Attacking Angiogenesis Anew: Novel Agents and Strategies Keep Focus on Complex Cancer Hallmark

A decade after bevacizumab (Avastin) debuted as the first anticancer therapy to target angiogenesis, new strategies to attack this hallmark of cancer continue to be a major research focus, resulting in the development of novel agents and fresh treatment settings for existing drugs.

Earlier this year, the FDA approved ramucirumab (Cyramza) for the treatment of patients with advanced gastric or gastroesophageal junction adenocarcinoma that progresses after prior therapies. Additional expansion in this field has come from new indications for previously approved agents, including bevacizumab, and several novel agents hold particular promise as treatments for gynecologic malignancies and non—small cell lung cancer (NSCLC).

Yet despite these advances, researchers are far from reaching a complete understanding of the intricacies of tumor vasculature, and significant barriers prevent antiangiogenic therapy from reaching its full potential.

Forming New Blood Vessels From Old

In contrast to neovascularization, in which new blood vessels are formed from circulating precursor endothelial cells, angiogenesis is the formation of new blood vessels from preexisting ones. While the former occurs predominantly during early development to establish a primitive vascular network, the latter allows for expansion of this network through branching, remodeling, and maturation.

In adults, a delicate balance between pro- and antiangiogenic signaling pathways is maintained so that angiogenesis is only switched on when required for physiological processes such as wound healing or menstruation.

The central angiogenic signaling pathway is governed by the vascular endothelial growth factor receptor (VEGFR). Three VEGFRs (VEGFR 1, 2, and 3) mediate the effects of their ligands; these ligands comprise a family of secreted growth factors, VEGF A through E, that induce proliferation and migration of endothelial cells, the primary cell type involved in the formation of new blood vessels.

What a Tangled Web It Weaves

In the early 1970s, Judah Folkman, MD, who was posthumously honored with a Giants of Cancer Care Award last year, became the founding father of the field of tumor angiogenesis with the observation that tumors are unable to grow beyond a cluster of cells of 2 mm to 3 mm without establishing their own vascular network. Beyond this size, the cells at the outermost perimeter of the tumor are far from the blood supply and begin to be starved of oxygen and nutrients.

In response to their hypoxic environment and genetic alterations that are common in cancer, it is believed that cancer cells induce an angiogenic switch; the cells of the tumor and its microenvironment begin to secrete angiogenic growth and survival factors that tip the balance toward proangiogenic signaling pathways, such as the VEGFR pathway. The new blood vessels are unlike normal vasculature; they are poorly developed, chaotic, and tortuous, which results in aberrant functions.

Key Angiogenesis Elements and Agents

FLT indicates Fms-like tyrosine kinase; KIT, mast/stem cell growth factor receptor; MAPK, mitogen-activated protein kinase; PDGFR, platelet-derived growth factor receptor; PRKC, protein kinase C; RAF1, proto-oncogene c-RAF; VEGF, vascular endothelial growth factor; VEGFR, vascular endothelial growth factor receptor.

Wehland M et al. Biomarkers for anti-angiogenic therapy. Int J Mol Sci. 2013;14(5):9338-9364. http://goo.gl/MdALSj. Adapted with permission.

The establishment of new blood vessels supplies the tumor with oxygen and nutrients, while at the same time providing a potential route for metastasis. In subsequent years, the key role of tumor angiogenesis was cemented when Douglas Hanahan and Robert Weinberg named the process as one of the essential biological capabilities required for the transformation of a normal cell to a cancerous one.

Many Roles for Bevacizumab

Given its critical role in angiogenic signaling, the VEGFR pathway has been a substantial focus for the development of therapies that would target aberrant signaling, prevent the formation of tumor vasculature, and cut off tumor blood supply.

In 2004, the FDA approved bevacizumab, a monoclonal antibody targeting VEGF-A, for the first-line treatment of metastatic colorectal cancer in combination with standard chemotherapy. It is now approved in a number of other tumor types and settings (Table).

