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Experimental Therapeutics |
Millennium Pharmaceuticals, Inc., South San Francisco, California 94080 [N. A. L., C. M. S., S. J. H., N. A. G.], and Preuss Laboratory, Department of Neurological Surgery, University of California San Francisco, San Francisco, California 94143 [M. A. I.]
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ABSTRACT |
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 Top ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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and ß PDGF receptor (PDGFR) tyrosine kinases. Numerous studies have demonstrated expression of PDGF-A, PDGF-B, and the PDGFRs in gliomablastomas, but such studies have not been conducted for the newly identified PDGF-C and -D. Therefore, we examined the expression of all PDGF ligands and receptors in 11 glioma cell lines and 5 primary glioblastoma tumor tissues by quantitative reverse transcription-PCR. Expression of PDGF/PDGFR pairs that are known to functionally interact were identified in all of the samples. Interestingly, PDGF-C expression was ubiquitous in brain tumor cells and tissues but was very low or absent in normal adult and fetal brain. PDGF-D was expressed in 10 of 11 brain tumor cell lines and 3 of 5 primary brain tumor samples. As a strategy for blocking PDGFR signaling, CT52923, a potent selective small molecule piperazinyl quinazoline kinase inhibitor of the PDGFR, was identified. In model systems using NIH/3T3 cells, CT52923 blocked PDGF autocrine-mediated phosphorylation of PDGFR, Akt, and mitogen-activated protein kinase (MAPK), while having no effect on v-fms or V12-ras-mediated Akt or extracellular signal-regulated protein kinase (Erk) phosphorylation. More importantly, p.o. administration of CT52923 to nude mice caused a significant 61% reduction (P < 0.006) in tumor growth of NIH/3T3 cells transformed by PDGF, whereas tumor formation by cells expressing v-fms was unaffected. We next characterized PDGF autocrine signaling in five glioblastoma cell lines. In all of the cases, PDGF autocrine signaling was evident because treatment with 1–10 µM CT52923 inhibited PDGFR autophosphorylation when present at a detectable level and blocked downstream Akt and/or Erk phosphorylation. The functional significance of PDGF autocrine signaling in these cells was demonstrated by the fact that the CT52923 inhibited soft agar colony formation, and, when given p.o. to nude mice, it effectively reduced tumor formation by 44% (P < 0.0019) after s.c. injection of C6 glioblastoma cells. This study of glioblastoma cells and primary tissues is the first to implicate PDGF-C and -D in brain tumor formation and confirms the existence of autocrine signaling by PDGF-A and -B. More importantly, treatment with the PDGFR antagonist CT52923 inhibited survival and/or mitogenic pathways in all of the glioblastoma cell lines tested and prevented glioma formation in a nude mouse xenograft model. Together these findings demonstrate the potential therapeutic utility of this class of compounds for the treatment of glioblastoma. |
INTRODUCTION |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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The PDGF family consists of four members, PDGF-A, -B, -C, and -D, which signal through the and ß PDGF-receptor (PDGFR) tyrosine kinases. Biosynthesis and processing of the PDGFs results in the formation of full-length disulfide-linked homodimers PDGF-AA, BB, CC, and DD and the heterodimer PDGF-AB (reviewed in Ref. 8
). Although PDGF-AA, BB, and AB undergo additional processing it is not required for their biological activity. In contrast, PDGF-CC and -DD require proteolytic cleavage for activity (9, 10, 11, 12)
. The PDGF-A and -C chains selectively bind PDGFR, whereas PDGF-D preferentially binds ß PDGFR, and PDGF-B displays similar affinity for both receptors (8, 9, 10, 11, 12)
. Numerous studies have demonstrated expression of PDGF-A, PDGF-B, and the PDGFRs in glioblastomas, but such studies have not been conducted for the newly identified PDGF-C and -D. Here, we demonstrate that these novel PDGFs are routinely expressed in glioma cell lines and in primary glioblastoma tissues along with their cognate PDGFR, which indicates a potential role in the development of brain tumors.
