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Results for “Molecular Targeted Therapy”

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PubMed2003

[Current screening for molecular target therapy of cancer].

Recent progress in molecular biology and cancer biology has revealed that many molecules, which are heavily involved in the un-limited growth, anti-apoptotic effects and invasion of tumors, would be targets of cancer therapy. Part of the drugs which inhibit these molecules have shown clinical response as well as clinical benefits. In this review article, the summary of mechanism based drug screening for cancer as well as recent status of new molecular target drugs for cancer, are described.

Angiogenesis Inhibitors↗

PubMed2004

Imatinib mesylate (Gleevec/Glivec) a molecular-targeted therapy for chronic myeloid leukaemia and other malignancies.

Imatinib mesylate (Gleevec/Glivec, Novartis, Basel, Switzerland), formerly called STI571, is a specific and potent inhibitor of the BCR-ABL tyrosine kinase, the molecular hallmark of chronic myeloid leukaemia. Several clinical trials have demonstrated the efficacy of imatinib in different phases of this disease. On the other hand, imatinib is also active against other tyrosine kinases, such as ABL, the stem cell factor receptor (c-kit) and the platelet-derived growth factor receptor, whose inhibition might have potential implications for the treatment of several malignancies. In this regard, imatinib has already shown a remarkable activity in patients with hypereosinophilic syndrome and gastrointestinal stromal tumours. Imatinib is an example of how a better understanding of the pathogenetic mechanisms of a neoplastic disease can lead to the development of a molecular-targeted therapy.

Antineoplastic Agents↗

PubMed2003

Platinum-taxane combinations in metastatic breast cancer: an evolving role in the era of molecularly targeted therapy.

Metastatic breast cancer is a partially chemotherapy-sensitive neoplasm. Docetaxel appears to be the most active single agent for this condition. The platinum coordination complexes are also active, but are seldom used. An emerging literature suggests that taxane-platinum combinations have substantial activity. Trastuzumab, a molecularly targeted therapy for metastatic breast cancer is active as a single agent in HER2-overexpressing disease, and has been demonstrated to augment the activity of other agents in random assignment trials. Preclinical data suggest a powerful synergistic interaction between trastuzumab and both platinum and docetaxel. In early trials, platinum-taxane-trastuzumab combinations have exhibited promising clinical activity. The potential for cardiac toxicity when trastuzumab is combined with the anthracyclines suggests a further rationale for the development of non-anthracycline regimens, especially in the adjuvant setting. Randomized, multicenter, phase III trials in the metastatic and adjuvant setting are currently underway to test the hypothesis that synergistic combinations of docetaxel, platinums, and trastuzumab will result in superior safety as well as efficacy.

Antibodies, Monoclonal↗

PubMed2003

A successful case of oral molecularly targeted therapy with imatinib for peritoneal metastasis of a gastrointestinal stromal tumor.

Gastrointestinal stromal tumors (GISTs) are a group of neoplasms arising from mesenchymal stem cells of the gastrointestinal tract. The prognosis of metastatic or recurrent GISTs is poor, because these tumors resist chemotherapy and radiotherapy. We report a patient with recurrent GIST who underwent molecularly targeted therapy with imatinib, a novel oral tyrosine kinase inhibitor. A 50-year-old woman presented with a huge intra-abdominal mass. The patient had a history of gastrectomy for GIST and hepatectomy for its metastases. She also underwent surgery for resection of peritoneal metastases 9 months before. The abdominal mass was 26 x 17 x 12 cm in size, as determined by magnetic resonance imaging, and was diagnosed as a peritoneal relapse of GIST. Treatment with 400 mg of imatinib daily was started. After 1 week of treatment with imatinib, reduction of the abdominal tumor began to be recognized on palpation. Computed tomographic scanning on day 28 revealed that the tumor had liquefactively regressed and had reduced in size by 66%. The major side effect was leg edema, which was easily manageable with furosemide. The patient has been receiving imatinib treatment in our outpatient clinic, and the tumor regression has continued for 9 months. Imatinib shows promise as a safe and effective drug for the treatment of patients with recurrent GISTs.

