Vorolanib (X-82), an oral anti-VEGFR/PDGFR/CSF1R tyrosine kinase inhibitor, with everolimus in solid tumors: results of a phase I study.

Background Anti-vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitors (TKI) combined with mTOR inhibitors, like everolimus, result in significant responses and prolonged progression-free survival (PFS) among patients with renal cell carcinoma (RCC) [1]. However, everolimus doses >5 mg are often not tolerated when combined with other TKIs2,3. Vorolanib (X-82), an oral anti-VEGFR/platelet derived growth factor receptor (PDGFR)/colony stimulating factor 1 receptor (CSF1R) multitarget TKI, has a short half-life and limited tissue accumulation. We conducted a Phase 1 study of vorolanib with everolimus (10 mg daily) in patients with solid tumors. Methods A 3 + 3 dose escalation design was utilized to determine dose limiting toxicities (DLT) and recommended Phase 2 dose (RP2D) of vorolanib/everolimus. Oral vorolanib at 100, 150, 200, 300, or 400 mg was combined with 10 mg oral everolimus daily. The phase 2 portion was terminated after enrolling two patients due to funding. Results Eighteen patients were evaluable for DLT among 22 treated subjects. Observed DLTs were grade 3 fatigue, hypophosphatemia, and mucositis. The RP2D is vorolanib 300 mg with everolimus 10 mg daily. In 15 patients evaluable for response, three had partial response (PR; 2 RCC, 1 neuroendocrine tumor [NET]) and eight had stable disease (SD; 2 RCC, 6 NET). Conclusions Vorolanib can safely be combined with everolimus. Encouraging activity is seen in RCC and NET. Further studies are warranted. Trial Registration Number: NCT01784861.

Differential effects of sorafenib on liver versus tumor fibrosis mediated by stromal-derived factor 1 alpha/C-X-C receptor type 4 axis and myeloid differentiation antigen-positive myeloid cell infiltration in mice.

UNLABELLED: Sorafenib--a broad kinase inhibitor--is a standard therapy for advanced hepatocellular carcinoma (HCC) and has been shown to exert antifibrotic effects in liver cirrhosis, a precursor of HCC. However, the effects of sorafenib on tumor desmoplasia--and its consequences on treatment resistance--remain unknown. We demonstrate that sorafenib has differential effects on tumor fibrosis versus liver fibrosis in orthotopic models of HCC in mice. Sorafenib intensifies tumor hypoxia, which increases stromal-derived factor 1 alpha (SDF-1α) expression in cancer and stromal cells and, subsequently, myeloid differentiation antigen-positive (Gr-1(+)) myeloid cell infiltration. The SDF-1α/C-X-C receptor type 4 (CXCR4) pathway directly promotes hepatic stellate cell (HSC) differentiation and activation through the mitogen-activated protein kinase pathway. This is consistent with the association between SDF-1α expression with fibrotic septa in cirrhotic liver tissues as well as with desmoplastic regions of human HCC samples. We demonstrate that after treatment with sorafenib, SDF-1α increased the survival of HSCs and their alpha-smooth muscle actin and collagen I expression, thus increasing tumor fibrosis. Finally, we show that Gr-1(+) myeloid cells mediate HSC differentiation and activation in a paracrine manner. CXCR4 inhibition, using AMD3100 in combination with sorafenib treatment, prevents the increase in tumor fibrosis--despite persistently elevated hypoxia--in part by reducing Gr-1(+) myeloid cell infiltration and inhibits HCC growth. Similarly, antibody blockade of Gr-1 reduces tumor fibrosis and inhibits HCC growth when combined with sorafenib treatment. CONCLUSION: Blocking SDF-1α/CXCR4 or Gr-1(+) myeloid cell infiltration may reduce hypoxia-mediated HCC desmoplasia and increase the efficacy of sorafenib treatment.

Anti-fibrotic effects of nintedanib in lung fibroblasts derived from patients with idiopathic pulmonary fibrosis.

