Abstract:Purpose: GSK461364 is an ATP-competitive inhibitor of polo-like kinase 1 (Plk1). A phase I study of two schedules of intravenous GSK461364 was conducted.Experimental Design: GSK461364 was administered in escalating doses to patients with solid malignancies by two schedules, either on days 1, 8, and 15 of 28-day cycles (schedule A) or on days 1, 2, 8, 9, 15, and 16 of 28-day cycles (schedule B). Assessments included pharmacokinetic and pharmacodynamic profiles, as well as marker expression studies in pretreatme… Show more
“…Future clinical studies should include the detection of pharmacodynamic biomarkers, such as phospho-histone H3, to validate Plk1 as the tumor target. In the first-in-humans phase I study of GSK461364 in advanced solid tumors, Plk1 inhibition in tumor cells was confirmed on the basis of the analysis of phospho-histone H3 expression in circulating tumor cells (59). Other promising biomarker assays for Plk1 inhibition in vivo have been developed, such as an immunohistochemical approach that measures serine 46-phosphorylation of the translational controlled tumor protein by Plk1 (62) and an ELISA-based assay that measures phosphorylation of the PBD-binding protein 1 (PBIP1, also known as MLF1 or CENP-U) by Plk1 (63).…”
Section: Discussionmentioning
confidence: 96%
“…The recommended phase II dose for GSK461364 was 225 mg on days 1, 8, and 15 in a 28-day cycle. Because of the high incidence (20%) of venous thromboembolism, GSK461364 should involve coadministration of prophylactic anticoagulation for further clinical evaluation (59).…”
Cytotoxic platinum-doublet chemotherapy that includes antimitotic agents is a current standard of care in advanced non-small cell lung cancer (NSCLC). Microtubule-targeting antimitotics, taxanes, and Vinca alkaloids are effective anticancer therapeutics that affect both dividing and nondividing cells. A new generation of antimitotic agents that target regulatory proteins-mitotic kinases and kinesins-has the potential to overcome the limitations related to the role of tubulin in nondividing cells that are associated with traditional antimitotics. This review concentrates on Polo-like kinase 1, a key regulator of mitosis, outlines a rationale for its development as an anticancer target, and discusses data from preclinical and clinical studies of Plk1 inhibitors with a particular focus on NSCLC. Clin Cancer Res; 17(20); 6459-66. Ó2011 AACR.
Current Treatment OptionsLung cancer is the second most common malignancy in the United States (219,440 cases) and was the leading cause of cancer-related mortality (159,390 deaths) in 2009 (1). Non-small cell lung cancer (NSCLC) represents 85% of all lung cancers (2); approximately 40% are diagnosed with advanced or metastatic disease (3) with a 5-year survival rate of 14% (4).Chemotherapy with platinum-based doublets (e.g. paclitaxel/carboplatin, docetaxel/cisplatin, gemcitabine/cisplatin, and pemetrexed/cisplatin) is the standard of care in first-line treatment of advanced NSCLC with median overall survival of approximately 8 months (5) and overall response rate of 19% to 30% (5, 6
“…Future clinical studies should include the detection of pharmacodynamic biomarkers, such as phospho-histone H3, to validate Plk1 as the tumor target. In the first-in-humans phase I study of GSK461364 in advanced solid tumors, Plk1 inhibition in tumor cells was confirmed on the basis of the analysis of phospho-histone H3 expression in circulating tumor cells (59). Other promising biomarker assays for Plk1 inhibition in vivo have been developed, such as an immunohistochemical approach that measures serine 46-phosphorylation of the translational controlled tumor protein by Plk1 (62) and an ELISA-based assay that measures phosphorylation of the PBD-binding protein 1 (PBIP1, also known as MLF1 or CENP-U) by Plk1 (63).…”
Section: Discussionmentioning
confidence: 96%
“…The recommended phase II dose for GSK461364 was 225 mg on days 1, 8, and 15 in a 28-day cycle. Because of the high incidence (20%) of venous thromboembolism, GSK461364 should involve coadministration of prophylactic anticoagulation for further clinical evaluation (59).…”
Cytotoxic platinum-doublet chemotherapy that includes antimitotic agents is a current standard of care in advanced non-small cell lung cancer (NSCLC). Microtubule-targeting antimitotics, taxanes, and Vinca alkaloids are effective anticancer therapeutics that affect both dividing and nondividing cells. A new generation of antimitotic agents that target regulatory proteins-mitotic kinases and kinesins-has the potential to overcome the limitations related to the role of tubulin in nondividing cells that are associated with traditional antimitotics. This review concentrates on Polo-like kinase 1, a key regulator of mitosis, outlines a rationale for its development as an anticancer target, and discusses data from preclinical and clinical studies of Plk1 inhibitors with a particular focus on NSCLC. Clin Cancer Res; 17(20); 6459-66. Ó2011 AACR.