Administration, Oral↗

PubMed2005

Novel molecular targeted therapy for esophageal cancer.

Esophageal cancers are highly lethal neoplasms which are generally refractory to conventional multidisciplinary interventions. Recent elucidation of the mechanisms of esophageal carcinogenesis, as well as preclinical studies utilizing chromatin remodeling agents and inhibitors of oncogene signaling in conjunction with conventional chemotherapeutic agents provide new opportunities for the development of potentially efficacious molecular targeted therapies for these malignancies.

Adenocarcinoma↗

PubMedDate not supplied

[Recent advances in molecular biology of central nervous system embryonal tumors and development of potential molecular targeted therapies].

Embryonal tumours constitute the largest group of malignant pediatric brain tumours. Their origin and histological classification is debated. Diagnosis is controversial and patients' response to therapy on the basis of morphologic appearance alone, is difficult to predict. Therefore accurate clinical staging remains a critical component of clinical management. In recent years real progress has been made in our understanding of the molecular genetic abnormalities that govern the initiation and/or progression of embryonal tumours. This review is focused on the principal molecular genetic abnormalities so far identified in embryonal brain tumours and discusses their possible biological and clinical applications in developing a molecular risk staging system which hopefully will lead to the molecular targeted therapies, curative non-toxic treatment for all children.

Brain Neoplasms↗

PubMed2002

New cytotoxic agents and molecular-targeted therapies in the treatment of metastatic breast cancer.

Cytotoxic chemotherapy is important for treatment of patients with hormone-insensitive advanced breast cancer. A variety of new cytotoxic agents are promising alone or in combination. The originality, the clinical activity and side effects, as well as the current development status of these agents are reviewed. These agents include the new antimicrotubules (analogues of taxanes and vinorelbine; epothilone derivatives), oral formulations of 5-fluorouracil and other antimetabolites (tomudex, alimta, gemcitabine), liposomal anthracyclines, platinum analogues, topoisomerase I inhibitors and other compounds such as ET-743. Finally, new molecular-targeted therapies of potential interest in the treatment of metastatic breast cancer are reviewed. The growing availability of such biological therapies given alone and mainly in combination with hormonal and chemotherapeutic agents may improve in the near future the outcome of patients with metastatic breast cancer.

Antineoplastic Agents↗

PubMed2004

Non-small cell lung cancer: from cytotoxic systemic chemotherapy to molecularly targeted therapy.

Surgery is the only method of cure in lung cancer. Seldom its application with radical intent is possible. Despite the efforts aimed at integrating all the therapeutic strategies, the overall outcome of the management of this disease remains disappointing. For this reason, in the last three decades, thousands of preclinical and clinical attempts have been realised in order to investigate any possible way to cure this disease and significant steps forward have been made on the basis of the increasing "molecular knowledge" in the so called "post-genomic era". Particularly the impressive step forward in the biological characterization of cancer as a result of genetic/epigenetic multistep process has brought in a multitude of variables with staggering classification potentialities. "Benchside" and "bedside" scientists have assembled in functional teams to move the common efforts "translationally" to bridge basic and clinical research for a mutual synergistic enhancement. This paper represents the effort of a lung cancer focused translational research team made up of molecular biologists, medical oncologists and thoracic surgeons to achieve a comprehensive, but simple, review of the current status of the shift from cytotoxic to molecularly targeted therapy in lung cancer treatment potentially useful in the planning of translational research trials.

Angiogenesis Inhibitors↗

PubMed2003

Imatinib mesylate: a molecularly targeted therapy for gastrointestinal stromal tumors.

Although their overall incidence is uncommon, gastrointestinal stromal tumors (GIST) are the most frequently encountered mesenchymal tumors of the GI tract. Their pathology has been recently defined by the presence of KIT (transmembrane receptor tyrosine kinase). The majority of GISTs have c-kit gain-of-function mutations mainly in exon 11 (highly conserved juxtamembrane region) that eventuates in constitutive activation of KIT, promoting proliferation and antiapoptotic signaling. Imatinib mesylate (Gleevec) is a specific inhibitor of KIT kinase activation, and in phase II clinical trials has proven to be remarkably efficacious in heavily pretreated GIST patients with advanced disease. The molecular and genomic determinants of response/resistance patterns are the subject of ongoing studies, and adjuvant studies are also under way. The initial evaluations of imatinib provide proof of concept for the hypothesis-driven design of selective molecularly targeted therapies for solid tumor malignancies.