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a progressive lung disease with poor prognosis. The kinase inhibitor nintedanib specific for vascular endothelial growth factor receptor (VEGFR), platelet-derived growth factor receptor (PDGFR) and fibroblast growth factor receptor (FGFR) significantly reduced the rate of decline of forced vital capacity versus placebo. AIM: To determine the in vitro effect of nintedanib on primary human lung fibroblasts. METHODS: Fibroblasts were isolated from lungs of IPF patients and from non-fibrotic controls. We assessed the effect of VEGF, PDGF-BB and basic FGF (bFGF) ± nintedanib on: (i) expression/activation of VEGFR, PDGFR, and FGFR, (ii) cell proliferation, secretion of (iii) matrix metalloproteinases (MMP), (iv) tissue inhibitor of metalloproteinase (TIMP), and (v) collagen. RESULTS: IPF fibroblasts expressed higher levels of PDGFR and FGFR than controls. PDGF-BB, bFGF, and VEGF caused a pro-proliferative effect which was prevented by nintedanib. Nintedanib enhanced the expression of pro-MMP-2, and inhibited the expression of TIMP-2. Transforming growth factor-beta-induced secretion of collagens was inhibited by nintedanib. CONCLUSION: Our data demonstrate a significant anti-fibrotic effect of nintedanib in IPF fibroblasts. This effect consists of the drug's anti-proliferative capacity, and on its effect on the extracellular matrix, the degradation of which seems to be enhanced.

A review of platelet derived growth factor playing pivotal role in bone regeneration.

This article is focused on the literature review and study of recent advances in the field of bone grafting, which involves platelet-derived growth factor (PDGF) as one of the facilitating factors in bone regeneration. This article includes a description of the mechanism of PDGF for use in surgeries where bone grafting is required, which promotes future application of PDGF for faster bone regeneration or inhibition of bone growth if required as in osteosarcoma. The important specific activities of PDGF include mitogenesis (increase in the cell populations of healing cells), angiogenesis (endothelial mitoses into functioning capillaries), and macrophage activation (debridement of the wound site and a second phase source of growth factors for continued repair and bone regeneration). Thus PDGF can be utilized in wound with bone defect to conceal the wound with repair of bony defect.

[Possibilities for inhibiting tumor-induced angiogenesis: results with multi-target tyrosine kinase inhibitors]. / A tumorindukált angiogenezis gátlásának lehetõségei: eredmények multi-target tirozinkináz-gátlókkal.

Functional blood vasculature is essential for tumor progression. The main signalization pathways that play a key role in the survival and growth of tumor vessels originate from the VEGF-, PDGF- and FGF tyrosine kinase receptors. In the past decade, significant results have been published on receptor tyrosine kinase inhibitors (RTKIs). In this paper, the mechanisms of action and the results so far available of experimental and clinical studies on multi-target antiangiogenic TKIs are discussed. On the one hand, notable achievements have been made recently and these drugs are already used in clinical practice in some patient populations. On the other hand, the optimal combination and dosage of these drugs, selection of the apropriate biomarker and better understanding of the conflicting role of PDGFR and FGFR signaling in angiogenesis remain future challenges.

Imatinib in pulmonary arterial hypertension patients with inadequate response to established therapy.

