VEGF

Anti-Angiogenic Therapy: Current Challenges and Future Perspectives

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abstract

Anti-angiogenic therapy is an old method to fight cancer that aims to abolish the nutrient and oxygen supply to the tumor cells through the decrease of the vascular network and the avoidance of new blood vessels formation. Most of the anti-angiogenic agents approved for cancer treatment rely on targeting vascular endothelial growth factor (VEGF) actions, as VEGF signaling is considered the main angiogenesis promotor. In addition to the control of angiogenesis, these drugs can potentiate immune therapy as VEGF also exhibits immunosuppressive functions. Despite the mechanistic rational that strongly supports the benefit of drugs to stop cancer progression, they revealed to be insufficient in most cases. We hypothesize that the rehabilitation of old drugs that interfere with mechanisms of angiogenesis related to tumor microenvironment might represent a promising strategy. In this review, we deepened research on the molecular mechanisms underlying anti-angiogenic strategies and their failure and went further into the alternative mechanisms that impact angiogenesis. We concluded that the combinatory targeting of alternative effectors of angiogenic pathways might be a putative solution for anti-angiogenic therapies.

Final Remarks

The failure of anti-VEGF strategies in the control of cancer can be in part related to two major factors. On one hand, the fact that the precise molecular mechanisms of cancer neo-angiogenesis still have secrets. On the other hand, because the abrogation of blood supply will also restrict drug delivery to the tumor, decrease their efficacy, and promote drug resistance [9]. In line, the paradox in the use of anti-angiogenic drugs arises from new findings showing that instead of eradicating blood supply, strategies focused on restoring the tumor vessels normalization would increase the delivery of therapeutic agents to cancer cells, improving the therapeutic efficacy and impairing cancer cells spread [125].

Interestingly, simvastatin, a statin with antioxidant properties, has been showed to reduce hypoxia-induced endothelium leakage and decrease ROS-induced HIF1α and VEGF expression, attenuating VEGF-derived tumor vessel hyperpermeability and improving cisplatin and cyclophosphamide efficacy [241]. In a theoretical scenario, cancer treatment might rely on multi-mechanisms targeting strategies focused on the induction of cancer cells death and in the promotion of tumor vascular regression or stabilization events (Figure 3). At the same time, these strategies will transform the remaining vessels into a more functional vascular network with decreased permeability, promoting drug delivery and impairing metastasis. Cancer cells under a certain threshold have adaptive antioxidant mechanisms controlling oxidative stress, however, above this threshold, ROS accumulation disrupts redox homeostasis and causes severe damage in cancer cells, ultimately leading to cell death [242]. Given these results, strategies to enhance lethal ROS production in cancer cells have a promising anti-cancer effect.

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Increased oxidative stress activates endothelial cells (ECs) and kills cancer cells, and antioxidant mechanisms can stabilize vessels and improve anti-cancer chemotherapy. (A) A pro-angiogenic oxidative microenvironment, through the increased generation of ROS, the accumulation of lipid peroxides and glutathione (GSH) depletion is implicated in the promotion of ECs hyperactivation, vessels leakiness, and cancer cells migration and intravasation. (B) ROS scavenging activity is anti-angiogenic, since on one hand, it impairs the ECs activation, and on other hand, it promotes vessels normalization, pivotal to impair metastasis and improve the delivery of chemotherapeutic agents.

Angiogenesis-based cancer therapeutic strategies must accompany the microenvironmental and metabolic drift, which tumor cells (malignant and stromal) undergo in order to progress. Therefore, by presenting different metabolic patterns and adaptive redox mechanisms, ECs and cancer cells would present a disparate behavior, and whereas oxidative stress activates ECs and stabilizes blood vessels that will be more competent in drugs delivery; cancer cells would be endangered by oxidative stress and by drugs aggression.

