Showing papers by "Joseph Negri published in 2006"
TL;DR: These data provide both insights into the molecular mechanisms of antitumor activity of proteasome inhibitors and the rationale for future clinical trials of bortezomib, alone or in combination with conventional chemotherapy, to improve patient outcome in medullary and anaplastic thyroid carcinomas.
Abstract: Context: The ubiquitin-proteasome pathway is a major pathway for degradation of intracellular proteins. Proteasome inhibitors constitute a novel class of antitumor agents with preclinical and clinical evidence of activity against hematological malignancies and solid tumors. The proteasome inhibitor bortezomib (PS-341, Velcade) has been approved by the Food and Drug Administration for the treatment of multiple myeloma and is being studied intensely in several other malignancies. Its mechanism of action is complex but appears to include the inhibition of inhibitory-B degradation, which leads to inactivation of the transcriptional factor nuclear factor-B (NF-B). NF-B has been implicated in the pathophysiology of the most aggressive forms of thyroid carcinoma, i.e. medullary and anaplastic. Objective and Methods: We evaluated the effect of bortezomib on a panel of thyroid carcinoma cell lines, originating from papillary, follicular, anaplastic, and medullary carcinomas. Results: Bortezomib induced apoptosis in medullary and anaplastic cell lines with IC50 values well within the range of clinically achievable concentrations and much lower than respective IC50 values for other solid malignancies. Bortezomib inhibited NF-B activity; increased p53, p21, and jun expression; and induced caspase-dependent apoptosis. Sensitivity of thyroid carcinoma cells to bortezomib was partially decreased by overexpression of Bcl-2 or treatment with IGF-I, whereas the combination of bortezomib with chemotherapy (doxorubicin) was synergistic. Conclusions: These data provide both insights into the molecular mechanisms of antitumor activity of proteasome inhibitors and the rationale for future clinical trials of bortezomib, alone or in combination with conventional chemotherapy, to improve patient outcome inmedullaryandanaplasticthyroidcarcinomas.(JClinEndocrinol Metab 91: 4013–4021, 2006)
117 citations
TL;DR: Thyroid carcinoma cells overall are poorly responsive to clinically relevant concentrations of AEE788 in vitro, and the presence of EGFR-activating TK domain mutations may identify a small minority of thyroid cancer patients that may benefit from EGFR inhibitors, but additional preclinical evidence of efficacy is needed.
Abstract: Context: The epidermal growth factor receptor (EGFR), a transmembrane tyrosine kinase (TK) receptor that mediates proliferation and survival signaling, is expressed in a wide variety of normal and neoplastic tissues. EGFR inhibitors have produced objective responses in patients with non-small-cell lung carcinomas harboring activating EGFR TK domain somatic mutations. Objective and Methods: Because the EGFR pathway has been reported to be important for the pathophysiology of thyroid carcinoma, we investigated the expression and mutational status of EGFR in 14 thyroid carcinoma cell lines as well as its functional role by evaluating their in vitro sensitivity to AEE788, a new dual-family EGFR/ErbB2 and vascular endothelial growth factor receptor TK inhibitor. We also evaluated the mutational status, mRNA and protein expression, as well as phosphorylation status of EGFR in a panel of thyroid carcinoma specimens. Results: EGFR expression and phosphorylation in the thyroid carcinoma cell lines and tissue speci...
63 citations
TL;DR: In vitro studies of multiple myeloma cells with reversine suggest that reversine may represent a distinct class of agents with therapeutic potential for specific subset(s) of MM and perhaps other hematologic neoplasias, and supports a broader conclusion that reversal has distinct profiles of molecular effects and anti-MM activity.
2 citations
TL;DR: In vitro evidence for induction of MM cell death and therapeutic window for the anti-MM effect of VE465, its ability to overcome protective effect of BM-derived cytokines, and the clearly distinct pattern of molecular sequelae of Ve465 compared to several other agents in the current anti- MM therapeutic armamentarium suggest that Aurora kinase inhibition represents an intriguing novel targeted treatment strategy in MM.
2 citations
14 Nov 2006
TL;DR: In this paper, Dasatinib can be administered alone or in combination with a second anti-neoplastic agent such as dexamethasone or bortezomib.
Abstract: Methods for treating multiple myeloma comprising administering a therapeutically effective amount of dasatinib to a patient in need of treatment thereof. Dasatinib can be administered alone or in combination with a second anti-neoplastic agent such as dexamethasone or bortezomib. The patient may be refractory to prior treatment with an anti-neoplastic agent other than dasatinib.
2 citations
Patent•
14 Nov 2006TL;DR: In this paper, Dasatinib can be administered alone or in combination with a second anti-neoplastic agent such as dexamethasone or bortezomib.
Abstract: Methods for treating multiple myeloma comprising administering a therapeutically effective amount of dasatinib to a patient in need of treatment thereof. Dasatinib can be administered alone or in combination with a second anti-neoplastic agent such as dexamethasone or bortezomib. The patient may be refractory to prior treatment with an anti-neoplastic agent other than dasatinib.