Angiogenesis Inhibitors
Angiogenesis inhibitors block tumor blood vessel formation by targeting VEGF signaling, starving tumors of oxygen and nutrients.
Overview
Tumors require angiogenesis (new blood vessel formation) beyond a size of ~2mm to obtain oxygen and nutrients. Folkman's hypothesis that tumors can be starved by blocking angiogenesis led to the development of anti-angiogenic drugs. VEGF (vascular endothelial growth factor) is the dominant pro-angiogenic signal, making it the primary therapeutic target.
VEGF Biology
VEGF-A binds VEGFR-1 and VEGFR-2 on endothelial cells, stimulating proliferation, migration, vascular permeability, and survival. Tumor hypoxia drives HIF-1α transcription, which activates VEGF expression — creating a positive feedback loop. Additional pro-angiogenic factors include FGF, PDGF, and angiopoietins.
Anti-VEGF Antibodies
Bevacizumab (Avastin) binds and neutralizes VEGF-A, preventing receptor engagement. Approved in colorectal, NSCLC, ovarian, cervical, glioblastoma, and RCC. Toxicities include hypertension (managed with antihypertensives), proteinuria, thromboembolism (both arterial and venous), wound healing impairment (hold 4-6 weeks perioperatively), and bowel perforation/fistula (contraindicated in bowel-invasive tumors).
Ramucirumab binds VEGFR-2, blocking VEGF binding. Approved in gastric, NSCLC, colorectal, and HCC cancers.
Aflibercept (VEGF Trap) is a fusion protein that acts as a decoy receptor, binding VEGF-A, VEGF-B, and PlGF with high affinity. Used in colorectal cancer (FOLFIRI + aflibercept).
VEGFR TKIs
Sunitinib, sorafenib, pazopanib, and axitinib inhibit VEGFR kinase domains along with PDGFR and other kinases. Class effects: hypertension, hand-foot skin reaction, diarrhea, hypothyroidism, hepatotoxicity. These agents are standard of care in RCC, HCC (sorafenib, lenvatinib), and GIST.
Mechanisms of Resistance
Anti-angiogenic resistance occurs via: upregulation of alternative pro-angiogenic factors (FGF, angiopoietins), vessel co-option (tumors use existing vessels), pericyte-mediated vessel stabilization, and recruitment of bone marrow-derived pro-angiogenic cells.
Key Takeaways
- VEGF is the dominant pro-angiogenic signal; bevacizumab neutralizes VEGF-A
- Anti-VEGF therapy causes hypertension (pharmacodynamic effect), proteinuria, and impaired wound healing
- VEGFR TKIs simultaneously target VEGFR, PDGFR, and other kinases
- Anti-angiogenic resistance involves upregulation of alternative angiogenic pathways