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Biomedical subjects

Constantine S Mitsiades

Publications and source records attributed to Constantine S Mitsiades.

At least 19 recordsLinked to original sources
PubMed2007

Serum proteome profiling detects myelodysplastic syndromes and identifies CXC chemokine ligands 4 and 7 as markers for advanced disease.

Myelodysplastic syndromes (MDS) are among the most frequent hematologic malignancies. Patients have a short survival and often progress to acute myeloid leukemia. The diagnosis of MDS can be difficult; there is a paucity of molecular markers, and the pathophysiology is largely unknown. Therefore, we conducted a multicenter study investigating whether serum proteome profiling may serve as a noninvasive platform to discover novel molecular markers for MDS. We generated serum proteome profiles from 218 individuals by MS and identified a profile that distinguishes MDS from non-MDS cytopenias in a learning sample set. This profile was validated by testing its ability to predict MDS in a first independent validation set and a second, prospectively collected, independent validation set run 5 months apart. Accuracy was 80.5% in the first and 79.0% in the second validation set. Peptide mass fingerprinting and quadrupole TOF MS identified two differential proteins: CXC chemokine ligands 4 (CXCL4) and 7 (CXCL7), both of which had significantly decreased serum levels in MDS, as confirmed with independent antibody assays. Western blot analyses of platelet lysates for these two platelet-derived molecules revealed a lack of CXCL4 and CXCL7 in MDS. Subtype analyses revealed that these two proteins have decreased serum levels in advanced MDS, suggesting the possibility of a concerted disturbance of transcription or translation of these chemokines in advanced MDS.

Biomarkers↗
PubMed2006

Antitumor effects of the proteasome inhibitor bortezomib in medullary and anaplastic thyroid carcinoma cells in vitro.

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-kappaB degradation, which leads to inactivation of the transcriptional factor nuclear factor-kappaB (NF-kappaB). NF-kappaB 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 IC(50) values well within the range of clinically achievable concentrations and much lower than respective IC(50) values for other solid malignancies. Bortezomib inhibited NF-kappaB 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 in medullary and anaplastic thyroid carcinomas.

Antineoplastic Agents↗
PubMed2006

A randomized phase 2 study of lenalidomide therapy for patients with relapsed or relapsed and refractory multiple myeloma.

This multicenter, open-label, randomized phase 2 study evaluated 2 dose regimens of lenalidomide for relapsed, refractory myeloma. Seventy patients were randomized to receive either 30 mg once-daily or 15 mg twice-daily oral lenalidomide for 21 days of every 28-day cycle. Patients with progressive or stable disease after 2 cycles received dexamethasone. Analysis of the first 70 patients showed increased grade 3/4 myelo-suppression in patients receiving 15 mg twice daily (41% versus 13%, P = .03). An additional 32 patients received 30 mg once daily. Responses were evaluated according to European Group for Blood and Marrow Transplantation (EBMT) criteria. Overall response rate (complete, partial, or minor) to lenalidomide alone was 25% (24% for once-daily and 29% for twice-daily lenalidomide). Median overall survival in 30-mg once-daily and twice-daily groups was 28 and 27 months, respectively. Median progression-free survival was 7.7 months on once-daily versus 3.9 months on twice-daily lenalidomide (P = .2). Dexamethasone was added in 68 patients and 29% responded. Time to first occurrence of clinically significant grade 3/4 myelosuppression was shorter in the twice-daily group (1.8 vs 5.5 months, P = .05). Significant peripheral neuropathy and deep vein thrombosis each occurred in only 3%. Lenalidomide is active and well tolerated in relapsed, refractory myeloma, with the 30-mg once-daily regimen providing the basis for future studies as monotherapy and with dexamethasone.

Adult↗
PubMed2006

Epidermal growth factor receptor as a therapeutic target in human thyroid carcinoma: mutational and functional analysis.

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 specimens were present but not stronger than in noncancerous thyroid tissue. EGFR TK domain mutations were detected in two of 62 histological specimens (3.2%) but not in cell lines. All thyroid carcinoma cell lines were significantly less sensitive (IC(50) at least 25-fold higher) in vitro to AEE788 than a primary culture of EGFR-mutant lung carcinoma cells. CONCLUSIONS: Thyroid carcinoma cells overall are poorly responsive to clinically relevant concentrations of AEE788 in vitro. 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.

Adolescent↗
PubMed2006

Fas signaling in thyroid carcinomas is diverted from apoptosis to proliferation.