RATIONALE: Pulmonary arterial hypertension (PAH) is a progressive condition with a poor prognosis. Platelet-derived growth factor receptor (PDGFR) signaling plays an important role in its pathobiology. OBJECTIVES: To assess safety, tolerability, and efficacy of the PDGFR inhibitor imatinib in patients with PAH. METHODS: Patients with PAH in functional classes II-IV were enrolled in a 24-week randomized, double-blind, placebo-controlled pilot study. Patients received imatinib (an inhibitor of PDGFR activity) 200 mg orally once daily (or placebo), which was increased to 400 mg if the initial dose was well tolerated. The primary endpoints were safety and change from baseline in the 6-minute-walk distance (6MWD). Secondary endpoints included hemodynamics and functional classification. MEASUREMENTS AND MAIN RESULTS: Fifty-nine patients enrolled (imatinib [n = 28]; placebo [n = 31]); 42 completed the study. Dropouts were equally matched between the two groups. In the intention-to-treat (ITT) population there was no significant change in the 6MWD (mean ± SD) in the imatinib versus placebo group (+22 ± 63 versus -1.0 ± 53 m). There was a significant decrease in pulmonary vascular resistance (imatinib -300 ± 347 versus placebo -78 ± 269 dynes · s · cm⁻5, P < 0.01) and increase in cardiac output (imatinib +0.6 ± 1.2 versus placebo -0.1 ± 0.9 L/min, P = 0.02). Serious adverse events occurred in 11 imatinib recipients (39%) and 7 placebo recipients (23%). Three deaths occurred in each group. Post hoc subgroup analyses suggest that patients with greater hemodynamic impairment may respond better than patients with less impairment. CONCLUSIONS: These data from a Phase II study are consistent with imatinib being well tolerated in patients with PAH, and provide proof of concept for further studies evaluating its safety, tolerability, and efficacy in PAH. Clinical trial registered with www.clinicaltrials.gov (NCT00477269).

Chimeric tyrosine kinase-HDAC inhibitors as antiproliferative agents.

Combined treatment with tyrosine kinase inhibitors (TKi) and additional drugs is emerging as a promising strategy for cancer therapy. TKi and histone-deacetylase inhibitors (HDI) are two classes of anti-tumor agents with distant mechanisms of action. We have designed and synthesized chimeric compounds, which comprise structural elements of the TKi imatinib, and of prototypical HDI compounds. These compounds retain TKi activity similar to imatinib, exemplified by the inhibition of the platelet-derived growth factor receptor, and c-Kit kinase in intact cells. In addition, the chimeric compounds have in vitro and cellular HDI activity, and potently inhibit growth of cancer cell lines, including that of imatinib-resistant cell lines. Chimeric molecules with combined TKi and HDI activity may simplify combination treatment and be applicable to overcome clinical resistance to TKi single-agent therapy.

Nintedanib-induced glomerular microangiopathy: a case report.

Nintedanib, a triple tyrosine kinase inhibitor of vascular endothelial growth factor receptor, platelet-derived growth factor receptor, and fibroblast growth factor receptor, has been used in idiopathic pulmonary fibrosis and adenocarcinoma in advanced non-small cell lung cancer. Although vascular endothelial growth factor inhibitors have been reported to cause endothelial injury and glomerular microangiopathy, nintedanib-induced glomerular microangiopathy has not been reported. A 68-year-old man with a history of primary aldosteronism, idiopathic pulmonary fibrosis, and pleomorphic carcinoma of the lung developed proteinuria and leg edema after nintedanib initiation. Kidney biopsy revealed prominent endothelial and mesangial injury. Proteinuria improved after nintedanib withdrawal. To the best of our knowledge, this is the second case report of nintedanib-induced glomerular microangiopathy. Although the incidence of nephropathy among patients receiving nintedanib is unknown at this moment, we recommend monitoring urinary protein excretion and blood pressure in patients receiving nintedanib and performing kidney biopsy to determine any histopathological change.

Lead acetate induces EGFR activation upstream of SFK and PKCalpha linkage to the Ras/Raf-1/ERK signaling.

