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At least 1,009 records · Page 56Linked to original sources
PubMed2002

Mechanisms and future directions for angiogenesis-based cancer therapies.

Targeting angiogenesis represents a new strategy for the development of anticancer therapies. New targets derived from proliferating endothelial cells may be useful in developing anticancer drugs that prolong or stabilize the progression of tumors with minimal systemic toxicities. These drugs may also be used as novel imaging and radiommunotherapeutic agents in cancer therapy. In this review, the mechanisms and control of angiogenesis are discussed. Genetic and proteomic approaches to defining new potential targets on tumor vasculature are then summarized, followed by discussion of possible antiangiogenic treatments that may be derived from these targets and current clinical trials. Such strategies involve the use of endogenous antiangiogenic agents, chemotherapy, gene therapy, antiangiogenic radioligands, immunotherapy, and endothelial cell-based therapies. The potential biologic end points, toxicities, and resistance mechanisms to antiangiogenic agents must be considered as these therapies enter clinical trials.

Angiogenesis Inhibitors↗
PubMed2005

The realisation of targeted antitumour therapy.

Better understanding of the pathways regulating proliferation and metastasis of cancer cells has led to the development of novel molecular-targeted therapies. The number of molecular-targeted agents approved for use in the clinic is growing, with many more in clinical trials. Most of these compounds can be broadly classified into two main categories: monoclonal antibodies and small-molecule tyrosine kinase inhibitors. The pathological processes targeted include vascular endothelial growth factor-dependent tumour angiogenesis and epidermal growth factor receptor-dependent tumour cell proliferation and survival. Unlike conventional chemotherapy, molecular-targeted agents offer the potential advantages of a relatively high therapeutic window and use in combination with other anticancer strategies without overlapping toxicity. It is hoped that these drugs will become valuable therapeutic tools within the multimodal approach to treating cancer. Recent progress in targeted antitumour therapy is discussed, with a focus on antiangiogenesis.

Antibodies, Monoclonal↗
PubMed2000

Radioimmunoconjugates for targeted alpha therapy of malignant melanoma.

Effective targeted cancer therapy requires high selectivity and cytotoxicity. To this end we have prepared and tested a new alpha-emitting radioimmunoconjugate (RIC) against malignant melanoma. The melanoma antibody 9.2.27 is specific for most melanoma cell lines. This antibody was labelled with an a emitter, bismuth-213 (213Bi), and a positron emitter, terbium-152 (152Tb), which is an analogue of the alpha-emitting radioisotope terbium-149. The chelators cDTPAa (a cyclic anhydride of diethylenetriamine pentacetic acid) and CHX-A" (a 2-(p-SCN-Bz)-cyclohexyl-DTPA ligand) were used in order to obtain high labelling yields for both isotopes with either chelator. The labelling efficiency with 213Bi was found to be 96% and 92% with cDTPAa and CHX-A", respectively. With 152Tb it was 93% and 89%, respectively. Serum stability studies showed 20% leaching with 213Bi over a period of 2.5 half-lives. For 152Tb the leaching was 13%. There was no difference in the melanoma cell binding of the labelled and unlabelled antibodies. DNA synthesis data were compared for both isotopes with either chelator. Based on these results, the therapeutic activity ratio for 213Bi a particles and 152Tb positrons for the same endpoint was calculated to be 120. The stability of the bismuth and terbium RICs, together with the outstanding cytotoxicity of the alpha emitter, provides the basis for a new approach to the potential control of micrometastatic melanoma.

Antibodies, Monoclonal↗
PubMed2004

Finding a place for tumor-specific T cells in targeted cancer therapy.

A goal in cancer therapeutics is to develop targeted modalities that distinguish malignant from normal cells. T cells can discriminate diseased cells based on subtle alterations in peptides displayed in association with MHC molecules at the cell surface. Recent success using the adoptive transfer of tumor-specific T cells has fueled optimism that this approach may find a place as a targeted therapy for some human cancers.

Antigen-Presenting Cells↗
PubMed2003

Application of MINERVA Monte Carlo simulations to targeted radionuclide therapy.

