D816Y-bearing cells were 10-fold more sensitive to dasatinib than KIT D816V/F-carrying cells, suggesting that conformational changes within the Kit activation loop greatly influence the inhibitory activity of dasatinib.66 Shah et al. compared the activity of dasatinib and imatinib on MC lines and primary neoplastic MCs.67 Dasatinib inhibited the kinase activity of wild-type Kit 20-fold more efficiently than imatinib, and Kit D816V was inhibited with efficiency comparable to that for the inhibition of wild-type Kit (IC50, 37 nM and 79 nM, respectively). Dasatinib inhibited Kit V560G kinase phosphorylation in HMC-1.1 cells at concentrations of 10 nM, whereas Kit D816V kinase phosphorylation in HMC-1.2 cells was inhibited at concentrations in the high-nanomolar range. Dasatinib retained growth inhibition activity against both cell lines, although it was more remarkable against HMC-1.1 cells than against HMC-1.2 cells (IC50, 4.6 nM vs. 43 nM, respectively). Using a flow- cytometry-based assay of MC viability, dasatinib showed preferential cytotoxicity against neoplastic MCs in bone marrow mononuclear cell cultures established from patients with SM in the presence of 0.1 μM dasatinib with increased activity at 1 μM. One micromolar of imatinib, as expected, imatinib had no significant activity.67

PKC412

PKC412 is an N-benzoylstaurosporine with potent inhibitory activity against protein kinase C, vascular endothelial growth factor receptor 2 (VEGFR-2), PDGFRα, FMS-like tyrosine kinase 3 (FLT3), kinase insert domain receptor (KDR) and Kit.68 In vitro studies have revealed that PKC412 inhibits the growth of Ba/F3 cells transfected with KIT D816V with an IC50 from 30 nM to 40 nM.69, 70 Therapy with PKC412 was administered to 1 patient with MCL who had associated myelodysplastic syndrome (MDS)/myeloproliferative disorder and bore the KIT D816V mutation, resulting in transient, significant reductions in the peripheral blood MC burden and serum histamine level and a significant improvement in liver function tests.67 However, the patient died after 3 months on therapy because of progression of AHNMD. In contrast to peripheral blood, there was minimal MC reduction in the bone marrow of this patient.

Data on the activity of PKC412 in neoplastic human MCs and MC lines recently have been reported.57 PKC412 (1 μM) decreased Kit phosphorylation in both HMC-1.1 cells and HMC-1.2 cells. The maximum effect of PKC412 on growth inhibition was dose-dependent and was maximal after 36 hours to 48 hours, with an IC50 from 50 nM to 250 nM for both HMC-1 subclones and 100 nM to 300 nM for Ba/F3 cells transfected with KIT D816V. This effect was coupled with the induction of apoptosis. Similar activity was observed on primary MCs from a patient with SM. Therefore, PKC412 is the first inhibitor able to suppress with equal efficacy the growth of human MCs bearing KIT mutations either in the kinase domain or in the juxtamembrane domain. In addition, it was observed that PKC412 cooperated with AMN107 against both HMC-1 subclones, suggesting alternative therapeutic options in the event of emergence of PKC412 resistance.57

Other small-molecule Kit tyrosine kinase inhibitors

Several agents have shown promising preclinical activity against neoplastic MCs by virtue of their Kit tyrosine kinase-inhibitory activity. The identification of a series of novel 2,3-substituted thiophenes led to the development of OSI-930, a heterocyclic anthranilamide analogue with potent inhibitory activity against the tyrosine kinases KDR, PDGFRβ, and Kit.71, 72 Examination of the cocrystal structure of OSI-930 bound to the Kit kinase domain showed that the compound binds to the adenosine triphosphate (ATP)-binding site when the enzyme is in an inactive conformation.72 Exposure of HMC-1.1 cells to 100 nM OSI-930 markedly reduced Kit autophosphorylation and inhibited the phosphorylation of multiple key elements involved in downstream Kit signaling pathways.71 OSI-930 inhibited both wild-type (NCI-H526 cells) and V560G mutant (HMC-1.1 cells) forms of KIT with IC50 values <100 nM in intact, cell-based assays and led to cell proliferation inhibition and induction of apoptosis in HMC-1.1 cells at the same concentration. Pharmacokinetic analysis of OSI-930 in an HMC-1.1 xenograft mouse model revealed that the area under the curve increased linearly up to a dose of 300 mg/kg and that the oral bioavailability of the drug was ≈100% at that dose.73 OSI-930 suppressed Kit phosphorylation by >90% over a 24-hour period after a single oral dose of 50 mg/kg.72 Despite these results, the therapeutic potential of OSI-930 in SM warrants demonstration of its activity against the Kit D816V mutant kinase found in the majority of patients with SM.18–20, 73