Because of the numerous genetic and physiological alterations observed in human glioma, the relative importance of PDGF signaling is not fully understood. To demonstrate a causative role, reversion of the transformed phenotype of glioblastoma cells or tumor growth has been achieved with antibodies that neutralize PDGF, with dominant negative mutants of PDGF or PDGFR or with the small molecule PDGFR kinase inhibitor STI571 (13, 14, 15, 16, 17) . Recently, we identified CT52923, a potent selective small molecule antagonist of the PDGFR that effectively inhibits PDGF-induced cell proliferation and migration in cultured cells and the in vivo PDGF-mediated response to vascular injury in rats (18) . Using a panel of five glioblastoma cell lines, we, demonstrate in all cases, that treatment with CT52923 inhibits PDGFR autophosphorylation, blocks the ras/MAPK proliferative pathway or the PI3k/Akt survival pathway and causes a reversion of the transformed phenotype. Oral administration of CT52923 to nude mice in a xenograft tumor model produces a significant inhibition of glial cell solid-tumor growth demonstrating the therapeutic potential of this small molecule PDGFR kinase inhibitor.
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MATERIALS AND METHODS |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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. A stock solution of 3 mM CT52923 was prepared in DMSO and stored at -20°C. Dilutions for all assays were made before use.
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Cell Transfections.
Fugene 6 (Roche Molecular Biochemicals) was used to transfect the above expression vectors into NIH/3T3 cells according to the manufacturer’s protocol, and cells stably expressing each construct were selected by growing them in 750 µg/ml G418 in DMEM, 10% calf serum, 1% penicillin/streptomycin, and 1% L-glutamine.
Western Blotting.
Cells were plated in 10-cm Petri dishes in the absence or presence of the indicated amounts of CT52923 (from a 3-mM stock in DMSO) for 5 h in serum-free medium. Cell lysates were prepared as described earlier (18)
, and proteins were immunoprecipitated when indicated on Figures 2
and 4
, using standard techniques, separated by SDS-PAGE (Novex; 4–20% gradient gels), and transferred onto nitrocellulose. Blots were blocked in 5% milk in TTBS (Tris-buffered saline with 0.02% Tween 20) and immunoblotted with antiphosphotyrosine antibodies, phospho-Akt, phospho-Erk, PY99, or phospho-ßPDGFR-PY769, as specified in Figure
legends 2, 4, and 5. Anti-phospho-Erk antibody was purchased from UBI; anti-Erk antibody, anti-Akt, anti-phospho-Akt antibodies from New England Biolabs; and anti-ßPDGFR-PY769 from UBI. Appropriate horseradish peroxidase-labeled secondary antibodies (Roche Molecular Biochemicals) were used followed by chemiluminescent detection (Amersham). All of the blots were stripped and reblotted with anti-Erk, anti-Akt, or anti-PDGFR antibodies, as noted in Figure legends, to determine total protein amounts loaded.
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- and ß-PDGFR expression in multiple cell lines and tissues, we used the ABI Prism 7700 Sequence Detection System (PE Biosystems) that uses TaqMan (real-time quantitative PCR) chemistry. cDNA was synthesized in a 50-ul reaction using a TaqMan reverse transcription kit (PE Biosystems). RNAs were normalized using primers, and a TaqMan probe corresponding to human Cyc for glioblastoma cell lines and GAPDH for primary glioma tissues and expression of each PDGF or PDGFR gene was measured relative to these housekeeping genes. Because each experimental sample has this endogenous reference standard, correction for the amount of cDNA added to any individual reaction is not needed. Primers and TaqMan probes to PDGF ligands and receptors were designed using the Primers Express software (PE Biosystems) and synthesized by ABI Prism Primers and Probes (PE Biosystems). TaqMan probes were labeled with 6-carboxy-fluorescein phosphoamidite (FAM) at the 5' end and as quencher 6-carboxy-tetramethyl-rhodamine (TAMRA) at the 3' end (Table 1)
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Colony Soft Agar Assay.
Glioma cells (105) were cultured in 60-mm dishes in 0.5% low gelling agarose (Sea Plaque) on a base layer of 1% noble agar (Difco) in the presence of indicated amounts of CT52923 (added on day 1 only) or vehicle control in complete medium (according to American Type Culture Collection recommendations) and colonies were scored after 21 days. During the experiment, 0.5 ml of fresh complete medium (without CT52923) was added every 5 days.
Xenograft Tumor Growth in Nude Mice.
