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PubMed2001

Criteria for TNF-targeted therapy in rheumatoid arthritis: estimates of the number of patients potentially eligible.

Tumour necrosis factor (TNF) antagonists or blocking agents represent a major advance in the treatment of rheumatoid arthritis (RA), but their use raises economic concerns because of the high drug cost. Population-based patient registers with clinical data allow the estimation of the proportion of patients with RA who are eligible for TNF antagonist therapy according to recent consensus statements on TNF-targeted therapy. Data were derived from a representative county-based (500,000 population) register of patients with RA. Of 894 patients aged between 18 and 70 years, 636 (71%) [females 80%, mean (SD) age 53.6 (12.2) years and mean (SD) disease duration 12.2 (9.3) years] had a clinical and radiographic examination. The eligibility for TNF-targeted therapy was estimated from the following criteria: (i) previous or current therapy with at least one disease-modifying antirheumatic agent (DMARD); and (ii) active disease. Disease activity criteria were set to 28-swollen joint count (28-SJC) > or = 6, 28-tender joint count > or = 6, and erythrocyte sedimentation rate (ESR) > or = 28 mm/hour or C-reactive protein (CRP) > or = 20 mg/L. Sensitivity analyses were performed varying some of these disease activity parameters. Of the 636 patients, as many as 526 (83%) had previously or were currently using DMARDs and 98 (15%) fulfilled both the DMARD and activity criteria, thus being the maximum number of patients considered for TNF-targeted therapy. If the most stringent criteria were used (ever DMARD, 28-SJC > or = 12 and ESR > or = 50 mm/hour or CRP > or = 40 mg/L) only 15 of the 626 (2%) would be candidates for TNF-targeted therapy. In a population of 1 million, assuming a prevalence of 2000 patients with RA under the age of 70 years, the number of candidates for TNF-targeted therapy would be 40 to 300, depending on the disease activity criteria. Stringent ESR and CRP criteria would lead to a major reduction in the number of eligible patients. These utilisation data imply annual drug costs in the range of $US 480,000 to $US 3,600,000 for TNF antagonists for RA per 1 million population. Further economic evaluations are needed to determine for which groups such treatment is warranted from a health economics perspective.

Adolescent↗
PubMed1990

Preliminary trial of specific targeting therapy against malignant glioma.

The results of specific targeting therapy by use of lymphokine-activated killer (LAK) cells treated with bispecific antibody in 10 patients with malignant glioma were compared with the results of therapy with untreated LAK cells in 10 other patients. Both treated and untreated cells were given locally. The bispecific antibody was an anti-CD3 monoclonal antibody (mAb) chemically conjugated to anti-glioma mAb. Of the 10 patients given specific targeting therapy, 4 showed regression of tumour, and in another 4 patients computed tomography and histology suggested eradication of the glioma cells left behind after surgery. No recurrence was detected in the 10 to 18 months of follow-up. Patients receiving untreated LAK cells had recurrences within 1 year except in 1 case, and 8 patients died within 4 years. So far specific targeting therapy seems to be a new useful form of adoptive immunotherapy.

Adult↗
PubMed2004

New targeted therapies in breast cancer.

Targeted therapy for breast cancer has existed since 1986, when Beatson published his observations on oophorectomy. In the past 5 years monoclonal antibodies and tyrosine kinase inhibitors have been evaluated in phase I and II clinical trials of breast cancer. Trastuzumab (Herceptin; Genentech, Inc, South San Francisco, CA) was the first such agent to be approved by the US Food And Drug Administration, following findings that it improved survival in patients with metastatic breast cancer. Gefitinib (ZD1839, Iressa; AstraZeneca, Wilmington, DE) has little activity as a single agent in unselected patients, but, preclinical data have suggested synergy with tamoxifen and other hormonal agents, as well as other growth factor inhibitors. Bevacizumab (Avastin; Genentech, Inc), a monoclonal antibody against vascular endothelial growth factor is being evaluated in metastatic breast cancer. Furthermore, agents targeting other pathways, such as the Ras pathway with farnesyl transferase inhibitors, and mTOR with rapamycin analogues are currently under investigation. In the next few years, and as trials with the above agents mature, we will further define the role of these targeted agents in the treatment of breast cancer.

