Genomic-based therapy: targeting interleukin-1 for autoinflammatory diseases.
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Autoimmune Diseases↗
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Signal transduction pathways: the molecular basis for targeted therapies.
The elucidation of the signal transduction pathways that regulate cell growth and differentiation has led to a number of exciting opportunities for novel cancer therapies. It is now well known that growth factors and cell matrix molecules activate cognate growth factor receptors and integrins, respectively, to initiate a complex signaling cascade that ultimately targets the nucleus, cell surface, and mitochondria. Signaling to these target molecules results in the regulation of gene transcription, cell adhesion and motility, and cell survival, all of which are integral parts of cellular growth control mechanisms. As a result of increased understanding of cell growth regulation mechanisms, a number of novel therapeutic agents have been developed and tested in preclinical models and, to some extent, in clinical trials. Based on our current understanding of growth regulation in normal and cancer cells, one would predict that these new agents could influence proliferation and survival of cancer cells, as well as their response to traditional cytotoxic therapies. In this overview, the mechanistic basis for the use of signal transduction-targeted novel therapeutics is presented, along with predictions regarding how they may interact with ionizing radiation in different subgroups of patients.
Antineoplastic Agents↗
Pilot trial of bone-targeted therapy with zoledronate, thalidomide, and interferon-gamma for metastatic renal cell carcinoma.
BACKGROUND: The purpose of the study was to evaluate the efficacy and safety of a bone-targeted regimen consisting of zoledronate, thalidomide, and interferon-gamma in patients with renal cell carcinoma and bone metastases. METHODS: Eligible patients had radiographic evidence of bone metastasis. Impending pathologic fractures or spinal cord compressions must have been controlled by surgery or radiation therapy before enrollment. Zoledronate (4 mg) was given intravenously every 4 weeks, thalidomide (300 mg) was given orally once a day, and interferon-gamma (100 microg) was given subcutaneously once a week. Patients were evaluated for time to skeletal-related events, the appearance of calcification in osteolytic metastases, and levels of the bone formation/resorption markers. RESULTS.: Fifteen patients were treated between November 2002 and November 2003; 12 had previously undergone surgery, radiation, or embolization for their bone metastases; 11 had more than 3 sites of bone involvement; and 9 also had nonosseous metastases in the lung, liver, lymph node, pancreas, or adrenal gland. The median time to progression was 8.3 weeks (range, 2.1-48 weeks). The median time to a skeletal-related event was 12.0 weeks (range, 3.9-46.4 weeks). Two patients discontinued treatment because of adverse drug reactions (1 deep venous thrombosis and 1 myocardial infarction). Two patients experienced pain improvement and developed calcification in osseous metastases; these patients also showed favorable changes in bone marker levels. CONCLUSIONS: In this pilot study a bone-targeted regimen combining zoledronate, thalidomide, and interferon-gamma was well tolerated and might provide clinical benefit for a small subset of patients with renal cell carcinoma and bone metastases.
Adult↗
Progress in targeted therapy against human immunodeficiency virus [corrected].
Acquired immunodeficiency syndrome (AIDS) and its related disorders are caused by a retrovirus termed human immunodeficiency virus (HIV). HIV has nine known genes, and each gene provides a target of opportunity for a therapeutic intervention. Knowledge of the life cycle of this virus has already yielded clinically useful therapies and will likely make a major impact against AIDS in the near future, provided that the principles of controlled trials are followed.
Acquired Immunodeficiency Syndrome↗
StpC-based gene therapy targeting latent reservoirs of HIV-1.
The ability of HIV-1 to form latent reservoirs presents a major obstacle to eradication. One approach to elimination of the latent reservoir is induction therapy, whereby cells harboring latent virus are activated and therefore initiate virus replication. We have constructed a lentiviral vector encoding Herpesvirus saimiri subgroup C saimiri transformation-associated protein (StpC), which has been shown to modulate HIV-1 replication, under the control of a cytomegalovirus promoter in order to determine the ability of StpC to upregulate latent HIV-1. We have included a suicide gene, herpes simplex virus thymidine kinase (TK), under the control of the HIV-1 long terminal repeat (LTR) promoter. We hypothesized that upon StpC expression in latently infected cells induction of virus replication and subsequent production of viral transactivators of the LTR will activate expression of the tk gene, sensitizing the cells to the nucleoside analogue ganciclovir (GCV). Transduction of the latently infected cell line J1.1 resulted in increased virus replication. In the presence of GCV transduced cells exhibited decreased HIV-1 replication, inhibition of cell proliferation, and increased apoptosis. This prototype vector serves as a proof of concept of the utility of gene-based induction agents and suicide genes as a new method for targeting reservoirs of latent HIV-1.
