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1. Mautner VF, Nguyen R, Kutta H, Fuensterer C, Bokemeyer C, Hagel C, Friedrich RE, Panse J: Bevacizumab induces regression of vestibular schwannomas in patients with neurofibromatosis type 2. Neuro Oncol; 2010 Jan;12(1):14-8
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  • [Title] Bevacizumab induces regression of vestibular schwannomas in patients with neurofibromatosis type 2.
  • Bilateral vestibular schwannomas are the hallmark of neurofibromatosis type 2 (NF2), and these tumors impair hearing and frequently lead to deafness.
  • Neurosurgical intervention, the only established treatment, often damages the vestibular nerve.
  • We report 2 cases in which treatment with bevacizumab (for 3 months in one case and 6 months in the other) induced regression of progressive vestibular schwannomas by more than 40% and substantially improved hearing in the patient treated for 6 months.
  • Bevacizumab therapy may thus provide an effective treatment for progressive vestibular schwannomas in patients with NF2.
  • [MeSH-major] Antibodies, Monoclonal / therapeutic use. Antineoplastic Agents / therapeutic use. Neurofibromatosis 2 / drug therapy. Neuroma, Acoustic / drug therapy
  • [MeSH-minor] Adolescent. Antibodies, Monoclonal, Humanized. Audiometry. Bevacizumab. Hearing Loss / drug therapy. Hearing Loss / etiology. Hearing Loss / pathology. Humans. Magnetic Resonance Imaging. Male. Young Adult

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  • (PMID = 20150363.001).
  • [ISSN] 1523-5866
  • [Journal-full-title] Neuro-oncology
  • [ISO-abbreviation] Neuro-oncology
  • [Language] eng
  • [Publication-type] Case Reports; Journal Article
  • [Publication-country] United States
  • [Chemical-registry-number] 0 / Antibodies, Monoclonal; 0 / Antibodies, Monoclonal, Humanized; 0 / Antineoplastic Agents; 2S9ZZM9Q9V / Bevacizumab
  • [Other-IDs] NLM/ PMC2940556
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2. Ammoun S, Cunliffe CH, Allen JC, Chiriboga L, Giancotti FG, Zagzag D, Hanemann CO, Karajannis MA: ErbB/HER receptor activation and preclinical efficacy of lapatinib in vestibular schwannoma. Neuro Oncol; 2010 Aug;12(8):834-43
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  • [Title] ErbB/HER receptor activation and preclinical efficacy of lapatinib in vestibular schwannoma.
  • Vestibular schwannomas (VS) arising sporadically or in patients with neurofibromatosis type 2 (NF2) consistently lack expression of Merlin, a tumor suppressor.
  • Conventional treatment options include surgery and radiotherapy but there is no validated medical option.
  • Recent evidence suggests that Merlin deficiency may result in abnormal activation of receptor tyrosine kinases (RTKs) and downstream signaling, promoting tumor growth.
  • Although small-molecule RTK inhibitors are widely available for clinical use, no such therapy has been validated in patients with vs. To screen for RTK activation, surgical VS specimens from patients with and without NF2 were analyzed by phospho-RTK profiling arrays.
  • Based on the findings, the small-molecule EGFR/ErbB2 kinase inhibitor lapatinib was selected for evaluation of target inhibition and treatment efficacy in our in vitro human schwannoma model.
  • EGFR/ErbB2 targeted therapy with lapatinib inhibited ErbB2 phosphorylation and survivin upregulation, as well as downstream ERK1/2 and AKT activation, resulting in decreased proliferation.
  • We conclude that EGFR family receptor activation is a consistent feature of both sporadic and NF2-related vs. Molecular targeted therapy with lapatinib downregulates survivin and has antiproliferative activity in a preclinical VS model.
  • Based on these findings, a clinical trial with lapatinib for the treatment of VS is currently underway.
  • [MeSH-major] Antineoplastic Agents / pharmacology. Neuroma, Acoustic / metabolism. Quinazolines / pharmacology. Receptor, ErbB-2 / metabolism. Signal Transduction / drug effects
  • [MeSH-minor] Blotting, Western. Cell Line, Tumor. Cell Survival / drug effects. Humans. Immunohistochemistry. Mitogen-Activated Protein Kinases / metabolism. Protein Array Analysis. Receptor, Epidermal Growth Factor / metabolism


3. Kokkinakis DM, Liu X, Neuner RD: Modulation of cell cycle and gene expression in pancreatic tumor cell lines by methionine deprivation (methionine stress): implications to the therapy of pancreatic adenocarcinoma. Mol Cancer Ther; 2005 Sep;4(9):1338-48
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  • [Title] Modulation of cell cycle and gene expression in pancreatic tumor cell lines by methionine deprivation (methionine stress): implications to the therapy of pancreatic adenocarcinoma.
  • Although methionine stress-induced toxicity is not solely dependent on p53, the gain in p21 and loss in CDK1 transcription are more enhanced in wild-type p53 tumors.
  • Up-regulation of SMAD7, a TGF-beta signaling inhibitor, suggests that SMAD7 does not restrict the TGF-beta-mediated induction of p21, although it may prevent up-regulation of p27. cDNA oligoarray analysis indicated a pleiotropic response to methionine stress.
  • Cell cycle and mitotic arrest is in agreement with up-regulation of NF2, ETS2, CLU, GADD45alpha, GADD45beta, and GADD45gamma and down-regulation of AURKB, TOP2A, CCNA, CCNB, PRC1, BUB1, NuSAP, IFI16, and BRCA1.
  • PIN1, FEN1, and cABL up-regulation and LMNB1, AREG, RhoB, CCNG, TYMS, F3, and MGMT down-regulation suggest that methionine stress sensitizes the tumor cells to DNA-alkylating drugs, 5-fluorouracil, and radiation.
  • [MeSH-minor] Antimetabolites, Antineoplastic / pharmacology. Antineoplastic Agents, Alkylating / pharmacology. Blotting, Western. Cell Cycle / physiology. Cell Line, Tumor. Cell Proliferation. Cyclin-Dependent Kinase Inhibitor p21 / metabolism. Dacarbazine / analogs & derivatives. Dacarbazine / pharmacology. Fluorouracil / pharmacology. Gene Expression Profiling. Humans. Neoplasm Proteins / analysis. O(6)-Methylguanine-DNA Methyltransferase / metabolism. Oligonucleotide Array Sequence Analysis. Phosphorylation / drug effects. Retinoblastoma Protein / metabolism. Signal Transduction. Transforming Growth Factor beta / metabolism


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4. Lee TX, Packer MD, Huang J, Akhmametyeva EM, Kulp SK, Chen CS, Giovannini M, Jacob A, Welling DB, Chang LS: Growth inhibitory and anti-tumour activities of OSU-03012, a novel PDK-1 inhibitor, on vestibular schwannoma and malignant schwannoma cells. Eur J Cancer; 2009 Jun;45(9):1709-20
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  • [Title] Growth inhibitory and anti-tumour activities of OSU-03012, a novel PDK-1 inhibitor, on vestibular schwannoma and malignant schwannoma cells.
  • BACKGROUND: Vestibular schwannomas (VS) frequently express high levels of activated AKT.
  • Small-molecule inhibitors of AKT signalling may have therapeutic potential in suppressing the growth of benign VS and malignant schwannomas.
  • METHOD: Primary VS and Schwann cells, human malignant schwannoma HMS-97 cells and mouse Nf2(-/-) Schwann cells and schwannoma cells were prepared to investigate the growth inhibitory and anti-tumour activities of OSU-03012, a celecoxib-derived small-molecule inhibitor of phosphoinositide-dependent kinase-1.
  • Similarly, mouse Nf2(-/-) schwannoma and Nf2(-/-) Schwann cells were more sensitive to growth inhibition by OSU-03012 than wild-type mouse Schwann cells and mouse schwannoma cells established from transgenic mice carrying the NF2 promoter-driven SV40 T-antigen gene.
  • Like VS cells, malignant schwannoma HMS-97 cells expressed high levels of activated AKT.
  • In vivo xenograft analysis showed that OSU-03012 was well tolerated and inhibited the growth of HMS-97 schwannoma xenografts by 55% after 9 weeks of oral treatment.

