Medulloblastoma cells (green) are growing around this cerebellar blood vessel and inducing growth of new vessels nearby (red). Courtesy Matija Snuderl & Rakesh Jain.
An update last week on angiogenesis research revealed surprising twists in the story of fighting cancer by cutting off the tumor’s blood supply. The latest findings, reported by top researchers at an international pediatric oncology meeting in Boston, show that the story is much more nuanced. If big questions seem to go begging in the emerging story, you’re not alone in thinking so!
Anti-angiogenic drugs can kill some tumors by cutting off their blood supply. But surprisingly, in two animal studies using very high doses, the drugs turned some tumors more malignant and metastatic, said Rakesh Jain, PhD, by increasing the hypoxic zone; low oxygen conditions somehow promote tumor progression in these models.
A smaller tumor with less blood supply and more hypoxia can be more metastatic than a better-oxygenated larger tumor, confirmed Raghu Kalluri, PhD, in a later talk. Hypoxia can prompt blood vessels to grow and change the communal nature of cells lining the blood vessels into a more independent, mobile and aggressive phenotype, he said.
However, Jain noted that the doses used in the published animal studies are much higher than those that would ever be prescribed to patients. Moreover, Genentech, which produces the anti-angiogenic drug Avastin, has reported no evidence of metastasis stimulation in the hundreds of people tested. All of this highlights the need for further investigation.
Rehabilitating vessels
Jain’s group is working on how to exploit and expand another paradoxical feature of anti-angiogenic drugs. The typical tumor blood supply, Jain said, is “highly tortuous, dilated, dysfunctional and abnormal.” But, as he first proposed many years ago, there’s a window of time in which the blood vessels that survive the anti-angiogenic drugs actually function better. That can be a good thing: better blood flow means more oxygen to the tumor and better delivery of cancer-killing chemotherapy.
Repairing tortuous vessels can also bring relief of other symptoms. In an adult brain cancer study, for example, one drug’s “vessel normalization” window was too short to deliver the full chemotherapy course, but relief from the leaky abnormal vessels reduced brain swelling. “The bottom line is that patients may be living longer because their edema is reduced,” Jain said. “Patients with the highest normalization index had the longest survival.” In another study, an antiangiogenic drug temporarily restored hearing in people whose auditory nerves were pinched by swollen vascularized tumor tissue.
“The concept of vascular normalization has significantly modified the way in which combinations of chemotherapy/radiotherapy and antiangiogenic agents are combined,” moderator Mark Kieran, MD, PhD, later told me via email. “Jain’s newer findings that angiogenesis rebounds after treatment will likely lead to further modification of treatment strategies.”
An option for children
The concept of angiogenesis was born at Children’s Hospital Boston, in the lab of the late Judah Folkman, and has spawned new treatments for cancer as well as eye disease. To date, use in children has been extremely limited. Preclinical studies have shown that blocking a potent angiogenic factor can stop bone growth in baby mice, raising concern about side effects in children.
Another option for medulloblastoma, the most common malignant brain tumor in children, may be to target placental growth factor (PlGF), an angiogenic factor that is not essential for normal childhood development but apparently is important in brain tumor angiogenesis, studies in Jain’s lab show. “Genetic and pharmacologic inhibition of PlGF in mice with medulloblastomas in the cerebellum significantly delayed tumor growth and prolonged mouse survival,” Jain reported in preliminary findings.
Silent tumors…
In promoting the concept of angiogenesis, Folkman famously cited autopsy evidence of dormant tumors in people who died of other causes, such as car crashes. Subsequent studies have reported similarly high microscopic incidence of cancer in people unlikely to die of those cancers. Kalluri has begun a project to investigate those dormant tumors in upward of 10,000 to 25,000 people who died of other causes, working with 15 centers in Europe, India and China to collect tissue samples.
In a preliminary analysis of the first several hundred samples, Kalluri’s group found that about 35 percent of people over age 40 have dormant tumors, consistent with previous studies. But also, surprisingly, “many of the things that cancer biologists are telling us are important for the progression of cancer are usually present,” Kalluri said. These include several prominent oncogenes as well as a potent angiogenic factor — raising tantalizing new questions.
…can be spotted turning on
The lab of Marsha Moses, PhD, director of the Vascular Biology program at Children’s, studies the mechanisms of tumor growth and progression. It has also established the largest urine repository in the world approved for clinical study — a strategic decision that’s facilitating her search for noninvasive biomarkers of cancer. As a postdoctoral fellow, Moses discovered the first endogenous anti-angiogenic inhibitor, which blocks an enzyme that breaks down the scaffolding of cells and other tissue in the cancer. The enzyme is part of a family called matrix metalloproteases (MMPs), which play complex and contradicting roles in angiogenesis.
“Over the years, in a variety of cancers, our studies show that there appear to be tumor-specific MMP signatures,” said Moses, who has validated them in 37 clinical studies involving 8,500 samples so far.
The biomarkers may help scientists develop what some believe is the most effective use of anti-angiogenic drugs: To keep a silent tumor dormant at the time when it appears to be turning on.
“Her work is of pivotal importance, because being able to detect tumors before patients are sick, before a spot is visible on a scan, and before the tumor has spread will be invaluable,” Kieran said. “To have a test that can also detect when the tumor is coming back, or has completely gone and thus additional therapy is not needed, will also be critical. She already has these tests in prospective clinical trials and so these markers may be available soon.”