Anti-HIV Agents↗
Resolution of trauma-related guilt following treatment of PTSD in female rape victims: a result of cognitive processing therapy targeting comorbid depression?
BACKGROUND AND METHODS: Although Resick et al. [Resick, P.A., Nishith, P., Weaver, T.L., Astin, M.C., Feuer, C.A., 2002. A comparison of cognitive-processing therapy with prolonged exposure and a waiting condition for the treatment of chronic posttraumatic stress disorder in female rape victims. J. Consult. Clin. Psychol. 70, 867-879.] reported comparable results for treating rape-related posttraumatic stress disorder (PTSD) using either cognitive-processing therapy (CPT) or prolonged exposure (PE), there was some suggestion that CPT resulted in better outcomes than PE for certain aspects of trauma-related guilt. The present study revisited these findings to examine whether this effect was a function of improvement in a subset of participants with both PTSD and major depressive disorder (MDD). RESULTS: Results indicated that CPT was just as effective in treating "pure" PTSD and PTSD with comorbid MDD in terms of guilt. Clinical significance testing underscored that CPT was more effective in reducing certain trauma-related guilt cognitions than PE. LIMITATIONS: Findings cannot be generalized to men, and only one measure of guilt was used. CONCLUSIONS: The observed superiority of CPT over PE for treating certain guilt cognitions was not due to participant comorbidity. Further research is recommended to untangle the relationship between guilt, depression and differential response to treatment in PTSD following sexual assault trauma.
Adult↗
Cancer gene therapy targeting angiogenesis: an updated review.
Since the relationship between angiogenesis and tumor growth was established by Folkman in 1971, scientists have made efforts exploring the possibilities in treating cancer by targeting angiogenesis. Inhibition of angiogenesis growth factors and administration of angiogenesis inhibitors are the basics of anti-angiogenesis therapy. Transfer of anti-angiogenesis genes has received attention recently not only because of the advancement of recombinant vectors, but also because of the localized and sustained expression of therapeutic gene product inside the tumor after gene transfer. This review provides the up-to-date information about the strategies and the vectors studied in the field of anti-angiogenesis cancer gene therapy.
Angiogenesis Inhibitors↗
Targeted therapy for colorectal cancer.
There has been a revolution in the treatment of colorectal cancer over the last decade. Part of this revolution has been the discovery of agents that target particular aspects of cancer, namely vascular endothelial growth factor and epidermal growth factor receptor. Novel targeted agents have been evaluated in clinical trials and have demonstrated significant anticancer activity. Furthermore, a number of these compounds have been approved for clinical use. Data supporting the use of targeted agents in the treatment of colorectal cancer are reviewed, and the "future for potential novel agents and pathways are discussed.
Animals↗
Epidermal growth factor receptor mutations and susceptibility to targeted therapy in lung cancer.
According to 2002 estimates, 1.35 million people were diagnosed with and 1.18 million died of lung cancer worldwide. Recently, a new class of medications targeting signal transduction pathways has come into focus in the treatment of various malignancies. In lung cancer, the molecules gefitinib and erlotinib which target the intracellular kinase domain of the epidermal growth factor receptor (EGFR), cause significant tumour responses and, in the case of erlotinib, a survival benefit in patients with previously treated cancers. Responses were most pronounced in female non-smokers with adenocarcinoma histology. These patients were found more likely to harbour mutations of the receptor kinase domain, including in-frame deletions in exon 19 (such as deletions of codons 746-750) and point deletions in exon 21 (such as L858R). Other EGFR kinase domain mutations have been found to confer resistance (T790M) or differential susceptibility to erlotinib and gefitinib (E884K). Gene amplification of EGFR also may predict sensitivity, although the mechanism by which this occurs is unclear, because level of expression detected by immunohistochemistry has not been correlated with increased sensitivity. Phenotypic and genotypic epithelial to mesenchymal transition may be an indicator of resistance to EGFR kinase inhibitors. In this article, we review efforts that have been undertaken to identify genomic determinants of drug susceptibility to EGFR tyrosine kinase inhibitors, with particular focus on the role of gene mutations.
Antineoplastic Agents↗
Human malignant melanomas express receptors for luteinizing hormone releasing hormone allowing targeted therapy with cytotoxic luteinizing hormone releasing hormone analogue.