PURPOSE: The death receptor Fas is present in thyroid carcinomas, yet fails to trigger apoptosis. Interestingly, Fas has been reported to be actually overexpressed in papillary thyroid carcinomas, suggesting that it may confer a survival advantage. EXPERIMENTAL DESIGN: We investigated the expression and activation status of Fas pathway mediators in thyroid carcinoma cell lines and tumor specimens. RESULTS: All cell lines tested express Fas-associated death domain, procaspase-8, procaspase-9, and procaspase-3; resistance to Fas-mediated apoptosis could not be attributed to lack of any of these apoptosis mediators. Moreover, Fas death domain mutations were not found in our study. The proteasome inhibitors MG132 and PS-341 (bortezomib, Velcade), which lead to accumulation of the nuclear factor kappaB (NF-kappaB) inhibitor IkappaB, did not sensitize SW579 cells to Fas-mediated apoptosis, suggesting that resistance to Fas-mediated apoptosis is not due to proteasome or NF-kappaB activity. Cross-linking of Fas in vitro induced recruitment of Fas-associated death domain-like interleukin-1beta-converting enzyme inhibitory protein (FLIP) instead of procaspase-8. Inhibition of FLIP expression with a FLIP antisense oligonucleotide resulted in significant sensitization to Fas-mediated apoptosis. Fas cross-linking promoted BrdUrd incorporation; activated the mitogen-activated protein kinase/extracellular signal-regulated kinase kinase/extracellular signal-regulated kinase, NF-kappaB, and activator protein-1 pathways in thyroid carcinoma cells in vitro; and protected cells from tumor necrosis factor-related apoptosis-inducing ligand-induced apoptosis. We also found that good prognosis papillary thyroid carcinoma specimens exhibited higher immunoreactivity for cleaved (activated) caspase-8 than poor prognosis tumors. CONCLUSIONS: In thyroid carcinomas, the proteolytic cleavage and activation of caspase-8 depends on the balance between expression levels for procaspase-8 and FLIP and correlates with favorable clinical prognosis. Fas may actually stimulate proliferation and confer a survival advantage to thyroid cancer cells.

Apoptosis↗
PubMed2006

The role of the bone microenvironment in the pathophysiology and therapeutic management of multiple myeloma: interplay of growth factors, their receptors and stromal interactions.

The close relationship between the biological behaviour of malignant cells and the local microenvironment where they reside is a feature of diverse neoplasias. Multiple myeloma (MM) is considered a main disease model for the study of such interactions and the mechanisms that can lead to bone-related clinical complications, as well as the role of these interactions in attenuating the activity of conventional anti-MM therapeutics, such as dexamethasone and cytotoxic chemotherapeutics. This review focuses on recent progress in the study of interactions of MM cells with their local microenvironment. Major emphasis is placed on how bone marrow stromal cells (BMSCs) and other normal constituents of the bone marrow milieu promote, through cell adhesion- and cytokine-mediated mechanisms, the ability of MM cells to resist conventional anti-MM therapies. The review also addresses ongoing research into these mechanisms, which has already provided several new molecular targets and corresponding therapeutic strategies, such as the proteasome inhibitor bortezomib and thalidomide derivatives (e.g. lenalidomide), for the management of myeloma.

Bone Diseases↗
PubMed2006

Proteasome inhibition as a new therapeutic principle in hematological malignancies.

The intracellular concentration of proteins in both normal and tumor cells are regulated by the balance between the rates of protein synthesis vs. degradation. The ubiquitin-proteasome pathway is the main intracellular cascade for controlled degradation of proteins and has attracted in recent years major interest not only because of its biochemical complexity and the intricate regulation of its function, but also because diverse cell cycle regulators and modulators of apoptosis are subject to regulation by proteasome function, and can therefore be significantly affected by small molecule inhibitors of the proteolytic activity of the proteasome. In fact, bortezomib, the prototypic member of this class of agents, was recently approved by the U.S. Food and Drug Administration for the treatment of advanced multiple myeloma patients. This review article focuses on the exciting recent progress in the use of proteasome inhibitors, with emphasis on the bench-to-bedside research effort which provided the foundation for clinical development of bortezomib for the treatment of multiple myeloma, as well as other hematologic malignancies, such as mantle cell lymphoma.

Animals↗
PubMed2005

FGFR3 as a therapeutic target of the small molecule inhibitor PKC412 in hematopoietic malignancies.