Alkyl and Aryl Transferases↗
PubMed2006

[Targeted therapies and radiotherapy in lung cancer].

Targeted therapies are now more often used in lung cancer. Inhibitors of EGFR and of angiogenesis have demonstrated a certain activity in this disease. Some experimental in vitro or in vivo studies are in favour of combined targeted therapies and radiation. For example, additive or supra-additive effects have been shown when inhibitors of the EGFR tyrosine kinase were given with radiation. In advanced lung cancer, the combination of bevacizumab with chemotherapy was demonstrated to produce better survival outcomes. But a high rate of fatal hemoptysis was reported with this drug, particularly for central and squamous tumors. This could be a limitation for its use in combination with radiation. Drugs with multiple targets are becoming available; their association with radiation seems to be promising.

Angiogenesis Inhibitors↗
PubMed2006

EGFR targeted therapy: view from biological standpoint.

Activating mutations in the kinase domain of the epidermal growth factor receptor (EGFR) in nonsmall cell lung cancers (NSCLCs) correlate with responsiveness to EGFR kinase inhibitors. In vitro cell culture studies have demonstrated that EGFR kinase domain mutants but not wild type (wt) EGFR are transforming and essential for cancer cell survival. We and others have recently demonstrated that the induction of EGFR kinase domain mutants specifically in murine lung epithelium in vivo led to development of adenocarcinoma with bronchioloalveolar carcinoma (BAC) features. These tumors depend completely on the sustained expression of EGFR kinase domain mutants for tumor maintenance. The murine tumors with EGFR kinase domain mutations are sensitive to EGFR targeted therapy similarly to NSCLC patients whose tumors harbor EGFR mutations. In contrast, initial results suggest that overexpression of wt EGFR in murine lungs does not seem to be transforming. We therefore divide EGFR targeted therapy in NSCLC patients into two parts: "EGFR mutant targeted therapy" and "wt EGFR targeted therapy". The "EGFR mutant targeted therapy" targets the oncogene essential for tumor initiation and maintenance and is frequently correlated with effective clinical outcome. In contrast, "wt EGFR targeted therapy" likely targets the proto-oncogene product wt EGFR, which is not directly involved in tumor initiation and maintenance, and in these cases, the response has been considerably less dramatic.

Adenocarcinoma↗
PubMedDate not supplied

Targeted therapies in breast cancer.

Targeted therapeutic agents in breast cancer are representing a larger proportion of new drugs entering clinical testing. Carcinogenesis is a multistep process characterized by genetic alterations that influence key cellular pathways involved in growth and development. Therefore, there are numerous opportunities for pharmacologic targeting. Hormonal therapy is the prototype of a treatment targeting hormone receptors, and this class of drugs still provides the greatest overall impact on outcome. Even though chemotherapy is considered a cytotoxic and nonspecific therapy, it does modulate many key cellular pathways and therefore shares characteristics of biologic drugs. It is clear that targeted therapies are going to play a greater role in improving survival and quality of life in advanced breast cancer, with trastuzumab (Herceptin) serving as a successful model that is a relatively nontoxic agent associated with survival benefits. However, several challenges to the successful identification and application of therapeutic targets remain. These include the dissection of complicated and interacting biologic pathways and the limitations of preclinical models that will allow for a better prioritization of which drugs and combinations will succeed best in the clinic. Better methods for selecting ideal candidates for therapy need to be based on known modes of action. Mechanisms of intrinsic and acquired resistance need further exploration in order to refine drug design. Toxicities that might result from modulation of the targeted pathway must be expected and fully characterized. Some biologic strategies may need to be tested in less refractory cases, or even in early stages, even though this may be more costly and could raise safety concerns. Fortunately progress in all of these areas is expected with the availability of new technologies and a growing infrastructure for preclinical and clinical testing.