Lead acetate (Pb), a probable human carcinogen, can activate protein kinase C (PKC) upstream of extracellular signal-regulated kinase 1 and 2 (ERK1/2). Yet, it remains unclear whether Pb activation of PKC --> ERK1/2 involves receptor/non-receptor tyrosine kinases and the Ras signaling transducer. Here we demonstrate a novel mechanism elicited by Pb for transmitting ERK1/2 signaling in CL3 human non-small-cell lung adenocarcinoma cells. Pb induction of higher steady-state levels of Ras-GTP was essential for increasing phospho-Raf-1(S338) and phospho-ERK1/2. Pre-treatment of the cells with a conventional PKC inhibitor Gö6976 or depleting PKCalpha using specific small interfering RNA blocked Pb induction of Ras-GTP. Pb also activated cellular tyrosine kinases. Specific pharmacological inhibitors, PD153035 for epidermal growth factor receptor (EGFR) and SU6656 for Src family tyrosine kinases (SFK), but not AG1296 for platelet-derived growth factor receptor, could suppress the Pb-induced tyrosine kinases, PKCalpha, Ras-GTP, phospho-Raf-1(S338) and phospho-ERK1/2. Furthermore, phosphorylation of tyrosines on the EGFR multiple autophosphorylation sites and the conserved SFK autophosphorylation site occurred during exposure of cells to Pb for 1-5 min and 5-30 min, respectively. Intriguingly, Pb activation of EGFR required the intrinsic kinase activity but not dimerization of the receptor. Inhibition of SFK or PKCalpha activities did not affect EGFR phosphorylation, while knockdown of EGFR blocked SFK phosphorylation and PKCalpha activation following Pb. Together, these results indicate that immediate activation of EGFR in response to Pb is obligatory for activation of SFK and PKCalpha and subsequent the Ras-Raf-1-MKK1/2-ERK1/2 signaling cascade.

Distinct roles for the p110alpha and hVPS34 phosphatidylinositol 3'-kinases in vesicular trafficking, regulation of the actin cytoskeleton, and mitogenesis.

We have examined the roles of the p85/ p110alpha and hVPS34 phosphatidylinositol (PI) 3'-kinases in cellular signaling using inhibitory isoform-specific antibodies. We raised anti-hVPS34 and anti-p110alpha antibodies that specifically inhibit recombinant hVPS34 and p110alpha, respectively, in vitro. We used the antibodies to study cellular processes that are sensitive to low-dose wortmannin. The antibodies had distinct effects on the actin cytoskeleton; microinjection of anti-p110alpha antibodies blocked insulin-stimulated ruffling, whereas anti-hVPS34 antibodies had no effect. The antibodies also had different effects on vesicular trafficking. Microinjection of inhibitory anti-hVPS34 antibodies, but not anti-p110alpha antibodies, blocked the transit of internalized PDGF receptors to a perinuclear compartment, and disrupted the localization of the early endosomal protein EEA1. Microinjection of anti-p110alpha antibodies, and to a lesser extent anti-hVPS34 antibodies, reduced the rate of transferrin recycling in CHO cells. Surprisingly, both antibodies inhibited insulin-stimulated DNA synthesis by 80%. Injection of cells with antisense oligonucleotides derived from the hVPS34 sequence also blocked insulin-stimulated DNA synthesis, whereas scrambled oligonucleotides had no effect. Interestingly, the requirement for p110alpha and hVPS34 occurred at different times during the G1-S transition. Our data suggest that different PI 3'-kinases play distinct regulatory roles in the cell, and document an unexpected role for hVPS34 during insulin-stimulated mitogenesis.

Growth factor receptors signaling in glioblastoma cells: therapeutic implications.

In this study, we investigated the protein expression of platelet-derived growth factor receptor (PDGFR), insulin like growth factor-1 receptor (IGF-1R), phosphatidylinositol 3-kinase (PI3-K) and extracellular signal-regulated kinase (ERK1/2) in five primary glioblastoma (GB), with a view to their possible use as therapeutic targets. Our results demonstrated that appreciable levels of these proteins could be detected in the analysed GB cell lines, except for a low level of PDGFR and ERK1/2 expression in one GB cell line. The small molecule inhibitors towards IGF-1R, PDGFR, PI3-K and ERK1/2 respectively, have only modest or no anti-tumour activity on GB cells and therefore their combination with other therapy modalities was analysed. The interaction between small inhibitors and radiation was mostly additive or sub-additive; synergistic interaction was found in five of forty analysed combinations. Our results showed that GB cells are in general resistant to treatment and illustrate the difficulties in predicting the treatment response in malignant gliomas.