Most recently, the FDA approved bevacizumab in combination with paclitaxel plus either cisplatin or topotecan as a treatment for patients with persistent, recurrent, or metastatic cervical cancer, based on the extension of overall survival (OS) in the GOG 240 study. Bevacizumab combined with chemotherapy increased OS to 16.8 months compared with 12.9 months for chemotherapy alone.

The FDA also is considering a new indication for bevacizumab in patients with recurrent, platinumresistant ovarian cancer. The agency granted the drug priority review status based on the phase III AURELIA trial, which demonstrated that bevacizumab with chemotherapy reduced the risk of disease progression by 52% compared with chemotherapy alone (6.7 months vs 3.4 months; HR = 0.48).

And in breast cancer, findings from two phase III trials presented at the 2014 ESMO Congress in September support the use of bevacizumab for patients with HER2-negative metastatic disease.

In the IMELDA study, the addition of capecitabine to maintenance bevacizumab resulted in a statistically significant advantage in median progression-free survival (PFS) compared with bevacizumab alone (11.9 months vs 4.3 months, respectively). In the TANIA trial, continuing or reintroducing bevacizumab to patients receiving chemotherapy after progression on first-line bevacizumab improved PFS compared with chemotherapy alone (6.3 months vs 4.2 months).

Notably, the FDA had approved bevacizumab in combination with paclitaxel in metastatic HER2-negative breast cancer in 2008 but revoked the indication about 3½ years later after concluding that the benefits did not outweigh the potential risks.

Search for Single-Agent Efficacy

Despite its established use in a range of cancer types, bevacizumab has limited efficacy as a single agent and its effects in combination with chemotherapy are often transient. Efforts to improve on the single-agent efficacy of antiangiogenic therapies have driven the creation of a number of other agents that target this process.

These include multitargeted tyrosine kinase inhibitors (TKIs), which are aimed at TKI receptors that play a key role in angiogenic signaling pathways, including platelet-derived growth factor receptors (PDGFRs) and fibroblast growth factor receptors (FGFRs).

First-generation TKIs include sorafenib (Nexavar), sunitinib (Sutent), and pazopanib (Votrient), which have shown efficacy in the treatment of renal cell carcinoma and other cancer types (Table). They continue to be evaluated in clinical trials, with varied success. In recent years, the FDA has approved several second- generation multitargeted TKIs, including axitinib (Inlyta), regorafenib (Stivarga), and vandetanib (Caprelsa). These agents also are the focus of ongoing phase III trials.

Finally, several multitargeted novel agents are being evaluated in late-state clinical testing. Like regorafenib, nintedanib and cediranib target FGFR in addition to VEGFR and PDGFR, while dovitinib is a TKI that targets solely FGFR3.

Nintedanib is pending approval from the European Medicines Agency in combination with docetaxel for patients with locally advanced, metastatic, or recurrent adenocarcinoma NSCLC after first-line chemotherapy.

Promising data from the randomized phase III LUME-Lung 1 trial, which involved 1314 patients, were presented at ESMO. After a prespecified number of events, there was a significant PFS improvement among patients who received nintedanib plus docetaxel as second-line therapy compared with those who received placebo plus docetaxel (3.4 months vs 2.7 months; P = .0019). An OS improvement reached statistical significance among patients with adenocarcinoma histology (HR = 0.83) and in patients with fast-growing adenocarcinoma (HR = 0.75), but not among the population as a whole.

Cediranib, on the other hand, failed in phase II trials and did not progress to phase III development for patients with NSCLC, but continues to be evaluated in a number of other cancer types. Phase II data presented at the 2014 American Society of Clinical Oncology Annual Meeting demonstrated that combining cediranib with the PARP inhibitor olaparib resulted in a neardoubling of median PFS among women with recurrent ovarian cancer compared with olaparib alone (17.7 months vs 9 months).

Meanwhile, dovitinib failed to show improvement over sorafenib in patients with metastatic RCC in phase III trial results reported last year, but remains under active investigation in other treatment settings.

