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Current Challenges of Gene Therapy for Prostate CancerGene therapy for prostate cancer faces hurdles similar to those being encountered for other cancers and nonmalignant processes. The greatest obstacle is the identification of efficient delivery systems, since numerous animal models and cell culture systems have shown potential efficacy when most cells express the introduced genetic material. Early prostate cancers are easily accessible to gene vector introduction, and the predictable metastatic patterns of this cancer may offer additional advantages for gene therapy. This article reviews gene vectors and gene products, as well as ongoing trials of gene therapy that have recently begun in prostate cancer. [ONCOLOGY 11(6):845-856, 1997]
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Thymidylate Synthase as a Predictor of ResponseIt has been hypothesized that intratumoral thymidylate synthase (TS) gene expression might be used to select therapy for patients with disseminated colorectal cancer. We recently
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Vaccine Therapy for Patients With MelanomaInvestigation into the therapeutic use of vaccines in patients with metastatic melanoma is critically important because of the lack of effective conventional modalities. The most extensively studied melanoma vaccines in clinical trials are whole-cell preparations or cell lysates that contain multiple antigens capable of stimulating an immune response. Unfortunately, in the majority of studies, immune responses to these vaccines have not translated into a survival advantage. Advances in tumor cell immunology have led to the identification of candidate tumor cell antigens that can stimulate an immune response; this, in turn, has allowed for refinements in vaccine design. However, the exact tumor antigens that should be targeted with a specific vaccine are unknown. The univalent antigen vaccines, which have greater purity, ease of manufacturing, and reproducibility compared with polyvalent vaccines, may suffer from poorer efficacy due to immunoselection and appearance of antigen-negative clones within the tumor. Novel approaches to vaccine design using gene transfection with cytokines and dendritic cells are all promising. However, the induction of immune responses does not necessarily confer a therapeutic benefit. Therefore, these elegant newer strategies need to be studied in carefully designed clinical trials so that outcomes can be compared objectively with standard therapy. If survival is improved with these vaccine approaches, their ease of administration and lack of toxicity will firmly entrench active specific vaccine immunotherapy as a standard modality in the treatment of the melanoma patient.[ONCOLOGY 13(11):1561-1574, 1999].
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Vaccine Therapy for Patients With MelanomaInvestigation into the therapeutic use of vaccines in patients with metastatic melanoma is critically important because of the lack of effective conventional modalities. The most extensively studied melanoma vaccines in clinical trials are whole-cell preparations or cell lysates that contain multiple antigens capable of stimulating an immune response. Unfortunately, in the majority of studies, immune responses to these vaccines have not translated into a survival advantage. Advances in tumor cell immunology have led to the identification of candidate tumor cell antigens that can stimulate an immune response; this, in turn, has allowed for refinements in vaccine design. However, the exact tumor antigens that should be targeted with a specific vaccine are unknown. The univalent antigen vaccines, which have greater purity, ease of manufacturing, and reproducibility compared with polyvalent vaccines, may suffer from poorer efficacy due to immunoselection and appearance of antigen-negative clones within the tumor. Novel approaches to vaccine design using gene transfection with cytokines and dendritic cells are all promising. However, the induction of immune responses does not necessarily confer a therapeutic benefit. Therefore, these elegant newer strategies need to be studied in carefully designed clinical trials so that outcomes can be compared objectively with standard therapy. If survival is improved with these vaccine approaches, their ease of administration and lack of toxicity will firmly entrench active specific vaccine immunotherapy as a standard modality in the treatment of the melanoma patient.[ONCOLOGY 13(11):1561-1574, 1999].
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CYP2D6 Testing for Breast Cancer Patients: Is There More to the Story?The promise of pharmacogenetics is personalization of therapy for individuals through refinement of the risk/benefit profile of pharmaceuticals based on inherited gene mutations. Classic examples of the impact of pharmacogenetics in clinical practice include variants in dihydropyrimidine dehydrogenase and treatment with fluorouracil.
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HDAC Inhibitors in Cancer CareThe epigenetic control of gene expression has been shown to play an important role in cancer initiation, progression, and resistance. Thus, agents that modify the epigenetic environment of tumors will likely be an important addition to the anticancer arsenal. Specifically, there is much interest in modulating histone acetylation using a new class of drugs, histone deacetylase (HDAC) inhibitors. Preclinical data have demonstrated the efficacy of various HDAC inhibitors as anticancer agents, with the greatest effects shown when HDAC inhibitors are used in combination with other therapies. As a result of encouraging preclinical data, numerous HDAC inhibitors are being investigated in clinical trials either as monotherapies or in conjunction with other treatments such as chemotherapy, biologic therapy, or radiation therapy. In fact, vorinostat and depsipeptide, two actively studied HDAC inhibitors, were recently approved for the treatment of refractory cutaneous T-cell lymphoma. Although the use of HDAC inhibitors has generated great enthusiasm, a significant amount of work still needs to be done in order to understand their mechanisms of action, as well as to determine the appropriate patient characteristics and subsets of cancer for which HDAC inhibitors hold the most potential for effective treatment.
