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Oncology Reports Feb 2004Antisense oligonucleotide (ASO) technology offers a novel approach for the development of anti-cancer drugs. For example, the ASO aprinocarsen has been developed to... (Review)
Review
The role of protein kinase C-alpha in malignancies of the nervous system and implications for the clinical development of the specific PKC-alpha inhibitor aprinocarsen (Review).
Antisense oligonucleotide (ASO) technology offers a novel approach for the development of anti-cancer drugs. For example, the ASO aprinocarsen has been developed to specifically inhibit the intracellular signal transduction protein, protein kinase C-alpha (PKC-alpha). The clinical development of such specific or "new targeted" agents in cancer requires a comprehensive understanding of the target protein. This understanding is expected to improve the identification of patients who most likely will benefit from treatment with a specific inhibitor, such as aprinocarsen. In order to better understand the role of PKC-alpha in nervous system malignancies we here review the published literature on PKC-alpha expression in nervous system tumors, including glioblastoma multiforme. In pre-clinical experiments aprinocarsen had demonstrated anti-tumor activity, in particular in animal models of glioblastoma. Thus, clinical study CS10 with aprinocarsen was undertaken in patients with central nervous system (CNS) malignancies. The results of this study and considerations for future clinical studies in CNS tumors are reviewed.
Topics: Antineoplastic Agents; Central Nervous System Neoplasms; Enzyme Inhibitors; Humans; Nervous System Neoplasms; Oligonucleotides, Antisense; Phosphorothioate Oligonucleotides; Protein Kinase C; Protein Kinase C-alpha
PubMed: 14719093
DOI: No ID Found -
Annals of the New York Academy of... Dec 2003Antisense oligonucleotides (ASOs) offer a novel pharmacological platform to develop highly specific drugs. As shown by the clinical development of aprinocarsen, an ASO... (Clinical Trial)
Clinical Trial Review
Antisense oligonucleotides (ASOs) offer a novel pharmacological platform to develop highly specific drugs. As shown by the clinical development of aprinocarsen, an ASO directed against protein kinase C-alpha (PKC-alpha), this platform has made a remarkable advance from the bench to the bedside. This review summarizes the rationale of the early development of aprinocarsen and current clinical experience.
Topics: Humans; Oligonucleotides, Antisense; Protein Kinase C; Protein Kinase C-alpha; RNA, Messenger
PubMed: 14751841
DOI: 10.1196/annals.1281.029 -
Current Pharmaceutical Design 2004As our understanding of tumorigenesis increases, interference with the various signaling pathways of tumor cells has become an attractive approach to arresting tumor... (Review)
Review
As our understanding of tumorigenesis increases, interference with the various signaling pathways of tumor cells has become an attractive approach to arresting tumor cell growth and overcoming chemoresistance. Among many intracellular signaling proteins, protein kinase C (PKC) isoenzymes have been identified as possible targets to render tumor cells more susceptible to apoptosis and growth arrest. We review the known biology of the alpha-isoenzyme of PKC in different cancers to provide a rational approach for developing targeted therapies using PKC modulators, including aprinocarsen, an antisense oligonucleotide (ASO) against PKC-alpha.
Topics: Animals; Enzyme Inhibitors; Humans; Neoplasms; Oligodeoxyribonucleotides, Antisense; Protein Kinase C; Protein Kinase C-alpha; Thionucleotides
PubMed: 15180529
DOI: 10.2174/1381612043384376 -
Advances in Biological Regulation May 2021Protein kinase C α (PKCα) is a ubiquitously expressed member of the PKC family of serine/threonine kinases with diverse functions in normal and neoplastic cells. Early... (Review)
Review
Protein kinase C α (PKCα) is a ubiquitously expressed member of the PKC family of serine/threonine kinases with diverse functions in normal and neoplastic cells. Early studies identified anti-proliferative and differentiation-inducing functions for PKCα in some normal tissues (e.g., regenerating epithelia) and pro-proliferative effects in others (e.g., cells of the hematopoietic system, smooth muscle cells). Additional well documented roles of PKCα signaling in normal cells include regulation of the cytoskeleton, cell adhesion, and cell migration, and PKCα can function as a survival factor in many contexts. While a majority of tumors lose expression of PKCα, others display aberrant overexpression of the enzyme. Cancer-related mutations in PKCα are uncommon, but rare examples of driver mutations have been detected in certain cancer types (e. g., choroid gliomas). Here we review the role of PKCα in various cancers, describe mechanisms by which PKCα affects cancer-related cell functions, and discuss how the diverse functions of PKCα contribute to tumor suppressive and tumor promoting activities of the enzyme. We end the discussion by addressing mutations and expression of PKCα in tumors and the clinical relevance of these findings.