The adaptor protein Tom1L1 is a negative regulator of Src mitogenic signaling induced by growth factors.

The Src family of protein-tyrosine kinases (SFK) play important roles in mitogenesis and morphological changes induced by growth factors. The involved substrates are, however, ill defined. Using an antiphosphotyrosine antibody to screen tyrosine-phosphorylated cDNA expression library, we have identified Tom1L1, an adaptor protein of the Tom1 family and a novel substrate and activator of the SFK. Surprisingly, we found that Tom1L1 does not promote DNA synthesis induced by Src. Furthermore, we report that Tom1L1 negatively regulates SFK mitogenic signaling induced by platelet-derived growth factor (PDGF) through modulation of SFK-receptor association: (i) Tom1L1 inhibits DNA synthesis induced by PDGF; (ii) inhibition is overcome by c-myc expression or p53 inactivation, two regulators of SFK mitogenic function; (iii) Src or Fyn coexpression overrides Tom1L1 mitogenic activity; (iv) overexpression of the adaptor reduces Src association with the receptor; and (v) protein inactivation potentiates receptor complex formation, allowing increased SFK activation and DNA synthesis. However, Tom1L1 affects neither DNA synthesis induced by the constitutively active allele SrcY527F nor SFK-regulated actin assembly induced by PDGF. Finally, overexpressed Tom1 and Tom1L2 also associate with Src and affected mitogenic signaling in agreement with some redundancy among members of the Tom1 family. We concluded that Tom1L1 defines a novel mechanism for regulation of SFK mitogenic signaling induced by growth factors.

Artificial control of subtype-specific platelet-derived growth factor-receptor signaling.

Platelet-derived growth factor (PDGF) signaling controls various physiological functions via two receptor subtypes: PDGF receptor (PDGFR) alpha and PDGFRbeta. Nevertheless, our understanding of their roles is limited because of a lack of pharmacological tools to discriminate subtype-specific signaling. We developed a chimeric receptor by combining ligand-binding-domain truncated PDGFRbeta with anti-fluorescein single chain antibody, expecting the control of PDGFRbeta-specific signaling by oligomerized fluorescein as an artificial agonist. Results show that calcium mobilization, Cdc42 activation, and cell migration were elicited specifically by the artificial ligand in cells expressing the chimeric receptor. Our method is expected to be useful to understand the subtype-specific roles of PDGFRs in various cellular functions.

TSU68, an antiangiogenic receptor tyrosine kinase inhibitor, induces tumor vascular normalization in a human cancer xenograft nude mouse model.

PURPOSE: Combination therapy using antiangiogenic and cytotoxic agents is a useful strategy for advanced cancer, but the mechanism has not yet been elucidated. Moreover, there is a persistent paradox that destroying tumor vasculature with antiangiogenic agents disturbs the delivery of cytotoxic agents. It has been hypothesized that antiangiogenic agents can lead to normalization of tumor vessels that are structurally and functionally abnormal. The normalization means enhancing the deliver of cytotoxic agents. Our purpose was to investigate whether TSU68, a multiple receptor tyrosine kinase inhibitor that targets vascular endothelial growth factor receptor-2 (VEGFR2), platelet-derived growth factor receptor (PDGFR), and fibroblast growth factor receptor (FGFR), would induce the normalization of tumor vessels. METHODS: TSU68 was administered for 7 days to mice with xenografted tumors. Tumors of interstitial fluid pressure (IFP) were measured before and after administration of agents. Immunofluorescence double staining for CD31 and alpha-SMA was performed, and a medical video endoscopy system with narrowband illumination (NBI) was used to visualize the vascular pattern. RESULTS: TSU68 treatment decreased IFP significantly. Immunofluorescence double staining showed a significant increase in the fraction of pericyte coverage in the TSU68-treated group. NBI endoscopy showed that many tumor vessels in TSU68-treated mice were pruned and the diameters of remaining vessels were reduced. CONCLUSION: The data supported our hypothesis of tumor vascular normalization by the antiangiogenic agent TSU68.

