Angiogenesis and Angiogenic Tyrosine Kinase Receptor Expression in Pediatric Brain Tumors

Tumor angiogenesis and receptor tyrosine kinases (RTK) are major novel targets in anticancer molecular therapy. Accordingly, we characterized the vascular network and the expression pattern of angiogenic RTK in the most frequent pediatric brain tumors. In a retrospective collection of 44 cases (14 astrocytoma, 16 ependymoma and 14 medulloblastoma), immunohistochemistry for VEGFR1, VEGFR2, PDGFRα, PDGFRβ, and c-Kit as well as microvessel labeling with CD34 and SMA were conducted on surgical specimens. We found a significantly higher vascular density in ependymoma. Glomeruloid formations were abundant in medulloblastoma but rare or almost absent in astrocytoma and ependymoma, respectively. C-Kit and VEGFR2 labeled blood vessels were more abundant in ependymoma than in the other two types of tumors. In contrast, medulloblastoma contained higher number of PDGFRα expressing vessels. In tumor cells, we found no VEGFR2 but VEGFR1 expression in all three tumor types. PDGFRα was strongly expressed on the tumor cells in all three malignancies, while PDGFRβ tumor cell expression was present in the majority of medulloblastoma cases. Interestingly, small populations of c-Kit expressing cancer cells were found in a number of medulloblastoma and ependymoma cases. Our study suggests that different angiogenic mechanisms are present in ependymoma and medulloblastoma. Furthermore ependymoma patients may benefit from anti-angiogenic therapies based on the high vascularization as well as the endothelial expression of c-kit and VEGFR2. The expression pattern of the receptors on tumor cells also suggests the targeting of specific angiogenic tyrosine kinase receptors may have direct antitumor activity. Further preclinical and biomarker driven clinical investigations are needed to establish the application of tyrosine kinase inhibitors in the treatment of pediatric brain tumors.     

Brief Report: Activity of Imatinib in a Patient with Platelet-Derived-Growth-Factor Receptor Positive Malignant Solitary Fibrous Tumor of the Pleura

Malignant solitary fibrous tumor (MSFT) of the pleura is a rare neoplasm, with unpredictable biologic behavior and a low sensitivity to chemotherapy. To the authors' knowledge, no other effective medical treatment is available for this disease. Imatinib mesylate is a tyrosine kinase inhibitor targeting the platelet-derived growth factor (PDGFR-α and PDGFR-β), the BCR-ABL, and c-KIT receptors. We report the first evidence of the activity of imatinib in a symptomatic patient with a chemo- and radio-resistant advanced MSFT, who obtained a 21-months lasting major clinical benefit with a consistent reduction in tumor metabolism. Immunostaining of tumor cells demonstrated the positivity for PDGFR-α and PDGFR-β and the absence of c-KIT over-expression, in the absence of c-KIT and PDGRFR mutations; all the cells strongly and diffusely expressed the ligand PDGF A in the cytoplasm. This profile suggests that the observed tumor response was mediated through the inhibition of the tyrosine kinase activity of PDGFR. Treatment with imatinib should be considered for patients with recurrent or unresectable MSFTs with PDGFR expression.     

Identification of a subset of pericytes that respond to combination therapy targeting PDGF and VEGF signaling