Topics: Antineoplastic Agents; Biomarkers, Tumor; Cell Line, Tumor; Cell Movement; Cell Proliferation; Cell Survival; Cell Transformation, Neoplastic; Cytoskeleton; Drug Resistance, Neoplasm; Gene Expression Regulation, Neoplastic; Humans; Isoenzymes; Mutation; Neoplasm Metastasis; Neoplasms; Phosphorothioate Oligonucleotides; Protein Kinase C-alpha; Signal Transduction
PubMed: 33307285
DOI: 10.1016/j.jbior.2020.100769 -
Investigational New Drugs Jun 2005Aprinocarsen is a specific antisense oligonucleotide inhibitor of protein kinase C-alpha. This study aimed to evaluate the response rate to combination therapy with... (Clinical Trial)
Clinical Trial Randomized Controlled Trial
Aprinocarsen is a specific antisense oligonucleotide inhibitor of protein kinase C-alpha. This study aimed to evaluate the response rate to combination therapy with aprinocarsen, gemcitabine and cisplatin, in chemonaive patients with advanced/metastatic NSCLC. Secondary objectives included comparison of response rate, time to event efficacy parameters, and toxicities on the 2 treatment arms. Patients with stage IV, or stage IIIB disease (N3 and/or pleural/pericardial effusion), were randomized to either control or experimental arm. Patients on both arms received gemcitabine 1250 mg/m2 on days 1 and 8, and cisplatin 80 mg/m2 on day 1 of a 3-week cycle. Additionally, on the experimental arm, aprinocarsen was administered as 2 mg/kg continuous iv infusion on days 1-14, every 21 days. A total of 18 enrolled patients were randomized on the 2 arms. Further enrollment was terminated in March 2003 as a result of a phase III trial suggesting that aprinocarsen did not have an added survival benefit when combined with paclitaxel and carboplatin therapy in patients with NSCLC. Patients received a median of 4 cycles on control arm and 2.5 cycles on experimental arm. The response rate was 16.7% in the experimental arm and 44.4% in the control arm. Most frequent grade 3/4 toxicities were hematologic, with a higher incidence of thrombocytopenia in the experimental arm (87.5% vs. 33.3%). Despite the 14-day continuous infusion schedule, infection rate was not increased in the experimental arm. The present study did not show any advantage, in response rate or secondary endpoints, with aprinocarsen; however, the toxicity was not unduly increased, and aprinocarsen regimen was safely administered.
Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Non-Small-Cell Lung; Cisplatin; Deoxycytidine; Female; Humans; Lung Neoplasms; Male; Middle Aged; Oligonucleotides, Antisense; Phosphorothioate Oligonucleotides; Gemcitabine
PubMed: 15868384
DOI: 10.1007/s10637-005-6736-x -
Investigational New Drugs Oct 2005A phase I study was performed to determine the maximum tolerated dose (MTD), safety profile and pharmacology of aprinocarsen (ISIS 3521), an antisense oligonucleotide to...
A phase I trial of aprinocarsen (ISIS 3521/LY900003), an antisense inhibitor of protein kinase C-alpha administered as a 24-hour weekly infusion schedule in patients with advanced cancer.
PURPOSE
A phase I study was performed to determine the maximum tolerated dose (MTD), safety profile and pharmacology of aprinocarsen (ISIS 3521), an antisense oligonucleotide to protein kinase C-alpha, in patients with refractory solid tumors.
EXPERIMENTAL DESIGN
Fourteen patients were treated in sequential cohorts of aprinocarsen by 24-hour continuous infusion (CIV), weekly, at doses of 6, 12, 18 and 24 mg/kg.
RESULTS
One grade 4 toxicity was observed, transient grade 4 neutropenia at 18 mg/kg. Grade 3 toxicities included neutropenia at 12 mg/kg, fever and hemorrhage at 18 mg/kg, and neutropenia, nausea, and chills at 24 mg/kg. Grade 2 toxicities included thrombocytopenia myalgias, chills, headache, fatigue, fever and nausea/vomiting. Mean prothrombin times and activated partial thromboplastin times (aPTT) increased by 10% and 29% from baseline (p = 0.006 and 0.005). Mean complement split products (Bb and C3a) increased 1.6-fold and 3.6-fold (from p = 0.014 and 0.004, respectively). These changes correlated with dose and were transient with recovery to baseline by day 7. Steady state plasma concentrations (Css) of aprinocarsen were achieved within four hours. Css better described changes in aPTT than dose. Clinical evidence of complement activation was not observed.
CONCLUSIONS
In contrast to 21-day protracted infusion schedules, delivery of aprinocarsen over a 24-hour infusion schedule showed concentration-dependent effects on coagulation and complement, which are consistent with nonclinical toxicology studies performed in the phosphorothioate DNA antisense drug class. These coagulation and complement changes resulted in a maximum tolerated dose 24 mg/kg.