Imatinib mesylate attenuates fibrosis in coxsackievirus b3-induced chronic myocarditis.

AIMS: Coxsackievirus B3 (CVB3)-induced chronic myocarditis in mice is accompanied by severe fibrosis and by sustained elevation of platelet-derived growth factor (PDGF)-A, -B, and -C levels in the cardiac tissue. To test if PDGF stimulation of resident fibroblasts causally contributes to fibrosis, we employed inhibition of PDGF receptor signalling with the orally available kinase inhibitor Imatinib. METHODS AND RESULTS: Chronic myocarditis was induced by CVB3 infection of major histocompatibility complex (MHC) class II knockout (B6Aa(0)/Aa(0)) mice. The mice were treated with 100 mg/kg Imatinib or vehicle, respectively, twice daily for 34 days. Expression of PDGF-C and of inflammatory cytokines were analysed by semi-quantitative RT-PCR. PDGFalpha receptor phosphorylation was detected by immunoblotting of cardiac tissue extracts and in situ by immunohistochemistry. Fibrosis formation was analysed by Sirius-Red staining and hydroxyproline (HP) determination. Fibronectin, and tenascin expression was analysed by RT-PCR and immunohistochemistry. Matrix metalloproteinase (MMP) activity was assessed with collagen, synthetic peptides, and gelatine as substrates. Imatinib significantly inhibited the myocarditis-related PDGFalpha receptor activation in the heart tissue. The virus titres in the hearts, inflammatory infiltrations, and elevated PDGF levels were unaffected by the Imatinib treatment. A significant attenuation of fibrosis occurred in Imatinib-treated animals. The Sirius Red-stained fibrotic area was reduced from 5.30 +/- 0.50 to 3.21 +/- 0.35%, and the HP content was reduced from 362 +/- 43 to 238 +/- 32 microMol/10 mg dry weight vs. 190 +/- 27 in uninfected controls. The expression of fibronectin, EIIIA+ fibronectin, and tenascin C were likewise reduced. The diminished matrix protein deposition was not caused by elevated MMP activity, since MMP activity was not changed or even reduced under Imatinib. CONCLUSION: The data suggest a causal role for elevated PDGF expression and PDGF receptor activity in the pathogenesis of cardiac fibrosis.

Nilotinib: a phenylamino-pyrimidine derivative with activity against BCR-ABL, KIT and PDGFR kinases.

The BCR-ABL kinase inhibitor imatinib mesylate is currently the standard therapy for patients with chronic myeloid leukemia (CML). However, mutations within the ABL kinase domain interfering with drug binding have been identified as the main mechanism of resistance to imatinib. Multiple distinct BCR-ABL kinase mutant isoforms conferring varying degrees of resistance to tyrosine kinase inhibitors have been reported. Nilotinib is a tyrosine kinase inhibitor 30-fold more potent than imatinib against BCR-ABL kinase. Nilotinib is active against a wide range of imatinib-resistant BCR-ABL mutant isoforms, except for T315I. Results from Phase II studies of nilotinib for patients with CML after failure or intolerance to imatinib therapy have shown a favorable toxicity profile and confirmed the high efficacy of nilotinib in this setting. Studies addressing the activity of nilotinib in newly-diagnosed patients with CML are underway. Furthermore, nilotinib is a potent inhibitor of KIT and PDGFR kinases. Here, we review the preclinical development of nilotinib and the activity of this agent in patients with CML and in tumors driven by KIT and/or PDGFR mutant kinases, such as gastrointestinal stromal tumors and some forms of clonal hypereosinophilia.

Intracellular signalling. PI 3-kinase puts GTP on the Rac.

Phosphoinositide 3-kinase, an enzyme that is known to transduce signals received by a variety of receptor types, has been found to mediate agonist-dependent membrane ruffling via the small GTP-binding protein Rac.