Antineoplastic Agents↗
PubMed2026

Matched targeted therapy use after broad genomic profiling in advanced Non-Small cell lung cancer.

INTRODUCTION: While broad genomic profiling is increasingly used in advanced NSCLC (aNSCLC), the impact of test results on subsequent guideline-concordant targeted therapy selection remains incompletely understood. METHODS: Using a merged dataset of two large, nationwide, patient-level databases, we identified patients who were diagnosed with aNSCLC 2017-2023, had potentially actionable genomic profiling findings, and initiated systemic therapy. Patients were categorized into actionability subgroups based on contemporaneous regulatory approvals and NCCN guideline recommendations. Within each subgroup, we assessed receipt of guideline-concordant targeted therapy within 24 months, including potential underuse (non-receipt of recommended treatment) and overuse (receipt of non-recommended treatment). RESULTS: Among 6620 patients (67.4% ≥65 years, 54.6% female, 68.9% White), guideline-concordant targeted therapy use varied substantially by actionability category: 2313 (89.6%) of 2582 patients with available 1st-line on-label options received them (10.4% underuse), while 212 (67.3%) of 315 patients with available later-line on-label options received them after 1st-line (32.7% underuse). Among 441 patients with available guideline-concordant off-label options, only 122 (27.7%) received them (72.3% underuse). Conversely, 238 (8.6%) of 3282 patients received matched but guideline-discordant off-label options, representing overuse of ineffective or unestablished therapies. Smoking history, squamous histology, and high PD-L1 expression were associated with lower targeted therapy receipt. CONCLUSIONS: In this cohort study of aNSCLC care, the guideline concordance of targeted therapy use varied by clinical actionability of molecular testing results. Underuse was more common in patients with later-line and off-label targeted therapy options. Patients with classical smoking-related risk profiles were substantially less likely to receive targeted therapy even when actionable alterations were identified.

Journal Article↗
PubMed2001

[Molecule targeted therapy for hematological malignancies].

Over the past 20 years, there has been a marked increase in our knowledge of the molecular mechanisms of human hematological malignancies. The development of mechanism-based therapy is expected to extend the frontiers of chemotherapy. All-trans retinoic acid (ATRA) therapy for acute promyelocytic leukemia (APL), initially established as differentiation therapy, has been recognized to target PML-RAR alpha protein, an APL-specific chimeric transcriptional factor, and to modulate the function. Recently, encouraging results have emerged in the treatment of chronic myeloid leukemia with a tyrosine-kinase inhibitor. In addition to the oncoprotein-targeted therapy, the clinical effectiveness of humanized monoclonal antibodies to differentiation antigens has been recognized. Molecule-targeted therapy is reviewed herein.

Antibodies, Monoclonal↗
PubMed2004

Opportunities and challenges in the development of targeted therapies.

Expanding knowledge about basic biology and a detailed understanding of the signaling pathways that participate in the growth and metastasis of breast cancer have identified opportunities for diagnostic and therapeutic intervention. Endocrine therapy represents the first and most successful example of targeted therapy in breast cancer. Trastuzumab (Herceptin; Genentech, Inc, South San Francisco, CA) is now part of the management of metastatic disease and is under evaluation as adjuvant therapy. Other pathways have been targeted, and several candidate drugs are being developed. While these developments represent opportunities for better therapies, they have also identified limitations in identification of targets and development of targeted therapies. Validation of targets is critical, and it is also critical to determine whether the putative target can be identified in a consistent, practical, and inexpensive manner. Finally, it is imperative that targeted therapies are devoid of toxicities secondary to the ubiquitous nature of the target, and we must improve our understanding of interactions that provide specificity of signaling under physiologic conditions.

Antibodies, Monoclonal↗
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↗
PubMed2003

Integration of targeted therapies in gemcitabine chemotherapy regimens.