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  • (PMID = 19359162.001).
  • [ISSN] 1879-0852
  • [Journal-full-title] European journal of cancer (Oxford, England : 1990)
  • [ISO-abbreviation] Eur. J. Cancer
  • [Language] ENG
  • [Grant] United States / NIDCD NIH HHS / DC / DC005985-04; United States / NIDCD NIH HHS / DC / R01 DC005985; United States / NIDCD NIH HHS / DC / R01 DC005985-04
  • [Publication-type] Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, Non-P.H.S.
  • [Publication-country] England
  • [Chemical-registry-number] 0 / Antineoplastic Agents; 0 / OSU 03012; 0 / Protein Kinase Inhibitors; 0 / Pyrazoles; 0 / Sulfonamides; EC 2.7.11.1 / Protein-Serine-Threonine Kinases; EC 2.7.11.1 / Proto-Oncogene Proteins c-akt; EC 2.7.11.2 / pyruvate dehydrogenase (acetyl-transferring) kinase
  • [Other-IDs] NLM/ NIHMS103963; NLM/ PMC2692816
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5. Plotkin SR, Singh MA, O'Donnell CC, Harris GJ, McClatchey AI, Halpin C: Audiologic and radiographic response of NF2-related vestibular schwannoma to erlotinib therapy. Nat Clin Pract Oncol; 2008 Aug;5(8):487-91
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  • [Title] Audiologic and radiographic response of NF2-related vestibular schwannoma to erlotinib therapy.
  • BACKGROUND: A 48-year-old man presented to a neurologist with complaints of bilateral hearing loss and tinnitus.
  • The patient was a member of a large family affected by neurofibromatosis type 2 and first noted hearing loss 10 years before presentation.
  • DIAGNOSIS: Progressive neurofibromatosis-type-2-related vestibular schwannomas.
  • MANAGEMENT: Annual cranial MRI and audiology, surgical resection of right vestibular schwannoma, high-power behind-the-ear hearing aid, erlotinib therapy for progressive left vestibular schwannoma.
  • [MeSH-major] Cochlear Implantation / methods. Ear Neoplasms / drug therapy. Ear Neoplasms / surgery. Hearing Loss, Sensorineural / prevention & control. Neurofibromatosis 2 / drug therapy. Neurofibromatosis 2 / surgery. Quinazolines / administration & dosage
  • [MeSH-minor] Audiometry, Pure-Tone. Auditory Threshold. Combined Modality Therapy. Erlotinib Hydrochloride. Humans. Magnetic Resonance Imaging. Male. Middle Aged. Protein Kinase Inhibitors / administration & dosage. Treatment Outcome. Vestibular Diseases / complications. Vestibular Diseases / drug therapy. Vestibular Diseases / surgery

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  • (PMID = 18560388.001).
  • [ISSN] 1743-4262
  • [Journal-full-title] Nature clinical practice. Oncology
  • [ISO-abbreviation] Nat Clin Pract Oncol
  • [Language] eng
  • [Publication-type] Case Reports; Journal Article; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, Non-P.H.S.
  • [Publication-country] England
  • [Chemical-registry-number] 0 / Protein Kinase Inhibitors; 0 / Quinazolines; DA87705X9K / Erlotinib Hydrochloride
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6. Kalamarides M, Stemmer-Rachamimov AO, Takahashi M, Han ZY, Chareyre F, Niwa-Kawakita M, Black PM, Carroll RS, Giovannini M: Natural history of meningioma development in mice reveals: a synergy of Nf2 and p16(Ink4a) mutations. Brain Pathol; 2008 Jan;18(1):62-70
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  • [Title] Natural history of meningioma development in mice reveals: a synergy of Nf2 and p16(Ink4a) mutations.
  • Meningiomas account for approximately 30% of all primary central nervous system tumors and are found in half of neurofibromatosis type 2 patients often causing significant morbidity.
  • Biallelic inactivation of the neurofibromatosis 2 (NF2) tumor suppressor is associated with meningioma formation in all NF2 patients and 60% of sporadic meningiomas.
  • Previously, we inactivated Nf2 in homozygous conditional knockout mice by adenoviral Cre delivery and showed that Nf2 loss in arachnoid cells is rate-limiting for meningioma formation.
  • In addition, by using magnetic resonance imaging (MRI) to screen a large cohort of mutant mice, we were able to detect meningothelial proliferation and meningioma development opening the way to future studies in which therapeutic interventions can be tested as preclinical assessment of their potential clinical application.
  • [MeSH-minor] Animals. Cell Proliferation. Disease Models, Animal. Disease Progression. Drug Screening Assays, Antitumor / methods. Female. Gene Deletion. Genetic Predisposition to Disease / genetics. Humans. Immunohistochemistry. Magnetic Resonance Imaging. Male. Mice. Mice, Knockout. Mice, Mutant Strains. Mutation / genetics. Neoplasm Invasiveness / genetics. Neurofibromatosis 2 / complications. Neurofibromatosis 2 / genetics. Neurofibromatosis 2 / physiopathology

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  • (PMID = 17924978.001).
  • [ISSN] 1015-6305
  • [Journal-full-title] Brain pathology (Zurich, Switzerland)
  • [ISO-abbreviation] Brain Pathol.
  • [Language] eng
  • [Publication-type] Journal Article; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, Non-P.H.S.
  • [Publication-country] Switzerland
  • [Chemical-registry-number] 0 / Cyclin-Dependent Kinase Inhibitor p16; 0 / Neurofibromin 2
  • [Other-IDs] NLM/ PMC2253711
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7. Hirokawa Y, Tikoo A, Huynh J, Utermark T, Hanemann CO, Giovannini M, Xiao GH, Testa JR, Wood J, Maruta H: A clue to the therapy of neurofibromatosis type 2: NF2/merlin is a PAK1 inhibitor. Cancer J; 2004 Jan-Feb;10(1):20-6
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  • [Title] A clue to the therapy of neurofibromatosis type 2: NF2/merlin is a PAK1 inhibitor.
  • BACKGROUND: Neurofibromatosis type 2 is a group of tumors caused by loss-of-function mutations of a tumor suppressor gene encoding NF2/merlin.
  • Development of chemotherapeutics for this disease, which often threatens the life of young children, has been hampered by a limited information on the signaling function of NF2.
  • NF2 can inhibit Ras-induced malignant transformation.
  • However, the primary (signaling) target of NF2 in the oncogenic pathway has not been previously identified.
  • RESULTS: Here, using a series of NF2 constructs, we show that NF2 inhibits directly the Rac/CDC42-dependent Ser/Thr kinase PAK1, which is essential for both Ras transformation and neurofibromatosis type 1 (NF1), through two separate domains.
  • A mutant of NF2, that lacks the PAK1-inhibiting domain of 78 amino acids (NF78C, residues 447-524), fails to suppress Ras transformation.
  • Furthermore, PAK1-specific inhibitors CEP-1347 and WR-PAK18 selectively inhibit the growth of NF2-deficient cancer cells, but not NF2-positive cells.
  • CONCLUSIONS: These results suggest that PAK1 is essential for the malignant growth of NF2-deficient cells, and that PAK1-blocking drugs could be potentially useful forthe treatment of neurofibromatosis types 2, in addition to Ras-induced cancers and neurofibromatosis type 1.
  • [MeSH-major] Genes, Neurofibromatosis 2 / physiology. JNK Mitogen-Activated Protein Kinases. Neurofibromatosis 2 / drug therapy. Neurofibromin 2 / pharmacology. Protein-Serine-Threonine Kinases / antagonists & inhibitors
  • [MeSH-minor] Animals. Cell Transformation, Neoplastic / drug effects. Cell Transformation, Neoplastic / genetics. Gene Expression Regulation, Enzymologic / drug effects. Gene Expression Regulation, Enzymologic / physiology. Gene Expression Regulation, Neoplastic / drug effects. Gene Expression Regulation, Neoplastic / physiology. Genes, ras / physiology. Humans. MAP Kinase Kinase 4. Mitogen-Activated Protein Kinase Kinases / antagonists & inhibitors. Mitogen-Activated Protein Kinase Kinases / metabolism. Reverse Transcriptase Polymerase Chain Reaction. Signal Transduction. Tumor Cells, Cultured. p21-Activated Kinases