Reccurent chromosomal translocation t(4;14) (p16.3;q32.3) occurs in patients with multiple myeloma (MM) and is associated with ectopic overexpression of fibroblast growth factor receptor 3 (FGFR3) that sometimes may contain the activation mutations such as K650E thanatophoric dysplasia type II (TDII). Although there have been significant advances in therapy for MM including the use of proteasome inhibitors, t(4;14) MM has a particularly poor prognosis and most patients still die from complications related to their disease or therapy. One potential therapeutic strategy is to inhibit FGFR3 in those myeloma patients that overexpress the receptor tyrosine kinase due to chromosomal translocation. Here we evaluated PKC412, a small molecule tyrosine kinase inhibitor, for treatment of FGFR3-induced hematopoietic malignancies. PKC412 inhibited kinase activation and proliferation of hematopoietic Ba/F3 cells transformed by FGFR3 TDII or a TEL-FGFR3 fusion. Similar results were obtained in PKC412 inhibition of several different t(4;14)-positive human MM cell lines. Furthermore, treatment with PKC412 resulted in a statistically significant prolongation of survival in murine bone marrow transplant models of FGFR3 TDII-induced pre-B cell lymphoma, or a peripheral T-cell lymphoma associated TEL-FGFR3 fusion-induced myeloproliferative disease. These data indicate that PKC412 may be a useful molecularly targeted therapy for MM associated with overexpression of FGFR3, and perhaps other diseases associated with dysregulation of FGFR3 or related mutants.

Animals↗
PubMed2005

Antimyeloma activity of heat shock protein-90 inhibition.

We show that multiple myeloma (MM), the second most commonly diagnosed hematologic malignancy, is responsive to hsp90 inhibitors in vitro and in a clinically relevant orthotopic in vivo model, even though this disease does not depend on HER2/neu, bcr/abl, androgen or estrogen receptors, or other hsp90 chaperoning clients which are hallmarks of tumor types traditionally viewed as attractive clinical settings for use of hsp90 inhibitors, such as the geldanamycin analog 17-AAG. This class of agents simultaneously suppresses in MM cells the expression and/or function of multiple levels of insulin-like growth factor receptor (IGF-1R) and interleukin-6 receptor (IL-6R) signaling (eg, IKK/NF-kappaB, PI-3K/Akt, and Raf/MAPK) and downstream effectors (eg, proteasome, telomerase, and HIF-1alpha activities). These pleiotropic proapoptotic effects allow hsp90 inhibitors to abrogate bone marrow stromal cell-derived protection on MM tumor cells, and sensitize them to other anticancer agents, including cytotoxic chemotherapy and the proteasome inhibitor bortezomib. These results indicate that hsp90 can be targeted therapeutically in neoplasias that may not express or depend on molecules previously considered to be the main hsp90 client proteins. This suggests a more general role for hsp90 in chaperoning tumor- or tissue-type-specific constellations of client proteins with critical involvement in proliferative and antiapoptotic cellular responses, and paves the way for more extensive future therapeutic applications of hsp90 inhibition in diverse neoplasias, including MM.

Androgens↗
PubMed2005

FTY720 induces apoptosis in multiple myeloma cells and overcomes drug resistance.

The novel immunomodulator FTY720 down-modulates sphingosine-1-phosphate receptor 1 on lymphocytes at low nanomolar concentrations, thereby inhibiting sphingosine-1-phosphate receptor 1-dependent egress of lymphocytes from lymph nodes into efferent lymphatics and blood. At high micromolar concentration, FTY720 has been shown to induce growth inhibition and/or apoptosis in human cancer cells in vitro. In this study, we investigated the biological effects of FTY720 on multiple myeloma cells. We found that FTY720 induces potent cytotoxicity against drug-sensitive and drug-resistant multiple myeloma cell lines as well as freshly isolated tumor cells from multiple myeloma patients who do not respond to conventional agents. FTY720 triggers activation of caspase-8, -9, and -3, followed by poly(ADP-ribose) polymerase cleavage. Interestingly, FTY720 induces alterations in mitochondrial membrane potential (DeltaPsim) and Bax cleavage, followed by translocation of cytochrome c and Smac/Diablo from mitochondria to the cytosol. In combination treatment studies, both dexamethasone and anti-Fas antibodies augment anti-multiple myeloma activity induced by FTY720. Neither interleukin-6 nor insulin-like growth factor-I, which both induce multiple myeloma cell growth and abrogate dexamethasone-induced apoptosis, protect against FTY720-induced growth inhibition. Importantly, growth of multiple myeloma cells adherent to bone marrow stromal cells is also significantly inhibited by FTY720. Finally, it down-regulates interleukin-6-induced phosphorylation of Akt, signal transducers and activators of transcription 3, and p42/44 mitogen-activated protein kinase; insulin-like growth factor-I-triggered Akt phosphorylation; and tumor necrosis factor alpha-induced IkappaBalpha and nuclear factor-kappaB p65 phosphorylation. These results suggest that FTY720 overcomes drug resistance in multiple myeloma cells and provide the rationale for its clinical evaluation to improve patient outcome in multiple myeloma.

