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Results for “Molecular targeted therapy”

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At least 19 recordsLinked to original sources

PubMed2003

[Molecular therapy targets in lung cancer].

Molecular targeted therapies offer great hope in lung cancer because they are supposed to act upon biologic abnormalities specific to cancer cells. In the present review, we will describe the major pathways of tumor cell growth, apoptosis, angiogenesis and invasion as well as the targeted therapies interacting with these pathways. We will provide an overview of the trials involving targeted therapies in lung cancer, along with the specific problems related to the development of these new therapies.

Antineoplastic Agents↗

PubMed2006

Old and new perspectives in the pharmacological treatment of advanced or recurrent endometrial cancer: Hormonal therapy, chemotherapy and molecularly targeted therapies.

Hormonal therapy and chemotherapy play a major role in the management of advanced or recurrent endometrial cancer. Progesterone therapy obtains overall response rates ranging from 11% to 25% in patients with endometrioid-type tumours, and oral medroxyprogesterone acetate 200mg daily appears to be a reasonable therapeutic option for those lesions that are well differentiated and/or have a high progesterone receptor (PgR) content. However, the activity of progestins is often compromised by the down-regulation of PgR within the target tissues, and therefore therapeutic strategies designed to enhance PgR expression are warranted. Little data are currently available about the new aromatase inhibitors and selective estrogen receptor modulators. As for chemotherapy, the combination of doxorubicin [DOX]+cisplatin [CDDP] achieves overall response rates ranging from 34% to 60%, and the addition of paclitaxel (TAX) seems to improve response rates, progression-free survival and overall survival, but to worsen toxicity profile. A phase III study is currently comparing TAX+DOX+CDDP versus the less toxic combination of TAX+carboplatin. Chemotherapy is active against both endometrioid-type carcinoma and uterine serous papillary carcinoma. However, this latter endometrial malignancy is less chemosensitive than the histologically similar high-grade serous ovarian carcinoma. Interesting fields of research are represented by investigational agents directed against specific intracellular signal transduction pathways involved in the proliferation, invasiveness and metastatic spread of endometrial cancer. Mammalian target of the rapamycin (mTOR) inhibitors, epidermal growth factor receptor inhibitors (gefitinib, erlotinib, lapatinib, the monoclonal antibody cetuximab), imatinib, the monoclonal antibody trastuzumab, and the Clostridium perfrigens enterotoxin are currently under evaluation as molecularly targeted therapies for endometrial cancer. Further investigations addressed to better understand the signal transduction pathways that are disregulated in endometrial carcinogenesis could identify novel biological targets suitable for tailored therapies.

Antineoplastic Combined Chemotherapy Protocols↗

PubMed2004

Apoptosis induced by molecular targeting therapy in hematological malignancies.

Molecular targeting therapies for hematological malignant diseases such as monoclonal antibodies and small molecules have been reviewed. Imatinib mesylate (STI571) targets the tyrosine kinase activity of the BCR-ABL fusion protein in CML, and was superior to IFN-alpha plus low-dose cytarabine in newly diagnosed chronic-phase CML in a phase III randomized study. Imatinib induced apoptosis in BCR-ABL-positive cells in vitro, and activates several signaling pathways such as PI3K/Akt, STAT5 and Ras/MAPK. Combination therapies with imatinib and new strategies for downregulation of intracellular BCR-ABL protein levels have also been investigated from the phenomenon of resistance to imatinib. Anti-CD20 (rituximab) became the first monoclonal antibody approved for the treatment of a relapsed/refractory follicular/low-grade NHL and promising results were obtained from a phase III randomized study. Although antibody-dependent cell-mediated cytotoxicity and complement-mediated cytotoxicity are likely to be the major effectors of B-cell depletion in vivo, direct cytotoxicity by CD20 monoclonal antibody on B-cell lines in vitro has been reported. Anti-CD33 (Mylotarg) and FLT3 inhibitors for AML have also been used in clinical trials and signaling pathways induced by these agents are under intensive investigation. Arsenic trioxide, like all-TRANS-retinoic acid (ATRA), downregulates promyelocytic leukemia protein/retinoic acid receptor-alpha (PML/RARalpha) fusion protein and induced apoptosis in APL cells, and promising results were obtained from ATRA-resistant APL patients. Finally we show our promising in vitro and in vivo data of R-etodolac (a non-steroidal anti-inflammatory drug lacking cyclooxygenase inhibitor activity) against chronic lymphocytic leukemia (CLL) cells.

