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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.
Current trends foretell the use of cancer treatments customized to each patient. Genetic and molecular profiling of tumors and an increasing number of molecule-targeted therapies contribute to making this a reality. However, as targets of anticancer therapies become specific proteins or pathways, unanticipated side effects may emerge. In addition, the chronic use of these treatments may contribute to the development of degenerative toxicity not predicted by short-term clinical trials. Here we review and propose how genetically engineered mouse models can serve as valuable tools to predict targeted therapy toxicity, as well as to identify allelic variants that predispose individuals to side effects.
BACKGROUND: Pancreatic cancer is the fourth commonest cause of death from cancer in men and women. Advantages in surgical techniques, radiation therapy techniques, chemotherapeutic regimes, and different combined-modality approaches have yielded only a modest impact on the prognosis of patients with pancreatic cancer. Thus there is clearly a need for additional strategies. One approach involves using the identification of a number of molecular targets that may be responsible for the resistance of cancer cells to radiation or to other cytotoxic agents. As such, these molecular determinants may serve as targets for augmentation of the radiotherapy or chemotherapy response. Of these, the epidermal growth factor receptor (EGFR) has been a molecular target of considerable interest and investigation, and there has been a tremendous surge of interest in pursuing targeted therapy of cancers via inhibition of the EGFR. METHODS/DESIGN: The PARC study is designed as an open, controlled, prospective, randomized phase II trial. Patients in study arm A will be treated with chemoradiation using intensity modulated radiation therapy (IMRT) combined with gemcitabine and simultaneous cetuximab infusions. After chemoradiation the patients receive gemcitabine infusions weekly over 4 weeks. Patients in study arm B will be treated with chemoradiation using intensity modulated radiation therapy (IMRT) combined with gemcitabine and simultaneous cetuximab infusions. After chemoradiation the patients receive gemcitabine weekly over 4 weeks and cetuximab infusions over 12 weeks. A total of 66 patients with locally advanced adenocarcinoma of the pancreas will be enrolled. An interim analysis for patient safety reasons will be done one year after start of recruitment. Evaluation of the primary endpoint will be performed two years after the last patient's enrollment. DISCUSSION: The primary objective of this study is to evaluate the feasibility and the toxicity profile of trimodal therapy in pancreatic adenocarcinoma with chemoradiation therapy with gemcitabine and intensity modulated radiation therapy (IMRT) and EGFR-targeted therapy using cetuximab and to compare between two different methods of cetuximab treatment schedules (concomitant versus concomitant and sequential cetuximab treatment). Secondary objectives are to determine the role and the mechanism of cetuximab in patient's chemoradiation regimen, the response rate, the potential of this combined modality treatment to concert locally advanced lesions to potentially resectable lesions, the time to progression interval and the quality of life.
The high remission rates observed in patients with chronic myelogenous leukemia who receive Imatinib mesylate (Gleevec) indicate that targeted therapy for hematological malignancies is achievable. At the same time, progress in cellular biology over the past decade has resulted in a better understanding of the process of malignant transformation, a better classification of subtypes of each disease on the basis of molecular markers, and a better characterization of the molecular targets for drug development. These advances have already spawned the development of such effective agents as monoclonal antibodies and specific enzyme inhibitors. This review attempts to provide a practical introduction to the complex and growing field of targeted therapy in hematological malignancies.
BACKGROUND: Initial studies have shown improved outcomes in patients receiving cancer therapies matched to their molecular alterations. To improve the chances of finding a therapeutic match for patients, this study evaluated the preliminary antitumor activity of 3 commercially available multitargeted agents in the United States, regorafenib, afatinib, and cabozantinib. METHODS: In this phase II trial, patients who did not benefit from first-line treatment for non-small cell lung cancer (NSCLC), upper aerodigestive tract cancers, non-colon gastrointestinal cancers, and urothelial carcinoma underwent next-generation sequencing to identify actionable genomic alterations. Eligible patients, based on identified mutations deemed treatable by regorafenib, cabozantinib, or afatinib, were enrolled to receive matched targeted therapies. Outcomes were monitored via Response Evaluation Criteria in Solid Tumors criteria, with dose modifications per National Cancer Institute Common Terminology Criteria for Adverse Events, v4.03 guidelines for adverse events (AEs). RESULTS: One hundred patients with metastatic cancers were enrolled across tumor types. Median treatment durations were 12 weeks (regorafenib), 10.7 weeks (afatinib), and 24.1 weeks (cabozantinib). The overall objective response rate was 7.0%, with 1 complete response and 8 partial responses. The clinical benefit rate, including responses and stable disease >6 months, was 16.0%. Median progression-free survival ranged from 1.9 months for urothelial carcinoma to 3.2 months for NSCLC. Toxicities were common for all medications; for regorafenib, 90.7% of patients had AEs (50% Grade 3/4); for afatinib, 86% of patients had AEs (54% Grade 3/4); for cabozantinib, 100% of patients had AEs (36% Grade 3/4). The most common AEs were diarrhea, fatigue, nausea, decreased appetite, and stomatitis. CONCLUSIONS: Regorafenib, afatinib, and cabozantinib had modest effects when used as molecularly matched targeted therapies in patients with NSCLC, upper aerodigestive tract cancers, non-colon gastrointestinal cancers, and urothelial carcinoma in the second-line setting. Future research could examine more precise matching of therapies to genomic alterations and evaluate combination therapies.