Corbin et al. investigated the activity of the small-molecule inhibitors MLN518 and PD180970 against different classes of Kit kinase mutants.74 MLN518 is a quinazoline-based kinase inhibitor that initially was designed as an FLT3 inhibitor and has shown inhibitory activity against wild-type Kit kinase with an IC50 of 170 nM.75 MLN518 potently inhibited cell proliferation and Kit phosphorylation of HMC-1.1 cells and Ba/F3 cells that were transfected with KIT D816V with IC50 values of 40 nM and 250 nM, respectively. Induction of apoptosis in 90% of HMC-1.1 cells and in 74% of D816V Ba/F3 cells was observed at 200 nM MLN518 and 2 μM MLN518, respectively. The dose-limiting toxicity of this compound in clinical trials of patients with AML was 2 μM, above the IC90 for growth inhibition of KIT D816V-carrying cells, supporting a therapeutic potential for this agent in human SM. PD180970, a pyrido[2,3-d]pyrimidine inhibitor of Abl, Src, and Kit,76, 77 inhibited cell proliferation and Kit phosphorylation with IC50 values of 40 nM and 25 nM, respectively, in HMC-1.1 cells but had no appreciable effect on D816V Ba/F3 cells. Similarly, it has been demonstrated that the pyrido[2,3-d]pyrimidine derivative PD173955 has a dual-inhibitory effect on Bcr-Abl and Kit (IC50 < 50 nM) kinases.77

The ATP-based 2,6,9-trisubstituted purine analog AP23464 inhibited phosphorylation of Kit and its downstream targets Akt and STAT3 in Ba/F3 cells that expressed KIT D816V, D816F, and D816Y mutants (IC50, 5–11 nM) with greater efficacy than wild-type KIT-bearing Mo7e and HMC-1.1 cells and without disrupting normal hematopoietic progenitor-cell growth.78 A related compound, AP23848, showed a similar pharmacodynamic profile; and, in a murine mastocytoma model, AP23848 inhibited KIT D814Y (homolog of human D816V) and cell growth.78

The multitargeted tyrosine kinase inhibitor, indolinone-based compounds SU11652, SU11654, and SU11655 induced inhibition of cell growth, Kit autophosphorylation, and induction of apoptosis in canine and murine MC lines carrying wild-type and juxtamembrane domain mutant forms of Kit with IC50 values from 0.01 μM to 0.1 μM and in MC lines carrying kinase domain mutants with IC50 values from 0.25 μM to 0.5 μM.79 Another class of Kit inhibitors includes quinoxaline derivatives, such as AGL2043, which also reportedly inhibited FLT3 and PDGFR tyrosine kinases.80 The role of these agents against human MC disease has not been defined to date.

Nontyrosine Kinase Kit Signaling Inhibitors

  1. Top of page
  2. Abstract
  3. Classification of SM
  4. Pathogenesis of SM
  5. Standard Therapeutic Approaches to SM
  6. Investigational Therapeutic Approaches to SM
  7. KIT Tyrosine Kinase Inhibitors
  8. Nontyrosine Kinase Kit Signaling Inhibitors
  9. Monoclonal Antibodies
  10. DISCUSSION
  11. REFERENCES