Recent clinical results have demonstrated the promise of targeted radionuclide therapy for advanced cancer. As the success of this emerging form of radiation therapy grows, accurate treatment planning and radiation dose simulations are likely to become increasingly important. To address this need, we have initiated the development of a new, Monte Carlo transport-based treatment planning system for molecular targeted radiation therapy as part of the MINERVA system. The goal of the MINERVA dose calculation system is to provide 3-D Monte Carlo simulation-based dosimetry for radiation therapy, focusing on experimental and emerging applications. For molecular targeted radionuclide therapy applications, MINERVA calculates patient-specific radiation dose estimates using computed tomography to describe the patient anatomy, combined with a user-defined 3-D radiation source. This paper describes the validation of the 3-D Monte Carlo transport methods to be used in MINERVA for molecular targeted radionuclide dosimetry. It reports comparisons of MINERVA dose simulations with published absorbed fraction data for distributed, monoenergetic photon and electron sources, and for radioisotope photon emission. MINERVA simulations are generally within 2% of EGS4 results and 10% of MCNP results, but differ by up to 40% from the recommendations given in MIRD Pamphlets 3 and 8 for identical medium composition and density. For several representative source and target organs in the abdomen and thorax, specific absorbed fractions calculated with the MINERVA system are generally within 5% of those published in the revised MIRD Pamphlet 5 for 100 keV photons. However, results differ by up to 23% for the adrenal glands, the smallest of our target organs. Finally, we show examples of Monte Carlo simulations in a patient-like geometry for a source of uniform activity located in the kidney.

Algorithms↗
PubMed2004

Targeted photodynamic therapy via receptor mediated delivery systems.

Targeted photodynamic therapy (PDT) offers the opportunity of enhancing photodynamic efficiency by directly targeting diseased cells and tissues. While antibody-conjugates have received the most attention, cellular transformations offer numerous other potent targets to exploit during the delivery of photosensitizers (PSs) for PDT. Alterations in receptor expression, increased levels of specific cell surface membrane lipids and proteins as well as changes in the cellular microenvironment all occur in diseased cells. Along with other biochemical and physiological changes that occur during diseased and malignant cell transformation, these factors have been utilized in order to improve the efficacy of PDT. Attempts have been made to either increase the uptake of the dye by the target cells and tissues or to improve subcellular localization so as to deliver the dye to photosensitive sites within the cells. This review discusses various PS bioconjugates that utilize these factors and summarizes the results obtained to date.

Blood Proteins↗
PubMed2005

[Perspectives in biological modulation of radiotherapy].

Although the term "targeted therapy" is used to described new molecular approaches derived from the recent increase in the knowledge of cancer biology, radiation therapy is a "targeted therapy" used against cancer. Dose fractionation changes and time treatment duration modifications are used to specifically increase the anti tumor effects of ionising radiation while minimising normal tissue impact of these changes. The implementation of 3 dimensional radiation therapy and IMRT allowed specific tumor targeting and tumor radiation dose increase with normal tumor surrounding tissue relative protection. Clinical research has widely used those concepts with the development of hyper fractionation which showed positive results for head and neck tumours in clinical trials. The development of IMRT has allowed tumor dose escalation in the case of prostate cancer without significant increase in normal tissue toxicity. Beside these approaches, a better understanding of cancer biology and in particular of tumor radiation resistance mechanisms led to the identification of new molecular targets that could be used to increase the therapeutic ratio of radiation therapy. These approaches attempt to widen the therapeutic ratio of radiation, i.e. to increase specifically tumor radiation response with little impact on normal tissue response.

Cell Cycle↗
PubMed2026

A Biomimetic Dual-Targeting Nano-APA-Editor Reprograms the 3'UTR Landscape for Tongue Squamous Cell Carcinoma Therapy.

Targeting post-transcriptional dysregulation of tumor suppressors represents a new frontier in cancer therapy. Here, we identify the alternative polyadenylation (APA) regulator NUDT21 as a pivotal therapeutic target in oral squamous cell carcinoma (OSCC). NUDT21 is highly upregulated, correlating strongly with poor survival and advanced clinical stage. We outline a pathogenic mechanism whereby NUDT21 drives this phenotype by forcing a network of tumor suppressor transcripts, notably PTEN, into translationally-repressed, long-3'UTR isoforms. To therapeutically "re-engineer" this APA switch, we design a "Nano-APA-editor." This platform features an HMSN core with an sgRNA-NUDT21 payload and a hierarchical targeting strategy: a cancer-educated dendritic cell (DC) membrane for biomimetic camouflage and homotypic affinity, "gated" by a TA-aptamer for final precision. This system enables potent and selective NUDT21 silencing, driving a shift toward short-3'UTR isoforms. Consequently, the Nano-APA-editor effectively reinstates PTEN and associated suppressors and inhibits multiple malignant phenotypes in vitro. In an orthotopic OSCC model, it demonstrates profound tumor regression, outperforming conventional chemotherapy (PTX) with excellent biocompatibility. In vivo analysis confirmed target engagement (NUDT21-down) and functional restoration (PTEN-, WEE1-, TGF-β-up). This work validates a "post-transcriptional re-engineering" strategy, executed by a logically designed nanoplatform, as a powerful and safe modality for precision gene therapy.

