Read and writing about malignant brain cancers, gliomas or glioblastoma multiforme (GBM) always makes me sad as life span from diagnosis is often only a year. Over the last decade we have seen many advances in surgery, radiation, chemotherapy and targeted therapies in many cancers, yet this one remains largely immune to significant progress.
Angiogenesis inhibitors targeting the VEGF signaling pathway have been shown to be effective both in preclinical cancer models and in clinical trials. This has led to the approval of several agents targeting VEGF in cancer, including bevacizumab (Avastin), sorafenib (Nexavar) and sunitinib (Sutent). To date, bevacizumab, has been approved for the treatment of relapsed glioblastomas in the US, at a dose of 10 mg/kg IV every 2 weeks. The approval in GBM was based on objective response rate, not survival.
There have been concerns in the past about the use of anti-angiogenic therapy (see references below) with malignant gliomas, principally malignant progression of the tumours with increased local invasion and distant metastasis. In other words, the cancer become more aggressive, which is not a good thing. Still, the concerns and risk involved must be balanced with the severity of the disease and relatively poor prognosis. Development of resistance is also an ongoing problem.
This morning though, I was a little more cheered about the topic after someone kindly sent me a new clinical paper on angiogenesis and GBM.
Brunkhorst et al., (2010) looked more closely at the mechanisms underlying tumour angiogenesis, principally angiopoeitins, and found some interesting relationships:
"We establish that Ang-4 is upregulated in human GBM tissues and cells. We show that, like endothelial cells, human GBM cells express Tie-2 RTK."
In simple terms, angiopoietins (Ang-1, Ang-2, and Ang-4) are the ligands of the Tie-2 receptor tyrosine kinase (RTK). More details can be found in an excellent review of angiopoietins and Tie2 in a review by Huang et al., (2010). While the roles of Ang-1 and Ang-2 are reasonably well known, little is understood about the role of Ang-4, so Brunkhorst et al., set out to research this in more detail.
What they found was really interesting:
"Our results establish the novel effects of Ang-4 on tumor angiogenesis and GBM progression and suggest that this pro-GBM effect of Ang-4 is mediated by promoting tumor angiogenesis and activating Erk1/2 kinase in GBM cells.
Together, our results suggest that the Ang-4–Tie-2 functional axis is an attractive therapeutic target for GBM."
There aren't too many inhibitors of Tie-2 in development, as this is a relatively new area of research. That said, I did find a couple in my database:
- ARRY-614 (Array): inhibits p38, Abl, Tie2 and VEGFR2, research in MDS
- XL-184 (Exelixis): inhibits VEGFR-2, MET, c-KIT, FLT-3, and Tie2
- ABT-869/linifarnib (Abbott): Inhibits VEGF, FLT3, Tie2, c-FMS, PDGF, c-kit
- AP-24534/ponatinib (Ariad): inhibits BCR-ABL, FLT3, VEGFR, FGFR, Tie2
- AMG-386 (Amgen): inhibits angiopoeitin 1 and 2, thus Tie2 is indirectly inhibited.
Regarding the relationship between angiopoetin and Tie2, Herbst et al., summarised it succinctly:
"AMG 386 is an investigational peptide-Fc fusion protein (ie, peptibody) that inhibits angiogenesis by preventing the interaction of angiopoietin-1 and angiopoietin-2 with their receptor, Tie2."
Mita et al., (2010) have generated some initial research looking at this compound in a catch-all phase I trial in advanced solid tumours with the standard combinations and dose finding approach. It's too early to say whether the agent will pan out, but some evidence of anti-tumour activity was seen.
In the original article on GBM and angiopoeitins, Brunckhorst et al., (2010) demonstrated that Ang-4 promotes GBM progression by promoting tumour angiogenesis. What was also clear from their data is that Ang-4 seems to display a more potent proangiogenic activity than Ang-1.
More importantly, they found that GBM cells express Tie-2 and thus there may be a novel role for Ang-4 in promoting Erk1/2 kinase activation in GBM cells and in enhancing GBM cell viability.
Clearly, we still have a long way to go in figuring out the precise details around the broader angiogenesis process involved in tumour growth and development, but expanding the potential targets beyond VEGF into angiopoeitins, Tie2 and even platelet derived growth factor (PDGF), fibroblast growth factor (FGFR) and others will hopefully yield some productive bench to bedside success in the near future.
Brunckhorst, M., Wang, H., Lu, R., & Yu, Q. (2010). Angiopoietin-4 Promotes Glioblastoma Progression by Enhancing Tumor Cell Viability and Angiogenesis Cancer Research, 70 (18), 7283-7293 DOI: 10.1158/0008-5472.CAN-09-4125
Verhoeff, J., van Tellingen, O., Claes, A., Stalpers, L., van Linde, M., Richel, D., Leenders, W., & van Furth, W. (2009). Concerns about anti-angiogenic treatment in patients with glioblastoma multiforme BMC Cancer, 9 (1) DOI: 10.1186/1471-2407-9-444
Pàez-Ribes, M., Allen, E., Hudock, J., Takeda, T., Okuyama, H., Viñals, F., Inoue, M., Bergers, G., Hanahan, D., & Casanovas, O. (2009). Antiangiogenic Therapy Elicits Malignant Progression of Tumors to Increased Local Invasion and Distant Metastasis Cancer Cell, 15 (3), 220-231 DOI: 10.1016/j.ccr.2009.01.027
Herbst, R., Hong, D., Chap, L., Kurzrock, R., Jackson, E., Silverman, J., Rasmussen, E., Sun, Y., Zhong, D., Hwang, Y., Evelhoch, J., Oliner, J., Le, N., & Rosen, L. (2009). Safety, Pharmacokinetics, and Antitumor Activity of AMG 386, a Selective Angiopoietin Inhibitor, in Adult Patients With Advanced Solid Tumors Journal of Clinical Oncology, 27 (21), 3557-3565 DOI: 10.1200/JCO.2008.19.6683
Mita, A., Takimoto, C., Mita, M., Tolcher, A., Sankhala, K., Sarantopoulos, J., Valdivieso, M., Wood, L., Rasmussen, E., Sun, Y., Zhong, Z., Bass, M., Le, N., & LoRusso, P. (2010). Phase 1 Study of AMG 386, a Selective Angiopoietin 1/2-Neutralizing Peptibody, in Combination with Chemotherapy in Adults with Advanced Solid Tumors Clinical Cancer Research, 16 (11), 3044-3056 DOI: 10.1158/1078-0432.CCR-09-3368
Huang, H., Bhat, A., Woodnutt, G., & Lappe, R. (2010). Targeting the ANGPT–TIE2 pathway in malignancy Nature Reviews Cancer, 10 (8), 575-585 DOI: 10.1038/nrc2894