Antineoplastic Agents↗
PubMed2005

Novel histone deacetylase inhibitors in the treatment of thyroid cancer.

Histone deacetylases (HDAC) and histone acetyltransferases exert opposing enzymatic activities that modulate the degree of acetylation of histones and other intracellular molecular targets, thereby regulating gene expression, cellular differentiation, and survival. HDAC inhibition results in accumulation of acetylated histones and induces differentiation and/or apoptosis in transformed cells. In this study, we characterized the effect of two HDAC inhibitors, suberoylanilide hydroxamic acid (SAHA) and m-carboxycinnamic acid bis-hydroxamide, on thyroid carcinoma cell lines, including lines originating from anaplastic and medullary carcinomas. In these models, both SAHA and m-carboxycinnamic acid bis-hydroxamide induced growth arrest and caspase-mediated apoptosis and increased p21 protein levels, retinoblastoma hypophosphorylation, BH3-interacting domain death agonist cleavage, Bax up-regulation, down-regulation of Bcl-2, A1, and Bcl-x(L) expression, and cleavage of poly(ADP-ribose) polymerase and caspase-8, -9, -3, -7, and -2. Transfection of Bcl-2 cDNA partially suppressed SAHA-induced cell death. SAHA down-regulated the expression of the apoptosis inhibitors FLIP and cIAP-2 and sensitized tumor cells to cytotoxic chemotherapy and death receptor activation. Our studies provide insight into the tumor type-specific mechanisms of antitumor effects of HDAC inhibitors and a framework for future clinical applications of HDAC inhibitors in patients with thyroid cancer, including histologic subtypes (e.g., anaplastic and medullary thyroid carcinomas) for which limited, if any, therapeutic options are available.

Antineoplastic Agents↗
PubMed2005

Novel biological therapies for the treatment of multiple myeloma.

The therapeutic management of multiple myeloma (MM) for the last several decades has mainly involved regimens based on use of glucocorticoids and cytotoxic chemotherapeutics. Despite progress in delineating the activity of such regimens, at either conventional or high doses, MM has remained an incurable disease, without substantial improvement in the median overall survival. This has sparked major interest in the development of novel therapies that in part capitalize on recent advances in our understanding of the biology of MM, including the molecular mechanisms by which MM cell-host bone marrow (BM) interactions regulate tumor-cell growth, survival, and drug resistance in the BM milieu. The development of in vitro and in vivo models of MM-stromal interactions has allowed not only for better characterization of these molecular phenomena but also for identification of specific therapeutic strategies to overcome these interactions and achieve an enhanced anti-MM effect, even against MM resistant to conventional therapies. Herein, we review the latest progress in the development of these novel anti-MM therapies, with major focus on therapies which have translated from preclinical evaluation to clinical application, including thalidomide and its more potent immunomodulatory (IMiD) derivatives, the first-in-class proteasome inhibitor bortezomib (formerly known as PS-341), and arsenic trioxide (As2O3).

Apoptosis Regulatory Proteins↗
PubMed2005

Proteasome inhibitors as therapeutics.

The ubiquitin-proteasome pathway is a principle intracellular mechanism for controlled protein degradation and has recently emerged as an attractive target for anticancer therapies, because of the pleiotropic cell-cycle regulators and modulators of apoptosis that are controlled by proteasome function. In this chapter, we review the current state of the field of proteasome inhibitors and their prototypic member, bortezomib, which was recently approved by the U.S. Food and Drug Administration for the treatment of advanced multiple myeloma. Particular emphasis is placed on the pre-clinical research data that became the basis for eventual clinical applications of proteasome inhibitors, an overview of the clinical development of this exciting drug class in multiple myeloma, and a appraisal of possible uses in other haematological malignancies, such non-Hodgkin's lymphomas.

Boronic Acids↗
PubMed2005

Human retinoblastoma cells are resistant to apoptosis induced by death receptors: role of caspase-8 gene silencing.