Humans↗
PubMed2026

CircRNA-based CD19-targeted CAR-NK therapy for B-cell acute lymphoblastic Leukemia using a Coccidioides immitis-derived group II intron platform.

Chimeric antigen receptor (CAR)-T cell therapy targeting CD19 has demonstrated notable clinical efficacy in the treatment of B-cell acute lymphoblastic leukemia (B-ALL), but its wider clinical applicability is constrained by long manufacturing processes, substantial costs, and severe adverse events. A potentially safer and more accessible alternative is provided by CAR-Natural killer (CAR-NK) cell therapy. Currently, most CAR-NK cells are generated using viral transduction, which is labor-intensive and associated with risks of genomic integration. Electroporation of CAR-encoding mRNA provides a non-integrating alternative but results in only transient CAR expression. Circular RNA (circRNA), owing to its enhanced stability and prolonged protein expression capacity, has recently emerged as a promising alternative to linear mRNA. To overcome the limitations of transient mRNA expression, we generated circRNA using a Group II intron-mediated cyclization system incorporating a newly selected Coccidioides immitis-derived Group II intron. The newly established Coccidioides immitis-derived Group II intron circularization system efficiently generated circRNA and supported more durable EGFP expression than linear mRNA in both HEK293T and NK92 cells. Using this system, we successfully developed a circRNA-based CD19-targeted CAR-NK platform. CircRNA-engineered CD19-targeted CAR-NK92 cells maintained more durable CAR expression and showed stronger antitumor activity at later time points. In mouse models of B-ALL, circRNA-engineered CAR-NK92 cells demonstrated better tumor control and extended survival compared with their linear mRNA-engineered counterparts. These results support the potential of circRNA-based CAR-NK therapy as an effective approach for enhancing the safety and efficacy of cancer immunotherapy.

Humans↗
PubMed2006

Targeted molecular therapy of the PI3K pathway: therapeutic significance of PI3K subunit targeting in colorectal carcinoma.

OBJECTIVE: The phosphatidylinositol 3-kinase (PI3K) pathway promotes cancer cell proliferation and survival. The authors determined the pattern of distribution of PI3K pathway components (ie, the p85alpha regulatory subunit, p110alpha catalytic subunit, Akt1, Akt2, and the tumor suppressor PTEN) in human colorectal cancer. In addition, inhibition of in vitro proliferation and in vivo liver metastasis by p85alpha or p110alpha siRNA treatment was analyzed. SUMMARY BACKGROUND DATA: Small interfering RNA (siRNA) molecules suppress expression of target genes and may have therapeutic applications as target-specific therapies for cancer. Therefore, the purpose of this study was 2-fold: 1) to analyze the distribution pattern of PI3K pathway components in human normal colorectal cancers, and 2) to determine whether targeted inhibition of PI3K inhibits colon cancer growth in vitro and suppresses metastatic growth in vivo. METHODS: Immunohistochemical analysis was performed on colorectal adenocarcinomas and adjacent normal mucosa for PI3K pathway components, including p85alpha, p110alpha, Akt1, Akt2, and the tumor suppressor PTEN, which inhibits PI3K. HT29 and KM20 human colon cancer cells were treated with siRNA directed to p85alpha or p110alpha, and cell viability and apoptosis assessed. HT29 cells, transfected with a plasmid containing green fluorescent protein (GFP), were injected into the spleen of athymic nude mice to establish liver metastases; mice were randomized to receive either nontargeting control (NTC), p85alpha or p110alpha siRNA. RESULTS: PI3K pathway components p85alpha and Akt2 were highly expressed in glandular elements of colon cancers, with a correlation between staining intensity and clinical stage; PTEN expression was decreased in the colon cancers of all stages. PI3K-specific siRNA treatment decreased cell viability in vitro and suppressed metastatic tumor growth in vivo. CONCLUSIONS: Selective targeting of PI3K pathway components may enhance the effects of standard chemotherapeutic agents and provide novel adjuvant treatment of selected colorectal cancers.