Lung cancer is one of the most common malignancies in the United States and the most lethal. Non-small-cell lung cancer (NSCLC), which accounts for over 80% of all lung cancer cases, results in a particularly poor prognosis and a high mortality rate. The 5-year survival rate is still only 15%, and most patients ultimately die from this disease. Unfortunately, the therapeutic improvements resulting from the new generation of cytotoxic agents seems to have reached a plateau. Targeted therapeutics, or agents aimed at specific biologic pathways, represent a potential for great improvements in survival from this disease. Because of their greater specificity, targeted therapeutics have the potential for decreased toxicity and increased efficacy. The main categories of targeted therapies applicable for NSCLC include receptor-targeted therapy, signal transduction or cell-cycle inhibition, angiogenesis inhibition, gene therapy, and vaccines. These new agents are, in theory, more target-specific, less toxic, easier to administer, and may lead to enhanced safety and survival for patients with advanced NSCLC. Targeted therapies are in different phases of clinical testing and have shown encouraging activity as single agents or in combination with chemotherapy as well as radiation therapy. Herein we explore targeted therapy in combination with gemcitabine.

Journal Article↗
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↗
PubMed2005

Tumor vascular targeting therapy with viral vectors.

Tumor angiogenesis is crucial for the progression and metastasis of cancer. The vasculature of tumor tissue is different from normal vasculature. Therefore, tumor vascular targeting therapy could represent an effective therapeutic strategy with which to suppress both primary tumor growth and tumor metastasis. The use of viral vectors for tumor vascular targeting therapy is a promising strategy based on the unique properties of viral vectors. In order to circumvent the potential problems of antiviral neutralizing antibodies, poor access to extravascular tumor tissue, and toxicities to normal tissue, viral vectors need to be modified to target the tumor endothelial cells. Viral vectors that could be used for tumor vascular targeting therapy include adenoviral vectors, adeno-associated viral vectors, retroviral vectors, lentiviral vectors, measles virus, and herpes simplex viral vectors. In this review, we will summarize the strategies available for targeting viral vectors for tumor vascular targeting therapy.

Animals↗
PubMed2006

Targeted therapies: a nursing perspective.

OBJECTIVES: To review the development of targeted therapies and the biology of relevant therapeutic targets. To analyze the relevance of targeted agents as part of current clinical practice. DATA SOURCES: Research articles. CONCLUSION: Several targeted agents are now available for clinical use. Their mechanisms of action are more specific against tumor cells than traditional cytotoxics. Monotherapy regimens based on targeted agents tend to be better tolerated than chemotherapy, and most combination regimens with targeted agents have proven feasible. Their availability has greatly expanded cancer treatment options, especially for chemorefractory patients. IMPLICATIONS FOR NURSING PRACTICE: Nurses involved in the care of patients with cancer can benefit from an increased understanding of targeted therapies, including their mechanisms of action, their efficacy profile, as well as prophylaxis and management of adverse events and administration procedures.

Angiogenesis Inhibitors↗
PubMed2003

Targeted therapies for the treatment of cancer.

BACKGROUND: In contrast to conventional cytotoxic chemotherapy and radiation therapy, a new method of targeted cancer therapeutics is being directed towards molecular pathways that underlie the malignant phenotype. These therapies target specific tumor cell receptors or signaling events that are critical to tumor progression while reducing toxicity to normal cells. DATA SOURCES: The purpose of this review is to highlight several examples of novel targeted therapeutics that are currently approved by the FDA for treatment of patients with cancer. Rituxan is a humanized monoclonal antibody that binds to the CD20 antigen present on B cell lymphomas and is currently approved for the treatment of patients with relapsed or refractory low-grade CD20 positive follicular lymphoma. The humanized anti-HER-2/neu herceptin is approved for use in patients with metastatic breast cancer that demonstrates overexpression of HER-2/neu. Finally, Gleevec is a tyrosine kinase inhibitor that inhibits abl-specific phosphorylation and is approved for use in select patients with chronic myelogenous leukemia that is refractory to interferon therapy. CONCLUSIONS: The lessons learned from the use of these therapeutics will add to the growing knowledge of mechanistic approaches to the treatment of patients with cancer based upon targeted therapies, and herald a bright future that will improve the lives of patients with cancer.