Antineoplastic Agents↗

PubMed2005

[Molecular targeting therapy for leukemia by sphingolipid ceramide].

Ceramide has been recognized as a structural component to consist of the cell membrane. Since we reported that ceramide content increased in vitamin-D3-induced cell differentiation of human leukemia HL-60 cells, it has become evident that ceramide acts as an intracellular lipid mediator to transduce an extracellular stress into the cells. Ceramide is synthesized through serine-palmitoyl CoA transferase. Diversity of ceramide species derives from the changes of carbon length of fatty acid binding to amine part of sphingosine. A variety of stresses induce apoptosis through activation of pro-apoptotic signals as well as inhibition of antiapoptotic/survival signals by an increase of intracellular ceramide. Here, the recent problems and innovation in the medication of hematological malignancy are summarized, and it is suggested that the induction of apoptotic cell death by ceramide action is a potent, novel molecular targeting therapy for a chemoresistant and refractory hematological malignancy.

Apoptosis↗

PubMed2005

Molecularly targeted therapy in renal cell carcinoma.

Recent developments in the molecular biology of renal cell carcinoma have identified multiple pathways associated with the development of this cancer. Multiple strategies have been investigated targeting these pathways, with significant clinical benefits shown in early studies. This review aims to overview the findings of recent clinical trials and clarify the development of these compounds for use in renal cell carcinoma. The authors also aim to clarify the molecular pathways implicated in renal cell carcinoma and the clinical results in metastatic renal cell carcinoma with agents targeting these pathways. The relevant literature was reviewed concerning pathways implicated in the pathophysiology of renal cell carcinoma including pathways activated secondary to von Hippel-Lindau gene inactivation and PI-3 kinase/Akt/mammalian target of rapamycin pathway activation. Therapeutic targeting based upon underlying molecular biology in renal cell carcinoma has strong rationale. Substantial clinical activity has been reported with various agents targeting these pathways, most notably with vascular endothelial growth factor-targeted therapy. However, investigation is needed to optimally utilize these agents at the appropriate stage of disease and in the best combinations for maximal clinical benefit.

Animals↗

PubMed2004

[Tumor suppressor gene p53 and molecular targeting therapy].

p53 is a molecule which is activated upon a DNA stress, such as gamma irradiation, UV, hypoxia, virus infection, and DNA damage, leading protection of cells by inducing target genes. The molecules activated by p53 induce apoptosis, cell cycle arrest, and DNA repair to conserve genome. In order to kill cancer cells, many strategies targeting p53 have been reported. Preclinical studies have demonstrated that overexpression of wt-p53 by adenovirus vector is capable of inducing apoptosis in cancers. Furthermore, restoration of mt-p53 into wild type by compound has been under development. In this review, clinical application of molecular targeting therapy for p53 is discussed.

Apoptosis↗

PubMed2005

Disruption of fibroblast growth factor signal pathway inhibits the growth of synovial sarcomas: potential application of signal inhibitors to molecular target therapy.

PURPOSE: Synovial sarcoma is a soft tissue sarcoma, the growth regulatory mechanisms of which are unknown. We investigated the involvement of fibroblast growth factor (FGF) signals in synovial sarcoma and evaluated the therapeutic effect of inhibiting the FGF signal. EXPERIMENTAL DESIGN: The expression of 22 FGF and 4 FGF receptor (FGFR) genes in 18 primary tumors and five cell lines of synovial sarcoma were analyzed by reverse transcription-PCR. Effects of recombinant FGF2, FGF8, and FGF18 for the activation of mitogen-activated protein kinase (MAPK) and the growth of synovial sarcoma cell lines were analyzed. Growth inhibitory effects of FGFR inhibitors on synovial sarcoma cell lines were investigated in vitro and in vivo. RESULTS: Synovial sarcoma cell lines expressed multiple FGF genes especially those expressed in neural tissues, among which FGF8 showed growth stimulatory effects in all synovial sarcoma cell lines. FGF signals in synovial sarcoma induced the phosphorylation of extracellular signal-regulated kinase (ERK1/2) and p38MAPK but not c-Jun NH2-terminal kinase. Disruption of the FGF signaling pathway in synovial sarcoma by specific inhibitors of FGFR caused cell cycle arrest leading to significant growth inhibition both in vitro and in vivo. Growth inhibition by the FGFR inhibitor was associated with a down-regulation of phosphorylated ERK1/2 but not p38MAPK, and an ERK kinase inhibitor also showed growth inhibitory effects for synovial sarcoma, indicating that the growth stimulatory effect of FGF was transmitted through the ERK1/2. CONCLUSIONS: FGF signals have an important role in the growth of synovial sarcoma, and inhibitory molecules will be of potential use for molecular target therapy in synovial sarcoma.