Continuing Focus on VEGFR

VEGFR signaling remains a prime target for antiangiogenic therapy, and several of the next-generation antiangiogenic agents also target this pathway, but in ways than differ from bevacizumab. Ramucirumab is a monoclonal antibody like bevacizumab, but targets the receptor VEGFR2 rather than the ligand. In April, the FDA approved ramucirumab as a single agent for the treatment of advanced/metastatic gastric or gastroesophageal junction adenocarcinoma that has progressed after chemotherapy. Clinical trial findings demonstrated improved OS (5.2 months vs 3.8 months) for ramucirumab plus best supportive care (BSC) compared with placebo plus BSC among 355 patients with disease progression following fluoropyrimidine- or platinum-containing chemotherapy.

Ziv-aflibercept (Zaltrap) is a recombinant fusion protein consisting of the VEGF-binding portions of VEGFR1 and VEGFR2 fused to the complement region of human immunoglobulin. It has also been dubbed “VEGF trap” because it binds to circulating VEGFs and prevents them from binding to the VEGFRs. The FDA approved the agent in 2012 in combination with the chemotherapy regimen FOLFIRI as a treatment for patients with metastatic colorectal that is resistant to or has progressed following an oxaliplatin-based chemotherapy.

Alternative Antiangiogenic Strategies

In their quest for additional methods of targeting angiogenesis, researchers are exploring angiopoietins as anticancer targets. The family of vascular growth factors plays a role in angiogenic signaling, particularly angiopoietin 1 (Ang-1) and 2 (Ang-2), which act through the cognitive receptor tie-2.

Trebananib is an Ang-1/Ang-2-neutralizing peptibody designed to interfere with angiopoietin signaling by inhibiting the interaction between these growth factors and their receptor. It is currently undergoing late-stage clinical testing in ovarian cancer and is in earlier stages of development in a variety of different cancers, including NSCLC, recurrent glioblastoma, and breast cancer. Results from the TRINOVA-1 study of trebananib plus paclitaxel compared with placebo plus paclitaxel in patients with recurrent epithelial ovarian cancer were recently published in The Lancet Oncology. Over a median follow-up of 10.1 months, there was a significant improvement in PFS (7.2 months vs 5.4 months) in the trebananib arm. There was a trend toward improved OS, but this did not reach statistical significance.

Overcoming Barriers to Antiangiogenic Therapy

Although antiangiogenic therapy is an established treatment modality, this strategy still faces a number of barriers that limit its potential. As a class, the clinical benefit of these agents has been modest and they are associated with high costs and significant side effects. Furthermore, continued research in this field has highlighted the fact that the role of angiogenesis in tumor development is clearly vastly more complex than originally believed and the interaction between the tumor, the vasculature, and the tumor microenvironment remains poorly understood.

A significant concern that has emerged in recent years is the potential for antiangiogenic therapies to increase the metastatic potential of cancer cells as a result of the hypoxic environment they create.

Although the research is in its infancy, a number of potential mechanisms for this increased invasive potential have been posited, including enhanced transcription of the MET receptor that has a key role in invasion and metastasis. As a result, several clinical trials are evaluating the concurrent administration of antiangiogenic therapy with MET-targeting agents.

As with other treatment paradigms, resistance to therapy is a significant barrier to efficacy. Resistance typically occurs as a result of the tumor adapting to the antiangiogenic environment, and a number of different mechanisms of resistance have now been uncovered. Developing agents or combination strategies that can overcome resistance is a central focus of much research in this field.

The failure to identify reliable biomarkers that consistently predict clinical efficacy for antiangiogenic therapy has also proved to be a significant hurdle. Researchers continue to search for molecular signatures that may prove useful in this respect.

Indeed, researchers in Singapore recently reported the development of a molecular test kit for predicting treatment and survival outcomes among patients with clear cell RCC, including among those treated with antiangiogenic therapies. Scientists from the Institute of Bioengineering and Nanotechnology, Singapore General Hospital, and National Cancer Centre Singapore reported in European Oncology that they have co-developed an 8-gene molecular assay in formalin-fixed paraffin-embedded tissue.

For patients receiving antiangiogenic TKI therapy, the prognostic classification was associated with radiologic response to treatment and prolonged survival on TKI therapy.

Jane de Lartigue, PhD, is a freelance medical writer and editor based in Davis, California.

Key Research

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