7.8 Therapies: Angiogenesis Inhibition

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Therapies: Angiogenesis Inhibition

   Angiogenic processes nourish tumour growth and provide an increased potential for metastasis. Therefore, inhibiting angiogenesis is a promising method of cancer therapy and it is appealing for several reasons. First of all, anti-angiogenic therapy can be used in combination with conventional chemotherapy to produce synergistic effects (6). Second, in healthy adults, angiogenesis is not common in normal adult tissue so it is expected that inhibiting angiogenesis will interfere with cancer progression without producing strong adverse effects in the host (1). Third, tumor-induced vasculature differs greatly from that of normal tissues, and these differences provide potential targets for therapy (4).

 

History

   In 2004, the first angiogenesis inhibiting drug was approved by the US Food and Drug Administration (FDA) for cancer treatment (2). This drug, bevacizumab (commerical name Avastin), is a humanized monoclonal antibody that targets VEGF, neutralizing its activity by preventing binding to its receptor (2). Since VEGF plays such a central role in increasing vessel permeability and promoting endothelial cell migration, the initial hope was that inhibiting VEGF activity would block angiogenesis and starve tumors, restricting growth by cutting off blood supply (2).  Following FDA approval of bevacizumab, a phase III study was conducted by Hurwitz et al. (5). They found that metastatic colorectal cancer patients given bevacizumab in addition to other chemotherapy drugs had a median survival of 20.3 months, while those given chemotherapy alone had a median survival of 15.6 months (5). Subsequent studies originally suggested similar survival benefits for metastatic breast cancer, non-small cell lung cancer, glioblastoma multiforme, and metastatic renal cell carcinoma (3). However, research done after 2011 indicated that bevacizumab may not actually be as effective as previously believed in treating colon cancer (given in combination with chemotherapy) or breast cancer (12). Current studies are examining whether bevacizumab improves prognosis in advanced cervical cancer (12). The doubts about its effectiveness combined with the high price of the drug have created concerns about its benefit as an adjuvant. The most serious adverse affect associated with this drug is gastrointestinal perforation, occurring in 1-2% of patients (3). Other adverse affects include hypertension and proteinuria, occurring in approximately 1/3 of patients but causing serious complications in less than 2% (3).

Figure 7.8.1 Model of Avastin inhibition. Released under the Creative Commons Attribution-ShareAlike 4.0 International license (CC BY-SA 4.0).

 

Targeting the antigenic switches

   Other drugs targeting VEGF pathways have been approved by the FDA, and many more are in clinical trials.  These include pro-antigenic switches like receptor tyrosine kinase (RTK) inhibitors such as sorafenib (Nexavar), sunitinib (Sutent), and pazopanib (Votnent) which block VEGF receptor signaling; drugs such as temsirolimus (Torisel) that reduce the synthesis of VEGF by tumor cells; and decoy soluble VEGF receptors such as aflibercept, which act by reducing free VEGF levels (3). Like bevacizumab, these drugs have a significant yet small survival benefit, usually in the order of months (6). One possible explanation for this is that there are multiple pathways by which angiogenesis can be stimulated.  When VEGF is inhibited, angiogenic processes are stalled, but only until another pro-angiogenic pathway such as FGF (fibroblast growth factors) pathways can be activated (8). In fact, many cancers are known to express multiple pro-angiogenic proteins. For example, advanced neuroblastoma has been observed to heavily express as many as seven pro-angiogenic proteins (2).  The normalization hypothesis attempts to address this issue by using anti-angiogenic drugs in combination in order to tip the balance of tumor-induced vascularization back to a normal state. 

 

   Angiogenesis inhibitors that target pathways other than VEGF are currently under investigation. Thalidomide possesses great potential as it inhibits the activity of basic fibroblast growth factor-2 (bFGF), a pro-angiogenic protein. Unfortunately, the studies testing its effects on solid tumors have been disappointing, although it has been approved for treatment of multiple myeloma (3). Bikfalvi et al. investigated the ability of IL-6 inhibition to increase the efficacy of anti-VEGF therapy (8). Chemokines are also being studied because of their role in angiogenesis, and overexpression of a chemokine ligand CXCL4 has blocked tumor progression in vitro, suggesting this may be a good direction for further drug development avenues (8). Endogenous angiogenesis inhibitors are another potential source of therapy. Endostatin is an endogenous protein that targets angiogenesis regulatory genes, thereby inhibiting migration, proliferation and survival of endothelial cells. Phase III clinical trials of Endostar (commercially produced endostatin) showed a signigicant survival benefit in non-small-cell lung carcinoma patients (2). 