Antibodies, Monoclonal↗

PubMed2002

Treatment planning for molecular targeted radionuclide therapy.

Molecular targeted radionuclide therapy promises to expand the usefulness of radiation to successfully treat widespread cancer. The unique properties of radioactive tags make it possible to plan treatments by predicting the radiation absorbed dose to both tumors and normal organs, using a pre-treatment test dose of radiopharmaceutical. This requires a combination of quantitative, high-resolution, radiation-detection hardware and computerized dose-estimation software, and would ideally include biological dose-response data in order to translate radiation absorbed dose into biological effects. Data derived from conventional (external beam) radiation therapy suggests that accurate assessment of the radiation absorbed dose in dose-limiting normal organs could substantially improve the observed clinical response for current agents used in a myeloablative regimen, enabling higher levels of tumor control at lower tumor-to-normal tissue therapeutic indices. Treatment planning based on current radiation detection and simulations technology is sufficient to impact on clinical response. The incorporation of new imaging methods, combined with patient-specific radiation transport simulations, promises to provide unprecedented levels of resolution and quantitative accuracy, which are likely to increase the impact of treatment planning in targeted radionuclide therapy.

Antigens, Neoplasm↗

PubMed2003

[Target-based therapy against gastrointestinal stromal tumors--from molecular diagnosis to molecular target therapy].

Gastrointestinal stromal tumors (GIST) are composed of KIT-positive mesenchymal-origin spindle- or polygonal-shaped tumor cells in the gastrointestinal tract without immunoreactivity for desmin and S-100. The gain-of-function mutations in the c-kit gene (90%) or platelet-derived growth factor receptor alpha (PDGF-R alpha) gene (5%) are now considered to be causative for GIST. STI571 (Glivec), a molecule designed to selectively inhibit Bcr-Abl, KIT, and PDGF-R activity, shows high response rate and efficacy for non-resectable and/or relapsed GIST (PR 60%). Its serious adverse effects (more than Grade 3) were infrequent, thus, tolerability and safety are good. Glivec is the first successful case of molecular target therapy for solid tumors. However, new resistance against this new generation of drug is going to appear and becomes an urgent problem.

Antineoplastic Agents↗

PubMed2005

Renal cell carcinoma 2005: new frontiers in staging, prognostication and targeted molecular therapy.

PURPOSE: Renal cell carcinoma (RCC) has traditionally been staged using a purely anatomical staging system. Although current staging systems provide good prognostic information, data published in the last few years has led to significant controversies as to whether further revisions are needed and whether improvements can be made with the introduction of new, more accurate and predictive prognostic factors not currently included in traditional staging systems. This review highlights such controversies and provides an update on current staging modalities, prognostic factors and targeted molecular therapy for RCC. MATERIALS AND METHODS: A comprehensive review of the peer reviewed literature was performed on the topic of current staging modalities, validated prognostic factors, predictive nomograms, molecular markers and targeted molecular therapy for RCC. RESULTS: A staging system for malignant disease such as RCC uses various characteristics of tumors to stratify patients into clinically meaningful categories, which can be used to provide patients with counseling regarding prognosis, select treatment modalities and determine eligibility for clinical trials. The TNM staging system is currently the most extensively used one. However, it has undergone recent systematic revision due to rapidly emerging data from longer patient followup. The identification of various histological and symptomatic factors has led groups at many centers to develop more comprehensive staging systems that integrate these factors and include patients with metastatic and local disease. While integrated staging systems have improved RCC staging, the recent discovery of molecular tumor markers is expected to revolutionize RCC staging in the future and lead to the development of new therapies based on molecular targeting. CONCLUSIONS: Staging systems for RCC serve as a valuable prognostic tool. Several new patient and tumor characteristics have been reported to be important prognostic factors and they have been integrated into current staging systems. In addition, the field of RCC is rapidly undergoing a revolution led by molecular markers and targeted therapies. With this information urologists will be updated with the most current and comprehensive staging strategies, and be provided with a glimpse of the molecular and patient specific staging and treatment paradigms that will in our opinion transform the future management of this malignancy.