Topics: Adult; Aged; Antineoplastic Agents; Blood Coagulation; Complement Activation; Cytokines; Drug Administration Schedule; Female; Humans; Male; Middle Aged; Neoplasms; Oligonucleotides, Antisense; Phosphorothioate Oligonucleotides; Protein Kinase C-alpha
PubMed: 16133798
DOI: 10.1007/s10637-005-2906-0 -
Lung Cancer (Amsterdam, Netherlands) May 2006The antisense oligonucleotide aprinocarsen specifically inhibits the transcription of protein kinase C-alpha. This study evaluated the response rate of the combination... (Randomized Controlled Trial)
Randomized Controlled Trial
The antisense oligonucleotide aprinocarsen specifically inhibits the transcription of protein kinase C-alpha. This study evaluated the response rate of the combination therapy of aprinocarsen, gemcitabine, and carboplatin in previously untreated patients with advanced non-small cell lung cancer (NSCLC). Secondary objectives included the measurement of time-to-event efficacy parameters and toxicity. Patients with stage IV or stage IIIB disease (N(3) and/or pleural/pericardial effusion) were treated with gemcitabine 1,250 mg/m(2) on days 1 and 8 and carboplatin AUC 5 on day 1 every 21 days. Aprinocarsen was administered as 2mg/kg/day continuous iv infusion on the first 14 days of each cycle, following the carboplatin treatment. A total of 36 patients received a median of 3 treatment cycles, with 10 patients completing 6 cycles. No complete response was observed, while partial response was seen in 25% of patients. Stable disease and progressive disease was observed in 36.1% and 22.2% of patients. The median overall survival was 8.3 months, and the median duration of progression-free survival was 5.7 months (95% CI, 3.2-7.1 months). Thrombocytopenia (78%) and neutropenia (50%) were the major grade 3/4 toxicities. Enrollment for this study was stopped and the study was terminated in March 2003 due to the results of a large phase III study, which suggested that aprinocarsen did not improve response or add survival benefit to chemotherapy in advanced NSCLC. The addition of aprinocarsen to gemcitabine+carboplatin therapy in patients with NSCLC showed moderate activity. However, this combination resulted in severe thrombocytopenia in the majority of patients.
Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Carboplatin; Carcinoma, Non-Small-Cell Lung; Deoxycytidine; Dose-Response Relationship, Drug; Drug Therapy, Combination; Female; Follow-Up Studies; Humans; Immunosuppressive Agents; Lung Neoplasms; Male; Middle Aged; Neoplasm Staging; Oligonucleotides, Antisense; Phosphorothioate Oligonucleotides; Protein Kinase C; Retrospective Studies; Ribonucleotide Reductases; Treatment Outcome; Gemcitabine
PubMed: 16507327
DOI: 10.1016/j.lungcan.2005.12.012 -
Neuro-oncology Jan 2005Protein kinase C alpha (PKC-alpha) is a cytoplasmic serine threonine kinase involved in regulating cell differentiation and proliferation. Aprinocarsen is an antisense... (Clinical Trial)
Clinical Trial
Efficacy and toxicity of the antisense oligonucleotide aprinocarsen directed against protein kinase C-alpha delivered as a 21-day continuous intravenous infusion in patients with recurrent high-grade astrocytomas.
Protein kinase C alpha (PKC-alpha) is a cytoplasmic serine threonine kinase involved in regulating cell differentiation and proliferation. Aprinocarsen is an antisense oligonucleotide against PKC-alpha that reduces PKC-alphain human cell lines and inhibits a human glioblastoma tumor cell line in athymic mice. In this phase 2 study, aprinocarsen was administered to patients with recurrent high-grade gliomas by continuous intravenous infusion (2.0 mg/kg/day for 21 days per month). Twenty-one patients entered this trial. Their median age was 46 years (range, 28-68 years), median Karnofsky performance status was 80 (range, 60-100), median tumor volume was 58 cm3 (range, 16-254 cm3), and histology included glioblastoma multiforme (n = 16), anaplastic oligodendroglioma (n = 4), and anaplastic astrocytoma (n = 1). The number of prior chemotherapy regimens included none (n = 3), one (n = 10), and two (n = 8). No tumor responses were observed. Patients on this therapy rapidly developed symptoms of increased intracranial pressure with increased edema, enhancement, and mass effect on neuroimaging. The median time to progression was 36 days, and median survival was 3.4 months. The observed toxicities were mild, reversible, and uncommon (grade 3 thrombocytopenia [n = 3] and grade 4 AST [n = 1]), and no coagulopathy or CNS bleeding resulted from this therapy. Plasma concentrations of aprinocarsen during the infusion exhibited significant interpatient variability (mean = 1.06 mug/ml; range, 0.34-6.08 mug/ml). This is the first study to use an antisense oligonucleotide or a specific PKC-alpha inhibitor in patients with high-grade gliomas. No clinical benefit was seen. The rapid deterioration seen in these patients could result from tumor growth or an effect of aprinocarsen on bloodbrain barrier integrity.
