Molecular Targeting of Platelet-Derived Growth Factor B by Imatinib Mesylate in a Patient With Metastatic Dermatofibrosarcoma Protuberans

2002 ◽  
Vol 20 (17) ◽  
pp. 3586-3591 ◽  
Author(s):  
Brian P. Rubin ◽  
Scott M. Schuetze ◽  
Janet F. Eary ◽  
Thomas H. Norwood ◽  
Sohail Mirza ◽  
...  
Keyword(s):  
Growth Factor ◽  
Tyrosine Kinase ◽  
Imatinib Mesylate ◽  
Kinase Inhibitor ◽  
Dermatofibrosarcoma Protuberans ◽  
Response To Therapy ◽  
Platelet Derived Growth Factor ◽  
Response To Treatment ◽  
Resected Specimen ◽  
Factor B

PURPOSE: Dermatofibrosarcoma protuberans is caused by activation of the platelet-derived growth factor B (PDGFB) receptor, a transmembrane tyrosine kinase. We investigated the response of dermatofibrosarcoma protuberans to the tyrosine kinase inhibitor imatinib mesylate. PATIENTS AND METHODS: A patient with unresectable, metastatic dermatofibrosarcoma protuberans received imatinib mesylate (400 mg bid). Response to therapy was assessed by [18F]fluorodeoxyglucose (FDG) positron emission tomography, magnetic resonance imaging, and histopathologic and immunohistochemical evaluation. RESULTS: The patient was treated for 4 months with imatinib mesylate. The hypermetabolic uptake of FDG fell to background levels within 2 weeks of treatment, and the tumor volume shrank by over 75% during the 4 months of therapy, allowing for resection of the mass. There was no residual viable tumor in the resected specimen, indicating a complete histologic response to treatment with imatinib mesylate. CONCLUSION: Imatinib mesylate is highly active in dermatofibrosarcoma protuberans. The dramatic response seen in this patient demonstrates that inhibition of PDGFB receptor tyrosine kinase activity can significantly impact viability of at least one type of solid tumor.

Activity of STI571 in chronic myelomonocytic leukemia with a platelet-derived growth factor β receptor fusion oncogene

Blood ◽  
2002 ◽  
Vol 100 (3) ◽  
pp. 1088-1091 ◽  
Author(s):  
Magnus K. Magnusson ◽  
Kristin E. Meade ◽  
Ryotaro Nakamura ◽  
John Barrett ◽  
Cynthia E. Dunbar
Keyword(s):  
Growth Factor ◽  
Tyrosine Kinase ◽  
Kinase Inhibitor ◽  
Fusion Gene ◽  
Chronic Myelomonocytic Leukemia ◽  
Platelet Derived Growth Factor ◽  
Gene Transcript ◽  
Molecular Remission ◽  
Β Receptor ◽  
Myelomonocytic Leukemia

Abstract Platelet-derived growth factor β receptor (PDGFβR) fusion genes have been shown to be critical transforming oncogenes in a subset of patients with chronic myelomonocytic leukemia (CMML). The sensitivity of dysregulated tyrosine kinase oncogenes to the tyrosine kinase inhibitor STI571 (imatinib mesylate) makes it a potentially attractive treatment option in this subset of patients. We have recently cloned a novel member of the PDGFβR fusion oncogene family, rabaptin-5-PDGFβR. A patient with CMML carrying the rabaptin-5-PDGFβR fusion gene underwent allogeneic stem cell transplantation (SCT) and was monitored closely with a sensitive reverse transcriptase–polymerase chain assay to detect the novel fusion gene transcript. After achieving a molecular remission at 5 months after transplantation, 15 months after SCT the patient showed persistent and progressive evidence of molecular relapse. After demonstrating in vitro that cells transformed with this specific fusion oncogene are efficiently killed by STI571, the patient was started on STI571. The patient responded rapidly and entered molecular remission after 6 weeks of therapy, and he continues to be in remission 6 months later. These results suggest that STI571 may be an effective targeted therapy in patients with CMML related to PDGFβR fusion oncogenes.

Relationship between Clinical/Hematological Response and Increase of Plamacells in the Bone Marrow of Patients with Chronic Myelogenous Leukemia Imatinib Mesylate Treatment (631).

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 4552-4552
Author(s):  
Alessandro Poggi ◽  
Ivana Pierri ◽  
Silvia Catellani ◽  
Francesca Olcese ◽  
Antonella Marasco ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Tyrosine Kinase ◽  
Imatinib Mesylate ◽  
B Lymphocytes ◽  
Chronic Myelogenous Leukemia ◽  
Peripheral Blood ◽  
Kinase Inhibitor ◽  
Myelogenous Leukemia ◽  
Response To Treatment ◽  
Imatinib Treatment