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  • [CommentIn] Cancer J. 2004 Jan-Feb;10(1):8-11 [15000489.001]
  • (PMID = 15000491.001).
  • [ISSN] 1528-9117
  • [Journal-full-title] Cancer journal (Sudbury, Mass.)
  • [ISO-abbreviation] Cancer J
  • [Language] eng
  • [Grant] United States / NCI NIH HHS / CA / CA45745
  • [Publication-type] Journal Article; Research Support, U.S. Gov't, P.H.S.
  • [Publication-country] United States
  • [Chemical-registry-number] 0 / Neurofibromin 2; EC 2.7.11.1 / PAK1 protein, human; EC 2.7.11.1 / Protein-Serine-Threonine Kinases; EC 2.7.11.1 / p21-Activated Kinases; EC 2.7.11.24 / JNK Mitogen-Activated Protein Kinases; EC 2.7.12.2 / MAP Kinase Kinase 4; EC 2.7.12.2 / Mitogen-Activated Protein Kinase Kinases
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8. Clark JJ, Provenzano M, Diggelmann HR, Xu N, Hansen SS, Hansen MR: The ErbB inhibitors trastuzumab and erlotinib inhibit growth of vestibular schwannoma xenografts in nude mice: a preliminary study. Otol Neurotol; 2008 Sep;29(6):846-53
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  • [Title] The ErbB inhibitors trastuzumab and erlotinib inhibit growth of vestibular schwannoma xenografts in nude mice: a preliminary study.
  • OBJECTIVE: To analyze the ability of ErbB inhibitors to reduce the growth of vestibular schwannoma (VS) xenografts.
  • METHODS: Vestibular schwannoma xenografts were established in the interscapular fat pad in nude mice for 4 weeks.
  • Tumor growth was monitored by magnetic resonance imaging during the treatment period.
  • Control tumors demonstrated slight growth during the 12-week treatment period.
  • Erlotinib, but not trastuzumab, resulted in a significant increase in the percentage of terminal deoxynucleotidyl transferase-mediated dUTP-biotin end labeling of fragmented DNA-positive VS cells (p < 0.01).
  • CONCLUSION: In this preliminary study, the ErbB inhibitors trastuzumab and erlotinib decreased growth of VS xenografts in nude mice, raising the possibility of using ErbB inhibitors in the management of patients with schwannomas, particularly those with neurofibromatosis Type 2.

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  • (PMID = 18636037.001).
  • [ISSN] 1537-4505
  • [Journal-full-title] Otology & neurotology : official publication of the American Otological Society, American Neurotology Society [and] European Academy of Otology and Neurotology
  • [ISO-abbreviation] Otol. Neurotol.
  • [Language] ENG
  • [Grant] United States / NIDCD NIH HHS / DC / K08 DC006211; United States / NIDCD NIH HHS / DC / K08 DC006211-01A1; United States / NIDCD NIH HHS / DC / KO8 DC006211
  • [Publication-type] Journal Article; Research Support, N.I.H., Extramural
  • [Publication-country] United States
  • [Chemical-registry-number] 0 / Antibodies, Monoclonal; 0 / Antibodies, Monoclonal, Humanized; 0 / Protein Kinase Inhibitors; 0 / Quinazolines; DA87705X9K / Erlotinib Hydrochloride; P188ANX8CK / Trastuzumab
  • [Other-IDs] NLM/ NIHMS85822; NLM/ PMC2652856
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9. Diao JS, Xia WS, Guo SZ: Hearing improvement after bevacizumab for neurofibromatosis type 2. N Engl J Med; 2009 Oct 29;361(18):1810; author reply 1810-1
MedlinePlus Health Information. consumer health - Acoustic Neuroma.

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  • [Title] Hearing improvement after bevacizumab for neurofibromatosis type 2.
  • [MeSH-major] Angiogenesis Inhibitors / therapeutic use. Antibodies, Monoclonal / therapeutic use. Hearing Loss / drug therapy. Neurofibromatosis 2 / complications. Neuroma, Acoustic / drug therapy. Vascular Endothelial Growth Factor A / antagonists & inhibitors

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  • [CommentOn] N Engl J Med. 2009 Jul 23;361(4):358-67 [19587327.001]
  • (PMID = 19877310.001).
  • [ISSN] 1533-4406
  • [Journal-full-title] The New England journal of medicine
  • [ISO-abbreviation] N. Engl. J. Med.
  • [Language] eng
  • [Publication-type] Comment; Letter
  • [Publication-country] United States
  • [Chemical-registry-number] 0 / Angiogenesis Inhibitors; 0 / Antibodies, Monoclonal; 0 / Antibodies, Monoclonal, Humanized; 0 / Vascular Endothelial Growth Factor A; 2S9ZZM9Q9V / Bevacizumab
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10. Demestre M, Messerli SM, Celli N, Shahhossini M, Kluwe L, Mautner V, Maruta H: CAPE (caffeic acid phenethyl ester)-based propolis extract (Bio 30) suppresses the growth of human neurofibromatosis (NF) tumor xenografts in mice. Phytother Res; 2009 Feb;23(2):226-30
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  • [Title] CAPE (caffeic acid phenethyl ester)-based propolis extract (Bio 30) suppresses the growth of human neurofibromatosis (NF) tumor xenografts in mice.
  • Dysfunction of the NF1 gene coding a RAS GAP is the major cause of neurofibromatosis type 1 (NF1), whereas neurofibromatosis type 2 (NF2) is caused primarily by dysfunction of the NF2 gene product called merlin that inhibits directly PAK1, an oncogenic Rac/CDC42-dependent Ser/Thr kinase.
  • It was demonstrated previously that PAK1 is essential for the growth of both NF1 and NF2 tumors.
  • Thus, several anti-PAK1 drugs, including FK228 and CEP-1347, are being developed for the treatment of NF tumors.
  • However, so far no effective NF therapeutic is available on the market.
  • Since propolis, a very safe healthcare product from bee hives, contains anticancer ingredients called CAPE (caffeic acid phenethyl ester) or ARC (artepillin C), depending on the source, both of which block the oncogenic PAK1 signaling pathways, its potential therapeutic effect on NF tumors was explored in vivo.
  • Here it is demonstrated that Bio 30, a CAPE-rich water-miscible extract of New Zealand (NZ) propolis suppressed completely the growth of a human NF1 cancer called MPNST (malignant peripheral nerve sheath tumor) and caused an almost complete regression of human NF2 tumor (Schwannoma), both grafted in nude mice.
  • Thus, it would be worth testing clinically to see if Bio 30 and other CAPE-rich propolis are useful for the treatment of NF patients.
  • [MeSH-major] Caffeic Acids / pharmacology. Neurofibromatosis 1 / drug therapy. Neurofibromatosis 2 / drug therapy. Phenylethyl Alcohol / analogs & derivatives. Propolis / pharmacology. Xenograft Model Antitumor Assays

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  • [Copyright] Copyright (c) 2008 John Wiley & Sons, Ltd.
  • (PMID = 18726924.001).
  • [ISSN] 1099-1573
  • [Journal-full-title] Phytotherapy research : PTR
  • [ISO-abbreviation] Phytother Res
  • [Language] eng
  • [Grant] United States / NCRR NIH HHS / RR / P41 RR001395
  • [Publication-type] Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, Non-P.H.S.
  • [Publication-country] England
  • [Chemical-registry-number] 0 / Antineoplastic Agents; 0 / Caffeic Acids; 9009-62-5 / Propolis; EC 2.7.11.1 / PAK1 protein, human; EC 2.7.11.1 / p21-Activated Kinases; G960R9S5SK / caffeic acid phenethyl ester; ML9LGA7468 / Phenylethyl Alcohol
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11. Rosenbaum C, Kamleiter M, Grafe P, Kluwe L, Mautner V, Müller HW, Hanemann CO: Enhanced proliferation and potassium conductance of Schwann cells isolated from NF2 schwannomas can be reduced by quinidine. Neurobiol Dis; 2000 Aug;7(4):483-91
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  • [Title] Enhanced proliferation and potassium conductance of Schwann cells isolated from NF2 schwannomas can be reduced by quinidine.
  • Neurofibromatosis type 2 (NF2) is an autosomal dominant disease that is characterized mainly by schwannomas, as well as menigiomas and gliomas.
  • The NF2 gene product merlin/schwannomin acts as a tumor suppressor.
  • Schwann cells derived from NF2 schwannomas showed an enhanced proliferation rate, and electrophysological studies revealed larger K(+) outward currents as compared with controls.
  • Schwann cells isolated from schwannomas of NF2 patients or multiorgan donors were treated with different concentrations of the K(+) current blockers quinidine, tetraethylammonium chloride, and 4-aminopyridine and K(+) outward currents and proliferation rates of these cells were compared.
  • K(+) outward currents of both cell types can be blocked by quinidine.
  • Importantly, treatment with quinidine reduces proliferation of NF2 Schwann cells in a concentration dependent manner but did not reduce proliferation of normal Schwann cells.
  • Therefore, the use of quinidine or quinidine-like components would possibly provide a novel adjuvant therapeutic option for NF2 patients to slow down or freeze growth of schwannomas.
  • [MeSH-major] Antineoplastic Agents / pharmacology. Potassium Channel Blockers. Quinidine / pharmacology. Schwann Cells / drug effects
  • [MeSH-minor] Cell Division / drug effects. Cell Division / physiology. Cells, Cultured. Drug Screening Assays, Antitumor. Humans. Neurilemmoma / drug therapy. Neurilemmoma / physiopathology. Neurofibromatosis 2 / drug therapy. Neurofibromatosis 2 / physiopathology. Potassium Channels / physiology

