Medulloblastoma: need for targeted treatment

The established role of VEGF signaling in promoting tumor angiogenesis has led to the development and clinical validation of several agents that selectively target this pathway in patients with advanced-stage malignancies. These include neutralizing anti-VEGF monoclonal antibodies, soluble VEGF receptors and small-molecule inhibitors of VEGF receptor function, administered either as monotherapy or in combination with chemotherapy. Several modes of action have been identified, such as inhibition of new vessel growth, regression of newly formed vasculature, alteration of tumor vessel function and direct effects on tumor cells. VEGF-targeting drugs currently play an important role in the treatment of cancer and their impact will probably further increase in the future.     

Quinacrine synergistically enhances the antivascular and antitumor efficacy of cediranib in intracranial mouse glioma

Background

Despite malignant glioma vascularity, anti-angiogenic therapy is largely ineffective. We hypothesize that efficacy of the antiangiogenic agent cediranib is synergistically enhanced in intracranial glioma via combination with the late-stage autophagy inhibitor quinacrine.

Methods

Relative cerebral blood flow and volume (rCBF, rCBV), vascular permeability (K^trans), and tumor volume were assessed in intracranial 4C8 mouse glioma using a dual-bolus perfusion MRI approach. Tumor necrosis and tumor mean vessel density (MVD) were assessed immunohistologically. Autophagic vacuole accumulation and apoptosis were assessed via Western blot in 4C8 glioma in vitro.

Results

Cediranib or quinacrine treatment alone did not alter tumor growth. Survival was only marginally improved by cediranib and unchanged by quinacrine. In contrast, combined cediranib/quinacrine reduced tumor growth by >2-fold (P < .05) and increased median survival by >2-fold, compared with untreated controls (P < .05). Cediranib or quinacrine treatment alone did not significantly alter mean tumor rCBF or K^trans compared with untreated controls, while combined cediranib/quinacrine substantially reduced both (P < .05), indicating potent tumor devascularization. MVD and necrosis were unchanged by cediranib or quinacrine treatment. In contrast, MVD was reduced by nearly 2-fold (P < .01), and necrosis increased by 3-fold (P < .05, one-tailed), in cediranib + quinacrine treated vs untreated groups. Autophagic vacuole accumulation was induced by cediranib and quinacrine in vitro. Combined cediranib/quinacrine treatment under hypoxic conditions induced further accumulation and apoptosis.

Conclusion

Combined cediranib/quinacrine treatment synergistically increased antivascular/antitumor efficacy in intracranial 4C8 mouse glioma, suggesting a promising and facile treatment strategy for malignant glioma. Modulations in the autophagic pathway may play a role in the increased efficacy.     

Evaluation of novel combined carbogen USPIO (CUSPIO) imaging biomarkers in assessing the antiangiogenic effects of cediranib (AZD2171) in rat C6 gliomas

The recently described combined carbogen USPIO (CUSPIO) magnetic resonance imaging (MRI) method uses spatial correlations in independent imaging biomarkers to assess specific components of tumor vascular structure and function. Our study aimed to evaluate CUSPIO biomarkers for the assessment of tumor response to antiangiogenic therapy. CUSPIO imaging was performed in subcutaneous rat C6 gliomas before and 2 days after treatment with the potent VEGF-signaling inhibitor cediranib (n = 12), or vehicle (n = 12). Histological validation of Hoechst 33342 uptake (perfusion), smooth muscle actin staining (maturation), pimonidazole adduct formation (hypoxia) and necrosis were sought. Following treatment, there was a significant decrease in fractional blood volume (-43%, p < 0.01) and a significant increase in hemodynamic vascular functionality (treatment altered ΔR(2) *(carbogen) from 1.2 to -0.2 s(-1) , p < 0.05). CUSPIO imaging revealed an overall significant decrease in plasma perfusion (-27%, p < 0.05) following cediranib treatment, that was associated with selective effects on immature blood vessels. The CUSPIO responses were associated with a significant 15% reduction in Hoechst 33342 uptake (p < 0.05), but no significant difference in vascular maturation or necrosis. Additionally, treatment with cediranib resulted in a significant 40% increase in tumor hypoxia (p < 0.05). The CUSPIO imaging method provides novel and more specific biomarkers of tumor vessel maturity and vascular hemodynamics, and their response to VEGF-signaling inhibition, compared to current MR imaging biomarkers utilized in the clinic. Such biomarkers may prove effective in longitudinally monitoring tumor vascular remodeling and/or evasive resistance in response to antiangiogenic therapy.     

