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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↗
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↗
PubMed1996

Frequent deletion in the methylthioadenosine phosphorylase gene in T-cell acute lymphoblastic leukemia: strategies for enzyme-targeted therapy.

Methylthioadenosine phosphorylase (MTAP), an enzyme essential for the salvage of adenine and methionine, is deficient in a variety of cancers, including acute lymphoblastic leukemia (ALL). Because the MTAP gene is located adjacent to the tumor-suppressor gene p16 on chromosome 9p21 and more than 60% of T-cell ALL (T-ALL) patients have deletion in the p16 gene, we examined the status of the MTAP gene in T-ALL patients. Quantitative polymerase chain reaction amplification of exon 8 of MTAP showed a deletion in 16 of 48 (33.3%) patients at diagnosis and in 13 of 33 (39.4%) patients at relapse. Southern blot analysis showed that, in addition to deletion of the entire MTAP gene, a common break point was between exons 4 and 5, resulting in deletion of exons 5 through 8. The finding of frequent deficiency of MTAP in T-ALL offers the possibility of an enzyme targeted therapy for T-ALL. MTAP(-) T-ALL-derived cell line, CEM cells were very sensitive to methionine deprivation, with cell viability at 50% of control as early as 48 hours after methionine deprivation. In contrast, methionine deprivation had little effect on the viability of normal lymphocytes or on their proliferative response to phytohemagglutinin. Alanosine, an inhibitor of AMP synthesis, inhibited the growth of both MTAP(+) (Molt-4 and Molt-16) and MTAP(-) (CEM and HSB2) cell lines. However, the addition of methylthioadenosine, the substrate of MTAP, protected the MTAP(+) cells but not the MTAP(-) cells from alanosine toxicity. These findings suggest the possibility of targeting MTAP for selective therapy of T-ALL.

Adenosine Monophosphate↗
PubMed2005

[Targeted therapies in pediatric oncology: a new therapeutic approach?].

A multidisciplinary therapeutic approach has led to significant increase in survival of children with cancer, however often with a high rate of severe sequela. Better understanding in tumor cell biology and transformation process allowed to describe active tyrosine kinases (mainly growth factor receptors) as a new target for cancer treatment. This review presents 2 approaches to target receptor tyrosine kinase activity: on one hand, antibodies that target the extracellular domain, the natural ligand binding site, and on the other hand, small inhibiting molecules, such as imatinib, targeted against the activated intracellular receptor tyrosine kinase. We focus on their clinical development and current application in the treatment of childhood cancer. Targeted therapies are in full rise and new perspectives are explored, such as their association to other treatment modalities and the targeting of microenvironment. This new therapeutic approach necessitates well designed clinical trials that include relevant biomarkers to evaluate its real therapeutic potential.

Antineoplastic Agents↗
PubMed2004

Signal transduction pathways as novel therapy targets in lung cancer.

Cytotoxic therapy for lung-cancer patients has only moderately improved during the last decades. Simultaneously, efforts of intensive research to increase our understanding of the molecular basis of lung cancer have been undertaken. The cancer cell has been characterised by several genetic changes that lead to altered cellular functions. In addition, multiple factors of the cancer-cell environment further affect the tumour cell via various receptors and subsequent signaling pathways. The increased knowledge of cellular signaling offers the opportunity to develop novel substances that target specific pathway molecules. In the current review, some of the most essential receptors and signaling pathways involved in lung cancer will be described. In conjunction, examples of novel target-specific agents that have already found their way into clinical trials will be discussed.

Antineoplastic Agents↗
PubMed2000

Targeted therapies for the myeloid leukaemias.

Although the standard approach to myeloid leukaemias remains chemotherapy, the agents currently available rarely result in cure. Recent advances in understanding the biology of these disorders have lead to the development of targeted treatment strategies. In acute promyelocytic leukaemia (APL), all-trans retinoic acid (ATRA), sodium phenylbutyrate and arsenic trioxide are agents which either induce differentiation or apoptosis and have been used to successfully achieve remission. The tyrosine kinase inhibitor, STI-571, antisense oligonucleotides, and bcr-abl vaccines are strategies which focus on the oncogenic events in chronic myelogenous leukaemia (CML). Two anti-CD33 monoclonal antibody conjugates, Y90-HuM195 and CMA-676, have been used in acute myelogenous leukaemia (AML) and have shown some efficacy. Although the preliminary results with these targeted therapies are promising, further studies are needed to establish them as effective, less toxic alternatives to the current standard of care.

Animals↗
PubMed2006

Targeted therapies in solid tumors: monoclonal antibodies and small molecules.