The aim of our study was to further explore the use of anti-angiogenic therapy targeting the vascular endothelial growth factor receptor (VEGFR) on endothelial cells while simultaneously targeting platelet-derived growth factor receptors (PDGFRs) on adjacent pericytes. B16 mouse melanoma tumors exogenously expressing PDGF-BB (B16/PDGF-BB) display higher pericyte coverage on the vasculature compared to the parental B16 tumors (B16/mock). These models were used to investigate the effects of combination therapy targeting VEGFR and PDGFR signaling on size-matched tumors. Combination therapy using 25 mg/kg/day of the VEGFR inhibitor PTK787 and 100 mg/kg/day of the PDGFR inhibitor STI571 decreased the tumor growth rate of both tumor types, but the inhibition was only significant in the B16/PDGF-BB tumors. Combination therapy induced vessel remodeling, primarily by reducing the vessel density in B16/mock tumors, and by reducing the vessel size in B16/PDGF-BB tumors. When analyzing the effects of combination therapy on tumor vessel pericytes, it was found to primarily reduce the subpopulation of alpha-smooth muscle actin and PDGFRbeta-positive pericytes partly detached from the tumor vessels, without affecting the number of pericytes closely attached to the endothelium, which also express desmin. Taken together, these data demonstrate an increased benefit of targeting both VEGFR and PDGFR pathways in B16/PDGF-BB tumors, and demonstrates that the increased tumor growth inhibition in this model is accompanied by a reduction in a specific subset of pericytes, characterized by being loosely attached to endothelial cells and negative for the pericyte marker desmin.     

A phase II study of sorafenib in recurrent and/or metastatic salivary gland carcinomas: Translational analyses and clinical impact

BackgroundPre-clinical and clinical evidence suggests a rationale for the use of anti-angiogenic agents, including sorafenib, in recurrent and/or metastatic salivary gland carcinomas (RMSGCs). This study evaluates the activity of sorafenib in patients with RMSGCs and also investigates whether the activity of sorafenib could be related to its main tailored targets (i.e. BRAF, vascular endothelial growth factor receptor 2 [VEGFR2], platelet-derived growth factor receptor α [PDGFRα] and β, RET, KIT).Patients and methodsPatients received sorafenib at 400 mg BID. The primary end-point was response rate (RR) including complete response or partial response (PR); secondary end-points included RR according to Choi criteria, disease control rate (DCR), overall survival (OS), and progression-free survival (PFS).ResultsThirty-seven patients (19 adenoid cystic cancers, ACC) were enrolled. Six PRs were recorded. RR was 16% (95% confidence interval [CI]: 6–32; 11% in ACC and 22% in non-ACC). Choi criteria could be applied in 30 out of 37 cases with a RR of 50% (95% CI: 31–69%); DCR was 76% (95% CI: 59–88%). Incidence of ≥G3 adverse events was 29.7%. Median PFS and OS for the entire population were 5.9 months and 23.4 months, respectively. Median PFS and OS were 8.9 and 26.4 months for ACC versus 4.2 and 12.3 months for non-ACC patients.All the cases showed expression of PDGFRβ in the stroma and VEGFR2 in endothelial cells; PDGFRα positivity was found in the stroma of four (27%) cases. All except for two cases showed no PDGFRβ, VEGFR2 and PDGFRα expression in the tumour cells. KIT expression was restricted to ACC and a weak RET expression was limited to one adenocarcinoma, not otherwise specified (NOS). No BRAF mutation was found. No correlation was observed between the sorafenib activity and the expression of its markers although all six responders (two ACC, one adenocarcinoma, NOS, one salivary duct cancer [SDC], one high-grade mucoepidermoid [HG-MEC] and one poorly-differentiated cancer) are enriched in the stromal component showing a PDGFRβ immunodecoration. In ACCs, immunohistochemistry revealed MYB protein expression in 15/16 cases (94%) and the MYB-NFIB fusion oncogene was observed in 9/14 (64%).ConclusionsSorafenib is the first anti-angiogenic agent to demonstrate activity in RMSGC patients, particularly in some histotypes such as HG-MEC, SDC and adenocarcinoma, NOS. The PDGFRβ-positive rich stromal component characterising these histotypes and the lack of correlation between the activity of sorafenib and its targets suggests anti-angiogenic effect as the prevalent mechanism of action of sorafenib in SGCs.     

PDGFRα expression as a novel therapeutic marker in well-differentiated neuroendocrine tumors

Aims: To evaluate the biological significance of dense vascular networks associated with low-grade NENs, we assessed the impact of PDGFRα tissue expression in 77 GEP/NEN patients, associating PDGFRα expression with the morphological characterization in low-grade tumors.