Biomarkers, Tumor↗

PubMed2003

[Molecular-targeted therapy].

This article reviews the concept of molecular-targeted therapy and the current development status of molecular-targeted agents for lung cancer. Epidermal growth factor receptor inhibitors have shown promising antitumor activity against cisplatin-resistant non-small cell lung cancer in phase II trials. Appropriate clinical evaluation of these agents and collaboration with basic researchers are essential for further development.

Antibodies, Monoclonal↗

PubMed2006

Molecular targeted therapy: a strategy of disillusions or optimism?

Cytotoxic drugs were designed to kill tumor cells, whereas agents of molecular targeted therapy inhibit various molecular functions of the tumor cell. Consequently, their toxicity profiles also differ. Molecular targeted agents, except for monoclonal antibodies, are enumerated here in three classes: compounds active extracellularly, extra/intracellularly, and intracellularly. Although no major breakthrough has occurred in the drug treatment of neoplastic diseases yet, such compounds as trastuzumab, cetuximab, bevacizumab, gefitinib, erlotinib, imatinib, and bortezomib have shown considerable clinical promise. Major obstacles to the further development of molecular targeted compounds are described. The use of different endpoints, positron emission tomography for evaluation, and predictive genetic markers are recommended. Combination therapy with cytotoxic drugs and studies in an adjuvant setting are also recommended. It is concluded that cautious optimism about the future of molecular targeted therapy is reasonable.

Antineoplastic Agents↗

PubMed2006

[Molecular-targeted therapy for hormone-refractory prostate cancer].

Molecular-targeted therapy is to treat pathologic pathways specifically in tumor cell or tumor microenvironment. Specific molecular-targeted therapeutic agents for hormone-refractory prostate cancer (HRPC) include endothelin-A receptor antagonist, EGF receptor (EGFR) inhibitor, platelet derived growth factor receptor (PDGFR) inhibitor, nuclear factor of kappaB (NF-kappaB) inhibitor, cyclooxygenase-2 (COX2) inhibitor, and active form of Vitamin D. These agents have been investigated in clinical trials. So far, none of the above-mentioned agent has shown a sufficient clinical efficacy alone. However, docetaxel-based combinations with thalidomide or calcitriol have promising clinical activities. Further investigations are needed to optimize the molecular-targeted agents in the combinations with chemotherapeutic agents for the treatment of HRPC.

Angiotensin Receptor Antagonists↗

PubMed2006

Side effects of anti-cancer molecular-targeted therapies (not monoclonal antibodies).

PURPOSE OF REVIEW: Major advances have been achieved in the field of biologically based therapies for cancer in the last few years, and some of the recently approved 'molecular-targeted therapies' are now being used in daily clinical practice. We aim to review some aspects of the toxicity and safety of small-molecule anti-cancer molecular-targeted therapies, with some insights into the physiopathology and predictive factors of toxicity, its correlation with response, and how to prevent and overcome it. RECENT FINDINGS: As a whole, small-molecule molecular-targeted therapies are well tolerated. Their toxic profile is favorable, but during the drug development process some severe (sometimes lethal) toxicities have been observed, such as interstitial lung disease in patients treated with drugs targeting the epidermal growth factor receptor. Pharmacogenomic studies can help us to identify those patients with well characterized polymorphisms, and to define the best-tolerated and most effective treatments. SUMMARY: Molecular-targeted therapies have a good toxicity profile in general; however, some patients are exquisitely sensitive to developing particular and severe toxicities related to these drugs.

Antineoplastic Agents↗

PubMed2003

Management of molecular-targeted therapy for chronic myelogenous leukemia.