Geldanamycin (GA) is a benzoquinoid ansamycin antibiotic that binds to heat-shock protein 90 (hsp90), promoting the degradation of several hsp90-dependent kinases that are important in oncogenesis.81–83 In 1 study, 17-allylamino-17-demethoxy-GA (17-AAG), a chemical derivative of GA, caused dose-dependent decreases in the phosphorylation of Kit, Akt, and STAT3 in both HMC-1.1 cells and HMC-1.2 cells.84 Exposure to ≥500 nM 17-AAG led to significant cell growth inhibition and induction of apoptosis of both HMC-1 subclones and MCs from patients with SM carrying KIT D816V, suggesting potential in vivo activity in patients with SM.84 It was demonstrated recently that the dissociation of bcl-2 and hsp90β in MCs inhibits the antiapoptotic activity of bcl-2 by initiating the release of cytochrome c from mitochondria and increasing the activity of caspase 3 and caspase 7, resulting in MC apoptosis.85, 86 Exposure of rat basophilic leukemia (RBL-2H3) cells to increasing concentrations of GA for 15 hours resulted in a dramatic decrease in bcl-2 antiapoptotic activity and concentration-dependent MC toxicity.86 The dissociation of the complex began at 0.5 μM GA. Hence, the inhibition of MC proliferation caused by 17-AAG84 may be interpreted as a direct effect of this agent on the hsp90β-bcl-2 complex.

NF-κB is a dimeric transcription factor that is present in the cytoplasm in its inactive form by binding to its natural inhibitor IκB.87, 88 Among other functions, NF-κB modulates cell proliferation by up-regulating the transcription of D-type cyclins.89, 90 Exposure to exogenous stimuli, such as inflammatory cytokines, triggers the degradation of IκB by activating IκB kinase (IKK)-α and IKK-β, which induce IκB phosphorylation, ubiquitination, and proteolysis by the 26S proteasome.87, 88 Spontaneous activation of NF-κB has been demonstrated in HMC-1.2 cells.91 Exposure of HMC-1.2 cells to the selective IKK-β inhibitor IMD-0354 led to the inhibition of NF-κB activity and the suppression of cyclin D3 expression, which resulted in dose-dependent and time-dependent cell proliferation inhibition and apoptosis with an IC50 value of 0.28 μM.91 These data suggest that cell cycle progression in neoplastic MCs may be highly dependent on NF-κB and cyclin D3. Hence, therapies that target this signaling pathway warrant investigation in clinical trials.91 It is believed that bortezomib (Velcade&&num;142;®) is efficacious in multiple myeloma through the inhibition of NF-κB activation,92 and its efficacy in SM currently is being investigated in a clinical trial.

Kit activates the serine/threonine kinase mammalian target of rapamycin (mTOR), which regulates cell growth and cell cycle progression in MCs and is located downstream of PI3K/Akt.93 In 1 study, the mTOR inhibitor rapamycin induced marked cell growth inhibition of HMC-1.2 cells that harbored KIT D816V but not of α-155 cells that harbored KIT V560G, thus showing an opposite inhibitory pattern in relation to imatinib.94 It is noteworthy that this effect was observed at clinically achievable rapamycin doses (5 nM) in freshly isolated MCs from patients with SM who bore the D816V mutation. In keeping with this unexpected selectivity, rapamycin inhibits the phosphorylation of 4E-BP1, a downstream substrate of the mTOR pathway, only in KIT D816V-bearing HMC1.2 cells.94 These data provide the rationale for the clinical testing of rapamycin and its analogs in patients with SM.

Monoclonal Antibodies

  1. Top of page
  2. Abstract
  3. Classification of SM
  4. Pathogenesis of SM
  5. Standard Therapeutic Approaches to SM
  6. Investigational Therapeutic Approaches to SM
  7. KIT Tyrosine Kinase Inhibitors
  8. Nontyrosine Kinase Kit Signaling Inhibitors
  9. Monoclonal Antibodies
  10. DISCUSSION
  11. REFERENCES