Methods and results: Paraffin-embedded specimens of 77 GEP- NEN tissues, collected from January 2006 to March 2018, were evaluated for PDGFRα tissue expression and correlations with clinicopathological characteristics. PDGFRα tissue expression was significantly correlated with grade and the NEN growth pattern (p < 0.001) but not with gender, primary site or lymph nodes metastatic status. PDGFRα staining was mainly localized in the vascular pole of the neuroendocrine cells and in Enterochromaffin (EC) cells. In particular PDGFRα tissue expression was significantly more expressed in G2 (p < 0.001) than G1 and G3 cases (p 0.004; p < 0.0002;) and correlated with an insular growth pattern. PDGFRα tissue expression was associated with the Ki67 index and we found a significant negative trend of association with the Ki67 proliferation index (P < 0.001): thus PDGFRα expression is referred to morphological and not to proliferative data.

Conclusions: PDGFRα represents an effective target for new anti-angiogenic treatment in WD- GEP-NENs, in particular in G2 cases, and in G3 cases only when there is a mixed insular-acinar pattern. In this context, it is important to carefully delineate those tumors that might better respond to this type of treatment alone or in combination. Further investigation of the relationship between PD-L1 and PDGFRa is warranted, and may contribute to optimize the therapeutic approach in patients with GEP-NENs.     

Prognostic but not predictive role of platelet‐derived growth factor receptors in patients with recurrent glioblastoma

Platelet‐derived growth factor receptor (PDGFR) signaling has been implicated in the pathogenesis of glioblastomas and represents a target for the tyrosine kinase inhibitor imatinib. To examine the prognostic or predictive role of PDGFRs in recurrent glioblastomas, expression was examined in tumor samples of 101 patients of CSTI571BDE40, a randomized trial comparing hydroxyurea monotherapy and a combination of hydroxyurea and imatinib. Furthermore, PDGFRα phosphorylation was investigated using in situ proximity ligation assay. PDGFRα protein was expressed in 33% of tumors and was associated with male sex, young age, presence of R132H mutated isocitrate dehydrogenase 1 protein and short median survival (142 vs. 187 days, p = 0.028). Tumor PDGFRα phosphorylation was also associated with short survival (p = 0.030). The subset of patients with PDGFRα positive glioblastoma did not have longer survival on treatment with hydroxyurea and imatinib compared with hydroxyurea monotherapy. In conclusion, both PDGFRα protein expression and phosphorylation status had a prognostic role in recurrent glioblastomas but did not define a group that showed benefit from the combination therapy consisting of hydroxyurea and imatinib.     

Structural Basis for Hyperpermeability of Tumor Vessels in Advanced Lung Adenocarcinoma Complicated by Pleural Effusion

BackgroundMalignant pleural effusion (MPE) has a profound impact on quality of life and survival in patients with lung cancer. Identification of the factors within the tumor and its environment that mediate MPE is still lacking.Patients and MethodsIntratumoral microvessel density (MVD), endothelial cell and pericyte (PC) capillary coverage, endothelial cell (EC)-PC relationship, lymphatic endothelium integrity, and the expression of receptor tyrosine kinases were all assessed immunohistochemically in pleural tumor biopsy specimens from 24 patients with lung adenocarcinoma (ADC) with and without pleural disease, with the aim to evaluate the involvement with MPE.ResultsIn the effusion-positive (⁺) specimens, MVD values were found to be significantly higher, and a number of vessels were noted to lack immunoreactivity for ECs (CD31). Likewise, PC α–smooth muscle actin (αSMA) expression was also less extensive in the MPE⁺ cases. The observation of only sporadic staining of PCs can also explain the findings regarding platelet-derived growth factor receptors (PDGFRs), the expression of which, although more prominent in MPE⁺ samples, were almost exclusively detected on tumor stromal cells and not on vascular PCs. Conversely, vascular endothelial growth factor receptors (VEGFRs) appeared on both kinds of cells. With respect to lymphatic vessels, lymphatic intraluminal tumor cells were occasionally found in MPE⁺ specimens.ConclusionOur study suggests that disturbed vessel wall integrity, as well as abnormalities of fluid clearance by the lymphatic system, together with overexpression of growth factors, may take part in the pleural fluid accumulation in lung ADCs. Results of the decreased PC capillary coverage and PDGFR expression in MPE are discussed.     

