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HER2 Overexpression and Paclitaxel Sensitivity in Breast Cancer: Therapeutic ImplicationsOverexpression by the HER2 gene plays a significant role in breast cancer pathogenesis, and the phenomenon is commonly regarded as a predictor of a poor prognosis. HER2 overexpression has been linked to sensitivity and/or resistance to hormone therapy and chemotherapeutic regimens, including CMF (cyclophosphamide, methotrexate, and fluoro-uracil) and anthracyclines. Studies of patients with advanced disease demonstrate that, despite the association of HER2 overexpression with poor prognosis, the odds of HER2-positive patients responding clinically to taxanes were greater than three times those of HER2-negative patients. Further studies in preclinical models used combination therapy for breast cancer cells that overexpress HER2, and the use of agents that interfere with HER2 function plus paclitaxel (Taxol) resulted in significant antitumor effects. [ONCOLOGY 11(Suppl):43-48, 1997]
Latest:
HER2 Overexpression and Paclitaxel Sensitivity in Breast Cancer: Therapeutic ImplicationsOverexpression by the HER2 gene plays a significant role in breast cancer pathogenesis, and the phenomenon is commonly regarded as a predictor of a poor prognosis. HER2 overexpression has been linked to sensitivity and/or resistance to hormone therapy and chemotherapeutic regimens, including CMF (cyclophosphamide, methotrexate, and fluoro-uracil) and anthracyclines. Studies of patients with advanced disease demonstrate that, despite the association of HER2 overexpression with poor prognosis, the odds of HER2-positive patients responding clinically to taxanes were greater than three times those of HER2-negative patients. Further studies in preclinical models used combination therapy for breast cancer cells that overexpress HER2, and the use of agents that interfere with HER2 function plus paclitaxel (Taxol) resulted in significant antitumor effects. [ONCOLOGY 11(Suppl):43-48, 1997]
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Gene Therapy for Head and Neck CancersDespite advances in surgery, radiotherapy, and chemotherapy, survival of patients with squamous cell carcinoma of the head and neck has not significantly improved over the past 30 years. Locally recurrent or refractory disease is particularly difficult to treat. Repeat surgical resection and/or radiotherapy are often not possible, and long-term results for salvage chemotherapy are poor. Recent advances in gene therapy have been applied to recurrent squamous cell carcinoma of the head and neck. Many of these techniques are now in clinical trials and have shown some efficacy. This article discusses the techniques employed in gene therapy and summarizes the ongoing protocols that are currently being evaluated in clinical trials. [ONCOLOGY 15(3):303-314, 2001]
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Gene Therapy for Head and Neck CancersDespite advances in surgery, radiotherapy, and chemotherapy, survival of patients with squamous cell carcinoma of the head and neck has not significantly improved over the past 30 years. Locally recurrent or refractory disease is particularly difficult to treat. Repeat surgical resection and/or radiotherapy are often not possible, and long-term results for salvage chemotherapy are poor. Recent advances in gene therapy have been applied to recurrent squamous cell carcinoma of the head and neck. Many of these techniques are now in clinical trials and have shown some efficacy. This article discusses the techniques employed in gene therapy and summarizes the ongoing protocols that are currently being evaluated in clinical trials. [ONCOLOGY 15(3):303-314, 2001]
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Gene Therapy for Head and Neck CancersDespite advances in surgery, radiotherapy, and chemotherapy, survival of patients with squamous cell carcinoma of the head and neck has not significantly improved over the past 30 years. Locally recurrent or refractory disease is particularly difficult to treat. Repeat surgical resection and/or radiotherapy are often not possible, and long-term results for salvage chemotherapy are poor. Recent advances in gene therapy have been applied to recurrent squamous cell carcinoma of the head and neck. Many of these techniques are now in clinical trials and have shown some efficacy. This article discusses the techniques employed in gene therapy and summarizes the ongoing protocols that are currently being evaluated in clinical trials. [ONCOLOGY 15(3):303-314, 2001]
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Extending Survival in Extensive-Stage Small-Cell Lung CancerIn this phase III trial, investigators assessed the clinical efficacy and safety of durvalumab with or without tremelimumab with etoposide and carboplatin or cisplatin chemotherapy followed by durvalumab with or without tremelimumab maintenance therapy compared with EP alone as first-line treatment in extensive-stage small-cell lung cancer.