PURPOSE: To provide primary care providers with guidelines on the evaluation and management of treatment for patients with chronic myelogenous leukemia (CML) with emphasis on the molecular-targeted therapy imatinib mesylate. DATA SOURCES: Research-based articles in the medical literature, review articles, and clinical practice guidelines. CONCLUSIONS: CML is a clonal stem cell disorder causing 5,000 new cases annually. Research on molecular-targeted therapy confirms that specific protein kinases have broad consequences for the development of future drugs to treat CML. The most recent discovery is a new compound, imatinib mesylate, which has become commercially available. Currently, the standard of care for CML is this agent. This therapy has changed management strategies for treatment of patients with the diagnosis of CML. IMPLICATIONS FOR PRACTICE: Long-term observations and evaluations are needed for final determination of treatment effectiveness; thus, primary care providers will follow patients with CML in the community. Unforeseen toxicity may surface, requiring accurate assessment and evaluation. Primary care providers will be actively involved with providing symptom management for these patients.

Antineoplastic Agents↗

PubMedDate not supplied

[Idiopathic hypereosinophilic syndrome: toward a new molecular-targeted therapy and a new cytomorphological and molecular definition].

Idiopathic hypereosinophilic syndrome is characterised by chronic hypereosinophilia leading to tissue damage, and after exclusion of reactive eosinophilia. Until recently no specific or efficient therapeutic was available. In 2003, a recurrent interstitial deletion 4q12 leading to the fusion of the FIP1L1 and PDGFRA genes was detected in hypereosinophilic syndromes. The resulting protein has constitutive tyrosine kinase activity which explains clinical and cytological remission of hypereosinophilic syndrome after treatment by a specific tyrosine kinase inhibitor, imatinib mesylate or Glivec, usually used in chronic myeloid leukaemia. Here we report a patient with hypereosinophilic syndrome associated to peculiar morphology of neutrophilic series and the 4q12 deletion. He presented clinical and haematological remission since the introduction of imatinib mesylate therapy.

Adult↗

PubMed2003

Basic science going clinical: molecularly targeted therapy of chronic myelogenous leukemia.

Imatinib (STI571), a 2-phenylaminopyrimidine, specifically inhibits the tyrosine kinase activity of Abl, Kit, and platelet-derived growth factor receptor. Clinical trials in chronic myelogenous leukemia (CML), characterized by the constitutively active Bcr-Abl tyrosine kinase, and gastrointestinal stromal tumors, characterized by activating mutations of Kit, have shown excellent results. This success is proof of principle for the concept of molecularly targeted therapy: rational treatment based on the recognition of the causal lesion responsible for malignant growth. In this manuscript, the preclinical and clinical development of imatinib for the treatment of CML will be reviewed. Room will be given to problems and challenges that may be typical of molecularly targeted therapy in general, such as the emergence of resistance as a result of point mutations. Last, the question will be addressed, why imatinib is so successful, and whether its success might be reproducible in other malignant conditions.

Animals↗

PubMed2004

Potential role of molecularly targeted therapy in the management of advanced nonsmall cell lung carcinoma in the elderly.

BACKGROUND: More than 50% of all lung carcinoma cases are diagnosed in patients age > 65 years, and approximately 30% are diagnosed in patients age > 70 years. Elderly patients do not tolerate chemotherapy as well as their younger counterparts do, primarily because of the increased prevalence of comorbid conditions and organ failure. Thus, at present, the majority of elderly patients with malignant disease do not receive aggressive chemotherapy. For such elderly patients, alternatives to conventional chemotherapy, such as novel molecularly targeted therapy regimens, are of interest. METHODS: The current review summarizes contemporary approaches to and recent advances in the treatment of elderly patients with nonsmall cell lung carcinoma (NSCLC) and offers perspectives on the future of molecularly targeted therapy in this population. Inhibitors of epidermal growth factor receptor, vascular endothelial growth factor, and cyclooxygenase-2 are discussed in the current report, with such inhibitors being, in our opinion, among the best candidates for clinical development in the setting of interest. RESULTS: Novel biologic agents with putative activity against advanced NSCLC are at various stages of clinical development. Some of these agents have yielded benefits in terms of disease-related symptom reduction, quality of life, and survival. For elderly patients, the potential advantages of such agents include improved tolerability compared with conventional chemotherapy. This feature also makes these novel agents attractive alternatives for younger patients who cannot tolerate or are reluctant to receive conventional chemotherapy. CONCLUSIONS: Current studies are investigating the safety and efficacy of these novel biologic agents administered alone, in combination with other noncytotoxic agents, and in combination with conventional chemotherapy. These studies will help elucidate the role of targeted therapy in the management of elderly patients with advanced NSCLC.