New drugs in advanced non-small-cell lung cancer: searching for the correct clinical development

Importance of the field: Non-small-cell lung cancer (NSCLC) is one of the most active fields of research in oncology, with many drugs under clinical development. Most of these drugs offer novel mechanisms of action compared with drugs currently used in clinical practice.

Areas covered in this review: In this article, results recently obtained with most promising new drugs for advanced NSCLC are briefly described.

What the reader will gain: Most of the new drugs are currently being tested without a biomarker-driven selection, due to inadequate knowledge of predictive factors. A few drugs are tested in biologically selected samples of NSCLC patients. The results obtained with crizotinib in patients with ALK gene rearrangement are a good example of the speed with which biological discoveries can be translated to clinical testing.

Take home message: Emerging clinical and molecular data demonstrate that NSCLC is a family of related but distinct diseases. Some drugs tested in unselected population will probably obtain an incremental benefit compared to the current standard, but this will not substantially change the unfavorable prognosis of NSCLC patients. By contrast, unprecedented and much more cost-effective results can be obtained when targeted agents are administered following appropriate biomarker-driven patient selection.     

The role of Cediranib in ovarian cancer

Introduction: Treatment options for relapsed ovarian cancer have increased over the decade with the addition of targeted agents, such as PARP inhibitors and antiangiogenic agents. Bevacizumab, a monoclonal antibody binding vascular endothelial growth factor (VEGF), was the first anti-angiogenic agent to be incorporated in the ovarian cancer treatment landscape. Other molecules utilising different mechanisms of action to target angiogenesis have been developed, including cediranib, an oral potent inhibitor of VEGF Tyrosine Kinase Inhibitor that has demonstrated activity in both phase II and phase III studies.

Areas covered: Herein we will review cediranib as well as the evidence for its use in ovarian cancer, both as monotherapy and in combination with chemotherapy, PARP inhibitors and immunotherapy. A literature search was made in PubMed and on ClinicalTrials.gov for clinical trials with cediranib.

Expert opinion: The addition of cediranib for the treatment of ovarian cancer is promising, and has demonstrated a significant improvement in progression free survival in a phase III trial in combination with chemotherapy and maintenance treatment. Cediranib is currently being explored in ovarian cancer and other gynaecological malignancies aiming to improve patient care; further research will help define its role in standard clinical practice for patients with ovarian cancer.     

Effect of cediranib,an inhibitor of vascular endothelial growth factor receptor tyrosine kinase,in a mouse model of choroidal neovascularization

Background: This study was conducted to evaluate the effect of cediranib, an inhibitor of vascular endothelial growth factor receptor tyrosine kinase, in a mouse model of laser‐induced choroidal neovascularization. Methods: Choroidal neovascularization was induced in C57BL/6 mice by rupturing Bruch's membrane using laser photocoagulation. Following laser injury, the mice were divided into three groups and administered either vehicle, 1 mg/kg or 5 mg/kg of cediranib daily by oral gavage for 2 weeks. Two weeks after laser injury, the area of choroidal neovascularization lesions was measured by choroidal flat mounts using fluorescein‐labelled dextran. Immunofluorescence staining with isolectin IB4 was also used to quantify the choroidal neovascularization lesions. Results: Choroidal flat mount analysis revealed that orally administered cediranib reduced the extent of choroidal neovascularization. The groups treated with 1 and 5 mg/kg/day showed 57.2 and 66.0% reduction of choroidal neovascularization lesions, respectively, compared with the control group treated with vehicle alone (P = 0.012). The size of the fluorescently labelled choroidal neovascularization complex in cediranib‐treated groups was much smaller than that from vehicle‐treated group (P = 0.035). Conclusions: Cediranib inhibited laser‐induced choroidal neovascularization in mice and may have therapeutic potential for patients with neovascular age‐related macular degeneration.     