Current Treatment OptionsLung cancer is the second most common malignancy in the United States (219,440 cases) and was the leading cause of cancer-related mortality (159,390 deaths) in 2009 (1). Non-small cell lung cancer (NSCLC) represents 85% of all lung cancers (2); approximately 40% are diagnosed with advanced or metastatic disease (3) with a 5-year survival rate of 14% (4).Chemotherapy with platinum-based doublets (e.g. paclitaxel/carboplatin, docetaxel/cisplatin, gemcitabine/cisplatin, and pemetrexed/cisplatin) is the standard of care in first-line treatment of advanced NSCLC with median overall survival of approximately 8 months (5) and overall response rate of 19% to 30% (5, 6
“…Our study tests the PLK1 small-molecule inhibitor, BI2536, which has been evaluated in patients with cancer (33,34). Various other small molecule inhibitors to PLK1 have been designed and evaluated in phase I/II clinical trials including BI2536, BI6727, Rigosertib, and GSK461364 (35)(36)(37)(38)(39). None of these trials have specifically addressed the possibility that PLK1 inhibitors may be beneficial for the treatment of brain tumors.…”
Medulloblastoma is the most common malignant brain tumor in children. This disease is heterogeneous and is composed of four subtypes of medulloblastoma [WNT, Sonic Hedgehog (SHH), Group 3, and Group 4]. An immediate goal is to identify novel molecular targets for the most aggressive forms of medulloblastoma. Polo-like kinase 1 (PLK1) is an oncogenic kinase that controls cell cycle and proliferation, making it a strong candidate for medulloblastoma treatment. In this study, pediatric medulloblastomas were subtyped in two patient cohorts (discovery cohort, n ¼ 63 patients; validation cohort, n ¼ 57 patients) using NanoString nCounter analysis and PLK1 mRNA was assessed. We determined that the SHH and Group 3 subtypes were independently associated with poor outcomes in children as was PLK1 using Cox regression analyses. Furthermore, we screened a library of 129 compounds in clinical trials using a model of pediatric medulloblastoma and determined that PLK1 inhibitors were the most promising class of agents against the growth of medulloblastoma. In patient-derived primary medulloblastoma isolates, the PLK1 small-molecule inhibitor BI2536 suppressed the self-renewal of cells with high PLK1 but not low PLK1 expression. PLK1 inhibition prevented medulloblastoma cell proliferation, selfrenewal, cell-cycle progression, and induced apoptosis. In contrast, the growth of normal neural stem cells was unaffected by BI2536. Finally, BI2536 extended survival in medulloblastoma-bearing mice with efficacy comparable with Headstart, a standard-of-care chemotherapy regimen. We conclude that patients with medulloblastoma expressing high levels of PLK1 are at elevated risk. These preclinical studies pave the way for improving the treatment of medulloblastoma through PLK1 inhibition. Cancer Res; 73(22); 6734-44. Ó2013 AACR.
“…These results suggest that PLK1 and PLK4 may represent attractive therapeutic targets for this subgroup of breast cancer. We then focused on PLK1 because several PLK1 inhibitors have been evaluated in clinical trials (8,27,34,35).…”
Section: Plk1 Is Overexpressed In Triple-negative Breast Cancermentioning
Breast cancers are composed of molecularly distinct subtypes with different clinical outcomes and responses to therapy. To discover potential therapeutic targets for the poor prognosis-associated triple-negative breast cancer (TNBC), gene expression profiling was carried out on a cohort of 130 breast cancer samples. Polo-like kinase 1 (PLK1) was found to be significantly overexpressed in TNBC compared with the other breast cancer subtypes. High PLK1 expression was confirmed by reverse phase protein and tissue microarrays. In triple-negative cell lines, RNAi-mediated PLK1 depletion or inhibition of PLK1 activity with a small molecule (BI-2536) induced an increase in phosphorylated H2AX, G 2 -M arrest, and apoptosis. A soft-agar colony assay showed that PLK1 silencing impaired clonogenic potential of TNBC cell lines. When cells were grown in extracellular matrix gels (Matrigel), and exposed to BI-2536, apoptosis was observed specifically in TNBC cancerous cells, and not in a normal cell line. When administrated as a single agent, the PLK1 inhibitor significantly impaired tumor growth in vivo in two xenografts models established from biopsies of patients with TNBC. Most importantly, the administration of BI-2536, in combination with doxorubicin þ cyclophosphamide chemotherapy, led to a faster complete response compared with the chemotherapy treatment alone and prevented relapse, which is the major risk associated with TNBC. Altogether, our observations suggest PLK1 inhibition as an attractive therapeutic approach, in association with conventional chemotherapy, for the management of patients with TNBC. Cancer Res; 73(2); 813-23. Ó2012 AACR.
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