Platelet-derived growth factor receptor/platelet-derived growth factor (PDGFR/PDGF) system is a prognostic and treatment response biomarker with multifarious therapeutic targets in cancers

Progress in cancer biology has led to an increasing discovery of oncogenic alterations of the platelet-derived growth factor receptors (PDGFRs) in cancers. In addition, their overexpression in numerous cancers invariably makes PDGFRs and platelet-derived growth factors (PDGFs) prognostic and treatment markers in some cancers. The oncologic alterations of the PDGFR/PDGF system affect the extracellular, transmembrane and tyrosine kinase domains as well as the juxtamembrane segment of the receptor. The receptor is also involved in fusions with intracellular proteins and receptor tyrosine kinase. These discoveries undoubtedly make the system an attractive oncologic therapeutic target. This review covers elementary biology of PDGFR/PDGF system and its role as a prognostic and treatment marker in cancers. In addition, the multifarious therapeutic targets of PDGFR/PDGF system are discussed. Great potential exists in the role of PDGFR/PDGF system as a prognostic and treatment marker and for further exploration of its multifarious therapeutic targets in safe and efficacious management of cancer treatments.     

胃癌组织中CD105和CD31的表达及其生物学行为的关系

 目的 探讨CD105，CD31在胃癌组织中的表达情况及其与胃癌生物学行为之间的关系。方法 采用免疫组化S-P单染法检测63例胃癌组织及20例慢性胃炎组织中CD105，CD31所标染的微血管密度值（MVD）。结果 （1）胃癌组织中CD105-MVD平均值为40.97±15.67，高于CD31-MVD平均值25.87±10.54（P<0.01），而二者均明显高于慢性胃炎组织中测得的相应值，分别为（19.55±7.55，20.65±7.44）（P <0.01）。（2）CD105的表达与胃癌的浸润深度、分期、淋巴结转移呈正相关（P <0.01），而与肿瘤大小、分级无关（P >0.05）。结论 （1）CD105在胃癌组织微血管中高表达，在标染胃癌组织MVD方面，CD105比CD31具有明显优越性。（2）CD105的表达与胃癌的生物学行为密切相关；其检测对更准确地确定肿瘤的临床分期、指导治疗、判断预后具有积极的临床意义。     

Pazopanib: a promising new agent in the treatment of soft tissue sarcomas

Pazopanib (GW786034) is a novel, small-molecule tyrosine kinase inhibitor. The primary mechanism of action of pazopanib can be described through its antiangiogenic properties via inhibition of the intracellular tyrosine kinase of VEGF receptor (VEGFR) and PDGF receptor (PDGFR). It is an orally available angiogenesis inhibitor that targets VEGFR-1, -2 and -3, PDGFR-α and -β, and c-kit. Pazopanib exhibits distinct pharmacokinetic and toxicity profiles compared with other agents in that class. Phase I studies defined the recommended monotherapy dose of pazopanib as 800 mg once daily. In 2009, it was approved in the USA for the treatment of advanced and metastatic renal cell carcinoma, and subsequently approved in other countries and demonstrated clinically and statistically significant activity in Phase II and III studies in advanced soft tissue sarcoma patients. This article focuses on its emerging role in the treatment of advanced soft tissue sarcomas.     