Athymic nude mice (n = 15) received injections s.c. in the left flank region with 2 x 106 PDGF/3T3 or Fms/3T3 cells, or 3 x 106 C6 glial tumor cells. Animals were given CT52923 at 60 mg/kg twice a day by p.o. gavage. For the PDGF/3T3 and Fms/3T3 studies, CT52923 treatment began when tumors reached about 50 mg in size, between day 15 and day 20 and continued for up to 17 days when control tumors reached in average 800 mg. For the C6 glial cells, dosing started on the day of cell injections (day 1) and the study ran for 18 days, when control tumor weights reached in average 1250 mg.
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RESULTS |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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-PDGFR (Table 2)
. Because PDGF-C and -A preferentially bind the -PDGFR, they may cooperate to enhance -PDGFR autocrine signaling. PDGF-D was widely expressed in all of the cells with the exception of SF763 as was its preferred ß-PDGFR (11)
, which was undetectable in only SF763 and SF767 (Table 2)
. These findings are of particular interest because the other ß PDGFR ligand, PDGF-B, was not expressed in six of the cell lines that expressed PDGF-D and ß-PDGFR which suggests a previously unrecognized PDGF autocrine loop. To extend these studies, primary glioblastoma multiforme tissues obtained from five patients were evaluated by a similar TaqMan analysis of PDGF and PDGFR expression (Table 3)
. As with the glioma cell lines, PDGF-C was expressed with PDGF-A and -PDGFR in all of the primary glioblastoma tissues but was undetectable in normal fetal and adult brain tissues (Table 3)
. PDGF-D mRNA was detected in three of five primary tumors, whereas ß-PDGFR was expressed in all; a lower level of PDGF-D was observed in normal brain tissue. This study demonstrates that the novel PDGF-C and -D ligands are coexpressed with the PDGFRs in primary glioblastoma tissues and cell lines, which implies a potential role in mediating PDGF autocrine signaling.
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that is highly selective for PDGFR and c-kit, with little or no activity against the other PDGFR family members nor against a wide range of additional receptor tyrosine kinases or cytoplasmic kinases (18)
. We previously demonstrated that CT52923 inhibited PDGFR phosphorylation with an IC50 of 100–200 nM when Chinese hamster ovary (CHO) cells expressing recombinant ß-PDGFR were treated with PDGF-(18)
. To assess the ability of the compound to block autocrine-mediated PDGFR phosphorylation, serum-starved PDGF/3T3 cells were incubated for 1 h with increasing concentrations of CT52923, and then immunoprecipitated ß-PDGFR from cell lysates was evaluated by antiphosphotyrosine Western blot analysis. As shown in Fig. 2A
, the high level of ß-PDGFR phosphorylation detected in PDGF/3T3 cells was readily blocked by CT52923 treatment with an IC50 of 300 nM, and nearly complete inhibition was observed at 3 µM. To control for the amount of protein applied to the gels, the blot was also probed with anti-ß-PDGFR antibody.
NIH/3T3 cell transformation by PDGF-B, V12-ras, or v-fms causes constitutive activation of the MAPK and PI3k pathways leading to the phosphorylation of Erk and Akt, respectively (Fig. 2B)
. Therefore, the effects of CT52923 treatment on Erk and Akt phosphorylation was evaluated in PDGF/3T3, Ras/3T3, and Fms/3T3 cells by Western blot analysis of lysates using phospho-specific antibodies. Consistent with its effect on PDGFR autophosphorylation in PDGF/3T3 cells, CT52923 inhibited Erk and Akt phosphorylation at concentrations above 300 nM (Fig. 2B)
. In contrast, treatment with CT52923 at concentrations up to 30 µM had no effect on Erk or Akt phosphorylation in Ras/3T3 or Fms/3T3 cells. These studies demonstrate that CT52923 is a potent inhibitor of PDGFR autocrine activation. Furthermore, the specificity of inhibition was demonstrated by the fact that common signaling pathways, activated at a similar proximal location by v-fms or more distally by V12-ras, are insensitive to CT52923 treatment.