Angiogenesis Inhibitors↗

PubMed2001

ST1571, a tyrosine kinase inhibitor for the treatment of chronic myelogenous leukemia: validating the promise of molecularly targeted therapy.

The deregulated tyrosine kinase activity of the Bcr-Abl fusion protein has been established as the causative molecular event in chronic myelogenous leukemia (CML). Thus the Bcr-Abl tyrosine kinase is an ideal target for pharmacologic inhibition. ST1571 (formerly CGP57148B), is an Abl-specific tyrosine kinase inhibitor that in preclinical studies selectively kills Bcr-Abl-containing cells in vitro and in vivo. The results of clinical studies have demonstrated the potential of molecularly targeted therapies, and ST1571 is emerging as a new therapeutic agent for CML.

Antineoplastic Agents↗

PubMed2002

Signal transduction inhibitors (STI571): molecularly targeted therapy.

The therapy of chronic myeloid leukemia (CML), characterized by the presence of the Philadelphia chromosome in the clonal hematopoietic stem cells, has changed dramatically in the last year with the development of a specific inhibitor of the BCR-ABL tyrosine kinase. This medication, STI571 or imatinib, was recently approved by the Food and Drug Administration for CML patients refractory or intolerant to interferon. The medication has the potential to rapidly reverse the clinical and hematologic abnormalities of CML and is the paradigm of molecularly targeted therapy. STI571 is the first agent in Oncology that directly targets the molecular basis of a malignant disease, changing the way that we will treat these conditions in the future. This new field of molecular and cellular biology has the possibility of controlling not only malignant conditions but also diseases treated by other medical specialties.

Antineoplastic Agents↗

PubMed2003

Targeted molecular therapy of GBM.

Major advances in molecular biology, cellular biology and genomics have substantially improved our understanding of cancer. Now, these advances are being translated into therapy. Targeted therapy directed at specific molecular alterations is already creating a shift in the treatment of cancer patients. Glioblastoma (GBM), the most common brain cancer of adults, is highly suited for this new approach. GBMs commonly overexpress the oncogenes EGFR and PDGFR, and contain mutations and deletions of tumor suppressor genes PTEN and TP53. Some of these alterations lead to activation of the P13K/Akt and Ras/MAPK pathways, which provide targets for therapy. In this paper, we review the ways in which molecular therapies are being applied to GBM patients, and describe the tools of these approaches: pathway inhibitors, monoclonal antibodies and oncolytic viruses. We describe strategies to: i) target EGFR, its ligand-independent variant EGFRvIII, and PDGFR on the cell surface, ii) inhibit constitutively activate RAS/MAPK and PI3K/Akt signaling pathways, iii) target TP53 mutant tumors, and iv) block GBM angiogenesis and invasion. These new approaches are likely to revolutionize the treatment of GBM patients. They will also present new challenges and opportunities for neuropathology.

Animals↗

PubMed2004

[Inhibition of relapse in leukemia by using molecular targeting therapy].

Leukemias are generally chemosensitive, and a majority of leukemia patients undergo remission. However, since chemotherapy after remission generally causes gross systemic toxicity, patients cannot be administered enough anti-cancer drugs to be completely cured; thus, the rate of long-term disease-free survival remains low. Improved survival requires new strategies to prevent relapse. Molecular targeting therapies are remarkably specific and have been demonstrated to cause no gross systemic toxicity. Molecular targeting drugs for leukemia such as all-trans retinoic acid and imatinib are presently being used in clinical settings, and many other molecular targeting drugs are being evaluated in phase I/II clinical trials. This review presents an overview of some of these drugs.

Benzamides↗