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Adjuvant Treatment of Non-Small-Cell Lung Cancer: How Do We Improve the Cure Rates Further?Surgery remains the initial treatment for patients with early-stage non-small-cell lung cancer (NSCLC). Additional therapy is necessary because of high rates of distant and local disease recurrence after surgical resection. Early trials of adjuvant chemotherapy and postoperative radiation were often plagued by small patient sample size, inadequate surgical staging, and ineffective or antiquated treatment. A 1995 meta-analysis found a nonsignificant reduction in risk of death for postoperative cisplatin-based chemotherapy. Since then, a new generation of randomized phase III trials have been conducted, some of which have reported a benefit for chemotherapy in the adjuvant setting. The role of postoperative radiation therapy remains to be defined. It may not be beneficial in early-stage NSCLC but still may have utility in stage IIIA disease. Improvement in survival outcomes from adjuvant treatment are likely to result from the evaluation of novel agents, identification of tumor markers predictive of disease relapse, and definition of factors that determine sensitivity to therapeutic agents. Some of the molecularly targeted agents such as the angiogenesis and epidermal growth factor receptor inhibitors are being incorporated into clinical trials. Preliminary results with gene-expression profiles and lung cancer proteomics have been promising. These techniques may be used to create prediction models to identify patients at risk for disease relapse. Molecular markers such as ERCC1 may determine response to treatment. All of these innovations will hopefully increase cure rates for lung cancer patients by maximizing the efficacy of adjuvant therapy.
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Adjuvant Treatment of Non-Small-Cell Lung Cancer: How Do We Improve the Cure Rates Further?Surgery remains the initial treatment for patients with early-stage non-small-cell lung cancer (NSCLC). Additional therapy is necessary because of high rates of distant and local disease recurrence after surgical resection. Early trials of adjuvant chemotherapy and postoperative radiation were often plagued by small patient sample size, inadequate surgical staging, and ineffective or antiquated treatment. A 1995 meta-analysis found a nonsignificant reduction in risk of death for postoperative cisplatin-based chemotherapy. Since then, a new generation of randomized phase III trials have been conducted, some of which have reported a benefit for chemotherapy in the adjuvant setting. The role of postoperative radiation therapy remains to be defined. It may not be beneficial in early-stage NSCLC but still may have utility in stage IIIA disease. Improvement in survival outcomes from adjuvant treatment are likely to result from the evaluation of novel agents, identification of tumor markers predictive of disease relapse, and definition of factors that determine sensitivity to therapeutic agents. Some of the molecularly targeted agents such as the angiogenesis and epidermal growth factor receptor inhibitors are being incorporated into clinical trials. Preliminary results with gene-expression profiles and lung cancer proteomics have been promising. These techniques may be used to create prediction models to identify patients at risk for disease relapse. Molecular markers such as ERCC1 may determine response to treatment. All of these innovations will hopefully increase cure rates for lung cancer patients by maximizing the efficacy of adjuvant therapy.
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Treatment of Aggressive Non-Hodgkin’s Lymphoma: A North American PerspectiveThe most common subtype of aggressive non-Hodgkin’s lymphomais diffuse large B-cell lymphoma (DLBCL). Diffuse large B-cell lymphomarepresents a heterogeneous entity, with 5-year overall survivalrates ranging from 26% to 73%. Microarray gene expression studieshave confirmed that biologically distinct subgroups exist within DLBCL,and can be correlated with outcome. Initial management is usuallyguided by stage of disease at presentation. Approximately 25% of patientswith DLBCL present with limited-stage disease and are treatedwith combined-modality therapy (brief chemotherapy and involved-fieldradiation). Most patients present with advanced-stage disease and requiretreatment with an extended course of chemotherapy. The CHOP(cyclophosphamide, doxorubicin HCl, vincristine [Oncovin], prednisone)chemotherapy regimen has been the mainstay of therapy sinceits development in the 1970s, as more intensive chemotherapy regimensfailed to show additional benefit. The era of monoclonal antibodieshas transformed treatment practices for aggressive lymphoma andhas led to a significant improvement in outcome. A randomized trialcomparing the use of rituximab (Rituxan), a chimeric anti-CD20 IgG1monoclonal antibody, combined with CHOP chemotherapy vs CHOPchemotherapy alone for elderly patients with advanced-stage DLBCLdemonstrated a significant benefit for the combination approach. Thisfinding has now been confirmed in two additional randomized, controlledtrials and a population-based analysis, making CHOP andrituximab the standard of care for all newly diagnosed patients withDLBCL. Despite this advance, newer therapies are needed and manyare under active investigation. The insights gained from molecular techniquessuch as gene expression profiling should permit identificationof additional lymphoma-specific therapeutic targets and the developmentof novel agents that take into account underlying biology andallow for greater tailoring of therapy.