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  • [Copyright] Copyright 2000 Academic Press.
  • [ErratumIn] Neurobiol Dis 2001 Feb;8(1):181
  • (PMID = 10964617.001).
  • [ISSN] 0969-9961
  • [Journal-full-title] Neurobiology of disease
  • [ISO-abbreviation] Neurobiol. Dis.
  • [Language] eng
  • [Publication-type] Journal Article; Research Support, Non-U.S. Gov't
  • [Publication-country] UNITED STATES
  • [Chemical-registry-number] 0 / Antineoplastic Agents; 0 / Potassium Channel Blockers; 0 / Potassium Channels; ITX08688JL / Quinidine
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12. Benesch M, Weber-Mzell D, Gerber NU, von Hoff K, Deinlein F, Krauss J, Warmuth-Metz M, Kortmann RD, Pietsch T, Driever PH, Quehenberger F, Urban C, Rutkowski S: Ependymoma of the spinal cord in children and adolescents: a retrospective series from the HIT database. J Neurosurg Pediatr; 2010 Aug;6(2):137-44
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  • OBJECT: Reports on spinal cord ependymoma in children are rare.
  • The aim of this study was to evaluate the clinical spectrum, treatment, and outcome of children with primary ependymoma of the spinal cord who were registered in the database of the pediatric German brain tumor studies Hirntumor (HIT) '91 and HIT 2000.
  • METHODS: Between 1991 and 2007, 29 patients (12 male and 17 female, median age at diagnosis 13.6 years) with primary spinal cord ependymoma (myxopapillary ependymoma WHO Grade I, II, and III tumors in 6, 17, and 6 patients, respectively) were identified.
  • Four patients had neurofibromatosis Type 2.
  • Seven patients (24.1%) developed progressive disease or relapse, 2 after gross-total resection (GTR) and 5 after incomplete resection or biopsy.
  • One patient with anaplastic ependymoma (WHO Grade III) died 65 months after diagnosis of disease progression.
  • Primary adjuvant treatment (radiotherapy, chemotherapy, or both) was used in 8 (50%) of 16 patients following GTR and in 9 (82%) of 11 patients who underwent less than a GTR.
  • CONCLUSIONS: Gross-total resection is the mainstay of treatment for patients with primary spinal cord ependymoma and may be achieved in about 50% of the patients using modern surgical techniques.
  • Primary adjuvant treatment was commonly used in children with spinal cord ependymoma irrespective of the extent of resection or tumor grade.
  • The impact of adjuvant treatment on progression-free and overall survival has to be investigated in a prospective trial.
  • [MeSH-minor] Adolescent. Austria. Biopsy. Chemotherapy, Adjuvant. Child. Combined Modality Therapy. Disability Evaluation. Disease Progression. Female. Follow-Up Studies. Germany. Humans. Male. Neurofibromatosis 2 / diagnosis. Neurofibromatosis 2 / drug therapy. Neurofibromatosis 2 / pathology. Neurofibromatosis 2 / radiotherapy. Neurofibromatosis 2 / surgery. Postoperative Complications / diagnosis. Postoperative Complications / mortality. Prospective Studies. Radiotherapy, Adjuvant. Registries. Survival Rate

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  • (PMID = 20672934.001).
  • [ISSN] 1933-0715
  • [Journal-full-title] Journal of neurosurgery. Pediatrics
  • [ISO-abbreviation] J Neurosurg Pediatr
  • [Language] eng
  • [Publication-type] Journal Article; Multicenter Study; Research Support, Non-U.S. Gov't
  • [Publication-country] United States
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13. Guntinas-Lichius O: Hearing improvement after bevacizumab for neurofibromatosis type 2. N Engl J Med; 2009 Oct 29;361(18):1809-10; author reply 1810-1
MedlinePlus Health Information. consumer health - Acoustic Neuroma.

  • [Source] The source of this record is MEDLINE®, a database of the U.S. National Library of Medicine.
  • [Title] Hearing improvement after bevacizumab for neurofibromatosis type 2.
  • [MeSH-major] Angiogenesis Inhibitors / therapeutic use. Antibodies, Monoclonal / therapeutic use. Hearing Loss / drug therapy. Neurofibromatosis 2 / complications. Neuroma, Acoustic / drug therapy
  • [MeSH-minor] Antibodies, Monoclonal, Humanized. Bevacizumab. Hearing Tests / methods. Humans. Research Design

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  • [CommentOn] N Engl J Med. 2009 Jul 23;361(4):358-67 [19587327.001]
  • (PMID = 19864683.001).
  • [ISSN] 1533-4406
  • [Journal-full-title] The New England journal of medicine
  • [ISO-abbreviation] N. Engl. J. Med.
  • [Language] eng
  • [Publication-type] Comment; Letter
  • [Publication-country] United States
  • [Chemical-registry-number] 0 / Angiogenesis Inhibitors; 0 / Antibodies, Monoclonal; 0 / Antibodies, Monoclonal, Humanized; 2S9ZZM9Q9V / Bevacizumab
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14. Utermark T, Alekov A, Lerche H, Abramowski V, Giovannini M, Hanemann CO: Quinidine impairs proliferation of neurofibromatosis type 2-deficient human malignant mesothelioma cells. Cancer; 2003 Apr 15;97(8):1955-62
Hazardous Substances Data Bank. BROMODEOXYURIDINE .

  • [Source] The source of this record is MEDLINE®, a database of the U.S. National Library of Medicine.
  • [Title] Quinidine impairs proliferation of neurofibromatosis type 2-deficient human malignant mesothelioma cells.
  • They respond poorly to conventional tumor treatment and outcome is often fatal.
  • Inactivating mutations of the neurofibromatosis type 2 (NF2) tumor suppressor gene merlin have been described in nearly 60% of primary malignant mesothelioma and in approximately 20% of the mesothelioma cell lines.
  • Studies regarding human NF2 schwannoma cells revealed a higher proliferation and a larger noninactivating K(+) outward current compared with controls.
  • The enhanced proliferation of merlin-deficient NF2 schwannoma cells could be reduced in the presence of quinidine, a K(+) channel blocker, whereas the proliferation of normal Schwann cells is not affected.
  • The current study was undertaken to evaluate the effect of quinidine on the proliferation of HMM cell lines in relation to their NF2 status.
  • METHODS: Proliferation analyses using bromodeoxyuridine incorporation was performed by immunocytochemical staining and fluorescence assisted cell sorting.
  • The patch-clamp technique was applied for electrophysiologic characterization of the HMM cell lines.
  • The cytochrome P450 2D6 locus, known to be mutated at high frequencies in NF2 patients and to be specifically inhibited by quinidine, was screened for mutations by cycle sequencing.
  • The effect of quinidine on the proliferation of HMM cell lines appears to be correlated with the NF2 gene status but not with the K(+) outward current.
  • CONCLUSIONS: Quinidine or quinidine analogs are of potential therapeutic interest for the subset of merlin-deficient mesothelioma tumors.
  • [MeSH-major] Enzyme Inhibitors / pharmacology. Mesothelioma / pathology. Neoplasms, Mesothelial / pathology. Neurofibromatosis 2 / metabolism. Neurofibromin 2 / deficiency. Quinidine / pharmacology. Schwann Cells / drug effects
  • [MeSH-minor] Blotting, Western. Bromodeoxyuridine. Cell Division / drug effects. Cytochrome P-450 CYP2D6 / genetics. Cytochrome P-450 CYP2D6 / metabolism. Cytochrome P-450 CYP2D6 Inhibitors. DNA Primers / chemistry. Humans. Immunoenzyme Techniques. Patch-Clamp Techniques. Polymerase Chain Reaction. Tumor Cells, Cultured