Once transformed by PDGF, (13
, 36)
V12-ras (13)
or v-fms, (37
, 38)
NIH/3T3 cells readily form solid tumors when injected s.c. into nude mice. Therefore, we used this nude mouse tumor model to evaluate the in vivo effects of CT52923 at inhibiting a tumor mass. Approximately 15 days after an inoculation with 2 x 106 PDGF/3T3, or Fms/3T3 cells, when tumors had reached 
50 mg in size, CT52923 or vehicle alone was administered 60 mg/kg/twice a day by oral gavage for an additional 17 days at which time the mice were killed and tumor weights were determined. As shown in Fig. 3
, average tumor weights for PDGF/3T3 and Fms/3T3 vehicle control groups were in the 700–800-mg range, whereas PDGF/3T3 tumors in the CT52923 treatment group showed a 61% reduction in size (P < 0.006). In contrast, CT52923 treatment had no effect on Fms/3T3 tumor growth. These results demonstrate selective in vitro and in vivo inhibition of PDGFR autocrine signaling by CT52923 and provide the basis for its use to study the role of PDGF autocrine signaling in glioblastoma cells.
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. Rat C6 cells were selected because they have a well-characterized PDGF autocrine loop and readily form tumors in nude mice (16)
. The initial event in PDGF autocrine signaling, autophosphorylation of the PDGFR as detected by antiphosphotyrosine Western blot analysis of A172, U251, and C6 cells, was effectively inhibited by pretreatment with 1–3 µM CT52923 (Fig. 4)
. This antiphosphotyrosine signal was greatly increased by the stimulation of these cells with exogenous PDGF, which indicated that only a fraction of the available PDGFR is activated (data not shown).
The best-characterized mechanisms by which PDGF autocrine signaling mediates cellular oncogenic transformation involves the activation of the ras/MAPK pathway, which can increase cellular proliferation, and the PI3k/Akt pathway, which promotes cell survival (39, 40, 41)
. Therefore, we determined the effect of PDGFR inhibition by CT52923 on the phosphorylation of Akt and Erk in each of the glioblastoma cell lines. As shown in Fig. 5
, A172, A172, U251, T98G, and C6 cells displayed constitutive Akt phosphorylation that was inhibited by treatment of cells with 0.3–3.0 µM CT52923, as determined by Western blot analysis using anti-phospho-Akt antibodies. PDGF autocrine induction of Akt phosphorylation in these cells is likely to have been exaggerated because of the loss of PTEN function in human A172 and U251 cell lines, whereas Akt phosphorylation was below the level of detection in untreated SF188, which has wild-type PTEN (Fig. 5)
. All of the cell lines demonstrated constitutive Erk phosphorylation that was inhibited in each case by CT52923 (0.3–3.0 µM), with the exception of A172 (Fig. 5)
. It is possible that A172 cells have additional signaling defects leading to Erk activation that are independent of PDGFR. Remarkably, PDGFR inhibition by CT52923 effectively blocked constitutive Erk and/or Akt signaling in all of the other glioblastoma cell lines studied.
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, CT52923 blocked soft agar colony formation of all of the glioblastoma cells with an IC50 in the 1–10-µM range, with the most sensitive line, T98G, showing >90% inhibition at 1 µM. As a control, CT52923 treatment at concentrations of up to 30 µM had only minimal effects on colony formation by A431 and MDA468 carcinoma cells, which did not express PDGFR as confirmed by TaqMan analysis (Table 2
and data not shown).
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5
6)
, the C6 xenograft model was chosen to evaluate the ability of CT52923 to block glioblastoma formation in vivo. Nude mice received injections s.c. in the left flank with 3 x 106 C6 cells, and CT52923 treatment was initiated by p.o. gavages at 60 mg/kg twice daily for the entire duration of the 18-day study. As shown in Fig. 7
, tumors in vehicle control animals reached an average weight of 1.25 grams, and treatment with CT52923 caused a significant 44% reduction in tumor size (P < 0.0019). However, optimal treatment may not have been achieved because the monitoring of CT52923 levels during the study indicated that >4-µM (IC50, 2 µM in plasma) concentrations were maintained for 4 h after dosing, but nadir concentrations were undetectable. Thus, adequate levels for inhibiting PDGFR were maintained for up to 12 h/day.