The considerable progress in our understanding of the complex cellular, molecular, and genetic mechanisms underlying tumorigenesis over the last decade has fostered the development of novel and improved targeted therapies in cancer intervention. Because these therapies specifically interfere with signaling pathways essential for tumor cell proliferation, survival, and migration, they may be able to inhibit tumor growth and metastasis effectively, with fewer severe adverse events than seen with current chemotherapeutic interventions that have a narrow therapeutic index and are associated with severe toxic side effects. Monoclonal antibodies and protein tyrosine kinase inhibitors represent two classes among these promising new therapeutic interventions. This review discusses the advantages, limitations, and potential of monoclonal antibodies and protein tyrosine kinase inhibitors, and offers a perspective on the requirements and goals likely to propel the design of additional anticancer agents in the future.

Antibodies, Monoclonal↗
PubMed2003

HER-2-targeted therapy: lessons learned and future directions.

HER-2 is overexpressed in 20-25% of invasive breast cancers and is associated with an aggressive tumor phenotype and reduced survival rates. The HER-2 status of a tumor is the critical determinant of response to the HER-2-targeted antibody trastuzumab. Thus, accurate assessment of HER-2 expression levels is essential for identifying breast cancer patients who will benefit from HER-2-targeted therapy. Trastuzumab combined with chemotherapy increases response rates, time to progression, and survival. However, the majority of cancers that initially respond to trastuzumab begin to progress again within 1 year. This minireview describes HER-2 targeting strategies currently in use or in stages of development for the treatment of breast cancer.

Antibodies, Monoclonal↗
PubMed2026

Exploring Genetic Therapies Targeting Amyotrophic Lateral Sclerosis in Animal Models: A Systematic Review and Meta-Analysis.

BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a rare, neurodegenerative disease, for which there is currently no known cure. ALS primarily affects motor neurons, with rapid deterioration, meaning symptoms develop quickly, from problems with speech and muscle weakness to breathing issues and paralysis. This systematic review aimed to explore the preclinical efficacy of various genetic therapies used to target ALS using in&#xa0;vivo rodent models. METHODS: In vivo studies of genetic therapies targeting ALS and its symptoms published between January 2015 and December 2025 were included in this review. The following databases were used: Web of Science, Scopus and PubMed. The primary outcome investigated was the total number of motor neurons, with secondary outcomes of rodent survival and muscle function by observing rotarod performance also being analysed. The SYRCLE tool was used to assess risk of bias in included studies. RESULTS: Of the 451 studies identified by searching the databases, 53 studies were found to be eligible for this systematic review. The articles were divided into subcategories depending on the gene target of each therapy. Meta-analysis of outcomes within appropriate studies showed significant improvements for the majority of selected outcomes (p&#x2009;<&#x2009;0.05), favouring genetic therapy intervention. CONCLUSIONS: Results suggest that genetic therapies in rodent models targeting ALS are effective. However, due to a high risk of bias in preclinical studies, further high-quality studies are warranted to support this conclusion and onward translation into the clinic.

Animals↗
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↗
PubMed2004

[Targeted therapies: last focus on EGF receptor inhibitors in breast cancer].

EGF receptor is slightly expressed in breast cancer without any sufficiently impact on patient outcome. Nevertheless determination of EGFR level represents a certain interest in order to orientate a targeted therapy notably in the case of hormone therapy resistance. Based on preclinical findings, preliminary clinical study results confirms in vitro observations about the possibility to encompass the hormonotherapy or anti-HER2 resistance. But, future large clinical trials are necessary to redefine a new strategy to treat breast cancer patients.

Antibodies, Monoclonal↗
PubMed2005

Molecularly targeted therapy for pediatric brain tumors.

Treatment of pediatric brain tumors remains a challenge because of the toxicity associated with conventional treatment and the relative resistance of tumors at the time of recurrence. The traditional approach of administering cytotoxic agents at the maximum tolerated dose is being supplanted by the development of molecularly targeted agents aimed at critical cellular changes that are responsible for the growth and spread of cancer cells. These agents theoretically should be more specific for tumor cells and less toxic to normal cells. While the idea of targeted therapy has generated much excitement in the oncology community, the degree of benefit to patients with central nervous system (CNS) tumors remains unclear. Numerous challenges remain in the development of these agents, including identification of meaningful targets, delivery of agents in sufficient quantity at the target site, and determination of any biologic response to these agents. This article discusses the rationale behind several of these agents and their use in pediatric patients with brain tumors.

Antineoplastic Agents↗
PubMed2005

VEGF-targeted therapy in metastatic renal cell carcinoma.

PURPOSE: To review the biology of renal cell carcinoma (RCC) and the clinical results of vascular endothelial growth factor (VEGF) blockade in metastatic RCC. METHODS: A review of relevant published literature regarding VEGF, von Hippel-Lindau (VHL) gene inactivation, and VEGF overexpression in RCC was performed. Further, a review of the mechanism, toxicity, and clinical development of VEGF-targeted therapy in metastatic RCC was undertaken. RESULTS: VHL tumor suppressor gene inactivation is observed in the majority of clear cell RCC cases, leading to VEGF overexpression. Therapy with agents directed against the VEGF protein or the VEGF receptor have demonstrated initial clinical activity in metastatic RCC. CONCLUSIONS: Therapeutic targeting of VEGF in RCC has strong biologic rationale. Substantial clinical activity has been reported in initial clinical trials with VEGF-targeting agents. Further investigation is needed to optimally use these agents for maximal clinical benefit.