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  • [Copyright] Copyright 2003 American Cancer Society.
  • (PMID = 12673723.001).
  • [ISSN] 0008-543X
  • [Journal-full-title] Cancer
  • [ISO-abbreviation] Cancer
  • [Language] eng
  • [Publication-type] Journal Article; Research Support, Non-U.S. Gov't
  • [Publication-country] United States
  • [Chemical-registry-number] 0 / Cytochrome P-450 CYP2D6 Inhibitors; 0 / DNA Primers; 0 / Enzyme Inhibitors; 0 / Neurofibromin 2; EC 1.14.14.1 / Cytochrome P-450 CYP2D6; G34N38R2N1 / Bromodeoxyuridine; ITX08688JL / Quinidine
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15. Hashimoto H, Messerli SM, Sudo T, Maruta H: Ivermectin inactivates the kinase PAK1 and blocks the PAK1-dependent growth of human ovarian cancer and NF2 tumor cell lines. Drug Discov Ther; 2009 Dec;3(6):243-6
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  • [Title] Ivermectin inactivates the kinase PAK1 and blocks the PAK1-dependent growth of human ovarian cancer and NF2 tumor cell lines.
  • Ivermectin is an old anti-parasitic antibiotic which selectively kills nematodes at a very low dose (0.2 mg/kg) by inhibiting their GABA (gamma-aminobutyric acid) receptor, but not mammalian counterpart.
  • However, its anti-cancer mechanism still remained to be clarified at the molecular levels, that would determine the specific type of cancers susceptible to this drug.
  • The first hint towards its anti-PAK1 potential was a recent finding that Ivermectin at its sublethal doses dramatically reduces the litter size (number of eggs laid) of the tiny nematode C. elegans.
  • Interestingly, either a PAK1-deficiency (gene knock-out) or treatment with natural anti-PAK1 products such as CAPE (caffeic acid phenethyl ester) and ARC (artepillin C), the major anti-cancer ingredients in propolis, also causes the exactly same effect on this nematode, suggesting the possibility that the kinase PAK1 might be a new target of Ivermectin.
  • This kinase is required for the growth of more than 70% of human cancers such as pancreatic, colon, breast and prostate cancers and NF (neurofibromatosis) tumors.
  • Here we demonstrate for the first time that Ivermectin blocks the oncogenic kinase PAK1 in human ovarian cancer and NF2-deficient Schwannoma cell lines to suppress their PAK1-dependent growth in cell culture, with the IC50 between 5-20 μM depending on cell lines.

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  • (PMID = 22495656.001).
  • [ISSN] 1881-7831
  • [Journal-full-title] Drug discoveries & therapeutics
  • [ISO-abbreviation] Drug Discov Ther
  • [Language] eng
  • [Publication-type] Journal Article
  • [Publication-country] Japan
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16. James MF, Han S, Polizzano C, Plotkin SR, Manning BD, Stemmer-Rachamimov AO, Gusella JF, Ramesh V: NF2/merlin is a novel negative regulator of mTOR complex 1, and activation of mTORC1 is associated with meningioma and schwannoma growth. Mol Cell Biol; 2009 Aug;29(15):4250-61
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  • [Source] The source of this record is MEDLINE®, a database of the U.S. National Library of Medicine.
  • [Title] NF2/merlin is a novel negative regulator of mTOR complex 1, and activation of mTORC1 is associated with meningioma and schwannoma growth.
  • Inactivating mutations of the neurofibromatosis 2 (NF2) gene, NF2, result predominantly in benign neurological tumors, schwannomas and meningiomas, in humans; however, mutations in murine Nf2 lead to a broad spectrum of cancerous tumors.
  • The tumor-suppressive function of the NF2 protein, merlin, a membrane-cytoskeleton linker, remains unclear.
  • NF2 patient tumors and Nf2-deficient mouse embryonic fibroblasts demonstrate elevated mTORC1 signaling.
  • Conversely, the exogenous expression of wild-type merlin isoforms, but not a patient-derived L64P mutant, suppresses mTORC1 signaling.
  • Merlin does not regulate mTORC1 via the established mechanism of phosphoinositide 3-kinase-Akt or mitogen-activated protein kinase/extracellular signal-regulated kinase-mediated TSC2 inactivation and may instead regulate TSC/mTOR signaling in a novel fashion.
  • In conclusion, the deregulation of mTORC1 activation underlies the aberrant growth and proliferation of NF2-associated tumors and may restrain the growth of these lesions through negative feedback mechanisms, suggesting that rapamycin in combination with phosphoinositide 3-kinase inhibitors may be therapeutic for NF2.

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  • (PMID = 19451225.001).
  • [ISSN] 1098-5549
  • [Journal-full-title] Molecular and cellular biology
  • [ISO-abbreviation] Mol. Cell. Biol.
  • [Language] ENG
  • [Grant] United States / NINDS NIH HHS / NS / P30 NS045776; United States / NINDS NIH HHS / NS / NS 045776; United States / NIMH NIH HHS / MH / R21 MH079213; United States / NIMH NIH HHS / MH / MH 079213; United States / NINDS NIH HHS / NS / P01 NS024279; United States / NCI NIH HHS / CA / R01 CA122617-04; United States / NINDS NIH HHS / NS / NS 024279; United States / NCI NIH HHS / CA / CA122617-04; United States / NCI NIH HHS / CA / R01 CA122617
  • [Publication-type] Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't
  • [Publication-country] United States
  • [Chemical-registry-number] 0 / Antibiotics, Antineoplastic; 0 / Multiprotein Complexes; 0 / Neurofibromin 2; 0 / Proteins; 0 / RNA, Small Interfering; 0 / Transcription Factors; 0 / mechanistic target of rapamycin complex 1; EC 2.7.1.- / Phosphatidylinositol 3-Kinases; EC 2.7.1.1 / TOR Serine-Threonine Kinases; EC 2.7.11.1 / Proto-Oncogene Proteins c-akt; W36ZG6FT64 / Sirolimus
  • [Other-IDs] NLM/ PMC2715803
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17. Miettinen M: From morphological to molecular diagnosis of soft tissue tumors. Adv Exp Med Biol; 2006;587:99-113
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  • [Source] The source of this record is MEDLINE®, a database of the U.S. National Library of Medicine.
  • [Title] From morphological to molecular diagnosis of soft tissue tumors.
  • Many sarcomas are known to have such fusions, and the demonstration of the fusion transcripts in tumor tissue is of great value in specific diagnosis of synovial sarcoma (SYT-SSX), Ewing sarcoma (EWS-Fli1), clear cell sarcoma (EWS-ATF1), myxoid liposarcoma (FUS-CHOP), and other sarcomas.
  • These translocations are believed to be disease-specific and pathogenetic forces, despite occasional observations to the contrary.
  • Demonstration of SYT-SSX and EWS-ATF1 fusion assists in the diagnosis of synovial and clear cell sarcomas in unusual locations, such as the gastrointestinal tract, where these tumors occur with low frequency.
  • Thus, the target cell of the genetic change is an important factor to define the resulting disease.
  • Activating mutations in two related receptor tyrosine kinases (RTKs), KIT, and platelet-derived growth factor receptor alpha (PDGFRA) is central to the pathogenesis of gastrointestinal stromal tumors (GISTs), and countering the mutational activation by specific tyrosine kinase inhibitors, such as Imatinib mesylate, is now standard treatment for metastatic GISTs.
  • Mutation type influences therapy responsiveness, but fortunately very few GISTs carry primarily Imatinib-resistant mutations.
  • Secondary drug resistance acquired during Imatinib treatment based on new, Imatinib-resistant mutations is a major problem limiting treatment success.
  • Loss of NF2 tumor suppressor gene in a biallelic fashion is believed to be central in the pathogenesis of neurofibromatosis 2 (NF2) associated and sporadic schwannomas and meningiomas.
  • The mechanism includes nonsense or missense mutation in NF2 gene, and loss of the other NF2 allele as a part of losses in chromosome 22q.
  • Schwannoma types may differ in their pathogenesis: gastrointestinal schwannomas lack NF2 changes suggesting a different pathogenesis.
  • Intraneural and sclerosing perineuriomas display similar NF2 gene alterations as seen in meningioma, indicating a similar pathogenesis and molecular homology.

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  • (PMID = 17163160.001).
  • [ISSN] 0065-2598
  • [Journal-full-title] Advances in experimental medicine and biology
  • [ISO-abbreviation] Adv. Exp. Med. Biol.
  • [Language] eng
  • [Publication-type] Journal Article; Review
  • [Publication-country] United States
  • [Number-of-references] 70
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18. Wong HK, Lahdenranta J, Kamoun WS, Chan AW, McClatchey AI, Plotkin SR, Jain RK, di Tomaso E: Anti-vascular endothelial growth factor therapies as a novel therapeutic approach to treating neurofibromatosis-related tumors. Cancer Res; 2010 May 1;70(9):3483-93
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  • [Title] Anti-vascular endothelial growth factor therapies as a novel therapeutic approach to treating neurofibromatosis-related tumors.
  • Patients with bilateral vestibular schwannomas associated with neurofibromatosis type 2 (NF2) experience significant morbidity such as complete hearing loss.
  • We have recently shown that treatment with bevacizumab provided tumor stabilization and hearing recovery in a subset of NF2 patients with progressive disease.
  • In the current study, we used two animal models to identify the mechanism of action of anti-vascular endothelial growth factor (VEGF) therapy in schwannomas.
  • The human HEI193 and murine Nf2(-/-) cell lines were implanted between the pia and arachnoid meninges as well as in the sciatic nerve to mimic central and peripheral schwannomas.
  • In both models, tumor vessel diameter, length/surface area density, and permeability were significantly reduced after treatment.
  • After 2 weeks of treatment, necrosis in HEI193 tumors and apoptosis in Nf2(-/-) tumors were significantly increased, and the tumor growth rate decreased by an average of 50%.
  • This study shows that anti-VEGF therapy normalizes the vasculature of schwannoma xenografts in nude mice and successfully controls the tumor growth, probably by reestablishing a natural balance between VEGF and semaphorin 3 signaling.