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DISCUSSION |
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TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
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- and ß-PDGFR, PDGF-C or -D expression could induce autocrine signaling through both receptors. This may have important implications, because it was previously thought that PDGF-B expression, observed in only a subset of glioblastoma cells, was required for autocrine signaling through the ß-PDGFR (Table 2
; Ref. 3
). PDGF-C and -D also differ from PDGF-A and -B in that posttranslational cleavage by an unknown protease is required for biological activity, and whether this processing occurs in the tissues of malignant glioma has not been examined (11
, 12)
. Coexpression of PDGF and PDGFR has been shown at all brain tumor stages including low-grade astrocytomas, anaplastic astrocytomas, and glioblastoma multiforme (3 , 25) . These observations are consistent with PDGF autocrine signaling being an initiating event, and additional defects in cell signaling are then probably required for progression to glioblastoma multiforme (3 , 44 , 45) . This is underscored by the fact that, as brain tumors become more advanced, they accumulate alterations in additional genes that regulate cell survival and proliferation, including p53, PTEN, CDK4, Rb, and Ink4a-Arf (3 , 44) . The importance of additional genetic alterations in combination with PDGF autocrine signaling was recently investigated by Dai et al. (46) using retroviral transduction of PDGF-B into glial cells of newborn mice that are wild-type or null for Ink4a-Arf. On the wild-type background, PDGF-B expression resulted in low-grade gliomas as compared with high-grade tumors of shorter latency in the Ink4a-Arf null mice, which showed the importance of additional genetic defects. Because of the multiple alterations in cell signaling pathways in malignant gliomas, it remains an open question as to the therapeutic effectiveness of blocking a potential initiating event such as PDGFR autocrine signaling. Recent success in the treatment of chronic myelogenous leukemia, either in the acute or in the chronic phase, by targeting the BCR/ABL kinase demonstrates that such a strategy can be very effective, even after additional mutations have occurred (47 , 48) . Because these studies demonstrate that inhibiting an early initiating event can still revert the transformed phenotype even in the late stages of cancer, we chose to investigate the role of PDGF autocrine signaling in glioblastoma multiforme cells using our selective PDGFR antagonist CT52923.
PDGF autocrine expression initially induces PDGFR autophosphorylation on tyrosines, which creates the sites for physical interactions with a number of proteins that contain Src homology region 2 domains (reviewed in Ref. 49 ). These interactions affect the activation of intracellular signaling pathways that are critical for oncogenic transformation, including cell proliferation and survival. Common genetic alterations in glioblastoma multiforme include PTEN mutations that would enhance PDGFR signaling through the PI3k pathway and cell cycle defects that could complement MAPK signaling. In glioblastoma cells A172, U251, and C6, which have a high level of PDGF ligand and receptor expression along with PTEN mutations, it was demonstrated that CT52923 can block autocrine-mediated receptor autophosphorylation and the exaggerated Akt phosphorylation, thereby decreasing signaling through this cell survival pathway. Interestingly, mitogenic signaling through the MAPK pathway was also consistently inhibited by CT52923 in all of the cells tested except A172, in which the activation of alternative convergent pathways may play a larger role. These studies provide evidence that PDGF autocrine signaling continues to play an important role in mediating intracellular events in late-stage glioblastoma multiforme cells, even though multiple genetic alterations have accumulated; and the blockade of this pathway could decrease cell proliferation and survival.
To demonstrate that Akt and Erk signaling had biological significance, we showed that CT52923 significantly inhibited soft agar colony formation by glioblastoma cells but had little effect on A431 and MDA468 carcinoma cells. Similarly, p.o. administration of CT52923 to nude mice significantly inhibited xenograft C6 cell tumor formation. Other studies using neutralizing antibodies, dominant-negative mutants of PDGF or PDGFR, and PDGFR kinase inhibitors have shown the importance of PDGFR signaling for the maintenance of the transformed phenotype of glioblastoma cells and their ability to form tumors in mice (13, 14, 15, 16, 17) . In conclusion, these studies provide strong evidence that, even in advanced stages of brain tumors, PDGF autocrine signaling still plays a critical role in maintaining cell transformation and that selective blockade of PDGFR with a kinase inhibitor may provide an effective therapeutic intervention. This may be especially true for treatment of low-grade astrocytomas, a situation that may be similar to STI571 treatment of chronic myelogenous leukemia in the early chronic phase that has resulted in long-term remissions.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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1 To whom requests for reprints should be addressed, at Millennium Pharmaceuticals, Inc., 256 East Grand Avenue, South San Francisco, CA 94080. Phone: (650) 244-6832; Fax: (650) 244-9208; E-mail: nathalie.lokker{at}mpi.com 
2 Present address: Dartmouth-Hitchcock Medical Center, One Medical Center Drive, Lebanon, NH 03756.
3 The abbreviations used are: PDGF, platelet-derived growth factor; MAPK, mitogen-activated protein kinase; ERK, extracellular signal-regulated protein kinase; PI3k, phosphatidylinositol 3'-kinase; Cyc, cyclophilin; GAPDH, glyceraldehyde-3-phosphate dehydrogenase; ECL, enhanced chemiluminescence; RT-PCR, reverse transcription-PCR.