The PDGF pathway in breast cancer is linked to tumour aggressiveness,triple-negative subtype and early recurrence

Purpose

The platelet-derived growth factor (PDGF) signalling pathway is often dysregulated in cancer and PDGF-receptor expression has been linked to unfavourable prognostic factors in breast cancer (e.g. ER negativity, high Ki67 and high grade). This study aimed to evaluate the expression of PDGFRα, PDGFRβ and ligand PDGF-CC in breast cancer in relation to molecular subtypes and prognosis.

Methods

Protein expression of tumour and/or stromal cell PDGFRα, PDGFRβ and PDGF-CC was evaluated in primary tumours (N = 489), synchronous lymph node metastases (N = 135) and asynchronous recurrences (N = 39) using immunohistochemistry in a prospectively maintained cohort of primary breast cancer patients included during 1999–2003. Distant recurrence-free interval (DRFi) was the primary end-point.

Results

High expression of all investigated PDGF family members correlated to increasing Nottingham histopathological grade and high Ki67. Tumour cells displayed high expression of PDGFRα in 20%, and PDGF-CC in 21% of primary tumours, which correlated with the triple-negative subtype (TNBC). Patients with high PDGF-CC had inferior prognosis (P = 0.04) in terms of 5-year DRFi, whereas PDGFRα was up-regulated in lymph node metastasis and recurrences compared to primary tumours. High primary tumour PDGFRα was associated with increased risk of central nervous system (CNS) recurrence.

Conclusions

High PDGFRα and PDGF-CC expression were linked to breast cancer with an aggressive biological phenotype, e.g. the TNBC subtype, and high PDGF-CC increased the risk of 5-year distant recurrence. Tumour cell PDGFRα was significantly up-regulated in lymph node metastases and asynchronous recurrences. Our findings support an active role of the PDGF signalling pathway in tumour progression.

     

Simultaneous inhibition of EGFR, VEGFR, and platelet-derived growth factor receptor signaling combined with gemcitabine produces therapy of human pancreatic carcinoma and prolongs survival in an orthotopic nude mouse model

Although gemcitabine has been approved as the first-line chemotherapeutic reagent for pancreatic cancer, its response rate is low and average survival duration is still only marginal. Because epidermal growth factor receptor (EGFR), vascular endothelial growth factor receptor (VEGFR), and platelet-derived growth factor receptor (PDGFR) modulate tumor progression, we hypothesized that inhibition of phosphorylation of all three on tumor cells, tumor-associated endothelial cells, and stroma cells would improve the treatment efficacy of gemcitabine in an orthotopic pancreatic tumor model in nude mice and prolong survival. We implanted L3.6pl, a human pancreatic cancer cell, in the pancreas of nude mice. We found that tumor-associated endothelial cells in this model highly expressed phosphorylated EGFR, VEGFR, and PDGFR. Oral administration of AEE788, a dual tyrosine kinase inhibitor against EGFR and VEGFR, decreased phosphorylation of EGFR and VEGFR. PDGFR phosphorylation was inhibited by STI571. Although i.p. injection of gemcitabine did not inhibit tumor growth, its combination with AEE788 and STI571 produced >80% inhibition of tumor growth and prolonged survival in parallel with increases in number of tumor cells and tumor-associated endothelial cell apoptosis, decreased microvascular density, decreased proliferation rate, and prolonged survival. STI571 treatment also decreased pericyte coverage on tumor-associated endothelial cells. Thus, inhibiting phosphorylation of EGFR, VEGFR, and PDGFR in combination with gemcitabine enhanced the efficacy of gemcitabine, resulting in inhibition of experimental human pancreatic cancer growth and significant prolongation of survival.     

Expression of a novel endothelial marker,C-type lectin 14A,in epithelial ovarian cancer and its prognostic significance

Objective

The purpose of this study was to evaluate microvessel density (MVD) as assessed by C-type lectin 14A (CLEC14A), which is a new marker for endothelial cells, and compare its expression to CD31 and CD105 in epithelial ovarian cancer (EOC).