Adult↗
PubMed2000

Adenosine deaminase deficiency as the first target disorder in gene therapy.

In the past decade, the advent of gene therapy has been acclaimed as a revolutionary medical intervention, embraced with great enthusiasm. However, recent disappointing results of the considerable clinical trials have also clearly demonstrated that such an initial expectation was an overestimation of gene therapy. There are only a few successful cases despite the 3000 patients who have been treated with various forms of gene therapy. Gene therapy for severe combined immunodeficiency (SCID) caused by adenosine deaminase (ADA) deficiency is one of the few such cases where results have been promising. In particular, peripheral T-lymphocytes-directed gene therapy provides further immunological improvements for patients with ADA-SCID receiving the PEG-ADA treatment whereas gene therapy targeting haematopoietic stem cell has so far proved insufficient for clinical benefits. This report will review crucial problems elucidated in the past five clinical trials for ADA-SCID and gives an outline of the next generation of stem cell gene therapy in Japan.

Adenosine Deaminase↗
PubMedDate not supplied

Antibody therapy for breast cancer.

Targeted therapies against tumor biological properties are an essential part of individualized therapy concepts in breast cancer. Next to risk-adapted strategies using conventional chemo- and/or endocrine therapies, antibody therapy has become an additional option. The humanized monoclonal antibody trastuzumab (Herceptin) is the first novel targeted therapy approved for routine clinical application in advanced breast cancer. Patients with HER2/neu protein overexpression as assessed by immunohistochemistry (IHC) and/or gene amplification as assessed by fluorescence in-situ hybridization (FISH) in their tumors respond well to palliative trastuzumab therapy, either as single agent or in combination with chemotherapy. New combinations with endocrine therapy are currently being evaluated in clinical trials. Trastuzumab therapy is generally well-tolerated. So far, considerable cardiotoxicity was seen only in combination with doxorubicin. Thus, extensive cardiomonitoring is now performed in trials assessing further chemotherapeutic partners. Clinical trials looking at early trastuzumab therapy in the adjuvant (e.g. HERA, BOND 006) or neoadjuvant (e.g. TECHNO) setting are still open for recruitment in Germany. Since only about those 25 % of breast cancers which are HER2/neu-positive are eligible for trastuzumab, novel targeted therapeutics for the remaining HER2/neu-negative tumors are needed. Another therapeutic antibody, 2C4 (Pertuzumab, Omnitarg), is currently under clinical evaluation. It binds to a different epitope on HER2/neu than trastuzumab and inhibits heterodimerization with other HER receptors. Phase I data showed that 2C4 is well tolerated and clinically active.

Antibodies, Monoclonal↗
PubMed2001

[Progress in targeting gene therapy].

In recent years the research on targeting in gene therapy has made much exciting progress. Many new technologies show great promising prospects such as the delivery of therapeutic gene to targeted cells by some antibodies or ligands, the use of specific gene promoter to tightly control gene expression within disease microenvironment, the use of some orally taken drugs for regulating expression time and expression level of DNA, and the targeted correction of deleted or mutated gene using RNA/DNA oligonucleotides. Yet, researchers still have a long way to go in order to reach the goal of applying the targeting gene therapy in clinical practice.

Gene Expression↗
PubMed2025

Genomic and Transcriptomic Landscape of Epstein-Barr Virus-Positive Inflammatory Follicular Dendritic Cell Sarcoma: A Multicenter Study.

Epstein-Barr virus (EBV)-positive inflammatory follicular dendritic cell sarcoma (EBV+ IFDCS) is a rare indolent malignant neoplasm, which occurs almost exclusively in the liver or spleen and may arise from a common EBV-infected mesenchymal cell that differentiates along the follicular or fibroblastic dendritic cell pathway. Despite its rarity, it presents a pressing need for an improved understanding of its genetic underpinnings and potential treatment strategies for recurrent or disseminated cases. To address this, we conducted comprehensive whole-exome sequencing and transcriptome sequencing (mRNA-seq) analyses on 31 and 6 cases of EBV+ IFDCS, respectively, collected from multiple centers in China. We also compared the genetic features of EBV+ IFDCS with those of other EBV-associated malignancies. Our analyses revealed a relatively high somatic mutation rate and widespread copy number variations affecting the major histocompatibility complex-I/II in EBV+ IFDCS. Integrated mutational profiling identified key signaling pathways involved in epigenetic regulation, NF-κB signaling, RTK/RAS/PI(3)K, and the Hippo pathway. Furthermore, we identified several frequently altered genes that could serve as potential therapeutic targets in EBV+ IFDCS. Transcriptomic analysis unveiled significant upregulation of pathways related to virus infection, immune responses, and multiple immune checkpoint genes in EBV+ IFDCS. Comparative analysis demonstrated clear genetic distinctions between EBV+ IFDCS and other EBV-associated tumors. In conclusion, our study provides comprehensive insights into the unique genomic and transcriptomic landscape of EBV+ IFDCS. We have identified multiple genetic alterations that likely contribute to the development and progression of this malignancy. Our results suggest that targeted therapy and immune checkpoint inhibitors may hold promise as potential therapeutic approaches for patients with recurrent or disseminated EBV+ IFDCS.