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.
Over the last two decades cancer cure rates have not gone up as expected, and the effectiveness of chemotherapy has reached a plateau. This has prompted a search for targeted therapies with higher efficacy and lesser toxicities. Monoclonal antibodies against cancer cells offer targeted therapies with little or no toxicities against normal tissues. In this review we will discuss the concepts behind the development of monoclonal antibodies in cancer and their present status in the clinic. Specifically, we will discuss the clinical use of Rituximab (RituxanO), Trastuzumab (HerceptinO) and Bevacizumab (AvastinO) in various cancers and the key clinical trials that have led to their incorporation in cancer therapeutics.
BACKGROUND: In solid organ malignancies, no tumor type has seen a greater impact from the development of novel targeted therapies in 2004 than metastatic colorectal cancer. METHODS: We review the current progress to date with the use of monoclonal antibodies in colorectal cancer and look at newer therapies under investigation. RESULTS: Two monoclonal antibodies received Food and Drug Administration approval in early 2004, both for the indication of advanced, metastatic colorectal cancer. A large, randomized, placebo-controlled study demonstrated that the addition of a monoclonal antibody to vascular endothelial growth factor, bevacizumab, led to a statistically significant improvement in overall survival, with tolerable additional toxicity. Chimeric monoclonal antibody therapy directed at the epidermal growth factor receptor was associated with radiographic responses in a significant minority of patients with irinotecan-refractory colon cancer in a randomized phase II study of patients with irinotecan-refractory disease. CONCLUSIONS: These dramatic successes have led to further clinical studies of targeted therapy in colorectal cancer, making it one of the most promising areas of cancer research.
A number of novel genes that are up-regulated in diabetic kidneys have been identified. Recently, transforming growth factor-beta (TGF-beta)--driven secreted proteins, i.e., connective tissue growth factor (CTGF) and gremlin, were identified. They are up-regulated in kidneys of diabetic animals and modulate the biology of mesangial cells. CTGF mediates TGF-beta--induced matrix overproduction by the mesangial cells. Gremlin is a putative antagonist of bone morphogenetic protein-2 that blocks mesangial cell proliferation. Thus, gremlin may modulate the biology of mesangium by stimulating mesangial cell proliferation and in turn production of matrix. In addition, transcriptionally regulated kinases, serum glucocorticoid-regulated kinase and munc-13 have been identified. The former stimulates renal tubular Na+ transport and is involved in hyperfiltraion of diabetic kidneys by a Na+ transport feedback mechanism. Munc-13 has been shown to induce apoptosis in hyperglycemic state via diacylglycerol-activated, PKC-independent signaling pathway. Another pathway relevant to diabetic nephropathy is polyol pathway, where glucose is reduced to sorbitol by aldose reductase. Recently, a renal-specific reductase of the aldo-keto reductase family was isolated. It is up-regulated in diabetic mice, and this could serve as a suitable target for gene therapy in renal complications of diabetes. Several mitochondrial genome-encoded genes, such as, cytochrome oxidase and NADH dehydrogenase, are up-regulated in diabetic kidneys. A novel nuclear-encoded mitochondrial gene, i.e., translocase inner mitochondrial membrane 44 (Tim44), is up-regulated in diabetic kidneys, and it may also serve as another target for molecular therapeutic intervention at the core storage energy sites, i.e., mitochondria. In this review, these novel differentially regulated genes that respond to hyperglycemic stress are described, and they may serve as possible targets for gene therapy in the treatment of diabetic nephropathy.
HYPOTHESIS: Cyclooxygenase 2 (COX-2), vascular endothelial growth factor (VEGF), and epidermal growth factor receptor (EGFR) are useful biological determinants in targeted therapy for esophageal adenocarcinoma. DESIGN: Prospective analysis. SETTING: University tertiary referral center. PATIENTS: Sixteen patients with squamous mucosa and normal results of a pH study without mucosal injury (control group), 15 with Barrett esophagus (metaplasia group), and 44 with adenocarcinoma (carcinoma group). INTERVENTIONS: Biopsy specimens were obtained 3 cm above the gastroesophageal junction. Dysplastic tissue was additionally isolated from 9 of the patients in the carcinoma group. After laser-capture microdissection, quantitative real-time polymerase chain reaction was used to measure gene expression across the spectrum of the metaplasia-dysplasia-carcinoma sequence. MAIN OUTCOME MEASURES: Expression of COX-2, VEGF, and EGFR in each patient group. RESULTS: Expression of both COX-2 and VEGF was significantly up-regulated in patients with metaplasia, dysplasia, and cancer compared with controls (P<.01). Expression levels of both were significantly higher in cancer than in the metaplasia group (P<.05) and increased sequentially from metaplasia to dysplasia to cancer. Expression of VEGF was significantly higher in the dysplastic tissue than in nondysplastic Barrett epithelium (P<.05). No change in expression levels of EGFR was seen in the histologic progression to esophageal adenocarcinoma. CONCLUSION: Gene expression data suggest that pharmacologic inhibition of COX-2 and VEGF may be useful adjuncts in targeted therapy for esophageal adenocarcinoma.