The toxicity of anti-VEGF agents when coupled with standard chemotherapeutics

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Abstract

Bevacizumab (Avastin®, Genentech, CA) was granted accelerated approval by the FDA for metastatic breast cancer in 2008. This occurred after the initial clinical trial, E2100, demonstrated an improvement in progression-free survival (PFS) and overall survival (OS) with the addition of bevacizumab to a standard chemotherapy. Unfortunately, the approval was rescinded in 2011 when two subsequent trials, AVADO and RIBBON-1, failed to show survival benefit. We compare and analyze the landmark trials E2100, AVADO and RIBBON-1, and suggest that the present-day clinical trial model may not be suited for the investigation of targeted therapies such as bevacizumab. The existing clinical trial model does not allow for modification of chemotherapeutic doses in a manner that maximizes the effect of biologic response modifiers and does not account for its “chemosensitizing” effect. The E2100, AVADO, and RIBBON-1 trials differed in the type and dose of chemotherapy, the dose and frequency of bevacizumab, and in the trial design, making it difficult to effectively compare and evaluate the results. The efficacy of combining bevacizumab with a maximum tolerated dose (MTD) of chemotherapy is also discussed in view of the observation that increased tumor response did not translate to an increase in survival. We suggest that even though angiogenesis inhibitors are non-toxic as monotherapies, they increase the toxicity of standard chemotherapy, and consequently a re-design of the now classic clinical trial model should be considered. Modifying the existing clinical trial model will lead to a more accurate evaluation of the safety and efficacy of bevacizumab and other biological agents in treating metastatic cancer.

Effects of Vascular Endothelial Growth Factor Signaling Inhibition on Human Erythropoiesis.

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Inhibition of vascular endothelial growth factor (VEGF) signaling increases red blood cell (RBC) counts, and erythropoiesis markers have been proposed to guide antiangiogenic therapy in humans. We analyzed RBC measurements in patients enrolled in three studies: a phase II trial of axitinib in thyroid cancer; a study of sorafenib in advanced solid tumors; and a randomized trial of fluorouracil, hydroxyurea, and radiation with and without bevacizumab for head and neck cancer. In the sorafenib trial, plasma erythropoietin concentrations were measured at baseline, day 8, and day 35. Over the first 84 days of treatment, RBC counts increased for each day on sorafenib (2.7 M/μ L [95% confidence interval (CI), 1.5–3.9]) and axitinib (4.3 M/μ L [95% CI, 2.2–6.5]). RBCs declined over the first 68 days of cytotoxic chemoradiotherapy alone (−12.8 M/μ L per day [95% CI, −15.7 to −9.8]) but less so with added bevacizumab (−7.2 M/μ L per day [95% CI, −9.5 to −4.9]). Erythropoietin levels increased, on average, by 9.5 mIU/mL between day 8 and day 35 of sorafenib exposure. No significant relationships between elevations in RBCs and changes in volume status or blood pressure or between elevations in erythropoietin and smoking status were found. VEGF signaling inhibition is associated with increased RBC and erythropoietin production in humans. The effects of these changes are subtle at physiologic doses and are unlikely to be clinically useful biomarkers for guiding the administration of or predicting treatment responses to VEGF pathway inhibitors.

  • Source: the Oncologist

 

New options for second-line therapy of advanced renal cancer.

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kidney

Several drugs targeting VEGF or mTOR pathways have been approved for treatment of advanced renal-cell carcinoma because of improvements noted in progression-free survival (PFS) in phase 3 trials.1 Validation of prognostic models showed that treatment with such drugs can lead to a median overall survival of around 43 months for patients in favourable risk categories and 23 months for patients in intermediate risk categories.2 With few exceptions, patients on first-line therapy progress and proceed to need one or more subsequent lines of targeted therapy. In a population-based study,3 patients in a favourable risk group had progression on first-line VEGF-targeted therapy after a median of 16·6 months (compared with 15 months for patients in an intermediate risk group) and progression after 6·2 months on second-line targeted therapy (5·5 months for intermediate risk). Two phase 3 trials4, 5 assessed outcomes after failure of a previous VEGF-targeted therapy to establish evidence for the mTOR-inhibitor everolimus and the selective inhibitor of VEGF receptors 1—3, axitinib. The AXIS trial5 is the only study that directly compared two active compounds (axitinib vs sorafenib) after failure of an approved first-line regimen. In AXIS, more than a third of patients had received cytokines and over half had received sunitinib as first-line therapy. Axitinib led to an improvement in median PFS compared with sorafenib in the intention-to-treat analysis. However, the difference in PFS for patients after sunitinib treatment based on investigator and independent review committee assessments was only slight. Data for overall survival, a secondary endpoint, were immature before the first report was published in 2011. Because guidelines and clinical practice favour targeted therapy in preference to cytokines as first-line treatment,1 axitinib is regarded as a treatment option for second-line therapy of advanced renal-cell carcinoma.5