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Non-Small-Cell Lung Cancer Adjuvant Therapy: Translating Data Into RealitySurgery 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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Monoclonal Antibodies in Advanced B-cell Lymphomashe treatment of B-cell malignancies has been revolutionized by the availability of safe and effective monoclonal antibodies. The addition of rituximab to standard chemotherapy regimens prolongs the survival of patients with diffuse large B-cell lymphoma (DLBCL) and follicular non-Hodgkin lymphoma. Nevertheless, indolent and mantle cell lymphomas remain incurable, and 30% to 40% of patients with DLBCL still die from their disease. Much ongoing research has focused on optimizing monoclonal antibody use, integrating them into multiagent regimens, and developing newer antibodies. Attempts to improve on the efficacy of monoclonal antibody–based therapy have included altering the dosing schedule, optimizing patient selection, maintenance therapy, improving upon the rituximab molecule, radioimmunotherapy, as well as combinations with cytotoxic molecules and other novel agents. Preliminary data with a number of treatment regimens are promising in indolent and aggressive lymphomas. The eventual goal of targeted therapies is to individualize treatment to increase response and survival, while reducing treatment-related toxicity.
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Adjuvant Endocrine Therapy for Breast Cancer: Longer Therapy and the Need for Personalized Treatment-Should We Treat Beyond the Data?In the future, we also need to improve our ability to personalize the duration of endocrine therapy, with a goal of optimizing patient selection for extended therapy. Hopefully, clinical-pathologic indices and predictive biomarkers similar to the Oncotype DX 12-gene recurrence score or the PAM50 risk of recurrence score for adjuvant chemotherapy will soon emerge to guide adjuvant endocrine therapy.
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p53 Tumor Suppressor Gene Therapy for CancerGene therapy has the potential to provide cancer treatments based on novel mechanisms of action with potentially low toxicities. This therapy may provide more effective control of locoregional recurrence in diseases like non–small-cell lung cancer (NSCLC) as well as systemic control of micrometastases. Despite current limitations, retroviral and adenoviral vectors can, in certain circumstances, provide an effective means of delivering therapeutic genes to tumor cells. Although multiple genes are involved in carcinogenesis, mutations of the p53 gene are the most frequent abnormality identified in human tumors. Preclinical studies both in vitro and in vivo have shown that restoring p53 function can induce apoptosis in cancer cells. High levels of p53 expression and DNA-damaging agents like cisplatin (Platinol) and ionizing radiation work synergistically to induce apoptosis in cancer cells. Phase I clinical trials now show that p53 gene replacement therapy using both retroviral and adenoviral vectors is feasible and safe. In addition, p53 gene replacement therapy induces tumor regression in patients with advanced NSCLC and in those with recurrent head and neck cancer. This article describes various gene therapy strategies under investigation, reviews preclinical data that provide a rationale for the gene replacement approach, and discusses the clinical trial data available to date. [ ONCOLOGY 13(Suppl 5):148-154, 1999]
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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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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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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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Identification and Treatment of Aggressive Thyroid Cancers (Part 2)In part 2, we address risk assessment and staging, findings that suggest the presence of aggressive tumors, recurrent/metastatic disease, and treatment with chemotherapy and external-beam radiotherapy. Experimental treatments utilizing molecular targets, redifferentiation agents, and gene therapy are covered briefly as well.
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Identification and Treatment of Aggressive Thyroid Cancers (Part 2)In part 2, we address risk assessment and staging, findings that suggest the presence of aggressive tumors, recurrent/metastatic disease, and treatment with chemotherapy and external-beam radiotherapy. Experimental treatments utilizing molecular targets, redifferentiation agents, and gene therapy are covered briefly as well.
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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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New Directions in the Treatment of Advanced Colorectal CancerAs the chemotherapy horizons have expanded in colorectal cancer with development of oxaliplatin (Eloxatin) and irinotecan (CPT-11, Camptosar), so too have our approaches to therapy. Numerous immunotherapy and gene
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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:
Investigating CAR T-Cell Signals May Lead to New ApproachesRecent studies on CAR T-cell immunotherapy, and the recent approval of a new agent, add to evidence supporting the efficacy of these therapies.
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Gene Editing Leads to Successful Outcome for Pediatric ALL PatientWaseem Qasim, MBBS, PhD, and his team began researching a novel strategy to enable “off-the-shelf”’ therapy with mismatched donor chimeric antigen receptor (CAR)19 T cells.
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Bristol Myers Squibb Withdraws Nivolumab Indication for Treatment of SCLCNivolumab was previously granted accelerated approval by the FDA for the treatment of patients with small cell lung cancer (SCLC) whose disease had progressed after platinum-based chemotherapy and at least 1 other line of therapy, but phase 3 trial results led to a decision to withdraw the indication.
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The Promise of Chimeric Antigen Receptor T-Cell TherapyIn this review, we will describe the mechanism of action of CAR T cells, discuss outcomes of current clinical trials, and highlight emerging directions for this exciting approach to cancer treatment.
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David Porter, MD, on Researching CAR-T to Bring to Autoimmune Disease and BeyondThe director of Cell Therapy and Transplant at Penn Medicine discussed his outlook on CAR T-cell therapy research and the future.