Coagulation factor Xa stimulates platelet-derived growth factor release and mitogenesis in cultured vascular smooth muscle cells of rat.

The mitogenic effect of activated coagulation factor X (factor Xa) was examined in cultured aortic smooth muscle cells (VSMC) from Wistar-Kyoto rats (WKY). Factor Xa stimulated DNA synthesis and cell growth in VSMC, not through the phospholipase C-protein kinase C pathway because increase of inositol monophosphate (IP) accumulation and intracellular Ca2+ concentration was not observed, but probably via the PDGF receptor tyrosine kinase pathway since the pathway's components, Ras, Raf-1, MAPK (both 42 and 44 kD), and the transcription factors, c-Fos and c-Jun, were activated. These appeared to be effected by the serine protease activity of factor Xa, since in the presence of serine protease inhibitors such as PMSF, leupeptin, benzamidine, TAP anticoagulant, and TLCK, the latter three being specific inhibitors of the factor Xa, active site, the effects were completely blocked. Anti-factor Xa mAb, 5224, which specifically negated the activity of factor Xa, also inhibited completely the mitogenic effect of factor Xa, but not that of thrombin. Addition of PDGF did not affect the effect of factor Xa, which, however, was inhibited by anti-PDGF-AB antibody. This observation and the activation of PDGF receptor tyrosine kinase pathway suggested that the factor Xa might exert its effect via PDGF-like function. Direct measurement confirmed that factor Xa stimulated the release of PDGF from VSMC. Factor Xa, therefore, exerts serine protease activity on VSMC, causing somehow the release of PDGF, that in turn acts on the PDGF receptor tyrosine kinase; the pathway is then turned on, leading eventually to DNA synthesis and cell proliferation.

Novel mode of action of c-kit tyrosine kinase inhibitors leading to NK cell-dependent antitumor effects.

Mutant isoforms of the KIT or PDGF receptors expressed by gastrointestinal stromal tumors (GISTs) are considered the therapeutic targets for STI571 (imatinib mesylate; Gleevec), a specific inhibitor of these tyrosine kinase receptors. Case reports of clinical efficacy of Gleevec in GISTs lacking the typical receptor mutations prompted a search for an alternate mode of action. Here we show that Gleevec can act on host DCs to promote NK cell activation. DC-mediated NK cell activation was triggered in vitro and in vivo by treatment of DCs with Gleevec as well as by a loss-of-function mutation of KIT. Therefore, tumors that are refractory to the antiproliferative effects of Gleevec in vitro responded to Gleevec in vivo in an NK cell-dependent manner. Longitudinal studies of Gleevec-treated GIST patients revealed a therapy-induced increase in IFN-gamma production by NK cells, correlating with an enhanced antitumor response. These data point to a novel mode of antitumor action for Gleevec.

From molecular biology to targeted therapies for hepatocellular carcinoma: the future is now.

Hepatocellular carcinoma (HCC) is characterized as a highly chemoresistant cancer with no effective systemic therapy. Despite surgical or locoregional therapies, prognosis remains poor because of high tumor recurrence or tumor progression, and currently there are no well-established effective adjuvant therapies. The molecular biology of carcinogenesis and tumor progression of HCC has been increasingly understood with intense research in recent years. Several important intracellular signaling pathways such as the Ras/Raf/Mek/Erk pathway and PI3k/Akt/mTOR pathway have been recognized, and the role of several growth factors and angiogenic factors such as EGF and VEGF has been confirmed. Effective agents targeting these molecular abnormalities have been developed and widely tested in preclinical studies of HCC cell lines or xenograft models. Several agents have entered clinical trials in HCC patients, and recent data indicated that a multikinase inhibitor targeting Ras kinase and VEGFR-2, sorafenib, is effective in prolonging survival of patients with advanced HCC. The management of advanced HCC is entering the era of molecular targeting therapy, which is of particular significance for HCC in view of the lack of existing effective systemic therapy for this cancer.