VEGF blockade: Optimizing chemotherapy drug uptake

Share this article:
VEGF blockade: Optimizing chemotherapy drug uptake
VEGF blockade: Optimizing chemotherapy drug uptake

A growing arsenal of humanized monoclonal antibodies is providing targeted therapies that can disrupt specific molecular steps in carcinogenesis and the growth and spread of tumors—a critical step toward personalized clinical oncology. But the mechanisms of action of these agents are far more dauntingly complex, controversial, and less well-understood than those of systemic cytotoxic therapies, and researchers are still debating monoclonal antibodies' biomolecular effects and clinical outcomes—and even how best to measure these effects.1,2

Among the best-known monoclonal antibodies is bevacizumab (Avastin), which blocks receptor binding by vascular endothelial growth factor A (VEGF-A, or simply VEGF) and in this way disrupts tumor angiogenesis (the growth of new blood vessels). VEGF is over-expressed in many cancers, making it an attractive target for drug development over the past decade.2 Despite its early promise, anti-VEGF monotherapies have demonstrated relatively limited evidence of overall survival benefits for patients, prompting studies of its use in combination with standard anticancer chemotherapies.3

But now, a new study appears to challenge longstanding beliefs about how bevacizumab VEGF blockade affects tumor perfusion with cytotoxic chemotherapeutic agents.2 This and other new research suggests that both the timing of VEGF blockade and pairing anti-VEGF agents with c-Met-blocking monoclonal antibody therapies, demand further study as potentially crucial factors in optimizing VEGF blockade for cancer control.1

VEGF BLOCKADE: PROMISE AND CHALLENGES

The Food and Drug Administration (FDA) approved bevacizumab for use in combination with standard chemotherapy for metastatic colon cancer, for recurring glioblastoma multiforme brain cancer, and as a first-line therapy for advanced nonsquamous non-small-cell lung (NSCLC) and renal cell cancer.4,5 The FDA also provisionally approved bevacizumab for treatment of HER2-negative metastatic breast cancer, despite an FDA advisory panel's recommendation against approval.1

The provisional approval for bevacizumab's breast cancer indication was revoked in November 2011, citing insufficient evidence of efficacy and concern about adverse effects.6 Approvals for bevacizumab indications for colon, kidney, glioblastoma, and non-small-cell lung cancers were not affected.6 Subsequently published clinical trials have reported modest breast tumor pathological complete response to bevacizumab, with the variation possibly representing differences in study design and participant eligibility criteria.1 For example, one of these studies defined pathological complete response as the absence of residual tumor in both breast tissue and lymph nodes, yielding a 3.5% response rate; the other analyzed only tumor response within breast tissue, yielding a 6.3% response rate. When node tumor response was applied to data from the second study, the response rate fell to statistical nonsignificance.1

Compared to blood vessels in healthy tissues, tumors' vessels are profoundly disorganized and irregular.5 Tumor vessels are highly variable in size and cell wall structure, and tend to be tortuous, resulting in inefficient tumor perfusion with oxygen—and frequently impairing tumor uptake of anticancer drugs.5 Vascular inefficiency and tumor cell hypoxia can trigger increased angiogenesis and the development of more aggressive cancer clones.5

VEGF blockade therapy's central promise in combination with chemotherapy is that it inhibits angiogenesis and blood vessel branching, and triggers vascular pruning. This normalization of tumor vasculature is temporary but should improve drug perfusion by tumor tissues, Harvard Professor of Tumor Biology Rakesh K. Jain, PhD, and others have reasoned.7,8

Page 1 of 3
Share this article:
You must be a registered member of ONA to post a comment.

Sign Up for Free e-newsletters


What is this?

Regimen and Drug Listings

GET FULL LISTINGS OF TREATMENT Regimens and Drug INFORMATION

Bone Cancer Regimens Drugs
Brain Cancer Regimens Drugs
Breast Cancer Regimens Drugs
Endocrine Cancer Regimens Drugs
Gastrointestinal Cancer Regimens Drugs
Genitourinary Cancer Regimens Drugs
Gynecologic Cancer Regimens Drugs
Head and Neck Cancer Regimens Drugs
Hematologic Cancer Regimens Drugs
Lung Cancer Regimens Drugs
Other Cancers Regimens
Rare Cancers Regimens
Skin Cancer Regimens Drugs