In The Lancet Oncology, Robert Motzer and colleagues6 now report mature overall survival data for the AXIS trial. Such an analysis is important because crossover between the two study arms was not allowed. No significant differences in overall survival were noted between patients in both treatment arms who received the same first-line regimen (median overall survival 20·1 months [95% CI 16·7—23·4] with axitinib vs 19·2 months [17·5—22·3] with sorafenib; hazard ratio 0·969, 95% CI 0·800—1·174, p=0·3744). More than half the patients in each arm continued with a third-line treatment after progression on study drug and treatment after progression was allowed. This design confounded overall survival results and raises questions as to whether PFS is meaningful in this setting.7 Third-line therapy partly explains the long time interval noted between progression on second-line treatment and overall survival. However, inclusion of patients with a less aggressive tumour biology might have contributed to this outcome. Only a third of patients in the AXIS trial were Memorial Sloan Kettering Cancer Center (MSKCC) poor risk at entry,5 suggesting that individuals with rapid deterioration of performance or accelerated progression during first-line therapy are less likely to enter trials than are patients with more favourable risk profiles.

For patients previously treated with sunitinib in Motzer and colleagues’ study,6 median time on first-line therapy was about 10 months, with a median overall survival for all risk groups of 15·2 months (95% CI 12·8—18·3) for axitinib and 16·5 months (13·7—19·2) for sorafenib. Patients who received cytokines had first-line therapy for about 6 months and a median overall survival of 29·4 months (24·5—not assessable) for axitinib and 27·8 months (23·1—34·5) for sorafenib. After correction for the different length of first-line therapies, overall survival seemed to be increased by about 7—9 months in patients who had cytokines before VEGF-targeted therapy. Resistance to previous VEGF-targeted therapy, which might not be apparent in patients previously untreated with such an approach, cannot fully explain this difference. Motzer and colleagues noted a putative association of overall survival with length of previous sunitinib treatment for both axitinib and sorafenib, although there was substantial overlap in the 95% CIs.6 A retrospective Database Consortium analysis of 464 patients who had received two lines of VEGF-targeted therapies reported no correlation between first-line PFS and second-line PFS.8 Rather, a significant difference in multivariate analysis of baseline prognostic factors in favour of cytokine versus sunitinib pretreatment (HR 0·503, 95% CI 0·395—0·641; p<0·0001) suggested that patients with less advanced disease were most likely to start treatment with cytokines.6 However, information about the distribution of prognostic factors between patients who were pretreated with cytokines and sunitinib, which could have important implications for treatment sequences, is not provided in Motzer and colleagues’ study.

Data from trials and population-based analyses suggest that a ceiling has almost been reached in terms of outcome with present targeted therapies and prognosis that relies on models based on clinical factors.2 The mature AXIS data add axitinib to the choices for second-line treatment with similar outcome and different toxicity profiles.4—6 Despite prognostic factors assessed in the updated analysis and a correlation of development of hypertension during axitinib and sorafenib treatment with overall survival, the choice for a second-line drug or even treatment beyond progression at failure of first-line treatment remains an educated guess. The outcome of this study proves once again that renal-cell carcinoma is a heterogenous cancer9 that needs further research into predictive biomarkers to tailor treatment choices.

Source: Lancet

 

Magnesium sulfate therapy of preeclampsia: an old tool with new mechanism of action and prospect in management and prophylaxis.