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Quiz: The Role of CAR T Cells in Multiple MyelomaHow much do you know about the role of CAR T cells in multiple myeloma? Here's your chance to find out.
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Surgery in Non–Small-Cell Lung CancerSurgical management of the patient with non–small-cell lung cancer (NSCLC) is complex. When should stereotactic body radiation therapy be used? What are the advantages of video-assisted thoracic surgery? Test your knowledge in our latest quiz.
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Ji Luo Elucidates the CRISPR Gene Editing Technology, and How It May Affect Cancer Therapy in the FutureIn this interview we discuss the CRISPR technology currently being used to “edit” genes and when we might see the technology in mainstream practice.
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The Promise of Pharmacogenomics: Gemcitabine and PemetrexedAlthough no overall differences in survival have been observed betweenthe many chemotherapy combinations in non–small-cell lungcancer, the clinical application of mRNA expression levels of amplifiedgenes may disclose many genetic influences on cytotoxic drug sensitivityand enable clinicians to tailor chemotherapy according to eachindividual’s gene profile. Specifically, the assessment of ribonucleotidereductase subunit M1 and thymidylate synthase mRNA expression levelsmight select patients who benefit from gemcitabine (Gemzar) orpemetrexed (Alimta) combinations. Until recently, clinical prognosticfactors such as performance status, weight loss, and lactate dehydrogenasewere the only parameters used to predict chemotherapy responseand survival. However, accumulated data indicate that overexpressionof genes involved in cancer glycolysis pathways plays an important role,and might be an independent mechanism of chemoresistance. Thedysregulation of glycolytic genes is affected by growth signals involvingthe PI3K/Akt pathway and downstream genes such as hypoxiainduciblefactor-1-alpha. One can thus envision that substantial improvementsin therapeutic outcome could benefit from the integrationof tailored ribonucleotide reductase-dependent chemotherapy, ribonucleotidereductase antisense therapy, and targeted therapy.
Latest:
The Promise of Pharmacogenomics: Gemcitabine and PemetrexedAlthough no overall differences in survival have been observed betweenthe many chemotherapy combinations in non–small-cell lungcancer, the clinical application of mRNA expression levels of amplifiedgenes may disclose many genetic influences on cytotoxic drug sensitivityand enable clinicians to tailor chemotherapy according to eachindividual’s gene profile. Specifically, the assessment of ribonucleotidereductase subunit M1 and thymidylate synthase mRNA expression levelsmight select patients who benefit from gemcitabine (Gemzar) orpemetrexed (Alimta) combinations. Until recently, clinical prognosticfactors such as performance status, weight loss, and lactate dehydrogenasewere the only parameters used to predict chemotherapy responseand survival. However, accumulated data indicate that overexpressionof genes involved in cancer glycolysis pathways plays an important role,and might be an independent mechanism of chemoresistance. Thedysregulation of glycolytic genes is affected by growth signals involvingthe PI3K/Akt pathway and downstream genes such as hypoxiainduciblefactor-1-alpha. One can thus envision that substantial improvementsin therapeutic outcome could benefit from the integrationof tailored ribonucleotide reductase-dependent chemotherapy, ribonucleotidereductase antisense therapy, and targeted therapy.