Recently, was reported that CD25 is a useful immunohistochemical marker with which to identify the presence of neoplastic MCs and is a reliable minor criterion for SM diagnosis.95 These observations provide the rationale for the development of therapies targeting interleukin 2 receptor (IL-2R)-bearing MCs. In fact, it has been reported that the recombinant immunotoxin of anti-CD25 and pseudomonas exotoxin-A are effective in reducing the number of MCs in vitro,96 and the same effect was reported for the use of denileukin diftitox (Ontak&&num;142;&&num;142;®), which is a genetically engineered fusion protein that combines the full-length sequence of IL-2 and the enzymatically active domain of the diphtheria toxin.97, 98 Once it is bound to the IL-2R, denileukin diftitox is internalized by endocytosis and is cleaved proteolytically within the endosome, thus liberating the diphtheria toxin, which translocates into the cytosol and inhibits protein synthesis through ADP ribosylation of elongation factor 2, resulting in cell death.99, 100 Denileukin diftitox has been approved for the treatment of patients with advanced or refractory, cutaneous T-cell lymphoma.101 The efficacy and safety of denileukin diftitox in patients with SM is being assessed in an ongoing Phase II clinical trial. Other IL-2R-directed monoclonal antibodies that merit investigation in SM are daclizumab and basiliximab.

Gemtuzumab ozogamicin (Myelotarg&&num;142;®) is a fusion protein toxin that targets the surface marker CD33 and has proved very successful in patients with AML. Gemtuzumab conjugates a monoclonal antibody directed against CD33 with the highly potent toxin calicheamicin. The development of anti-CD33 therapy for SM still is in a preclinical stage. Exposure of the HMC-1 cell line to gemtuzumab resulted in reduced viability of CD33-positive MCs.96 It is noteworthy that the administration of gemtuzumab was associated with occasional, severe hepatic venooclusive disease in patients with hematologic malignancies.102 Because patients with advanced SM frequently have liver involvement caused by MC infiltration, great caution will need to be exerted when gentuzumab is used in clinical trials of SM.

The urokinase receptors CD87 and CD45 are expressed on the surface of neoplastic MCs. Monoclonal antibodies against these receptors have been conjugated to the radioactive isotope 131I or to the diphtheria toxin, and their activity has been demonstrated as part of conditioning regimens for patients with MDS103 and as therapy for patients with AML,104 respectively. The utility of these agents in SM warrants further investigation.

DISCUSSION

  1. Top of page
  2. Abstract
  3. Classification of SM
  4. Pathogenesis of SM
  5. Standard Therapeutic Approaches to SM
  6. Investigational Therapeutic Approaches to SM
  7. KIT Tyrosine Kinase Inhibitors
  8. Nontyrosine Kinase Kit Signaling Inhibitors
  9. Monoclonal Antibodies
  10. DISCUSSION
  11. REFERENCES

Kit has emerged as a major potential therapeutic target in SM. Several agents have been developed that inhibit the constitutively active Kit D816V mutant tyrosine kinase, which is encountered in the majority of patients with SM, and some of those agents are being evaluated in clinical trials. Although patients with SM are encouraged to participate, adequate patient selection is of critical importance. Patients with ISM and SSM may be suitable candidates for participation in trials of novel biologic agents if standard supportive measures and IFN-α fail to improve their quality of life. Conversely, patients with more aggressive forms of SM (SM-AHNMD, ASM, and MCL) who have failed on or declined to be treated with standard cytoreductive therapies should be encouraged to participate in trials with novel biologic agents. One exception is SM-HES associated with the FIP1L1-PDGFRα transcript, for which imatinib must be used as front-line therapy. In those patients who need new treatment but are not able to enter clinical trials, therapy with imatinib potentially may be beneficial when the KIT D816V mutation is not present.

These are exciting times for patients with SM and their physicians, because they are witnessing an unprecedented development of novel therapies for this disease. However, as we have learned from imatinib therapy in CML, remissions with kinase-targeting therapy may not result in permanent control of the disease in all patients because of the development of drug resistance, which suggests that therapy with tyrosine kinase inhibitors alone may not be sufficient to cure SM. The identification of Kit-activated signaling pathways that are crucial for MC transformation and of cell surface markers circumscribed to neoplastic MC has revealed novel targets for drug development. It will be particularly appealing to determine whether the combination of these novel therapies will translate into a major impact on the treatment of SM.

REFERENCES

  1. Top of page
  2. Abstract
  3. Classification of SM
  4. Pathogenesis of SM
  5. Standard Therapeutic Approaches to SM
  6. Investigational Therapeutic Approaches to SM
  7. KIT Tyrosine Kinase Inhibitors
  8. Nontyrosine Kinase Kit Signaling Inhibitors
  9. Monoclonal Antibodies
  10. DISCUSSION
  11. REFERENCES
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