Cytotoxic analogue of luteinizing hormone releasing hormone (LHRH), AN-207, binds with high affinity to LHRH receptors and can be targeted to tumors expressing these receptors. We investigated the expression of LHRH receptors in surgical specimens of human malignant melanoma and evaluated the effects of AN-207 in models of human melanoma. Human melanoma specimens derived from primary tumors or metastases were examined for LHRH receptor expression by immunohistochemistry. Binding assays, Western immunoblotting, and reverse transcription-PCR analyses were used to investigate LHRH receptors in MRI-H255 and MRI-H187 transplantable human melanoma tumor lines. Antitumor effects of AN-207 and its components were evaluated in vivo in nude mice bearing xenografts of either melanoma tumor line. All 19 human melanoma specimens examined showed positive staining for LHRH receptors. The mRNA for LHRH receptors, receptor protein and binding sites for LHRH were detected in both transplantable melanoma tumor lines. AN-207 significantly inhibited the growth of MRI-H255 and MRI-H187 xenografts in vivo, reducing tumor volume by 59.9% to 79.2% and tumor weight by 61.0% to 76.9% (all P < 0.05). The components of AN-207 (LH-RH analogue carrier and cytotoxic radical AN-201 as single drugs or as an unconjugated mixture) had no significant effects. Blockade of LHRH receptors by an excess of LHRH agonist Decapeptyl suppressed the effects of AN-207. LHRH receptors are expressed in a very high percentage of human malignant melanoma specimens and can be used for targeted chemotherapy with cytotoxic LHRH analogue AN-207.
Animals↗
Targeted therapy for epithelial ovarian cancer: current status and future prospects.
Despite advances in surgery and chemotherapy, less than 20% of patients with stage III or IV ovarian cancer survive long-term. In the past, cytotoxic regimens have been developed empirically, combining active agents at maximally tolerated doses, often without a clear rationale for their interaction. Advances in understanding the biology of ovarian cancer have identified multiple molecular targets that differ in normal and malignant cells. Targets include cell cycle regulators, growth factor receptors, signal transduction pathways, molecules that confer drug resistance, and angiogenic mechanisms. A number of targeted agents have entered clinical trials. Small molecular weight inhibitors, monoclonal antibodies, and antisense and gene therapy are all being evaluated alone and in combination with cytotoxic drugs. In contrast to earlier studies, the impact of each agent on the designated target can be assessed and agents can be matched to the genotype and phenotype of malignant and normal cells. In the long run, this should facilitate individualization of more effective, less toxic therapy for women with ovarian cancer.
Angiogenesis Inhibitors↗
Lung perfusion and other methods of targeting therapy to lung tumors.
As therapies for cancer and other diseases continue to evolve on a molecular and genetic basis, delivering these sophisticated agents will continue to be problematic. Although the agents may be highly effective in the laboratory, their true worth can only be measured by clinical responses. In certain instances, the skills of a thoracic surgeon may be called upon to provide the means of delivering therapy rather than to perform therapy, as is our custom. The techniques discussed in this review are just a few of the many possibilities for targeting agents in an effort to enhance their clinical efficacy.
Adenocarcinoma, Bronchiolo-Alveolar↗
Emerging immunomodulatory therapies targeting the co-stimulatory pathways for the prevention of transplant rejection.
The continued discovery of novel immune molecules and pathways over the last decade has spurred a tremendous amount of research into the targeting of these pathways for the prevention of transplant rejection. Of particular interest are members of the ever-growing family of T-cell co-stimulatory pathways; the classic co-stimulatory pathways are the CD28/CTLA4:B7-1/2 and CD40:CD154, while the ICOS:ICOSL and PD-1:PD-L1/PD-L2 pathways are novel. Various chimeric molecules and monoclonal antibodies have been developed for targeting these pathways with promising results, especially with the newer generation of agents and in combination among themselves, with other immunomodulatory therapies and/or with conventional immunosuppressive agents. These novel immunomodulatory strategies have the potential to bring us a step closer to achieving transplantation tolerance.
Adjuvants, Immunologic↗
Towards a more specific therapy: targeting nonmelanoma skin cancer cells.
Epithelial cancers of the skin, e.g. basal cell carcinoma and squamous cell carcinoma, are the most common tumours in humans with increasing incidence. Hence the development of new therapeutic strategies is of utmost interest. For many years the most often used conventional therapies for these diseases were surgical procedures such as curettage and electrodesiccation, excision or, with so far the best outcome in terms of remission rates, micrographic surgery. Other ablative treatment modalities are cryotherapy, radiation therapy or the use of lasers (Er:YAG, CO(2)). All those above-mentioned treatments have in common that they are quite unspecific and do not target the tumour itself or its environment, thus leading to unwanted effects in the surrounding tissue such as scar formation or other cosmetically disfiguring events. Therefore, the development of novel, more pathogenesis-based therapies such as the use of retinoids, cyclooxygenase inhibitors, topical immunomodulators, inhibitors of the sonic-hedgehog signalling pathway or photodynamic therapy are challenging new approaches.