 

   Given the important role of angiogenesis in the progression of cancer, inhibiting this process has been an important branch of cancer research that will be expanded upon in the years to come. As it has been described in the section Intussusceptive Angiogenesis, recognition of the splitting form of angiogenesis could help further the targeting of angiogenic factors to stop angiogenesis.

 

Side effects and adverse events

Anti-angiogenesis drugs tend to have milder side effects than chemotherapy drugs. Since chemotherapy drugs work by attacking cells in the body that grow and divide quickly, they can harm normal cells that divide quickly (9).  As a result, serious side effects like low blood cell counts, sores, ulcers, nausea, and diarrhea may develop.  In contrast to chemotherapy drugs, anti-angiogenesis drugs do not harm normal cells.  They only act where new blood vessels are forming, so they usually do not cause these kinds of side effects.  Yet, anti-angiogenesis drugs are not risk-free.  For some patients, they can still be serious, or even life-threatening (10).  The following lists some potential risks (11):

Bleeding or increase vascular permeability: Not surprisingly, most anti-angiogenesis drugs have been shown to raise the risk of internal bleeding or of developing a hole in the digestive tract (stomach or intestines).  In rare cases, this has been serious or even fatal.  These drugs are contra-indicated in people with a history of bleeding problems, where risks may outweigh the benefits.

Raised blood pressure: Though the mechanisms remain unclear, some angiogenesis inhibitors raise blood pressure. This problem is rarely serious and it seems to respond well to antihypertensives.  Still, patients with a history of high blood pressure, heart disease, or stroke may need to be cautious about taking these drugs.

Surgery risks: Because they may affect wound healing, anti-angiogenesis drugs may need to be stopped before surgery or not started until a few weeks after surgery.  This is to make sure blood vessels that are cut are able to repair.

Pregnancy risks:  These drugs have been shown to be teratogens, or cause defects in the developing fetus (10).  

 

References

1. Carmeliet P and Jain RK. (2011). Molecular mechanisms and clinical applications of angiogenesis. Nature 473, 298-307.

2. Folkman J. (2006). Antiangiogenesis in cancer therapy--endostatin and its mechanisms of action. Experimental Cell Research 312, 594-607. 

3. Eichholz A, Merchant S, and Gaya AM. (2010). Anti-angiogenesis therapies: their potential in cancer management. OncoTargets and Ther. 3, 69-82. 

4. Cao Y. (2004). Antiangiogenic cancer therapy. Seminars in Cancer Biology 14, 139-145. 

5. Hurwitz H et al. (2004). Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N. Engl. J. Med. 350, 2335-2342. 

6. Ferrara N and Kerbel RS. (2005). Angiogenesis as a therapeutic target. Nature 438, 967-974. 

7. Jain RK. (2005). Normalization of tumor vasculature: an emerging concept in antiangiogenic therapy. Science 307, 58-62.

8. Bikfalvi A, Moenner M, Javerzat S, North S and Hagedorn M. (2011). Inhibition of angiogenesis and the angiogenesis/invasion shift. Biochem. Soc. Trans. 39, 1560-1564. 

9. Fidler IJ, Langley RR, Kerbel RS, Ellis LM. Angiogenesis. In: DeVita VT, Hellman S, Rosenberg SA, eds. Cancer: Principles and Practice of Oncology. 7th ed. Philadelphia, Pa: Lippincott Williams & Wilkins 2005:129-137.

10. National Cancer Institute. Angiogenesis Inhibitors Therapy. Accessed March 3, 2009 at: www.cancer.gov/cancertopics/factsheet/therapy/angiogenesis-inhibitors.

11. Kerbel RS, Kamen BA. The anti-angiogenic basis of metronomic chemotherapy. Nat Rev Cancer. 2004;4:423-436.

12. Amit, L., Ben-Aharon, I., Vidal, L. Leibovici., L., Stemmer, S. (2013). The Impct of Bevacizumab (Avastin) on Survival in Metastatic Solid Tumors - A Meta-Analysis and Systematic Review. PLoS ONE; 8(7): doi: 10.1371/journal.pone.0051780.