Risk of thyroid dysfunction in patients with solid tumors treated with VEGF receptor tyrosine kinase inhibitors: a critical literature review and meta analysis

We performed a systematic review and meta-analysis of thyroid function abnormalities associated with seven vascular endothelial growth factor receptor (VEGFR) targeted tyrosine kinase inhibitors (sorafenib, sunitinib, axitinib, cediranib, pazopanib, regorafenib and vandetanib). Eligible studies included randomized Phase II and III trials of patients with solid tumors on sorafenib OR sunitinib OR axitinib OR cediranib OR pazopanib OR regorafenib OR vandetanib; describing events of hypothyroidism or hyperthyroidism. Our search strategy yielded 195 potentially relevant citations on the seven agents from Pubmed/Medline, CENTRAL Cochrane registry and ASCO meeting library. After exclusion of ineligible studies, a total of 12 clinical trials were considered eligible for the meta-analysis, including six sunitinib studies, four cediranib studies and two axitinib studies. Patients treated with these agents had a significantly increased risk of all-grade hypothyroidism and the relative risk (RR) of all-grade hypothyroidism was 3.59 (95% CI = 2.40–5.38, p ≤ 0.0001). Exploratory subgroup analysis showed no effect of tumor types or agent used on the RR of hypothyroidism. Our meta-analysis has demonstrated that these three agents are associated with a significantly increased risk of all-grade hypothyroidism; with no difference – on subgroup analysis – between sunitinib and cediranib. Clinicians should be aware of these risks and perform regular thyroid function monitoring.     

Vascular endothelial growth factor receptor-2 inhibitor cediranib causes regression of endometriotic lesions in a rat model

Vascular endothelial growth factor (VEGF) receptor-2 plays an essential role in angiogenesis, and it also expressed in the glandular epithelium and stromal cells of ectopic endometrium. Cediranib is a protein tyrosine kinase inhibitor that potently inhibits VEGF receptor-2, but there is no study about its effects on the endometriosis. We induced endometriosis on both sides of the abdominal wall in 20 female Sprague-Dawley rats and randomly divided them into 2 groups. They were administered: cediranib 4 mg/kg/day (group 1), equal saline (group 2) for 12 days. Then, the lesion volumes were calculated, and Masson trichrome was used to detect fibrosis. Angiogenesis was evaluated by CD-31 immunohistochemistry and serum VEGF levels. Proliferation was indicated by proliferating cell nuclear antigen immunohistochemistry. Apoptosis was measured by a TUNEL assay and cleaved caspase-3 immunohistochemistry. In the treatment group, the lesion volumes were smaller (P < 0.05), and the degree of fibrosis was greater. The microvessel density was lower (P < 0.05) than control, however, serum VEGF was up-regulated by a negative feedback mechanism (P < 0.01). In addition, proliferation was significantly suppressed (P < 0.01), and apoptosis in the lesions was more obvious in the treatment group. These data indicated that cediranib can inhibit development of endometriotic lesions in rats.     

卵巢癌的治疗药物研究进展

卵巢癌是女性生殖器官常见的恶性肿瘤之一,其死亡率居妇科恶性肿瘤首位,且发病率逐年增加。全球新批准并上市的治疗卵巢癌的药物有贝伐单抗、曲贝替定、人参皂苷以及一些新制剂,处于研发后期的抗卵巢癌药物有奥拉帕尼、西地尼布、nintedanib、trebananib以及一些抗卵巢癌药的新剂型品种等。对近年来上市和处于研发后期的卵巢癌的治疗药物进行了详细介绍,同时对抗卵巢癌药的未来发展方向进行了展望,以期为抗卵巢癌药物的研发提供参考。