Latest:
The Promise of Pharmacogenomics: Gemcitabine and PemetrexedAlthough no overall differences in survival have been observed betweenthe many chemotherapy combinations in non–small-cell lungcancer, the clinical application of mRNA expression levels of amplifiedgenes may disclose many genetic influences on cytotoxic drug sensitivityand enable clinicians to tailor chemotherapy according to eachindividual’s gene profile. Specifically, the assessment of ribonucleotidereductase subunit M1 and thymidylate synthase mRNA expression levelsmight select patients who benefit from gemcitabine (Gemzar) orpemetrexed (Alimta) combinations. Until recently, clinical prognosticfactors such as performance status, weight loss, and lactate dehydrogenasewere the only parameters used to predict chemotherapy responseand survival. However, accumulated data indicate that overexpressionof genes involved in cancer glycolysis pathways plays an important role,and might be an independent mechanism of chemoresistance. Thedysregulation of glycolytic genes is affected by growth signals involvingthe PI3K/Akt pathway and downstream genes such as hypoxiainduciblefactor-1-alpha. One can thus envision that substantial improvementsin therapeutic outcome could benefit from the integrationof tailored ribonucleotide reductase-dependent chemotherapy, ribonucleotidereductase antisense therapy, and targeted therapy.
Latest:
The Promise of Pharmacogenomics: Gemcitabine and PemetrexedAlthough no overall differences in survival have been observed betweenthe many chemotherapy combinations in non–small-cell lungcancer, the clinical application of mRNA expression levels of amplifiedgenes may disclose many genetic influences on cytotoxic drug sensitivityand enable clinicians to tailor chemotherapy according to eachindividual’s gene profile. Specifically, the assessment of ribonucleotidereductase subunit M1 and thymidylate synthase mRNA expression levelsmight select patients who benefit from gemcitabine (Gemzar) orpemetrexed (Alimta) combinations. Until recently, clinical prognosticfactors such as performance status, weight loss, and lactate dehydrogenasewere the only parameters used to predict chemotherapy responseand survival. However, accumulated data indicate that overexpressionof genes involved in cancer glycolysis pathways plays an important role,and might be an independent mechanism of chemoresistance. Thedysregulation of glycolytic genes is affected by growth signals involvingthe PI3K/Akt pathway and downstream genes such as hypoxiainduciblefactor-1-alpha. One can thus envision that substantial improvementsin therapeutic outcome could benefit from the integrationof tailored ribonucleotide reductase-dependent chemotherapy, ribonucleotidereductase antisense therapy, and targeted therapy.
Latest:
The Promise of Pharmacogenomics: Gemcitabine and PemetrexedAlthough no overall differences in survival have been observed betweenthe many chemotherapy combinations in non–small-cell lungcancer, the clinical application of mRNA expression levels of amplifiedgenes may disclose many genetic influences on cytotoxic drug sensitivityand enable clinicians to tailor chemotherapy according to eachindividual’s gene profile. Specifically, the assessment of ribonucleotidereductase subunit M1 and thymidylate synthase mRNA expression levelsmight select patients who benefit from gemcitabine (Gemzar) orpemetrexed (Alimta) combinations. Until recently, clinical prognosticfactors such as performance status, weight loss, and lactate dehydrogenasewere the only parameters used to predict chemotherapy responseand survival. However, accumulated data indicate that overexpressionof genes involved in cancer glycolysis pathways plays an important role,and might be an independent mechanism of chemoresistance. Thedysregulation of glycolytic genes is affected by growth signals involvingthe PI3K/Akt pathway and downstream genes such as hypoxiainduciblefactor-1-alpha. One can thus envision that substantial improvementsin therapeutic outcome could benefit from the integrationof tailored ribonucleotide reductase-dependent chemotherapy, ribonucleotidereductase antisense therapy, and targeted therapy.
Latest:
The Promise of Pharmacogenomics: Gemcitabine and PemetrexedAlthough no overall differences in survival have been observed betweenthe many chemotherapy combinations in non–small-cell lungcancer, the clinical application of mRNA expression levels of amplifiedgenes may disclose many genetic influences on cytotoxic drug sensitivityand enable clinicians to tailor chemotherapy according to eachindividual’s gene profile. Specifically, the assessment of ribonucleotidereductase subunit M1 and thymidylate synthase mRNA expression levelsmight select patients who benefit from gemcitabine (Gemzar) orpemetrexed (Alimta) combinations. Until recently, clinical prognosticfactors such as performance status, weight loss, and lactate dehydrogenasewere the only parameters used to predict chemotherapy responseand survival. However, accumulated data indicate that overexpressionof genes involved in cancer glycolysis pathways plays an important role,and might be an independent mechanism of chemoresistance. Thedysregulation of glycolytic genes is affected by growth signals involvingthe PI3K/Akt pathway and downstream genes such as hypoxiainduciblefactor-1-alpha. One can thus envision that substantial improvementsin therapeutic outcome could benefit from the integrationof tailored ribonucleotide reductase-dependent chemotherapy, ribonucleotidereductase antisense therapy, and targeted therapy.