Antibodies, Monoclonal↗
PubMed1993

[Targeting therapy using monoclonal antibody directed against growth factor receptors].

Targeting therapy is expected to be a new effective anti-cancer treatment in near future. Major advances are achieved by considerable effort in this area. Monoclonal antibodies that recognize tumour-associated antigens were conjugated to chemotherapeutic drugs, toxins and radionuclides with various procedures. To apply this new therapy for clinical use, many problems still remain to be clarified. These problems consist of human anti-mouse antibody, antigenic heterogeneity and low tumour uptake. By our experiment, growth factor receptor was an ideal target for targeting therapy and immunoconjugate directed against growth factor receptor showed selective cytotoxicity to cancer cells with expression of growth factor receptor. Moreover, cytotoxic effect was positively correlated with expression level of growth factor receptor.

Animals↗
PubMed2005

Targeted therapies for prostate cancer.

The development of targeted therapies for prostate cancer has exploited various elements of prostate biology. The androgen-dependence of prostate cancer continues to be the focus for the development of new drugs and the analysis of details of the intermolecular interactions of the androgen receptor. Importantly, new applications of androgen ablation therapy have proven to have the greatest effect on cause-specific and overall survival during the last decade. Prostate epithelial cells express a number of tissue-specific proteins that have been the target either for antibody-directed therapies, in the case of prostate-specific membrane antigen, or target-activated therapies in the case of prostate-specific antigen, a serine protease. Prostate-specific proteins have also been targeted by the development of vaccines that have entered clinical trials. Humanized monoclonal antibodies and small molecules designed to inhibit oncogenic signalling pathways have been subjected to clinical trials in prostate cancer with limited success. The application of pathway inhibitors to prostate cancer therapy has been limited because no common dominant oncogenic mutation affecting signal kinase activation in prostate cancer has yet been identified. The interaction of signal kinase inhibitors with androgen ablation and with cytotoxic chemotherapy remains to be explored.

Androgen Antagonists↗
PubMed2026

Molecular and Clinical Determinants of Targeted Therapy Treatment in Biliary Tract Cancer.

PURPOSE: Actionable genomic alterations occur in all anatomic subsets of biliary tract cancer; however, targeted therapies have not shown a survival advantage over cytotoxics, and resistance mechanisms require further characterization. EXPERIMENTAL DESIGN: We analyzed a prospectively maintained cohort of 1,254 patients with histologically confirmed biliary tract cancer who underwent molecular profiling using an FDA-authorized targeted next-generation sequencing (NGS) assay. We defined actionable alterations across anatomic subsets, compared outcomes with targeted therapy versus cytotoxics, and evaluated genomic correlates of resistance using longitudinal samples. RESULTS: Overall, 59% of patients harbored at least one OncoKB alteration, and 32.2% (intrahepatic 40%, extrahepatic 15%, and gallbladder 22%) had a level 1/2 alteration. Emerging targets included KRAS alterations (17%), MTAP deletions (12.8%), MDM2 amplification (6.5%), and MET amplification (1.5%). Targeted therapy was associated with improved progression-free survival but not overall survival. Co-occurring TP53/RAS pathway and SMAD4 alterations were associated with inferior outcomes in IDH1/FGFR2-and ERBB2-driven tumors, respectively. Longitudinal profiling demonstrated ERBB2 loss in ERBB2-driven tumors, whereas IDH-, FGFR-, BRAF-, and NTRK-driven tumors retained the primary oncogenic driver. Acquired resistance was associated with alterations in RAS, MEK, MET, MYC, and CDKN2A. CONCLUSIONS: This comprehensive molecular profiling study illustrates the real-world utility and limitations of targeted NGS of biliary tract cancer and affirms the use of precision medicine in patients with these diseases. Genomic heterogeneity and therapeutic resistance observed in this study has the potential to inform ongoing drug development efforts for biliary tract cancer.

Humans↗