Received 1/17/02. Accepted 5/ 2/02.
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 D. A. Reardon, M. J. Egorin, J. A. Quinn, J. N. Rich Sr, I. Gururangan, J. J. Vredenburgh, A. Desjardins, S. Sathornsumetee, J. M. Provenzale, J. E. Herndon II, et al. Phase II Study of Imatinib Mesylate Plus Hydroxyurea in Adults With Recurrent Glioblastoma Multiforme J. Clin. Oncol., December 20, 2005; 23(36): 9359 - 9368. [Abstract] [Full Text] [PDF]
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 M. Moore, H. W. Hirte, L. Siu, A. Oza, S. J. Hotte, O. Petrenciuc, F. Cihon, C. Lathia, and B. Schwartz Phase I study to determine the safety and pharmacokinetics of the novel Raf kinase and VEGFR inhibitor BAY 43-9006, administered for 28 days on/7 days off in patients with advanced, refractory solid tumors Ann. Onc., October 1, 2005; 16(10): 1688 - 1694. [Abstract] [Full Text] [PDF]
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G. Dresemann Imatinib and hydroxyurea in pretreated progressive glioblastoma multiforme: a patient series Ann. Onc., October 1, 2005; 16(10): 1702 - 1708. [Abstract] [Full Text] [PDF]
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J. W. Clark, J. P. Eder, D. Ryan, C. Lathia, and H.-J. Lenz Safety and Pharmacokinetics of the Dual Action Raf Kinase and Vascular Endothelial Growth Factor Receptor Inhibitor, BAY 43-9006, in Patients with Advanced, Refractory Solid Tumors Clin. Cancer Res., August 1, 2005; 11(15): 5472 - 5480. [Abstract] [Full Text] [PDF]
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 G. J. Gordon, G. N. Rockwell, R. V. Jensen, J. G. Rheinwald, J. N. Glickman, J. P. Aronson, B. J. Pottorf, M. D. Nitz, W. G. Richards, D. J. Sugarbaker, et al. Identification of Novel Candidate Oncogenes and Tumor Suppressors in Malignant Pleural Mesothelioma Using Large-Scale Transcriptional Profiling Am. J. Pathol., June 1, 2005; 166(6): 1827 - 1840. [Abstract] [Full Text] [PDF]
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 R. Ginnan and H. A. Singer PKC-{delta}-dependent pathways contribute to PDGF-stimulated ERK1/2 activation in vascular smooth muscle Am J Physiol Cell Physiol, June 1, 2005; 288(6): C1193 - C1201. [Abstract] [Full Text] [PDF]
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S. H. Lee, D. Lopes de Menezes, J. Vora, A. Harris, H. Ye, L. Nordahl, E. Garrett, E. Samara, S. L. Aukerman, A. B. Gelb, et al. In vivo Target Modulation and Biological Activity of CHIR-258, a Multitargeted Growth Factor Receptor Kinase Inhibitor, in Colon Cancer Models Clin. Cancer Res., May 15, 2005; 11(10): 3633 - 3641. [Abstract] [Full Text] [PDF]
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 C De Bustos, A Smits, B Stromberg, V P Collins, M Nister, and G Afink A PDGFRA promoter polymorphism, which disrupts the binding of ZNF148, is associated with primitive neuroectodermal tumours and ependymomas J. Med. Genet., January 1, 2005; 42(1): 31 - 37. [Abstract] [Full Text] [PDF]
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S. M. Wilhelm, C. Carter, L. Tang, D. Wilkie, A. McNabola, H. Rong, C. Chen, X. Zhang, P. Vincent, M. McHugh, et al. BAY 43-9006 Exhibits Broad Spectrum Oral Antitumor Activity and Targets the RAF/MEK/ERK Pathway and Receptor Tyrosine Kinases Involved in Tumor Progression and Angiogenesis Cancer Res., October 1, 2004; 64(19): 7099 - 7109. [Abstract] [Full Text] [PDF]