Methods

MVD was evaluated in tumors (n = 50) from patients with EOC who underwent primary surgery and in patients with EOC who received preoperative chemotherapy (n = 49) using immunohistochemistry with antibodies to CLEC14A, CD31 and CD105. The median duration of follow-up was 24.5 months (range 1?101 months). The effect of prognostic factors on event-free survival (EFS) and overall survival (OS) was assessed using the Cox regression model.

Results

The amount of residual disease was found to be an independent prognostic factor in multivariate analysis with respect to EFS (P = 0.009) and OS (P < 0.001). The mean MVD of CLEC14A (MVD = 6), in tumors from patients who underwent primary surgery, was significantly lower than that of CD31 (MVD = 25, P < 0.0001) and CD105 (MVD = 11, P = 0.018). However, there was no significant correlation between MVD as detected by these markers and clinical outcome. There was no expression of CLEC14A in tumors from patients who received preoperative chemotherapy and the MVD of CD31 and CD105 was significantly reduced (P = 0.001 and 0.006, respectively) in this set of patients.

Conclusion

This study demonstrates MVD as detected by CLEC14A in EOC. Treatment with chemotherapy reduces tumor blood vessels significantly. We suggest that CLEC14A may be a more specific endothelial marker to assess tumor angiogenesis.

     

Inhibition of activated receptor tyrosine kinases by Sunitinib induces growth arrest and sensitizes melanoma cells to Bortezomib by blocking Akt pathway

Despite the use of multiple therapeutic strategies, metastatic melanoma remains a challenge for oncologists. Thus, new approaches using combinational treatment may be used to try to improve the prognosis of this disease. In this report, we have analyzed the expression of receptor tyrosine kinases (RTKs) in melanoma specimens and in four metastatic melanoma cell lines. Both melanoma specimens and cell lines expressed RTKs, suggesting that they may represent eventual targets for multitargeted tyrosine kinase inhibitor, Suntinib. Sunitinib reduced the proliferation of two melanoma cell lines (M16 and M17) and increased apoptosis in one of them (M16). Moreover, the two metastatic melanoma cell lines harbored an activated receptor (PDGFRα and VEGFR, respectively), and Sunitinib suppressed the phosphorylation of the RTKs and their downstream targets Akt and ribosomal protein S6, in these two cell lines. Similar results were obtained when either PDGFRα or VEGFR2 expression was silenced by lentiviral-mediated short-hairpin RNA delivery in M16 and M17, respectively. To evaluate the interaction between Sunitinib and Bortezomib, median dose effect analysis using MTT assay was performed, and combination index was calculated. Bortezomib synergistically enhanced the Sunitinib-induced growth arrest in Sunitinib-sensitive cells (combination index < 1). Moreover, LY294002, a PI3K inhibitor, sensitized melanoma cells to Bortezomib treatment, suggesting that downregulation of phospho-Akt by Sunitinib mediates the synergy obtained by Bortezomib + Sunitinib cotreatment. Altogether, our results suggest that melanoma cells harboring an activated RTK may be clinically responsive to pharmacologic RTK inhibition by Sunitinib, and a strategy combining Sunitinib and Bortezomib, may provide therapeutic benefit.     

Bone marrow-derived cells are recruited by the melanoma tumor with endothelial cells contributing to tumor vasculature

Purpose

Tumor expansion is dependent on neovascularization, a process that requires sustained new vessel formation. Although the critical role of angiogenesis by endothelial sprouting in this process, controversy still prevails on whether angiogenesis involving bone marrow-derived endothelial cells, does contribute to this process. This study aims to evaluate the recruitment of bone marrow-derived cells by the melanoma tumor, including endothelial cells, and if they contribute to angiogenesis.

Methods

A chimeric mouse model of GFP bone marrow was used to induce melanoma tumors derived from murine B16-F10 cell line. These tumors were evaluated for the presence of myeloid cells (CD11b), T lymphocytes (CD3, CD4 and CD8) and endothelial cells (VEGFR2 and CD31) derived from bone marrow.