Current options for the second-line treatment of non-small cell lung cancer (NSCLC) include cytotoxic drugs, such as docetaxel and pemetrexed, and targeted therapies. Docetaxel was approved in the United States and Europe in 2000 after two phase III trials showed drug superiority versus best supportive care alone and versus alternative single-agent chemotherapy. Pemetrexed was approved in the United States and Europe in 2004 after a phase III trial showed that, compared with docetaxel, it had comparable activity (median survival time of approximately 8 months in both arms) and a more favorable toxicity profile: grade 3-4 neutropenia was observed in 5.3% versus 40.2% of patients in the pemetrexed and docetaxel arms, respectively, while febrile neutropenia was observed in 1.9% versus 12.7% of patients, respectively. In the United States, gefitinib and erlotinib have also been approved for the treatment of recurrent NSCLC (in 2003 and 2004, respectively), while in Europe the registration of these agents is currently under evaluation. This review focuses on the use of docetaxel and pemetrexed for the second-line treatment of NSCLC and compares these drugs with targeted therapies, highlighting the latest developments in pharmacogenomics that might lead to a more tailored approach to treatment.
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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.
Chronic lymphocytic leukemia (CLL) is most frequently diagnosed at early, asymptomatic stages (Rai 0/Binet A), in which a watch-and-wait strategy remains the standard of care, based on historical trials demonstrating no overall survival benefit from early treatment. Over the past two decades, however, substantial advances in genomic profiling-including immunoglobulin heavy-chain variable region (IGHV) mutational status, TP53 disruption, recurrent gene mutations, and complex karyotype-have uncovered marked biological heterogeneity among early-stage patients and substantially improved prediction of disease progression. In parallel, targeted therapies such as Bruton tyrosine kinase (BTK) inhibitors and venetoclax-based combinations have transformed the management of symptomatic CLL, raising renewed interest in whether early intervention might favorably alter the natural history of biologically high-risk disease. In this review, we critically examine the evolution of prognostication in early-stage CLL, integrate contemporary molecular and clinical risk models, and summarize evidence from both historical chemotherapy-era studies and modern early-intervention trials. We discuss key unresolved controversies, including reliance on surrogate endpoints, the risks of overtreatment, and the persistent absence of an overall survival benefit across all early-treatment strategies. Finally, we outline future research priorities, including refined genomic stratification, minimal residual disease-driven (MRD)-driven approaches, and combination targeted therapies currently under investigation. Despite renewed interest in preemptive treatment, available evidence supports continued observation for asymptomatic patients outside clinical trials.
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.
Targeted radionuclide therapy is an effective and cost efficient treatment for multi-site metastatic bone pain. This paper discusses the physical characteristics of the licensed radiopharmaceuticals (153)Sm ethylenediamine-N,N,N',N'-tetrakis(methylene phosphonic acid) ((153)Sm-EDTMP), (186)Re 1,1-hydroxyethylidenediphosphonate ((186)Re-HEDP) and (89)SrCl(2) and considers the factors influencing treatment choice in specific clinical settings. The advantages and practical limitations of this approach are discussed, with emphasis on defining criteria for patient selection and response monitoring. Opportunities for future research and development are outlined.
OBJECTIVES: To review novel targeted therapies for the treatment of leukemia. DATA SOURCES: Professional journals, books, and government publications. CONCLUSION: Nonspecific cytotoxic chemotherapeutic agents provide marginal therapeutic benefit and significant toxicity when used in the treatment of leukemia. There is a tremendous need for new therapies with increased efficacy and decreased adverse effects. Advances in molecular science, genetics, and immunology, along with improved laboratory technology, have led to the discovery of unique targets integral to the growth and proliferation of malignant cells which are providing the foundation for the development of a new generation of antitumor agents. IMPLICATIONS FOR NURSING PRACTICE: Nurses must be prepared to educate patients, administer novel therapies, and manage side effects.
Conjugates of monoclonal antibody (MAb) and adriamycin entrapped in liposome (MLA) were prepared by COC166-9. The MAb against ovarian serous adenocarcinoma was generated in our laboratory. Target therapies were done in nude mice model with subcutaneous tumor xenografts in 24 and ascitic carcinoma in 16 by MLA. The results demonstrated that MLA group presented the best therapeutic effect than all the other groups, which gave a very helpful clue to clinical target therapy of ovarian carcinoma in the future.