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 F. K. Johansson, J. Brodd, C. Eklof, M. Ferletta, G. Hesselager, C.-F. Tiger, L. Uhrbom, and B. Westermark Identification of candidate cancer-causing genes in mouse brain tumors by retroviral tagging PNAS, August 3, 2004; 101(31): 11334 - 11337. [Abstract] [Full Text] [PDF]
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A. H. Shih, C. Dai, X. Hu, M. K. Rosenblum, J. A. Koutcher, and E. C. Holland Dose-Dependent Effects of Platelet-Derived Growth Factor-B on Glial Tumorigenesis Cancer Res., July 15, 2004; 64(14): 4783 - 4789. [Abstract] [Full Text] [PDF]
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 R. E. Brown, M. Lun, J. W. Prichard, T. M. Blasick, and P. L. Zhang Morphoproteomic and Pharmacoproteomic Correlates in Hormone-Receptor-Negative Breast Carcinoma Cell Lines Ann. Clin. Lab. Sci., July 1, 2004; 34(3): 251 - 262. [Abstract] [Full Text] [PDF]
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R. R. Langley, D. Fan, R. Z. Tsan, R. Rebhun, J. He, S.-J. Kim, and I. J. Fidler Activation of the Platelet-Derived Growth Factor-Receptor Enhances Survival of Murine Bone Endothelial Cells Cancer Res., June 1, 2004; 64(11): 3727 - 3730. [Abstract] [Full Text] [PDF]
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L. Mahimainathan and G. G. Choudhury Inactivation of Platelet-derived Growth Factor Receptor by the Tumor Suppressor PTEN Provides a Novel Mechanism of Action of the Phosphatase J. Biol. Chem., April 9, 2004; 279(15): 15258 - 15268. [Abstract] [Full Text] [PDF]
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L. Fang, Y. Yan, L. G. Komuves, S. Yonkovich, C. M. Sullivan, B. Stringer, S. Galbraith, N. A. Lokker, S. S. Hwang, P. Nurden, et al. PDGF C Is A Selective {alpha} Platelet-Derived Growth Factor Receptor Agonist That Is Highly Expressed in Platelet {alpha} Granules and Vascular Smooth Muscle Arterioscler. Thromb. Vasc. Biol., April 1, 2004; 24(4): 787 - 792. [Abstract] [Full Text] [PDF]
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Q. Ding, J. Stewart Jr., M. A. Olman, M. R. Klobe, and C. L. Gladson The Pattern of Enhancement of Src Kinase Activity on Platelet-derived Growth Factor Stimulation of Glioblastoma Cells Is Affected by the Integrin Engaged J. Biol. Chem., October 10, 2003; 278(41): 39882 - 39891. [Abstract] [Full Text] [PDF]
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G. Siegfried, A.-M. Khatib, S. Benjannet, M. Chretien, and N. G. Seidah The Proteolytic Processing of Pro-Platelet-derived Growth Factor-A at RRKR86 by Members of the Proprotein Convertase Family Is Functionally Correlated to Platelet-derived Growth Factor-A-induced Functions and Tumorigenicity Cancer Res., April 1, 2003; 63(7): 1458 - 1463. [Abstract] [Full Text] [PDF]
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P. Guo, B. Hu, W. Gu, L. Xu, D. Wang, H.-J. S. Huang, W. K. Cavenee, and S.-Y. Cheng Platelet-Derived Growth Factor-B Enhances Glioma Angiogenesis by Stimulating Vascular Endothelial Growth Factor Expression in Tumor Endothelia and by Promoting Pericyte Recruitment Am. J. Pathol., April 1, 2003; 162(4): 1083 - 1093. [Abstract] [Full Text] [PDF]
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 M. C. Heinrich, C. L. Corless, A. Duensing, L. McGreevey, C.-J. Chen, N. Joseph, S. Singer, D. J. Griffith, A. Haley, A. Town, et al. PDGFRA Activating Mutations in Gastrointestinal Stromal Tumors Science, January 31, 2003; 299(5607): 708 - 710. [Abstract] [Full Text] [PDF]
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