Animals↗

PubMed2006

Modulation of Hsp90 function in neurodegenerative disorders: a molecular-targeted therapy against disease-causing protein.

Abnormal accumulation of disease-causing protein is a commonly observed characteristic in chronic neurodegenerative disorders such as Alzheimer's disease, Parkinson's disease, and polyglutamine (polyQ) diseases. A therapeutic approach that could selectively eliminate would be a promising remedy for neurodegenerative disorders. Spinal and bulbar muscular atrophy (SBMA), one of the polyQ diseases, is a late-onset motor neuron disease characterized by proximal muscle atrophy, weakness, contraction fasciculations, and bulbar involvement. The pathogenic gene product is polyQ-expanded androgen receptor (AR), which belongs to the heat shock protein (Hsp) 90 client protein family. 17-Allylamino-17-demethoxygeldanamycin (17-AAG), a novel Hsp90 inhibitor, is a new derivative of geldanamycin that shares its important biological activities but shows less toxicity. 17-AAG is now in phase II clinical trials as a potential anti-cancer agent because of its ability to selectively degrade several oncoproteins. We have recently demonstrated the efficacy and safety of 17-AAG in a mouse model of SBMA. The administration of 17-AAG significantly ameliorated polyQ-mediated motor neuron degeneration by reducing the total amount of mutant AR. 17-AAG accomplished the preferential reduction of mutant AR mainly through Hsp90 chaperone complex formation and subsequent proteasome-dependent degradation. 17-AAG induced Hsp70 and Hsp40 in vivo as previously reported; however, its ability to induce HSPs was limited, suggesting that the HSP induction might support the degradation of mutant protein. The ability of 17-AAG to preferentially degrade mutant protein would be directly applicable to SBMA and other neurodegenerative diseases in which the disease-causing proteins also belong to the Hsp90 client protein family. Our proposed therapeutic approach, modulation of Hsp90 function by 17-AAG treatment, has emerged as a candidate for molecular-targeted therapies for neurodegenerative diseases. This review will consider our research findings and discuss the possibility of a clinical application of 17-AAG to SBMA and other neurodegenerative diseases.

Age Factors↗

PubMed2006

Molecularly targeted therapies in myelodysplastic syndromes and acute myeloid leukemias.

Although there has been significant progress in acute myeloid leukemia (AML) treatment in younger adults during the last decade, standard induction therapy still fails to induce remission in up to 40% of AML patients. Additionally, relapses are common in 50-70% of patients who achieve a complete remission, and only 20-30% of patients enjoy long-term disease-free survival. The natural history of myelodysplastic syndrome (MDS) is variable, with about half of the patients dying from cytopenic complications, and an additional 20-30% transforming to AML. The advanced age of the majority of MDS patients limits the therapeutic strategies often to supportive care. To address these shortcomings, much effort has been directed toward the development of novel treatment strategies that target the evolution and proliferation of malignant clones. Presented here is an overview of molecularly targeted therapies currently being tested in AML and MDS patients, with a focus on FMS-like tyrosine kinase 3 inhibitors, farnesyltransferase inhibitors, antiangiogenesis agents, DNA hypomethylation agents, and histone deacetylase inhibitors.

Age Factors↗

PubMed2005

[Expression of Her2/neu in locally advanced bladder cancer: implication for a molecular targeted therapy].