Basal Cell Carcinoma↗
Gene therapy targeted at calcium handling as an approach to the treatment of heart failure.
Chronic congestive heart failure primarily of ischemic origin remains a leading cause of morbidity and mortality in the United States and other leading countries. The current main stream of therapy is, however, palliative and uses a complex regimen of drugs, the actions of which are not understood completely. On the other hand, unfavorable remodeling after cardiac injuries of multiple causes has been thought to lead to cardiac contractile dysfunction in heart failure, and a body of scientific evidence points to a central role of intrinsic defects in intracellular calcium handling in cardiomyocytes that arise from the distorted functions of several key regulatory molecules on plasma membrane or sarcoplasmic reticulum (SR), a muscle-specific intracellular membrane complex that stores calcium at high concentration. Accordingly, the initial appetite to use gene transfer strategies to modulate calcium regulatory proteins was to validate molecular targets for the development of new pharmaceuticals; however, remarkable therapeutic efficacies found in an initial series of studies using various heart failure animal models immediately promoted us to seek ways to directly apply gene transfer to cure clinical heart failure. The first part of this article reviews our up-to-date knowledge of various functional components to regulate calcium handling in cardiomyocytes, including beta-adrenergic receptor, L-type calcium channel, ryanodine receptor (RyR) and its associated proteins, sarco-endoplasmic reticulum calcium ATPase (SERCA), and phospholamban (PLN), and their abnormalities in failing hearts. A series of new somatic gene transfer attempts targeting calcium handling in cardiomyocytes are discussed thereafter.
Calcium↗
Cell-cycle targeted therapies.
Eukaryotic organisms depend on an intricate and evolutionary conserved cell cycle to control cell division. The cell cycle is regulated by a number of important protein families which are common targets for mutational inactivation or overexpression in human tumours. The cyclin D and E families and their cyclin-dependent kinase partners initiate the phosphorylation of the retinoblastoma tumour suppressor protein and subsequent transition through the cell cycle. Cyclin/cdk activity and therefore control of cell division is restrained by two families of cyclin dependent kinase inhibitors. A greater understanding of the cell cycle has led to the development of a number of compounds with the potential to restore control of cell division in human cancers. This review will introduce the protein families that regulate the cell cycle, their aberrations in malignant progression and pharmacological strategies targeting this important process.
Animals↗
Molecular targeting therapy for renal cell carcinoma.
Metastatic renal cell carcinoma (RCC) is currently one of the most treatment-resistant malignancies. However, significant advances in understanding the molecular mechanisms underlying RCC have led to the development of rationally designed therapies, which are now being tested clinically. To date, the vascular endothelial growth factor receptor (VEGFR) pathway has been the most promising target, and two agents (BAY 43-9006 and SU 11248) that inhibit not only VEGFR but also other receptors, including platelet-derived growth factor receptor (PDGFR), FMS-like tyrosine kinase 3 (FLT3), KIT, and Raf kinase, were recently approved by the FDA for advanced RCC. In addition, a phase III trial investigating the addition of VEGF inhibition to interferon alpha (IFN-alpha) in RCC is also now going on. Although the clinical activity of existing agents is to be further defined in ongoing trials, the exciting clinical response data with VEGF inhibition in RCC have demonstrated a key role in the treatment of this historically resistant malignancy.
Antibodies, Monoclonal↗
The future of targeted therapy: combining novel agents.
The anti-HER2 monoclonal antibody Herceptin demonstrates significant clinical benefits in patients with HER2-positive metastatic breast cancer (MBC). However, the combination of Herceptin plus anthracyclines, although efficacious, demonstrated a higher than expected incidence of cardiotoxicity. Therefore, studies are currently investigating Herceptin in combination with alternative anthracyclines, such as epirubicin and liposomal doxorubicin. Investigators are also beginning to examine the potential of Herceptin plus hormonal therapy, a combination that will delay the need to use cytotoxic chemotherapy. Furthermore, a plethora of novel agents have been developed that target the processes of tumorigenesis, including HER1 tyrosine-kinase inhibitors, farnesyl-transferase inhibitors, and cyclooxygenase 2 (COX2) inhibitors. Preclinical data demonstrate that the combination of Herceptin with these agents can produce at least additive effects and therefore a rationale exists to investigate these regimens in the clinical setting. As a result of the targeted nature of these agents, it is anticipated that such strategies will have favorable safety profiles. It is possible that through the development and use of biological anticancer agents, such as Herceptin, future anticancer regimens may be specifically tailored to each patient based on their molecular characteristics.
Antibiotics, Antineoplastic↗