Topics: Adult; Aged; Astrocytoma; Blood-Brain Barrier; Brain Edema; Brain Neoplasms; Female; Humans; Infusions, Intravenous; Male; Middle Aged; Neoplasm Recurrence, Local; Oligonucleotides, Antisense; Phosphorothioate Oligonucleotides; Protein Kinase C; Protein Kinase C-alpha; Treatment Outcome
PubMed: 15701280
DOI: 10.1215/S1152851703000353 -
Melanoma Research Apr 2004In the 1980s, protein kinase C (PKC) was identified as a contributing factor in skin tumorigenesis. As drugs targeting specifically PKC have become available, the intent... (Review)
Review
In the 1980s, protein kinase C (PKC) was identified as a contributing factor in skin tumorigenesis. As drugs targeting specifically PKC have become available, the intent of this review was to assess the role of PKC, in particular of PKC-alpha in melanoma or other skin cancers. We reviewed and summarized published studies examining the role of PKC-alpha in the development of melanoma or other skin cancers. Most studies to date have been cell-culture based. In models of melanoma, PKC-alpha activation is typically associated with increased tumour cell proliferation, invasiveness and decreased differentiation, suggesting that PKC-alpha inhibitors, such as aprinocarsen, an antisense oligonucleotide directed against PKC-alpha, may be appropriate in the treatment of skin malignancies. Because of the recent developments on selective or specific PKC-alpha inhibitors, including aprinocarsen, there is a growing need to conduct further translational research, especially in melanoma patients, to identify the patient population that might benefit most from PKC-alpha targeted therapy.
Topics: Animals; Humans; Melanoma; Protein Kinase C; Protein Kinase C-alpha; Skin Neoplasms
PubMed: 15057036
DOI: 10.1097/00008390-200404000-00002 -
Cancer Jan 2004It has been postulated that protein kinase C alpha (PKC-alpha) plays a pivotal role in signal transduction in tumor cancer cells. Aprinocarsen, a 20-base antisense... (Clinical Trial)
Clinical Trial
A Phase II trial of aprinocarsen, an antisense oligonucleotide inhibitor of protein kinase C alpha, administered as a 21-day infusion to patients with advanced ovarian carcinoma.
BACKGROUND
It has been postulated that protein kinase C alpha (PKC-alpha) plays a pivotal role in signal transduction in tumor cancer cells. Aprinocarsen, a 20-base antisense oligonucleotide, has shown ability to inhibit PKC-alpha protein expression and inhibit tumor growth in human xenograft models. In a previous Phase I trial, the authors demonstrated the safety and some evidence of activity in ovarian carcinoma of aprinocarsen administered as a 21-day, continuous, intravenous infusion.
METHODS
In this Phase II trial, 36 patients with advanced ovarian carcinoma were treated with aprinocarsen at a dose of 2 mg/kg per day delivered as a 21-day, continuous, intravenous infusion. The primary objective was to determine the antitumor response, and the secondary objectives were to evaluate toxicity and to evaluate effects on quality of life (QOL).
RESULTS
Between September 1997 and December 1999, 36 patients (median age, 58 years) were enrolled in this trial. Patients were stratified into 2 groups: a platinum-sensitive group (n = 12 patients) and a platinum-resistant group (n = 24 patients). All 36 patients were evaluable for toxicity, and 27 patients were fully assessable for antitumor response after 2 cycles of therapy. All patients had received prior treatments. No objective responses were noted in the platinum-sensitive group. In the platinum-resistant group, 1 patient had some evidence of antitumor activity indicated by a decrease in serum CA 125 and stable disease on imaging studies for 8 months. No changes were noted in overall patient ratings for any of the five QOL domains.
CONCLUSIONS
When it was administered as a single agent, aprinocarsen did not have significant clinical activity in patients with advanced ovarian carcinoma. Further study may be warranted in combination with platinum-based regimens.
Topics: Aged; Antineoplastic Agents; Drug Resistance, Neoplasm; Female; Humans; Infusions, Intravenous; Middle Aged; Oligodeoxyribonucleotides, Antisense; Oligonucleotides, Antisense; Ovarian Neoplasms; Protein Kinase C; Protein Kinase C-alpha; Quality of Life; Self-Assessment; Thionucleotides
PubMed: 14716767
DOI: 10.1002/cncr.11909