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  • [Copyright] (c)2010 AACR.
  • (PMID = 20406973.001).
  • [ISSN] 1538-7445
  • [Journal-full-title] Cancer research
  • [ISO-abbreviation] Cancer Res.
  • [Language] ENG
  • [Grant] United States / NCI NIH HHS / CA / P01 CA080124; United States / NCI NIH HHS / CA / P01CA80124
  • [Publication-type] Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't
  • [Publication-country] United States
  • [Chemical-registry-number] 0 / Angiogenesis Inhibitors; 0 / Antibodies, Monoclonal; 0 / Antibodies, Monoclonal, Humanized; 0 / N-(4-bromo-2-fluorophenyl)-6-methoxy-7-((1-methylpiperidin-4-yl)methoxy)quinazolin-4-amine; 0 / Neurofibromin 2; 0 / Piperidines; 0 / Quinazolines; 0 / Vascular Endothelial Growth Factor A; 2S9ZZM9Q9V / Bevacizumab
  • [Other-IDs] NLM/ NIHMS765417; NLM/ PMC4785015
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19. Kalamarides M, Hunter-Schaedle K, Blakeley J, Allen J, Babovic-Vuskanovic D, Belzberg A, Bollag G, Chen R, DiTomaso E, Golfinos J, Harris G, Jacob A, Kalpana G, Karajannis M, Korf B, Kurzrock R, Law M, McClatchey A, Packer R, Roehm P, Rubenstein A, Slattery W 3rd, Tonsgard JH, Welling DB, Widemann B, Yohay K: Consensus recommendations to accelerate clinical trials for neurofibromatosis type 2. Clin Cancer Res; 2009 Aug 15;15(16):5032-5039
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  • [Title] Consensus recommendations to accelerate clinical trials for neurofibromatosis type 2.
  • PURPOSE: Neurofibromatosis type 2 (NF2) is a rare autosomal dominant disorder associated primarily with bilateral schwannomas seen on the superior vestibular branches of the eighth cranial nerves.
  • Significant morbidity can result from surgical treatment of these tumors.
  • Meningiomas, ependymomas, and other benign central nervous system tumors are also common in NF2.
  • The lack of effective treatments for NF2 marks an unmet medical need.
  • Gareth Evans and Marco Giovannini, of 36 international researchers, physicians, representatives of the biotechnology industry, and patient advocates on how to accelerate progress toward NF2 clinical trials.
  • RESULTS: Workshop participants reached a consensus that, based on current knowledge, the time is right to plan and implement NF2 clinical trials.
  • Obstacles impeding NF2 clinical trials and how to address them were discussed, as well as the candidate therapeutic pipeline for NF2.
  • CONCLUSIONS: Both phase 0 and phase II NF2 trials are near-term options for NF2 clinical trials.
  • The number of NF2 patients in the population remains limited, and successful recruitment will require ongoing collaboration efforts between NF2 clinics.
  • [MeSH-major] Clinical Trials as Topic / methods. Consensus. Health Planning Guidelines. Neurofibromatosis 2 / therapy
  • [MeSH-minor] Animals. Auditory Brain Stem Implants. Cochlear Implants. Drug Evaluation, Preclinical / methods. Drug Evaluation, Preclinical / trends. Humans. Meningeal Neoplasms / therapy. Meningioma / therapy. Time Factors

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  • (PMID = 19671848.001).
  • [ISSN] 1078-0432
  • [Journal-full-title] Clinical cancer research : an official journal of the American Association for Cancer Research
  • [ISO-abbreviation] Clin. Cancer Res.
  • [Language] eng
  • [Grant] United States / NIDCD NIH HHS / DC / K08 DC009288
  • [Publication-type] Consensus Development Conference; Journal Article; Research Support, Non-U.S. Gov't
  • [Publication-country] United States
  • [Number-of-references] 36
  • [Other-IDs] NLM/ NIHMS707923; NLM/ PMC4513640
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20. Plotkin SR, Stemmer-Rachamimov AO, Barker FG 2nd, Halpin C, Padera TP, Tyrrell A, Sorensen AG, Jain RK, di Tomaso E: Hearing improvement after bevacizumab in patients with neurofibromatosis type 2. N Engl J Med; 2009 Jul 23;361(4):358-67
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  • [Source] The source of this record is MEDLINE®, a database of the U.S. National Library of Medicine.
  • [Title] Hearing improvement after bevacizumab in patients with neurofibromatosis type 2.
  • BACKGROUND: Profound hearing loss is a serious complication of neurofibromatosis type 2, a genetic condition associated with bilateral vestibular schwannomas, benign tumors that arise from the eighth cranial nerve.
  • There is no medical treatment for such tumors.
  • METHODS: We determined the expression pattern of vascular endothelial growth factor (VEGF) and three of its receptors, VEGFR-2, neuropilin-1, and neuropilin-2, in paraffin-embedded samples from 21 vestibular schwannomas associated with neurofibromatosis type 2 and from 22 sporadic schwannomas.
  • Ten consecutive patients with neurofibromatosis type 2 and progressive vestibular schwannomas who were not candidates for standard treatment were treated with bevacizumab, an anti-VEGF monoclonal antibody.
  • RESULTS: VEGF was expressed in 100% of vestibular schwannomas and VEGFR-2 in 32% of tumor vessels on immunohistochemical analysis.
  • Before treatment, the median annual volumetric growth rate for 10 index tumors was 62%.
  • After bevacizumab treatment in the 10 patients, tumors shrank in 9 patients, and 6 patients had an imaging response, which was maintained in 4 patients during 11 to 16 months of follow-up.
  • The median best response to treatment was a volumetric reduction of 26%.
  • Three patients were not eligible for a hearing response; of the remaining seven patients, four had a hearing response, two had stable hearing, and one had progressive hearing loss.
  • CONCLUSIONS: VEGF blockade with bevacizumab improved hearing in some, but not all, patients with neurofibromatosis type 2 and was associated with a reduction in the volume of most growing vestibular schwannomas.

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  • [Copyright] 2009 Massachusetts Medical Society
  • [CommentIn] N Engl J Med. 2009 Oct 29;361(18):1810; author reply 1810-1 [19877310.001]
  • [CommentIn] N Engl J Med. 2009 Oct 29;361(18):1809-10; author reply 1810-1 [19864683.001]
  • (PMID = 19587327.001).
  • [ISSN] 1533-4406
  • [Journal-full-title] The New England journal of medicine
  • [ISO-abbreviation] N. Engl. J. Med.
  • [Language] ENG
  • [Grant] United States / NCI NIH HHS / CA / P01 CA080124; United States / NINDS NIH HHS / NS / P01 NS024279; United States / NCI NIH HHS / CA / P01CA80124; United States / NINDS NIH HHS / NS / P01NS024279
  • [Publication-type] Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't
  • [Publication-country] United States
  • [Chemical-registry-number] 0 / Angiogenesis Inhibitors; 0 / Antibodies, Monoclonal; 0 / Antibodies, Monoclonal, Humanized; 0 / Neuropilin-2; 0 / Vascular Endothelial Growth Factor A; 144713-63-3 / Neuropilin-1; 2S9ZZM9Q9V / Bevacizumab; EC 2.7.10.1 / Vascular Endothelial Growth Factor Receptor-2
  • [Other-IDs] NLM/ NIHMS765691; NLM/ PMC4816642
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21. Evans DG: Neurofibromatosis 2 [Bilateral acoustic neurofibromatosis, central neurofibromatosis, NF2, neurofibromatosis type II]. Genet Med; 2009 Sep;11(9):599-610
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  • [Title] Neurofibromatosis 2 [Bilateral acoustic neurofibromatosis, central neurofibromatosis, NF2, neurofibromatosis type II].
  • Neurofibromatosis 2 is a dominantly inherited tumor predisposition syndrome caused by mutations in the NF2 gene on chromosome 22.
  • Affected individuals inevitably develop schwannomas typically affecting both vestibular nerves leading to deafness.
  • In excess of 50% of patients represent new mutations and as many as one third are mosaic for the underlying disease causing mutation.
  • Although truncating mutations (nonsense and frameshifts) are the most frequent germline event and cause the most severe disease, single and multiple exon deletions are common.
  • NF2 represents a difficult management problem with most patients facing substantial morbidity and reduced life expectancy.
  • Surgery remains the focus of current management, although watchful waiting and occasionally radiation treatment have a role.
  • In the future, the development of tailored drug therapies aimed at the genetic level are likely to provide huge improvements for this devastating, life limiting condition.
  • [MeSH-major] Genes, Neurofibromatosis 2. Neurofibromatosis 2 / diagnosis. Neurofibromatosis 2 / genetics
  • [MeSH-minor] Diagnosis, Differential. Genetic Counseling. Genetic Testing. Humans. Prenatal Diagnosis

