At the same time, we are also investigating ways of expanding the window of normalization so that survival improvements can be extended from months to years. Any potential strategy to repair vessels must recognize that VEGF blockade alone may not always be sufficient to achieve or sustain normalization, because tumors can substitute other growth factors to get around the loss of VEGF signaling. As tumors grow larger, for instance, they tend to make a diverse array of proangiogenic molecules in addition to VEGF, so their vessels may gradually lose responsiveness to a treatment such as Avastin.
In rectal cancer patients, for instance, our group discovered that blood levels of VEGF and PlGF (placental growth factor), a related molecule, actually increased after VEGF was mopped up with Avastin, suggesting that the tumor or other tissues began manufacturing more of those factors in response. And in recurrent glioblastoma patients, blood levels of multiple proangiogenic molecules rose as tumors escaped the Recentin treatment.
This diversification of progrowth signals illustrates that the challenge for the oncologist will be to formulate cocktails of agents specifically tailored to the molecular profile of each patient’s primary and metastatic tumors and to changes in those profiles that will likely occur over time. It is worth noting, however, that the available tools for promoting vascular normalization are not limited to drugs targeting VEGF or other growth factors directly. We have shown in mice, for example, that the drug Herceptin—an antibody that targets a tumor cell-surface protein called HER2 and that is given to about a quarter of women with breast cancer—can mimic the responses produced by an antiangiogenic cocktail and normalize tumor vessels. Herceptin indirectly lowers cellular manufacture of several proangiogenic molecules while increasing the cells’ production of the antiangiogenic thrombospondin-1.
In addition to identifying new and existing medications that can foster vascular normalization, it will be important to find minimally invasive and affordable ways for doctors to monitor the normalization process, to best exploit it when delivering treatments. To that end, my colleagues and I have been working to identify so-called biomarkers: readily identifiable signs that reflect what is happening inside the tumor and thereby reveal the onset and duration of the normalization window in individual patients. Such markers might include, for example, proteins in the bloodstream or in urine whose levels rise or fall during this time window.
Finding that antiangiogenesis drugs can normalize vasculature should not suggest that the original purpose for which they were developed is no longer valid. If a drug is sufficiently potent and specific to destroy enough tumor vasculature to starve the entire tumor and save a patient’s life, then that would be a happy outcome for everyone. But the ability to use these drugs for vascular repair as well makes them valuable tools for attacking tumors in more than one way. In the longer term, this research can also benefit the many millions of people around the world suffering from other diseases caused by abnormal vasculature, such as age-related macular degeneration and atherosclerosis.
More than 30 years ago, when I first set out to understand the tortuous and dysfunctional blood vessels of tumors, I never imagined where that road would lead. Nor could I have pictured a day when a patient with a disease of abnormal blood vessels could walk into a clinic, have various biomarkers measured, then receive a tailored regimen of normalizing drugs to repair those vessels. But now that day looks closer than ever before.