Abstract Tyrosine kinase inhibitors, such as imatinib mesylate (Gleevec, Novartis, formerly known as STI571) are the first line treatment of Chronic Myelogenous Leukemia (CML) and of a rare form of gastroenteric stromal cancer. It has been recently reported that in the latter case, tumor cells are refractory to imatinib antiproliferative effect in vitro and the response to the drug in vivo is due to immunocompetent cells, able to produce cytokines with antineoplastic activity. In this study, 20 CML patients, prior and during treatment with imatinib mesylate, underwent bone marrow (BM) aspirates every 6 months, including: morphologic and phenotypic analysis, cytogenetic and biomolecular evaluation, compared to peripheral blood. Plasma from BM and peripheral blood was also recovered for cytokyne-chemokine dosage. We report that in 12 out of 20 CML patients a significant increase in the percentage of BM lymphoplasmocytoid cells was observed upon treatment with imatinib mesylate, with >10% (range 10–16%) of CD20+CD126+cells. Among this population, two third of cells coexpressed IgM and one third was IgD+, while a smaller fraction of IgM+CD126+CD20– (3–4%) or IgD+CD126+CD20- (2–3%) cells was also found. The lasting 8 patients had<5% of CD20 +CD126+ lymphocytes (range2–4%), 2/3 coexpressing IgM and 1/3 coexpressing IgD. All patients with increased number of CD126+ B lymphocytes underwent hematologic remission, 7 of them with complete molecular and cytogenetic remission. On the other hand, among the patients with low or undetectable CD20+CD126+cells, only 4 underwent hemathological remission and none of them displayed stable cytogenetyc and molecular remission. In two patients relapsed after six months of treatment, the fraction of BM CD20+CD126+ lymphocytes decreased from 16% and 11% to 7 and 5%, respectively, with undetectable IgM+ CD126+CD20- or IgD+ CD126+CD20- cells. These data suggest that this population of lymphoplasmocytoid B cells depends on or contribute to the pharmacological response; by the way, this phenomenon might help in monitoring the outcome of disease and the response to treatment. To check this item and understand the biochemical mechanisms substaining the observed increase in BM lymphoplasmocitoid cells on imatinib treatment, we wonder if the production of cytokines able to induce B lymphocytes differentiation, such as interleukin (IL)-4, IL-6 (whose receptor is CD126), IL-3, IL10 or IL-21 was affected by imatinib administration. To this aim, both soluble cytokines (by ELISPOT) and their mRNA (by real time polymerase chain reaction) were evaluated in the BM of these patients: moreover, the expression of MCP-1, SDF-1, IP-10 and IL-8 were also measured, to verify whether the increse in BM CD20+ CD126+ lymphocytes was due to a redistribution rather than to “in situ” differentiation. Preliminary results seem to indicate that the latter hypothesis is unlikely; in addition, when CD20+ CD126+ were increased in the BM, they also raised in the peripheral blood. These immunological events might have a role in the response to tyrosine kinase inhibitor and need further investigations.

Fusion of Platelet-Derived Growth Factor β to a Novel Gene KIAA1509 on Chromosome 14 in an Atypical Myeloproliferative Disorder Associated with Eosinophilia.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 2437-2437
Author(s):  
Peter J. Browett ◽  
Anna O’Grady ◽  
Paul Oei ◽  
Duncan Holdsworth ◽  
Neil S. Van de Water
Keyword(s):  
Growth Factor ◽  
Tyrosine Kinase ◽  
Imatinib Mesylate ◽  
Myeloproliferative Disorders ◽  
Platelet Derived Growth Factor ◽  
Tyrosine Kinase Receptor ◽  
Fluorescence In Situ Hybridisation ◽  
Chromosome 14 ◽  
Cutaneous Manifestations ◽  
Novel Gene

Abstract Platelet-derived growth factor β (PDGFRβ), a tyrosine kinase receptor, has recently been shown to be constitutively activated by fusion to different gene partners in atypical, bcr-abl negative, myeloproliferative disorders. As a consequence, the activated PDGFRβ gene is a potential target for the tyrosine kinase inhibitor Imatinib mesylate. The objective of this study was to further characterise a t(5;9;14) translocation found in a 22 year old female patient with an atypical myeloproliferative characterised by eosinophilia, a severe paraneoplastic lichenoid eruption involving her skin and oral mucosa, and a poor response to conventional chemotherapy. G banded cytogenetic analysis of her bone marrow at diagnosis revealed an abnromal karyotype t(5;9;14)(q33;q22;q32) in 38 of 40 metaphases examined. There was no evidence of the bcr-abl fusion gene trancript by RT-PCR. Fluorescence in situ hybridisation using a CSF1-R probe suggested a breakpoint involving the PDGFRβ gene locus on chromosome 5q33 with an unknown partner gene on chromosome 14. 5′ RACE-PCR studies using a PDGFRβ primer generated a product of 220bp that on sequencing revealed a novel gene KIAA1509 fused in frame to the 3′ end of PDGFRβ in exon 11. KIAA1509 has previously been mapped to chromosome 14 and encodes a protein of 1935 amino acids that shows homology to HOOK proteins and contains coiled coiled domains. The resulting fusion protein preserves the tyrosine kinase domains of PDGFRβ, but lacks the transmembrane domain, and would be predicted to result in constitutive activation of the tyrosine kinase receptor. In view of these molecular findings, the patient was commenced on Imatinib mesylate, which resulted in a rapid haematologic response, including resolution of the mucosal and cutaneous manifestations, and a complete cytogenetic response after 3 months therapy. These findings highlight the importance of investigating the molecular basis of the myeloproliferative disorders to identify potential novel targets for Imatinib and similar molecules.

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