Article

Targeting aurora kinases with danusertib (PHA-739358) inhibits growth of liver metastases from gastroenteropancreatic neuroendocrine tumors in an orthotopic xenograft model.

I. Medizinische Klinik, Diagnostische und Interventionelle Radiologie, II. Medizinische Klinik, Onkologisches Zentrum, Universitätsklinikum Hamburg-Eppendorf; Labor Lademannbogen, Hamburg, Germany.
Clinical Cancer Research (Impact Factor: 7.84). 07/2012; 18(17):4621-32. DOI:10.1158/1078-0432.CCR-11-2968
Source: PubMed

ABSTRACT Aurora kinases play a crucial role in cell-cycle control. Uncontrolled expression of aurora kinases causes aneuploidy and tumor growth. As conservative treatment options for advanced gastroenteropancreatic neuroendocrine tumors (GEP-NET) are disappointing, aurora kinases may be an interesting target for novel therapeutic strategies.
Human GEP-NETs were tested for aurora kinase expression. The efficacy of the new aurora kinase inhibitor danusertib was evaluated in two human GEP-NET cell lines (BON1 and QGP) in vitro and in vivo.
The majority of ten insulinomas and all 33 nonfunctional pancreatic or midgut GEP-NETs expressed aurora A despite a mostly high degree of cell differentiation. Both human GEP-NET cell lines expressed aurora kinase A and B, and high Ser10 phosphorylation of histone H3 revealed increased aurora B activity. Remarkably, danusertib led to cell-cycle arrest and completely inhibited cell proliferation of the GEP-NET cells in vitro. Decreased phosphorylation of histone H3 indicated effective aurora B inhibition. In a subcutaneous murine xenograft model, danusertib significantly reduced tumor growth in vivo compared with controls or mice treated with streptozotocine/5-fluorouracil. As a consequence, decreased levels of tumor marker chromogranin A were found in mouse serum samples. In a newly developed orthotopic model for GEP-NET liver metastases by intrasplenic tumor cell transplantation, dynamic MRI proved significant growth inhibition of BON1- and QGP-derived liver metastases.
These results show that danusertib may impose a new therapeutic strategy for aurora kinase expressing metastasized GEP-NETs.

0 0
 · 
0 Bookmarks
 · 
93 Views
  • [show abstract] [hide abstract]
    ABSTRACT: Enteropancreatic (EP) neuroendocrine carcinomas (NECs) represent relatively rare and heterogeneous malignancies. They are the most common group among neuroendocrine tumors (NETs). In most cases they are advanced at diagnosis and slow-growing, therefore conditioning a better prognosis compared with non neuroendocrine carcinomas from the same sites. No standard medical therapy exists, except for somatostatin analogs in functioning tumors, and octreotide LAR in functioning or non functioning well differentiated NECs from small bowel. Several systemic therapeutic options exist, including chemotherapy, somatostatin analog, interferon, peptide receptor radionuclide therapy (PRRT), and molecular targeted drugs. Among them some therapies have specific biological tumor targets and can be defined as "biological targeted therapies". This review focuses on the status of EP NECs targeted therapies in the light of recent advances. Somatostatin receptors (SSTRs) are the first therapeutic target detected in EP NECs. Through them SS analogs and PRRT act, producing symptomatic, biochemical, and, to a lesser extent, antiproliferative effects. New SS analogs, covering a higher number of SSTR subtypes, were developed, including pasireotide (SOM230), which controls 25% of carcinoid syndromes resistant to full dose octreotide LAR. Chimeric analogs, which bind SSTR2/SSTR5 and dopamine-2 receptor subtype (D2), are in preclinical phase of development. Among the numerous molecular targeted agents investigated in NETs, mTOR inhibitors and VEGF/VEGFR/PDGFR inhibitors are in most advanced clinical phase of investigation. In particular, everolimus, sunitinib, and bevacizumab are all studied in phase III trials. Both everolimus and sunitinib produced significant survival benefit versus placebo in advanced progressing well-differentiated pancreatic NECs. Sunitinib data have been presented at the last ASCO in June 2010, and everolimus data will be presented at next ESMO in September 2010.
    Cancer Treatment Reviews 11/2010; 36 Suppl 3:S87-94. · 6.02 Impact Factor
  • [show abstract] [hide abstract]
    ABSTRACT: Tumors derived from hormone-producing cells are generally highly differentiated, and vast experience indicates benefit with combinations of surgical and medical treatment for metastatic disease. Tumor debulking surgery is an accepted approach for reducing hormonal symptoms and to establish better conditions for medical treatment. Radiofrequency treatment (RF), a novel method for destroying liver tumors, was used to treat 43 liver metastases in 21 patients with endocrine tumors (12 with midgut carcinoid disease; 4 with nonfunctional endocrine pancreatic tumors; 1 with a VIPoma; 1 with a glucagonoma; 1 with a gastrinoma; 2 with adrenal carcinomas). Among these patients we treated with intention to cure in 14 by RF alone or RF plus surgery. Ablation was performed either percutaneously or intraoperatively using a cooled-tip needle, applying 50 to 90 watts over 10 to 12 minutes under ultrasound guidance. Contrast-enhanced computed tomography, liver function tests, and tumor markers were followed before and after RF. There were two complications: One patient suffered from conservatively treated bile leakage, and another had pleural effusion and fever for 7 days post-RF. Two lesions developed signs of incomplete necrosis after 6 months, yielding a local recurrence rate of (4.6%). Of the 15 patients treated with curative intent, we attained cure (i.e., no residual macroscopic tumor) in 4 patients. We conclude that RF using cooled-tip needles is safe and efficient; it may be performed percutaneously and intraoperatively; and it may expand the indications for liver resection.
    World Journal of Surgery 09/2002; 26(8):1052-6. · 2.23 Impact Factor
  • Source
    [show abstract] [hide abstract]
    ABSTRACT: Targeted radiopeptide therapy with (90)Yttrium- or (177)Lutetium-labeled somatostatin analogs has been proven to improve significantly quality of life and survival in patients suffering from metastatic or unresectable neuroendocrine tumors (NETs). Roughly 25% of patients achieve partial remission; progression-free survival is estimated to be 30 to 40 months. A wide range of protocols using different somatostatin analogs, isotopes, injected activity per cycle of administration, and number of cycles are reported. More patient-based therapy protocols are under development, taking into consideration the complexity of NET cell biology, dosimetric issues, and the availability of different radiolabeled analogs. This article reviews the effectiveness and safety of the different protocols and discusses several clinical algorithms used in an attempt to optimize targeted radiopeptide therapy.
    Endocrinology and metabolism clinics of North America 03/2011; 40(1):187-204, ix-x. · 3.56 Impact Factor

Full-text

View
10 Downloads
Available from
Aug 27, 2013