Pharma Strategy Blog

As we learn more about the biology of cancer, I’m finding that rather becoming simpler, it actually seems much more complex and sophisticated than we may have first realised.

Sometimes, we don’t know what we don’t know.

Take for example, the recent AACR meeting on the molecular origins of lung cancer that I attended and wrote a few summary posts on (with more to come!) 

There was a particularly fascinating lecture from Robert Kerbel, who looked at the role of tyrosine kinase inhibitors (TKIs) in metastatic cancer.  He noted that there have been many successful trials with TKI’s, with a two month improvement in survival being typical.  There have also been failures, such as bevacizumab (Avastin) in 1st line pancreatic cancer, 2nd and 3rd line breast cancer and adjuvant colorectal cancer. 

Numerous theories associated with how anti-angiogenic agents work, including the normalisation of blood vessels, allowing more drug to be delivered to the tumour and several other hypotheses have also been floated around.

What struck me though, was that the switch to a different concept, one where there are early indications that anti-angiogenic therapy actually promotes invasion and metastasis, for example in glioblastoma.  Dr Kerbel then showed some scans clearly showing disease progression and growth and asked whether bevacizumab actually increases the aggressiveness of a metastatic tumour over time?

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The evidence for this concept came from an paper published in Cancer Cell in 2009 by Paez-Ribes et al.,:

“The realization that potent angiogenesis inhibition can alter the
natural history of tumors by increasing invasion and metastasis
warrants clinical investigation, as the prospect has important
implications for the development of enduring antiangiogenic therapies.”

This invasion effect has been shown in bevacizumab and sunitinib (Sutent), both potent inhibitors of VEGF, so clearly the effect is a class one.

Kerbel discussed what else could explain the results other than increased tumour hypoxia? 

Another idea looked at dose dependent circulating levels of plasma VEGF, which Ebos et al., proposed and was subsequently noted with sunitinib in phase II human breast cancer trials reported by Harold Burstein.

The issue then becomes one of potential consequences.  Thus, plasma VEGF levels may explain drug resistance seen with anti-angiogenic agents, rapid tumour regrowth and rebound revascularisation may occur once therapy is stopped and an increase in malignant aggressiveness may be seen as invasion and metastasis increases.

The other question on my mind is why is there differences observed in adjuvant and metastatic disease as we have discussed previously with the negative bevacizumab results in adjuvant colorectal cancer.  It is possible, based on these observations that treatment with anti-angiogenic agents may have the opposite effect to that intended by hastening progression and thus such therapies may be better suited to the metastatic setting.

The big question now is figuring out how to overcome the drug resistance seen with these agents while minimising the vascular stimulation effects seen.

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

Ebos, J., Lee, C., Cruz-Munoz, W., Bjarnason, G., Christensen, J., & Kerbel, R. (2009). Accelerated Metastasis after Short-Term Treatment with a Potent Inhibitor of Tumor Angiogenesis Cancer Cell, 15 (3), 232-239 DOI: 10.1016/j.ccr.2009.01.021

Loges, S., Mazzone, M., Hohensinner, P., & Carmeliet, P. (2009). Silencing or Fueling Metastasis with VEGF Inhibitors: Antiangiogenesis Revisited Cancer Cell, 15 (3), 167-170 DOI: 10.1016/j.ccr.2009.02.007

Ebos, J., Lee, C., Christensen, J., Mutsaers, A., & Kerbel, R. (2007). Multiple circulating proangiogenic factors induced by sunitinib malate are tumor-independent and correlate with antitumor efficacy Proceedings of the National Academy of Sciences, 104 (43), 17069-17074 DOI: 10.1073/pnas.0708148104

Burstein, H., Elias, A., Rugo, H., Cobleigh, M., Wolff, A., Eisenberg, P., Lehman, M., Adams, B., Bello, C., DePrimo, S., Baum, C., & Miller, K. (2008). Phase II Study of Sunitinib Malate, an Oral Multitargeted Tyrosine Kinase Inhibitor, in Patients With Metastatic Breast Cancer Previously Treated With an Anthracycline and a Taxane Journal of Clinical Oncology, 26 (11), 1810-1816 DOI: 10.1200/JCO.2007.14.5375

Ebos JM, Lee CR, Cruz-Munoz W, Bjarnason GA, Christensen JG, & Kerbel RS (2009). Accelerated metastasis after short-term treatment with a potent inhibitor of tumor angiogenesis. Cancer cell, 15 (3), 232-9 PMID: 19249681