PURPOSE: Fas ligand (FasL) and TNF-related apoptosis-inducing ligand (TRAIL)/Apo2L are members of the TNFalpha family that can trigger apoptosis in susceptible cells via respective death receptors (DRs). FasL cross-links its receptor Fas, resulting in recruitment and proteolytic activation of caspase-8, which initiates the downstream apoptotic cascade. TRAIL signals through its receptors DR4 and DR5, which can activate caspase-8 as well. This study was undertaken to investigate the functional status of the FasL and TRAIL apoptotic pathways in retinoblastoma (Rb) cells. METHODS: The human Rb cell lines Y79 and WERI-Rb1 were evaluated for their response to the Fas cross-linking antibody CH11 and recombinant TRAIL, as well as for cell surface presence and mutational status of Fas, DR4, and DR5 by flow cytometry and genomic DNA sequencing, respectively. The expression of caspase-8 and its inhibitor FLIP, as well as their recruitment to the DR signaling complex were studied by immunoblot analysis. RESULTS: Rb cells express Fas, DR4, and DR5 on their surfaces, yet were resistant to DR-mediated apoptosis. This was not due to DR mutations or secretion of the soluble decoy Fas, antiapoptotic NF-kappaB activity, or FLIP overexpression, but to the absence of caspase-8 expression. The demethylating agent 5-aza-2'-deoxycytidine restored caspase-8 expression and sensitivity to DR-mediated apoptosis. CONCLUSIONS: Rb cells are resistant to DR-mediated apoptosis because of a deficiency in caspase-8 expression secondary to epigenetic gene silencing by overmethylation. The data help delineate the apoptotic pathways in Rb cells and suggest that the combination of demethylating agents with DR-activating modalities, such as TRAIL receptor monoclonal antibodies, may benefit patients with retinoblastoma.

Apoptosis↗
PubMed2005

Proteasome inhibition as a therapeutic strategy for hematologic malignancies.

The ubiquitin-proteasome pathway is a principal intracellular mechanism for controlled protein degradation and has recently emerged as an attractive target for anticancer therapies since several cell cycle regulators and modulators of apoptosis are degraded through this pathway. The current state of the field of proteasome inhibitors and their prototypic member, bortezomib, which was recently approved by the US Food and Drug Administration for the treatment of advanced multiple myeloma, is reviewed. Particular emphasis is placed on the preclinical research data that became the basis for eventual clinical applications of proteasome inhibitors, an overview of the clinical development of this exciting drug class in multiple myeloma, and an appraisal of possible uses in other hematologic malignancies, such as non-Hodgkin's lymphomas.

Boronic Acids↗
PubMed2005

Treatment of hematologic malignancies and solid tumors by inhibiting IGF receptor signaling.

Insulin-like growth factors (IGF) and their receptors (IGF-1R) constitute a complex biologic system implicated in diverse regulatory levels of cell proliferation, viability, differentiation and metabolism. Extensive epidemiologic data have implicated the IGF/IGF-1R pathway in the establishment of human malignancies, consistent with experimental data on the role of this signaling cascade in promoting cell transformation, resistance to apoptosis, metastases and other aspects of the biology of human cancers. However, historically, the IGF/IGF-1R pathway has not been viewed as an attractive target for therapeutic intervention. The widespread IGF-1R expression in normal tissues and its close homology to the insulin receptor had led to the assumption that IGF-1R inhibition would cause unacceptable toxicities in vivo. Even though neutralizing antibodies against human IGF-1R have been efficacious against xenograft tumors, a lack of reactivity against the host rodent receptor has confounded the assessment of its therapeutic index. Furthermore, the lack of a clear understanding of the relevant significance for neoplastic cells in the function of IGF-1R versus other growth factor receptors provided an additional disincentive for the study of this pathway. However, recent reports from the authors' group and others have shown that small molecule inhibitors of tyrosine kinase activity of IGF-1R can be safely and efficaciously administered in vivo in clinically relevant orthotopic models of human neoplasias, such as multiple myeloma. This article reviews the data that validated IGF-1R as a therapeutic target for a broad spectrum of malignancies and provides in vivo proof-of-concept for the use of selective IGF-1R kinase inhibitors as primary antitumor therapy or in synergistic combination as chemosensitizers. These results have not only provided the rationale for clinical trials of small molecule IGF-1R inhibitors, but have also rekindled interest in other therapeutic modalities (e.g., monoclonal antibodies) aimed at suppressing the function of this critical pathway for tumor cell pathophysiology.

Hematologic Neoplasms↗