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  • (PMID = 19652604.001).
  • [ISSN] 1530-0366
  • [Journal-full-title] Genetics in medicine : official journal of the American College of Medical Genetics
  • [ISO-abbreviation] Genet. Med.
  • [Language] eng
  • [Publication-type] Journal Article; Research Support, Non-U.S. Gov't; Review
  • [Publication-country] United States
  • [Number-of-references] 85
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22. Mukherjee J, Kamnasaran D, Balasubramaniam A, Radovanovic I, Zadeh G, Kiehl TR, Guha A: Human schwannomas express activated platelet-derived growth factor receptors and c-kit and are growth inhibited by Gleevec (Imatinib Mesylate). Cancer Res; 2009 Jun 15;69(12):5099-107
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  • They can reoccur after surgery or radiation, current treatments each with significant inherent risks.
  • These risks are further amplified in neurofibromatosis type 2 (NF2), a germ line predisposition syndrome characterized by multiple schwannomas, underlying the need for biological targeted therapies.
  • In the present study, we show that human sporadic and NF2-associated schwannomas have increased expression along with activation of PDGFR-alpha, PDGFR-beta, and c-kit receptors, compared with normal or traumatic nerve.
  • Using the human NF2-null HEI-193 schwannoma cell line, Gleevec inhibited schwannoma viability, proliferation, and anchorage-independent growth, as well as induced apoptosis in a dose-dependent manner (IC(50) 5-10 micromol/L).
  • [MeSH-major] Antineoplastic Agents / pharmacology. Cell Division / drug effects. Neurilemmoma / metabolism. Piperazines / pharmacology. Proto-Oncogene Proteins c-kit / metabolism. Pyrimidines / pharmacology. Receptors, Platelet-Derived Growth Factor / metabolism

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  • (PMID = 19509233.001).
  • [ISSN] 1538-7445
  • [Journal-full-title] Cancer research
  • [ISO-abbreviation] Cancer Res.
  • [Language] eng
  • [Publication-type] Journal Article; Research Support, Non-U.S. Gov't
  • [Publication-country] United States
  • [Chemical-registry-number] 0 / Antineoplastic Agents; 0 / Benzamides; 0 / Piperazines; 0 / Pyrimidines; 8A1O1M485B / Imatinib Mesylate; EC 2.7.10.1 / Proto-Oncogene Proteins c-kit; EC 2.7.10.1 / Receptors, Platelet-Derived Growth Factor
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23. Plotkin SR, Halpin C, Blakeley JO, Slattery WH 3rd, Welling DB, Chang SM, Loeffler JS, Harris GJ, Sorensen AG, McKenna MJ, Barker FG 2nd: Suggested response criteria for phase II antitumor drug studies for neurofibromatosis type 2 related vestibular schwannoma. J Neurooncol; 2009 May;93(1):61-77
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  • [Source] The source of this record is MEDLINE®, a database of the U.S. National Library of Medicine.
  • [Title] Suggested response criteria for phase II antitumor drug studies for neurofibromatosis type 2 related vestibular schwannoma.
  • Neurofibromatosis type 2 (NF2) is a tumor suppressor gene syndrome characterized by multiple schwannomas, especially vestibular schwannomas (VS), and meningiomas.
  • Anticancer drug trials are now being explored, but there are no standardized endpoints in NF2.
  • We review the challenges of NF2 clinical trials and suggest possible response criteria for use in initial phase II studies.
  • We also identify research goals in NF2 to facilitate future trial conduct, such as identifying the expectations for time to tumor progression and time to measurable hearing loss in untreated NF2-related VS, and the relation of both endpoints to patient prognostic factors (such as age, baseline tumor volume, and measures of disease severity).
  • These data would facilitate future use of endpoints based on stability of tumor size and hearing, which might be more appropriate for testing certain drugs.
  • We encourage adoption of standardized endpoints early in the development of phase II trials for this population to facilitate comparison of results across trials of different agents.
  • [MeSH-major] Antineoplastic Agents / therapeutic use. Clinical Trials, Phase II as Topic / standards. Neurofibromatosis 2 / complications. Neurofibromatosis 2 / drug therapy. Neuroma, Acoustic / drug therapy

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  • (PMID = 19430883.001).
  • [ISSN] 1573-7373
  • [Journal-full-title] Journal of neuro-oncology
  • [ISO-abbreviation] J. Neurooncol.
  • [Language] eng
  • [Grant] United States / NCI NIH HHS / CA / P30 CA006973
  • [Publication-type] Journal Article; Review
  • [Publication-country] United States
  • [Chemical-registry-number] 0 / Antineoplastic Agents
  • [Number-of-references] 154
  • [Other-IDs] NLM/ NIHMS573252; NLM/ PMC4036446
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24. Yi C, Wilker EW, Yaffe MB, Stemmer-Rachamimov A, Kissil JL: Validation of the p21-activated kinases as targets for inhibition in neurofibromatosis type 2. Cancer Res; 2008 Oct 1;68(19):7932-7
The Lens. Cited by Patents in .

  • [Source] The source of this record is MEDLINE®, a database of the U.S. National Library of Medicine.
  • [Title] Validation of the p21-activated kinases as targets for inhibition in neurofibromatosis type 2.
  • Neurofibromatosis type 2 (NF2) is a dominantly inherited cancer disorder caused by mutations at the NF2 gene locus.
  • Merlin, the protein product of the NF2 gene, has been shown to negatively regulate Rac1 signaling by inhibiting its downstream effector kinases, the p21-activated kinases (Pak).
  • First, analysis of primary schwannoma samples derived from NF2 patients showed that in a significant fraction of the tumors, the activity of Pak1 was highly elevated.
  • Second, we used shRNAs to knockdown Pak1, 2, and 3 in NIH3T3 cells expressing a dominant-negative form of merlin, NF2(BBA) (NIH3T3/NF2(BBA)), and find that simultaneous knockdown of Pak1-3 in these cells significantly reduced their growth rates in vitro and inhibited their ability to form tumors in vivo.
  • Finally, while attempting to silence Pak1 in rat schwannoma cells, we found that these cells were unable to tolerate long-term Pak1 inhibition and rapidly moved to restore Pak1 levels by shutting down Pak1 shRNA expression through a methylation-dependent mechanism.
  • These data suggest that inhibiting Pak could be a beneficial approach for the development of therapeutics toward NF2.
  • In addition, the finding that the shRNA-mediated Pak1 suppression was silenced rapidly by methylation raises questions about the future application of such technologies for the treatment of diseases such as cancer.

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  • (PMID = 18829550.001).
  • [ISSN] 1538-7445
  • [Journal-full-title] Cancer research
  • [ISO-abbreviation] Cancer Res.
  • [Language] ENG
  • [Grant] United States / NCI NIH HHS / CA / R01 CA124495; United States / NCI NIH HHS / CA / F32 CA123752-01; United States / NCI NIH HHS / CA / F32 CA123752-03; United States / NINDS NIH HHS / NS / NS024279-19; United States / NCI NIH HHS / CA / CA101502-02; United States / NINDS NIH HHS / NS / P01 NS024279-19; United States / NCI NIH HHS / CA / CA123752-01; United States / NCI NIH HHS / CA / CA123752-02; United States / NCI NIH HHS / CA / F32 CA101502-02; United States / NCI NIH HHS / CA / CA123752-03; United States / NCI NIH HHS / CA / F32 CA101502; United States / NINDS NIH HHS / NS / P01 NS024279; United States / NCI NIH HHS / CA / F32 CA123752-02; United States / NCI NIH HHS / CA / F32 CA123752
  • [Publication-type] Journal Article; Research Support, Non-U.S. Gov't; Validation Studies
  • [Publication-country] United States
  • [Chemical-registry-number] 0 / RNA, Small Interfering; EC 2.7.11.1 / p21-Activated Kinases
  • [Other-IDs] NLM/ NIHMS112457; NLM/ PMC2707059
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25. Kobayashi H, Ishii N, Murata J, Saito H, Kubota KC, Nagashima K, Iwasaki Y: Cystic meningioangiomatosis. Pediatr Neurosurg; 2006;42(5):320-4
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  • A 14-year-old boy without any stigmata of neurofibromatosis type 2 presented intractable complex partial and generalized seizures since the age of 12 years.
  • The patient underwent surgical treatment because medical treatment with phenytoin and sodium valproate was not sufficient to control the seizures.
  • The patient did not have any seizures with anticonvulsants after surgery.
  • [MeSH-minor] Adolescent. Electroencephalography. Humans. Male. Seizures / drug therapy. Seizures / etiology. Seizures / surgery