Latest:
Anthracycline vs Nonanthracycline Adjuvant Therapy for Breast CancerThe treatment of breast cancer has progressed substantially overthe past 15 years. Data from randomized adjuvant trials have shownthat the risk of disease recurrence and death is significantly reducedwhen adjuvant chemotherapy and/or hormonal therapy is added to treatment.As new strategies are incorporated, one of the continued controversiesin patient management is whether adjuvant anthracyclinesshould be the preferred treatment for all patients. Data from randomizedand translational clinical trials have become available and arehelping to elucidate the proper role of anthracyclines, as well as their acuteand long-term toxicities. In most situations, an anthracycline is currentlypreferred, but other single and combination chemotherapies arecurrently under evaluation and appear promising for use in the adjuvantsetting. Continued breast cancer research using molecular markers(such as topoisomerase II–alpha and gene clusters) as predictors oftreatment response, could help individualize decisions regardingwhether to incorporate anthracyclines into adjuvant therapy regimens.
Latest:
Anthracycline vs Nonanthracycline Adjuvant Therapy for Breast CancerThe treatment of breast cancer has progressed substantially overthe past 15 years. Data from randomized adjuvant trials have shownthat the risk of disease recurrence and death is significantly reducedwhen adjuvant chemotherapy and/or hormonal therapy is added to treatment.As new strategies are incorporated, one of the continued controversiesin patient management is whether adjuvant anthracyclinesshould be the preferred treatment for all patients. Data from randomizedand translational clinical trials have become available and arehelping to elucidate the proper role of anthracyclines, as well as their acuteand long-term toxicities. In most situations, an anthracycline is currentlypreferred, but other single and combination chemotherapies arecurrently under evaluation and appear promising for use in the adjuvantsetting. Continued breast cancer research using molecular markers(such as topoisomerase II–alpha and gene clusters) as predictors oftreatment response, could help individualize decisions regardingwhether to incorporate anthracyclines into adjuvant therapy regimens.
Latest:
Anthracycline vs Nonanthracycline Adjuvant Therapy for Breast CancerThe treatment of breast cancer has progressed substantially overthe past 15 years. Data from randomized adjuvant trials have shownthat the risk of disease recurrence and death is significantly reducedwhen adjuvant chemotherapy and/or hormonal therapy is added to treatment.As new strategies are incorporated, one of the continued controversiesin patient management is whether adjuvant anthracyclinesshould be the preferred treatment for all patients. Data from randomizedand translational clinical trials have become available and arehelping to elucidate the proper role of anthracyclines, as well as their acuteand long-term toxicities. In most situations, an anthracycline is currentlypreferred, but other single and combination chemotherapies arecurrently under evaluation and appear promising for use in the adjuvantsetting. Continued breast cancer research using molecular markers(such as topoisomerase II–alpha and gene clusters) as predictors oftreatment response, could help individualize decisions regardingwhether to incorporate anthracyclines into adjuvant therapy regimens.
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Potency of CAR T-Cell Therapy for Myeloma May Vary by Disease StageCAR T cells are a more effective therapy if manufactured for patients with multiple myeloma prior to the onset of relapsed or refractory disease.
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ALLO-715, Off-the-Shelf CAR T-Cell Therapy, Produces Early Promise in Multiple MyelomaAn off-the-shelf CAR T-cell therapy that targets B-cell maturation antigen, ALLO-715, elicited responses in heavily pretreated patients with relapsed/refractory multiple myeloma in early findings from a first-in-human study presented at the 2020 ASH Meeting.
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ASCO Expert on the Analysis of Autologous Stem Cell Transplant in Relapsed DLBCLNirav Niranjan Shah, MD, discussed the use of autologous transplantation in patients with relapsed, chemosensitive DLBCL after the introduction of CAR T-cells.
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Cilta-Cel is Well-Tolerated with Durable Efficacy in R/R Multiple MyelomaThe recommended phase 2 dose of cilta-cel elicited deep and durable responses, along with a tolerable safety profile.
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Engineered CAR T Cells Show Promise in Multiple MyelomaChimeric antigen receptor T cells can eradicate large burdens of multiple myeloma, according to a new study presented at ASH.
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Targeted Therapy Proves Its Worth in Metastatic Kidney Cancer PatientsA new study looked at targeted vs nontargeted therapy in real world patients with renal cell carcinoma.
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Safety of Immune Checkpoint Inhibitors With Nephrectomy in mRCCA pilot study evaluated cytoreductive surgery combined with immune checkpoint therapy in patients with metastatic renal cell carcinoma.