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A disturbed balance between angiogenic and antiangiogenic growth factors is a highly accepted mechanism in the pathogenesis of pregnancy-induced hypertension and proteinuria, which is clinically known as preeclampsia (PE). We investigated the effect of magnesium sulfate (MgSO4) therapy on vascular endothelial growth factor (VEGF), placental growth factor (PlGF), nitric oxide (NO) metabolites, soluble fm-like tyrosine kinase-1 (sFlt-1) and endoglin levels in PE rats and the effect of this treatment on the feto-maternal outcome. The PE group showed hypertension, proteinuria and decreased number and weight of live pups relative to the control group. This result was associated with increased sFlt-1, VEGF receptor-2 (VEGFR-2), VEGFR-3 and endoglin levels but decreased NO metabolites. MgSO4 therapy ameliorated systolic hypertension and proteinuria and decreased sFlt-1, VEGFR-2, VEGFR-3 and endoglin levels but increased NO metabolites in the treated group. Physiological and biochemical changes and improved pup weight and viability were observed in the treated group. The vasodilator action of MgSO4 and increased NO production are expected to increase placental blood flow and help fetal nutrition and development. Relief of placental ischemia decreases the production of antiangiogenic growth factors and restores the bioavailability of angiogenic factors (PlGF and VEGF). These changes resulted in better fetal outcome and an improved clinical picture of PE. These findings are promising and encourage further study of the mechanism of action of MgSO4 to support its widespread use in the prevention and management of the etiopathological changes underlying the vast majority of the manifestations and complications of PE.

Source: Hypertension Research/nature.

 

 

 

Vandetanib Improves Progression-Free Survival in Differentiated Thyroid Cancer.

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Compared with placebo, this multikinase inhibitor nearly doubled PFS in patients with locally advanced, radioiodine-refractory differentiated disease in a phase II trial.

Effective treatments have been lacking for patients with radioiodine-resistant, locally advanced or metastatic differentiated thyroid carcinoma (papillary, follicular, or poorly differentiated). Over the past five years, numerous phase II studies of multitargeted kinase inhibitors such as sorafenib and vascular endothelial growth factor (VEGF) inhibitors such as axitinib have demonstrated clinical efficacy (JW Oncol Hematol Dec 2 2008). However, toxicity has been substantial with these agents, and data is limited because most of these reports are single-arm studies without a control group for comparison. More recently, vandetanib — an inhibitor of VEGF receptor, endothelial growth factor receptor, and RET proto-oncogene kinases — was shown in a phase III trial to significantly prolong progression-free survival (PFS) in patients with unresectable, locally advanced or metastatic medullary thyroid cancer (J Clin Oncol 2012 Jan 10; 30:134).

Now, investigators in Europe have conducted an industry-supported, multicenter, randomized, double-blind, placebo-controlled, phase II study to test the effectiveness and safety of vandetanib in patients with nonmedullary thyroid cancer. A total of 145 patients (age range, 23–87; performance status 2) with unresectable or metastatic undifferentiated thyroid cancer (papillary, follicular, or poorly differentiated without anaplastic features) who were deemed unsuitable for radioiodine therapy received either oral vandetanib (300 mg daily) or placebo until they experienced disease progression, death, or stable disease for 12 months.

PFS (the primary endpoint) was superior with vandetanib versus placebo (11.1 vs. 5.9 months; hazard ratio, 0.63; P=0.017). At 6 months, the disease control rate (including rates of complete response, partial response, and stable disease at 6 months) was also superior with vandetanib. However, overall survival (OS) was not improved. Of note, the PFS benefit was greater for patients with papillary thyroid cancer (16.2 months vs. 7.7 months), but when compared to other histologies, the difference was not statically significant. Grade 3 or greater toxicity was substantially higher in patients treated with vandetanib when compared to placebo. Of note, 74% of patients treated with vandetanib reported diarrhea, and 14% had QTc prolongation. Two treatment-related deaths occurred in the vandetanib group (from pneumonia and skin metastases hemorrhage) and one occurred in the placebo group (from pneumonia).

Comment: The data from this study bring up the ongoing debate regarding the use of pharmaceutical agents that demonstrate a benefit in PFS but fail to demonstrate an improvement in OS. The investigators state that phase III trials are needed to further define the clinical benefits of this agent in differentiated thyroid carcinoma. However, a cautionary note should be sounded. Given the toxicity of vandetanib, off-protocol use of this agent in differentiated thyroid carcinomas should be discouraged.

Source: Journal Watch Oncology and Hematology