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  • [Copyright] Copyright 2006 S. Karger AG, Basel.
  • (PMID = 16902347.001).
  • [ISSN] 1016-2291
  • [Journal-full-title] Pediatric neurosurgery
  • [ISO-abbreviation] Pediatr Neurosurg
  • [Language] eng
  • [Publication-type] Case Reports; Journal Article
  • [Publication-country] Switzerland
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26. Evans DG: Neurofibromatosis type 2 (NF2): a clinical and molecular review. Orphanet J Rare Dis; 2009;4:16
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  • [Source] The source of this record is MEDLINE®, a database of the U.S. National Library of Medicine.
  • [Title] Neurofibromatosis type 2 (NF2): a clinical and molecular review.
  • Neurofibromatosis type 2 (NF2) is a tumour-prone disorder characterised by the development of multiple schwannomas and meningiomas.
  • Affected individuals inevitably develop schwannomas, typically affecting both vestibular nerves and leading to hearing loss and deafness.
  • Vestibular schwannomas may also cause dizziness or imbalance as a first symptom.
  • Nausea, vomiting or true vertigo are rare symptoms, except in late-stage disease.
  • The other main tumours are schwannomas of the other cranial, spinal and peripheral nerves; meningiomas both intracranial (including optic nerve meningiomas) and intraspinal, and some low-grade central nervous system malignancies (ependymomas).
  • About 70% of NF2 patients have skin tumours (intracutaneous plaque-like lesions or more deep-seated subcutaneous nodular tumours).
  • Neurofibromatosis type 2 is a dominantly inherited tumour predisposition syndrome caused by mutations in the NF2 gene on chromosome 22.
  • More than 50% of patients represent new mutations and as many as one-third are mosaic for the underlying disease-causing mutation.
  • Although truncating mutations (nonsense and frameshifts) are the most frequent germline event and cause the most severe disease, single and multiple exon deletions are common.
  • Diagnosis is based on clinical and neuroimaging studies.
  • Presymptomatic genetic testing is an integral part of the management of NF2 families.
  • Prenatal diagnosis and pre-implantation genetic diagnosis is possible.
  • The main differential diagnosis of NF2 is schwannomatosis.
  • NF2 represents a difficult management problem with most patients facing substantial morbidity and reduced life expectancy.
  • Surgery remains the focus of current management although watchful waiting with careful surveillance and occasionally radiation treatment have a role.
  • In the future, the development of tailored drug therapies aimed at the genetic level are likely to provide huge improvements for this devastating condition.
  • [MeSH-major] Neurofibromatosis 2
  • [MeSH-minor] Adolescent. Adult. Genes, Neurofibromatosis 2. Humans. Mutation. Prognosis. Young Adult


27. Zhao ZS, Manser E: Do PAKs make good drug targets? F1000 Biol Rep; 2010;2:70
The Lens. Cited by Patents in .

  • [Source] The source of this record is MEDLINE®, a database of the U.S. National Library of Medicine.
  • [Title] Do PAKs make good drug targets?
  • There are six mammalian PAK isoforms that are divided into two groups, and for different reasons both groups are attractive targets for cancer therapy.
  • We describe the background and recent development of a PAK inhibitor, PF-3758309, which exhibits relatively good selectivity and high potency for PAKs.
  • The genetic loss of NF2 (neurofibromatosis type 2) leading to increased cell proliferation through a Ras-Rac-PAK pathway may represent a good test system to analyze this new PAK inhibitor.

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  • (PMID = 21173843.001).
  • [ISSN] 1757-594X
  • [Journal-full-title] F1000 biology reports
  • [ISO-abbreviation] F1000 Biol Rep
  • [Language] eng
  • [Publication-type] Journal Article
  • [Publication-country] England
  • [Other-IDs] NLM/ PMC2989626
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28. Ammoun S, Flaiz C, Ristic N, Schuldt J, Hanemann CO: Dissecting and targeting the growth factor-dependent and growth factor-independent extracellular signal-regulated kinase pathway in human schwannoma. Cancer Res; 2008 Jul 1;68(13):5236-45
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  • [Source] The source of this record is MEDLINE®, a database of the U.S. National Library of Medicine.
  • [Title] Dissecting and targeting the growth factor-dependent and growth factor-independent extracellular signal-regulated kinase pathway in human schwannoma.
  • Schwannomas are tumors of the nervous system that occur sporadically and in patients with the cancer predisposition syndrome neurofibromatosis type 2 (NF2).
  • Schwannomas and all NF2-related tumors are caused by loss of the tumor suppressor merlin.
  • Using our human in vitro model for schwannoma, we analyzed extracellular signal-regulated kinase 1/2 (ERK1/2) and AKT signaling pathways, their upstream growth factor receptors, and their role in schwannoma cell proliferation and adhesion to find new systemic therapies for these tumors that, to date, are very difficult to treat.
  • We show here that human primary schwannoma cells show an enhanced basal Raf/mitogen-activated protein/ERK kinase/ERK1/2 pathway activity compared with healthy Schwann cells.
  • Due to a strong and prolonged activation of platelet-derived growth factor receptor beta (PDGFRbeta), which is highly overexpressed, ERK1/2 and AKT activation was further increased in schwannoma, leading to increased proliferation.
  • Due to the complexity of signals leading to schwannoma cell proliferation, potential new therapeutic agents should target several signaling pathways.
  • The PDGFR and c-Raf inhibitor sorafenib (BAY 43-9006; Bayer Pharmaceuticals), currently approved for treatment of advanced renal cell cancer, inhibits both basal and PDGFRbeta-mediated ERK1/2 and AKT activity and decreases cell proliferation in human schwannoma cells, suggesting that this drug constitutes a promising tool to treat schwannomas.
  • We conclude that our schwannoma in vitro model can be used to screen for new therapeutic targets in general and that sorafenib is possible candidate for future clinical trials.
  • [MeSH-major] Drug Delivery Systems. Extracellular Signal-Regulated MAP Kinases / antagonists & inhibitors. Extracellular Signal-Regulated MAP Kinases / metabolism. Intercellular Signaling Peptides and Proteins / physiology. MAP Kinase Signaling System / physiology. Neurilemmoma / metabolism
  • [MeSH-minor] Cells, Cultured. Enzyme Activation / drug effects. Focal Adhesion Kinase 1 / genetics. Focal Adhesion Kinase 1 / metabolism. Gene Expression Regulation, Neoplastic. Humans. Lymphokines / pharmacology. MAP Kinase Kinase 1 / metabolism. MAP Kinase Kinase 2 / metabolism. Mitogen-Activated Protein Kinase 1 / metabolism. Mitogen-Activated Protein Kinase 3 / metabolism. Models, Biological. Neurofibromatosis 2 / complications. Oncogene Protein v-akt / metabolism. Platelet-Derived Growth Factor / pharmacology. Receptor, Platelet-Derived Growth Factor beta / genetics. Receptor, Platelet-Derived Growth Factor beta / metabolism

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  • (PMID = 18593924.001).
  • [ISSN] 1538-7445
  • [Journal-full-title] Cancer research
  • [ISO-abbreviation] Cancer Res.
  • [Language] eng
  • [Publication-type] Comparative Study; Journal Article; Research Support, Non-U.S. Gov't
  • [Publication-country] United States
  • [Chemical-registry-number] 0 / Intercellular Signaling Peptides and Proteins; 0 / Lymphokines; 0 / PDGFD protein, human; 0 / Platelet-Derived Growth Factor; EC 2.7.1.- / MAP2K1 protein, human; EC 2.7.1.- / MAP2K2 protein, human; EC 2.7.10.1 / Receptor, Platelet-Derived Growth Factor beta; EC 2.7.10.2 / Focal Adhesion Kinase 1; EC 2.7.10.2 / PTK2 protein, human; EC 2.7.11.1 / Oncogene Protein v-akt; EC 2.7.11.24 / Extracellular Signal-Regulated MAP Kinases; EC 2.7.11.24 / Mitogen-Activated Protein Kinase 1; EC 2.7.11.24 / Mitogen-Activated Protein Kinase 3; EC 2.7.12.2 / MAP Kinase Kinase 1; EC 2.7.12.2 / MAP Kinase Kinase 2
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