Results

Mice transplanted with GFP+ cells showed significant bone marrow chimerism (90.9 ± 0.87 %) when compared to the GFP transgenic mice (90.66 ± 2.1 %, p = 0.83) demonstrating successful engraftment of donor bone marrow stem/progenitor cells. Analysis of the murine melanoma tumor showed the presence of donor cells in the tumors (3.5 ± 1.7 %) and interestingly, these cells represent endothelial cells (CD31+ cells; 11.5 ± 6.85 %) and myeloid cells (CD11b+ cells; 80 ± 21 %), but also tumor-infiltrating lymphocytes (CD8+ T cells, 13.31 ± 0.2 %; CD4+ T-cells, 2.1 ± 1.2 %). Examination of the tumor endothelium by confocal microscopy suggests the presence of donor CD31+/GFP+ cells in the wall of some blood vessels.

Conclusion

This study demonstrates that bone marrow-derived cells are recruited by the murine melanoma tumor, with myeloid cells and CD4 and CD8 T lymphocytes migrating as antitumor immune response, and endothelial cells participating of the tumor blood vessels formation.

     

pN0期非小细胞肺癌组织中PDGF-B和PDGFR-α的表达及与淋巴结微转移的关系

目的:探究pN0期非小细胞肺癌组织中血管源性生长因子B(platelet-derived growth factor B,PDGF-B)和血小板源性生长因子受体α（platelet-derived growth factor receptor-α，PDGFR-α）的表达及与淋巴结微转移的关系。方法:选取河北北方学院附属第一医院2013年1月至2014年12月术后经常规病理检查证实为pN0期的非小细胞肺癌患者106例为研究组，同时选取手术治疗的非肺癌病例48例作为对照组，比较两组PDGF-B和PDGFR-α的表达水平，观察分析不同临床病理参数下及是否伴有微转移患者PDGF-B和PDGFR-α阳性率，并使用此项指标对患者进行微转移诊断，观察其诊断特异度及灵敏度。结果:不同性别、年龄、肿瘤分型、肿瘤直径、组织学分析及是否伴有吸烟史患者PDGF-B和PDGFR-α阳性率无显著差异（P＞0.05）；对照组PDGF-B和PDGFR-α的表达水平显著低于研究组。研究组II-III期PDGF-B、PDGFR-α阳性率显著高于I期患者，伴有微转移患者PDGF-B和PDGFR-α阳性率显著高于无微转移患者，差异具有统计学意义（P＜0.05）。结论:PDGF-B及PDGFR-α的表达对pN0期非小细胞肺癌患者微转移的判定具有重要意义，其过表达可能预示患者伴有微转移，能为术后患者治疗方案的制定提供一定依据。     

Imatinib mesylate inhibits Leydig cell tumor growth: evidence for in vitro and in vivo activity

Leydig cell tumors are usually benign tumors of the male gonad. However, if the tumor is malignant, no effective treatments are currently available. Leydig cell tumors express platelet-derived growth factor (PDGF), kit ligand and their respective receptors, PDGFR and c-kit. We therefore evaluated the effects of imatinib mesylate (imatinib), a selective inhibitor of the c-kit and PDGFR tyrosine kinases, on the growth of rodent Leydig tumor cell lines in vivo and in vitro, and examined, in human Leydig cell tumor samples, the expression of activated PDGFR and c-kit and the mutations in exons of the c-kit gene commonly associated with solid tumors. Imatinib caused concentration-dependent decreases in the viability of Leydig tumor cell lines, which coincided with apoptosis and inhibition of proliferation and ligand-stimulated phosphorylation of c-kit and PDGFRs. Mice bearing s.c. allografts of a Leydig tumor cell line treated with imatinib p.o., had an almost complete inhibition of tumor growth, less tumor cell proliferation, increased apoptosis, and a lesser amount of tumor-associated mean vessel density compared with controls. No drug-resistant tumors appeared during imatinib treatment but tumors regrew after drug withdrawal. Human Leydig cell tumors showed an intense expression of the phosphorylated form of c-kit and a less intense expression of phosphorylated PDGFRs. No activating mutations in common regions of mutation of the c-kit gene were found. Our studies suggest that Leydig cell tumors might be a potential target for imatinib therapy.     