PURPOSE: The Her2/neu oncoprotein, belonging to the erbB-receptor family, is known to contribute to physiological mechanisms of cell proliferation by intrinsic tyrosine-kinase-activity. Overexpression has been shown for several tumors and is known to influence malignant cell proliferation, metastasis and angiogenesis. The clinical use of Her2-targeting agents has emerged in clinical research. In our study, we analyzed Her2/neu expression in urothelial tumors. MATERIALS AND METHODS: Her2/neu expression was evaluated immunohistochemically (IHC) in 127 patients undergoing radical cystectomy (DAKO- Herceptest). Additionally, fluorescent-in-situ-hybridisation (FISH) was carried out in all immunohistochemically "2+" cases (n = 41) to assess gene amplification. After grading the Her2/neu-overall status, Her2/neu expression was correlated with clinicopathological parameters and survival data. RESULTS: An immunohistochemical Her2/neu expression was found in 95 of 127 cases (74.8 %). Of all 41 cases with "2+" staining (32.2 %), 11 cases (26.8 %) showed positive amplification by FISH. Therefore, including the IHC 3+ cases, a Her2/neu overall status of 22 positive (17.3 %) tumors was assessed. Correlation with clinical data showed a relation to lymph node metastasis (P = 0.06), lymph vessel invasion (P = 0.07) and metastasis (P = 0.002). No further associations with other parameters nor with overall survival (P = 0.73) or disease-free survival (P = 0.63) were found. CONCLUSIONS: Her2/neu upregulation is found in invasive bladder cancer with significant differences in protein expression and gene amplification. The association with lymphogenic and distant metastases implicates a late event in carcinogenesis. Moreover, there was no further association with clinicopathological parameters and survival. The possible role of a molecular targeted therapy of advanced bladder cancer with Her2/neu targeting agents should be assessed in further clinical trials.

Adult↗

PubMed2006

["Disease targeting therapy" for neurosurgical disorders: molecular targeting and drug delivery].

Recent progress in molecular biology introduced a concept of molecular targeting therapy against many diseases including neurosurgical disorders. Molecular targeting therapy is promising, because targeting a disease-specific molecule it may provide cure without inducing unfavorable side effects. Focusing mainly on CNS (central nervous system) malignancies, authors discuss the current development of molecular targeting therapy with a special concern to strategies using DNA, RNA, immunotoxin, and molecular selective inhibitors. Strategies using DNA include gene therapy and DNA vaccine. RNA interference (RNAi) is one of the promising molecular targeting strategies using RNA. Immunotoxins such as recombinant chimeric cytotoxin consisting of interleukin-13 and a truncated exotoxin produced by the Pseudomonas aeruginosa bacterium is now under clinical investigation. Many molecular targeted agents such as selective inhibitors for protein kinases are now in preclinical and clinical development for patients with malignant glioma. Additionally, authors introduce their attempts to visualize the local drug delivery using real-time MRI monitoring. Visualization of drug delivery, while achieving effective drug distribution using convection-enhanced delivery (CED), may also contribute to the disease targeting. These strategies together should help us develop the effective 'disease-targeting therapy' for CNS disorders.

Biotechnology↗

PubMed2004

[Novel angiogenesis inhibitors for molecular target therapy of cancer].

Angiogenesis, neovascularization from pre-existing vasculature, is essential to allow growth of primary solid tumors and to enable metastasis. Recent biological studies in both tumor and endothelial cells have begun to present a wide variety of molecular targets for developing angiogenesis inhibitors. Therefore, angiogenesis inhibitors including anti-angiogenic agents as well as anti-vascular targeting agents have become promising drugs in cancer chemotherapy. However current unsolved problems in anti-angiogenic therapy are the lack of surrogate markers for therapeutic efficacy, as well as of establishment of effective combinations with other therapeutic approaches including conventional anticancer therapy, radiotherapy, and immunotherapy. This article focuses on the promising drugs with anti-angiogenic activity and their molecular targets under clinical trials, as well as the significance of clinical evaluation for anti-angiogenic therapies.

Angiogenesis Inhibitors↗