Carcinoma, Renal Cell↗
PubMed2006

Use of novel second-line targeted therapies in non-small cell lung cancer.

Non-small cell lung cancer (NSCLC) is the leading cause of cancer death in the United States and throughout the world. This is largely because more than half of lung cancer cases present as metastatic disease, making local therapy for cure impossible. The last decade has seen significant improvement in first-line treatment of NSCLC, including the use of new chemotherapeutic agents with more effective therapeutic profiles. However, standard cytotoxic regimens are still limited and it remains critical to better understand and develop new treatment options for refractory disease. This has included some new second-line therapeutic approaches and has led to a focus on molecular targeted therapy, including agents that block the epidermal growth factor receptor (EGFR) or angiogenesis. EGFR-targeted agents such as gefitinib, erlotinib, and cetuximab have been successfully used for NSCLC treatment, with studies reporting overall response rates of 18.4%, 8.9%, and 3.3%, respectively. Angiogenesis inhibitors such as bevacizumab and ZD6474 have also improved treatment outcome. Bevacizumab had an overall response rate of 27% when used in combination with paclitaxel and carboplatin, and ZD6474 had an overall response rate of 26% when used in combination with docetaxel. Using these compounds alone or in combination may improve the survival and quality of life of patients with lung cancer in the refractory setting.

Angiogenesis Inhibitors↗
PubMed1994

[Target therapy by monoclonal antibody against ovarian carcinoma conjugated with liposomes and adriamycin].

Conjugates of monoclonal antibody COC166-9 and adriamycin entrapped in liposome (MLA) were prepared in our laboratory. In vitro growth inhibition of SKOV3 ovarian carcinoma cell line was carried out by MLA and controls. Target therapies by MLA, adriamycin, normal mouse IgG instead of MAb, and control were given for 24 nude mice models with subcutaneous human ovarian carcinoma xenografts and 16 ascitic ovarian carcinoma respectively. MLA group showed the best therapeutic effect than all the other groups which gave a helpful clue to clinical use.

Animals↗
PubMed2003

Role of targeted therapy in non-small cell lung cancer: hype or hope?

New cytotoxic therapies, including the taxanes, gemcitabine (Gemzar), vinorelbine (Navelbine) and irinotecan (Campto), have improved treatment outcome and expanded treatment options in advanced non-small cell lung cancer. However, despite their promise, a therapeutic plateau with response rates of 20-30% and 1-year survival rates of 30-40% has been reached. It is doubtful if exchanging one agent for another in various combinations will lead to any significant improvement. The thrust of current research focuses on targeted therapy and its careful integration into the standard treatment paradigm. These agents include compunds targeted at growth factor receptors, angiogenesis, cyclooxygenase, farnesyl transferase and protein kinase C-alpha. Preclinical models have demonstrated synergy for many of these agents in combination with either chemotherapy or radiation, although clinical challenges exist. These include the identification of an optimal biologic dose, the proper integration of these agents into systemic chemotherapy regimens, and selecting the best setting in which to test the compounds.

Antineoplastic Agents↗
PubMed2002

Targeted therapy in non-small-cell lung cancer.

Although treatment of advanced non-small-cell lung cancer has been improved with the availability of such new agents as the taxanes, topoisomerase inhibitors, vinorelbine (Navelbine), and gemcitabine (Gemzar), platinum-based combination therapy has appeared to reach a threshold of therapeutic effectiveness. A paradigm shift in approach to non-small-cell lung cancer and other tumors may be heralded by the development of agents targeting specific biologic pathways in tumor development. Such new agents include antibody epithelial growth factor receptor (EGFR) inhibitors (eg, the monoclonal antibodies trastuzumab [Herceptin] and cetuximab [IMC-C225, Erbitux]) and EGFR tyrosine kinase inhibitors (eg, ZD1839 [Iressa] and OSI-774), angiogenesis inhibitors (eg, matrix metalloproteinase inhibitors), vascular endothelial growth factor (VEGF) inhibitors (eg, monoclonal antibody to VEGF ligand and small-molecule tyrosine kinase), and signal transduction inhibitors (eg, ISIS-3521, an antisense oligonucleotide to protein kinase C-alpha). A number of these agents have entered advanced-phase clinical investigation. It is likely that targeted therapy will have applications in combination with cytotoxic chemotherapy or radiation therapy at all stages of treatment, including maintenance therapy. It is even possible that these new biologic therapies will be used together as rational combinations (based on pathologic diagnosis) for advanced non-small-cell lung cancer.

Angiogenesis Inhibitors↗
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↗