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In the U.S., there are currently thirteen approved
anti-cancer therapies with recognized antiangiogenic properties in oncology. These
agents, which interrupt critical cell signaling pathways involved in tumor
angiogenesis and growth, comprise three primary categories: 1) monoclonal
antibodies directed against specific proangiogenic growth factors
and/or their receptors; and 2) small molecule tyrosine kinase
inhibitors (TKIs) of multiple proangiogenic growth factor receptors; 3) inhibitors of mTOR (mammalian target of rapamycin). In addition, at least two other approved angiogenic agents may indirectly inhibit angiogenesis through mechanisms that are not completely understood. Finally, in the field of dermatology, there are several agents used for neoplasms of the skin.
Monoclonal
Antibody Therapies
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| One monoclonal antibody therapy is approved to treat several tumor types: bevacizumab (Avastin). |
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Bevacizumab
(Avastin |
Description |
| Genentech |
A humanized monoclonal
antibody that binds biologically active forms of vascular endothelial
growth factor (VEGF) and prevents its interaction with VEGF
receptors (VEGFR-1 and VEGFR-2), thereby inhibiting endothelial
cell proliferation and angiogenesis. |
| Approved
indications |
Metastatic colorectal
cancer (mCRC), non-small cell lung cancer (NSCLC), advanced breast cancer (Europe), glioblastoma, metastatic renal cell cancer (RCC), advanced ovarian cancer (Europe).
- In combination
with 5-FU-based chemotherapy as first-line and second-line
treatment of mCRC.
- In combination
with carboplatin and paclitaxel as first-line treatment
of patients with unresectable, locally advanced, recurrent
or metastatic non-squamous NSCLC.
- In combination with paclitaxel as first-line treatment in patients with locally recurrent or metastatic breast cancer (Europe only).
- Second-line treatment of patients with glioblastoma following temozolomide failure.
- In combination with interferon-alfa as first-line treatment of RCC.
- In combination with chemotherapy as first line treatment in patients with newly diagnosed, advanced ovarian cancer (Europe only).
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Small Molecule Tyrosine Kinase Inhibitors (TKIs)
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| Seven TKIs with antiangiogenic activity are currently approved as anticancer therapies: axitinib (Inlyta), cabozantinib (Cometriq), pazopanib (Votrient), regorafenib (Stivarga), sorafenib (Nexavar), sunitinib (Sutent), and vandetanib (Caprelsa). |
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Axitinib
(Inlyta |
Description |
| Pfizer |
Oral multikinase inhibitor that targets VEGFR-1, -2, -3. |
| Approved
indications: |
| Advanced renal cell carcinoma after failure of one prior systemic therapy.
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Cabozantinib
(Cometriq |
Description |
| Exelixis |
Small molecule tyrosine kinase inhibitor of c-Met and VEGFR2. |
| Approved
indications: |
| Progressive, metastatic medullary thyroid cancer.
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Pazopanib
(Votrient |
Description |
| GlaxoSmithKline |
Small molecule TK inhibitor of VEGF, PDGFR and c-kit |
| Approved
indications: |
Advanced renal cell carcinoma
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Regorafenib
(Stivarga |
Description |
| Bayer |
Oral multikinase inhibitor that targets VEGFR-1, -2, -3, TIE2, PDGFR, and FGFR, KIT, RET, RAF, BRAF, and BRAFV600E. |
| Approved
indications: |
| Patients with metastatic colorectal cancer (mCRC) who have ho had progressed after all approved standard therapies.
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Sorafenib
(Nexavar |
Description |
Bayer
Onyx |
Small molecule TK
inhibitor of VEGFR-1, VEGFR-2, VEGFR-3, PDGFR-ß, and Raf-1. |
| Approved
indications: |
Advanced renal cell carcinoma, advanced hepatocellular carcinoma.
- Treatment of unresectable hepatocellular carcinoma.
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Sunitinib
(Sutent |
Description |
| Pfizer |
Small molecule TK inhibitor of VEGFR-1, VEGFR-2, VEGFR-3, PDGFR- ß, and RET. |
| Approved
indications: |
Advanced renal cell
carcinoma, GIST, pancreatic neuroendocrine tumors
- Treatment of gastrointestinal stromal tumor (GIST) after disease progression on or intolerance to imatinib mesylate.
- Progressive neuroendocrine cancerous tumors located in the pancreas that cannot be removed by surgery or that have spread to other parts of the body (metastatic)
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Vandetanib
(Caprelsa |
Description |
| AstraZeneca |
Small molecule TK inhibitor of VEGFR and EGFR |
| Approved
indications: |
Medullary Thyroid Cancer
- Late-stage (metastatic) medullary thyroid cancer in adult patients who are ineligible for surgery.
