Phase I Study of the Plk1 Inhibitor BI 2536 Administered Intravenously on Three Consecutive Days in Advanced Solid Tumours

Frost, Annette; Mross, Klaus; Steinbild, Simone; Hedbom, Susanne; Unger, Clemens; Kaiser, Rolf; Trommeshauser, Dirk; Munzert, Gerd

doi:10.3747/co.19.866

Cited by 76 publications

(54 citation statements)

References 29 publications

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“…However, delayed toxicity, manifest as a drastic decrease in peripheral WBCs, was evident within 24-36 h after free drug administration. This type of toxicity was identical to that observed in human clinical trials (53)(54)(55). Although toxic to bone marrow, the free BI-2536 was able to induce a significant antitumor response, slowing tumor growth by ∼30% after two doses at its maximum tolerated dose (MTD) (Fig.…”

Section: Chemically Modified β-Cyclodextrins Can Encapsulate Small Hysupporting

confidence: 51%

Remote loading of preencapsulated drugs into stealth liposomes

Sur

Fries

Kinzler

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

124

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Loading drugs into carriers such as liposomes can increase the therapeutic ratio by reducing drug concentrations in normal tissues and raising their concentrations in tumors. Although this strategy has proven advantageous in certain circumstances, many drugs are highly hydrophobic and nonionizable and cannot be loaded into liposomes through conventional means. We hypothesized that such drugs could be actively loaded into liposomes by encapsulating them into specially designed cyclodextrins. To test this hypothesis, two hydrophobic drugs that had failed phase II clinical trials because of excess toxicity at deliverable doses were evaluated. In both cases, the drugs could be remotely loaded into liposomes after their encapsulation (preloading) into cyclodextrins and administered to mice at higher doses and with greater efficacy than possible with the free drugs.T here is currently wide interest in the development of nanoparticles for drug delivery (1-7). This area of research is particularly relevant to cancer drugs, wherein the therapeutic ratio (dose required for effectiveness to dose causing toxicity) is often low. Nanoparticles carrying drugs can increase this therapeutic ratio over that achieved with the free drug through several mechanisms. In particular, drugs delivered by nanoparticles are thought to selectively enhance the concentration of the drugs in tumors as a result of the enhanced permeability and retention (EPR) effect (8-18). The enhanced permeability results from a leaky tumor vascular system, whereas the enhanced retention results from the disorganized lymphatic system that is characteristic of malignant tumors.Much current work in this field is devoted to designing novel materials for nanoparticle generation. This new generation of nanoparticles can carry drugs-particularly those that are insoluble in aqueous medium-that are difficult to incorporate into conventional nanoparticles such as liposomes. However, the older generation of nanoparticles has a major practical advantage in that they have been extensively tested in humans and approved by regulatory agencies such as the Food and Drug Administration in the United States and the European Medicines Agency in Europe. Unfortunately, many drugs cannot be easily or effectively loaded into liposomes, thereby compromising their general use.In general, liposomal drug loading is achieved by either passive or active methods (9,(19)(20)(21)(22). Passive loading involves dissolution of dried lipid films in aqueous solutions containing the drug of interest. This approach can only be used for water-soluble drugs, and the efficiency of loading is often low. In contrast, active loading can be extremely efficient, resulting in high intraliposomal concentrations and minimal wastage of precious chemotherapeutic agents (9,23,24). In active loading, drug internalization into preformed liposomes is typically driven by a transmembrane pH gradient. The pH outside the liposome allows some of the drug to exist in an unionized form, able to migrate across the lipid bi...

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Section: Chemically Modified β-Cyclodextrins Can Encapsulate Small Hysupporting

confidence: 51%

Remote loading of preencapsulated drugs into stealth liposomes

Sur

Fries

Kinzler

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

124

View full text Add to dashboard Cite

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“…Furthermore, PLK1 is highly expressed in cancer cells but not in their normal cell counterparts (31,32), rendering this kinase a particularly attractive molecular target for cancer therapeutics. 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).…”

Section: Discussionmentioning

confidence: 99%

Personalizing the Treatment of Pediatric Medulloblastoma: Polo-like Kinase 1 as a Molecular Target in High-Risk Children

et al. 2013

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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.

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“…11 The pharmacological inhibition of PLK1 by BI 2536 is highly specific and has been proved to be well tolerated in intravenous dose regimens, efficiently crossed the brain-blood barrier, and inhibited tumor growth in vivo in several models, 12 and due to this, it has already been tested in patients in whom it has been seen to be safe in phase I clinical trials. 19,20 BI 2536 has been shown to have anticancer activities in different tumor cells, 21 mainly due to the G2/M arrest. Moreover, PLK1 has been proved to be essential to DNA damage repair, 22 and its depletion by BI 2536 could prevent the recovery from irradiation.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of Polo-Like Kinase 1 Induces Cell Cycle Arrest and Sensitizes Glioblastoma Cells to Ionizing Radiation

Pezuk

Brassesco

Morales

et al. 2013

Cancer Biotherapy and Radiopharmaceuticals

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Despite efforts to improve surgical, radiologic, and chemotherapeutic strategies, the outcome of patients with glioblastoma (GBM) is still poor. Polo-like kinase 1 (PLK1) is a serine/threonine kinase that plays key roles in cell cycle control and has been associated with tumor growth and prognosis. Here, we aimed at testing the radiosensitizing effects of the PLK1 inhibitor BI 2536 on eight GBM cell lines. For cell cycle analysis, T98G, U251, U343 MG-a, LN319, SF188, U138 MG, and U87 MG cell lines were treated with 10, 50, or 100 nM of BI 2536 for 24 hours. In addition, cell cultures exposed to BI 2536 50 nM for 24 hours were irradiated with c-rays from 60 Cobalt source at final doses of 2, 4, and 6 Gy. Combinatorial effects were evaluated through proliferation and clonogenic capacity assays. Treatment with BI 2536 caused mitotic arrest after 24 hours, and increased apoptosis in GBM cells. Moreover, our results demonstrate that pretreatment with this drug sensitized six out of seven GBM cell lines to different doses of c-irradiation as shown by decreased growth and abrogation of colony-formation capacity. Our data suggest that PLK1 blockage has a radiosensitizing effect on GBM, which could improve treatment strategies for this devastating tumor.

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Phase I Study of the Plk1 Inhibitor BI 2536 Administered Intravenously on Three Consecutive Days in Advanced Solid Tumours

Cited by 76 publications

References 29 publications

Remote loading of preencapsulated drugs into stealth liposomes

Remote loading of preencapsulated drugs into stealth liposomes

Personalizing the Treatment of Pediatric Medulloblastoma: Polo-like Kinase 1 as a Molecular Target in High-Risk Children

Inhibition of Polo-Like Kinase 1 Induces Cell Cycle Arrest and Sensitizes Glioblastoma Cells to Ionizing Radiation

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