Phase II study of MEDI-575, an anti-platelet-derived growth factor-α antibody,in patients with recurrent glioblastoma

MEDI-575, an immunoglobulin G2κ monoclonal antibody, selectively binds to platelet-derived growth factor-α receptor (PDGFR-α) with high specificity. This multicenter, single-arm, open-label, phase II study evaluated the efficacy and safety of MEDI-575 in patients with recurrent glioblastoma. Adults with first recurrence of glioblastoma following surgery, temozolomide, and radiation received MEDI-575 25 mg/kg intravenously over 60 min every 21 days until disease progression or unacceptable toxicity. Six-month progression-free survival rate (PFS-6) was the primary end point; secondary measures included response rate, overall survival (OS), and safety/tolerability. PDGFR-α expression was evaluated by immunohistochemistry. Fifty-six patients were enrolled; median age was 56.5 years (range 23–79), 66?% were male, and 66?% were aged ≥65 years. PFS-6 was 15.4?% [90?% confidence interval (CI) 8.1–24.9]. No complete or partial responses were observed; 23 (41.1?%) patients had stable disease as best response. Median PFS was 1.4 months (90?% CI 1.4, 1.8); median OS was 9.7 months (90?% CI 6.5, 11.8). The most common treatment-related adverse events (AEs) were diarrhea (16?%), nausea (13?%), and fatigue (13?%). Twelve (21?%) patients reported grade ≥3 AEs, with hydrocephalus (n?=?3), dysphagia (n?=?2), and convulsion (n?=?2) reported in more than 1 patient. Two patients had treatment-related Grade ≥3 AEs of decreased lymphocyte count and asthenia (n?=?1 each). Seven patients (13?%) discontinued MEDI-575 owing to AEs. Labeling of PDGFRα in glioblastoma cells and tumor-associated stromal cells was highly variable, with no correlation with PFS. MEDI-575, although well tolerated, had limited clinical activity in recurrent glioblastoma.     

Imatinib mesylate (Gleevec®) in advanced breast cancer-expressing C-Kit or PDGFR-β: clinical activity and biological correlations

BackgroundNovel molecular therapies for metastatic breast cancer (MBC) are necessary to improve the dismal prognosis of this condition. Imatinib mesylate (Gleevec®) inhibits several protein tyrosine kinases, including platelet-derived growth factor receptor (PDGFR) and c-kit, which are preferentially expressed in tumor cells. We tested the activity of imatinib mesylate in MBC with overexpression of PDGFR or c-kit. Additionally, we sought to determine the biological correlates and immunomodulatory effects.Patients and methodsThirteen patients were treated with Imatinib administered orally at 400 mg p.o. b.i.d. (800 mg/day), until disease progression. All patients demonstrated PDGFR-β overexpression and none showed c-kit expression.ResultsNo objective responses were observed among the 13 patients treated in an intention-to-treat analysis. All patients experienced disease progression, with a median time to progression of 1.2 months. Twelve patients have died, and the median overall survival was 7.7 months. No patient had a serious adverse event. Imatinib therapy had no effect on the plasma levels of the angiogenesis-related cytokines, vascular endothelial growth factor, PDGF, b-fibroblast growth factor, and E-selectin. Immune studies showed imatinib inhibits interferon-γ production by TCR-activated CD4⁺ T cells.ConclusionImatinib as a single agent has no clinical activity in PDGFR-overexpressing MBC and has potential immunosuppressive effects.