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Inhibitors of mTOR
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| Two mTOR inhibitors, temsirolimus (Torisel) and everolimus (Afinitor), are currently approved as anti-cancer therapy. |
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Temsirolimus
(Torisel |
Description |
| Wyeth |
A small molecule
inhibitor of mTOR (mammalian target of rapamycin), part of the PI3 kinase/AKT pathway involved
in tumor cell proliferation and angiogenesis. |
| Approved
indications |
Advanced renal
cell carcinoma, Relapsed or refractory mantle cell lymphoma/Non-Hodgkins Lymphoma (European Union)
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Everolimus
(Afinitor |
Description |
| Novartis |
A small molecule
inhibitor of mTOR (mammalian target of rapamycin), part of the PI3 kinase/AKT pathway involved
in tumor cell proliferation and angiogenesis. |
| Approved
indications |
Advanced renal
cell carcinoma, pancreatic neuroendocrine tumors, subependymal giant cell astrocytoma (SEGA).
- After failure of treatment with sunitinib or sorafenib.
- Treatment of progressive neuroendocrine tumors of pancreatic origin (PNET) in patients with unresectable, locally advanced, or metastatic disease.
- Patients with subependymal giant cell astrocytoma (SEGA) who require therapeutic intervention but are not candidates for curative surgical resection.
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Other Antiangiogenic Agents
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Interferon alfa
(Intron A and Roferon) |
Description |
Roche
Schering |
Pharmacologic version of an endogenous cytokine with antiangiogenic activity. |
| Approved
indications: |
Hairy Cell Leukemia, Malignant Melanoma, Follicular Lymphoma, AIDS-Related Kaposi's Sarcoma
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Lenalidomide
(Revlimid |
Description |
| Celgene |
Possesses immunomodulatory,
anti-inflammatory, and antiangiogenic properties, although the
precise mechanisms of action are not fully understood. |
| Approved
indications |
Myelodisplastic Syndrome associated with 5q deletion, Multiple myeloma.
- Treatment of
multiple myeloma in combination with dexamethasone in patients who have received at least
one prior therapy.
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Thalidomide
(Thalomid |
Description |
| Celgene |
Possesses immunomodulatory,
anti-inflammatory, and antiangiogenic properties, although the
precise mechanisms of action are not fully understood. |
| Approved
indications: |
Multiple myeloma.
- Administered in combination with dexamethasone in patients with newly diagnosed multiple myeloma.
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rhEndostatin
(Endostar/Endu-available only in China) |
Description |
| Simcere |
Endogenous angiogenesis inhibitor; recombinant protein; blocks VEGF-induced tyrosine phosphorylation of KDR-Flk-1 in endothelial cells, and down regulates MMP-2/9. |
| Approved
indications: |
| Non-small cell lung cancer (NSCLC). |
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Additionally, in the field of dermatology, a number of FDA-approved agents have antiangiogenic properties:
- Alitretinoin (Panretin 0.1% gel, Ligand) is a topical retinoid indicated for the treatment of AIDS-related Kaposi's sarcoma (KS). Retinoids, derivates of vitamin A, are antiangiogenic via downregulation of VEGF.
- Imiquimod (Aldara 5% cream, Zyclara 3.75% cream, Medicis) is a Toll-Like Receptor 7 agonist which is an immune response modifier that exerts antiangiogenic activity through local upregulation of interferons and interleukins, downregulation of FGF-2 and MMP-9, and induction of endothelial apoptosis. Imiquimod is indicated for both benign neoplasms (genital warts) and for malignant skin cancers (actinic keratosis and basal cell carcinoma).
- Polyphenon E (Veregen 15% ointment, Bradley/MediGene) is a defined composition of polyphenolic kunecatechins extracted from green tea leaves. The major green tea catechins, epigallocatechin-3 (EGCG), inhibits VEGF expression. Polyphenon E topical ointment indicated for genital warts.
Last updated January 3, 2013
References:
Folkman J. Tumor angiogenesis, in Harrision’s Texbook of Internal Medicine, 15th ed. Braunwald E, Fauci AS, Kasper DL, et al., eds. McGraw-Hill, New York, NY, 2000 pp.132-152
Folkman J. Antiangiogenesis Agents, in Cancer: Principles & Practice of Oncology, 6th ed. DeVita VT, Hellman S, Rosenberg SA, eds. Lippincott Williams & Wilkins, Philadelphia, PA, 2001, pp.509-519.
Li WW, Hutnik M, Gehr G, Antiangiogenesis in haematological malignancies. British Journal of Haematology 2008;07372:1365-2141.
Li WW, Hutnik M, Li VW, Angiogenesis-Based Medicine: Principles and Practices for Disease and Intervention. Angiogenesis: Basic Science and clinical applications (M.E. Maragoudakis and E. Papadimitrion, Editiors) in press.
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