Humans↗
PubMed2001

Drug-targeting strategies in cancer therapy.

Genetic changes in cell-cycle, apoptotic, and survival pathways cause tumorigenesis, leading to significant phenotypic changes in transformed cells. These changes in the tumor environment - elevated expression of surface proteases, increased angiogenesis and glucuronidase activity - can be taken advantage of to improve the therapeutic index of existing cancer therapies. Targeting cytotoxics to tumor cells by enzymatic activation is a promising strategy for improving chemotherapeutics.

Antineoplastic Agents↗
PubMedDate not supplied

Postoperative chemoradiotherapy of pancreatic cancer: what is the appropriate target volume of radiation therapy?

AIMS AND BACKGROUND: To evaluate the influence of radiation therapy target volume on the treatment outcome of adjuvant chemoradiotherapy for pancreatic cancer after curative resection. METHODS: Between February 1987 and July 2001, 70 patients treated with curative resection and adjuvant chemoradiotherapy for pancreatic adenocarcinoma were analyzed. There were 49 males and 21 females, with a median age of 57 years. Whipple's operation was performed in 44 patients, pylorus-preserving pancreaticoduodenectomy in 14, distal pancreatectomy in 9, and subtotal pancreatectomy in 3. Postoperative adjuvant radiotherapy was given up to 40 Gy at 2 Gy per fraction with a two-week planned rest. Intravenous 5-fluorouracil (500 mg/m2/day) was given on days 1 to 3 of each split course of radiotherapy. Until 1991, whole pancreas or preoperative tumor volume and retroperitoneal lymph nodes were irradiated (extended field, n=14). Thereafter, the target volume included the retroperitoneal lymph nodes and the involved pancreatic resection margin (limited field, n=56). The median follow-up period of all the patients was 16 months (range, 2-99). RESULTS: The overall 2- and 5-year survival rate of all patients was 29.7% and 14.0%, respectively. According to the radiotherapy target volume, the median survival time was 14 months in the extended field group and 16 months in the limited field group (P = 0.65). CONCLUSIONS: From the viewpoint of the target volume of radiotherapy, a limited field did not worsen the treatment outcome, although the survival rate was poor in both groups.

Adenocarcinoma↗
PubMed2005

Targeted CML therapy: controlling drug resistance, seeking cure.

Targeted cancer therapy with imatinib (Gleevec) has the capability to drive chronic myeloid leukemia (CML) into clinical remission. Some patients, particularly those with advanced disease, develop resistance to imatinib. To counteract this problem, two new BCR-ABL kinase inhibitors for imatinib-refractory disease are currently in clinical trials: the imatinib derivative AMN107 and the dual-specificity SRC/ABL inhibitor dasatinib. Using imatinib to reduce leukemic burden also facilitates the detailed investigation into how the persistence of CML disease depends on BCR-ABL signaling, particularly within the leukemic stem cell compartment. Mathematical models of drug resistance and disease relapse, in addition to experimental systems that recapitulate crucial aspects of advanced disease have deepened our understanding of CML biology. Together, these advances are contributing to a high level of disease control, and might ultimately lead to disease eradication.

Antineoplastic Agents↗
PubMed2006

Overview of dosimetry for Systemic Targeted Radionuclide Therapy (STaRT).

The purposes of systemic targeted radionuclide therapy dosimetry include compiling a database of normal organ radiation-absorbed doses that are carrier- and radionuclide-specific, and assuring that the normal organ radiation doses are within a safe range before therapy. Also of importance is quantitation of radiation delivery to tumors vs. normal tissues to correlate absorbed dose with tumor control. For agents with significant and variable excretion, estimates of individual patient distribution/clearance may be needed to optimize the dose-response relationship.

Brain↗