From bullish to bear-cubbish, the public’s present stock in drugs that starve growing tumors of their blood supply seems steady, subdued and sane. It’s less-than-sane, irrational exuberance peaked three years ago, on May 3, 1998, when a Page One story in the New York Times quoted James Watson of double-helix fame as hinting at imminent cancer cures by blocking angiogenesis.
“That New York Times article,” observed experimental oncologist Robert Kerbel, “created such a distorted, unrealistic level of euphoria and expectation about this type of therapy that when results typical of many Phase I trials were seen, maybe they proved [the anti-angiogenic protein] safe, but there were very few tumor-growth responders. Even though the safety profiles of these anti-angiogenic drugs have been rated very good compared to conventional chemotherapy, the clinical results have been viewed with disappointment. If you go by safety which is the major aim of a Phase I/II test the result was positive. But because so few responses were seen in the patients treated, many medical oncologists would say, We think this is a failure. We should have seen more tumors that shrunk.’”
Kerbel, who directs molecular and cell biology research at a University of Toronto teaching hospital, is senior author of a paper in Science dated Feb. 22, 2002. Its title: “Effect of p53 status on tumor response to anti-angiogenic therapy.”
“The overall finding of this paper,” Kerbel told BioWorld Today, “is to show probably for the first time that genetic mutations commonly expressed in cancer cells can impact the outcome of an anti-angiogenic therapy. Specifically,” he added, “it might lead to a gradual loss of anti-tumor response to that therapy. This is important because of a theory put forward 10 years ago that perhaps anti-angiogenic drugs, in contrast to all other types of antitumor treatment, might not run into the brick wall of acquired drug resistance. The investigator who put forward that theory,” Kerbel continued, “was me.”
L-O-N-G Dormancy For Treated Tumors
“My idea was that with anti-angiogenic drugs, we’re targeting the vasculature of a tumor its spreading blood vessel network freighted with oxygen and nutrients rather than the tumor-cell population itself. If the theory was right,” Kerbel went on, “this seemed to be a rather simple way of dealing with drug resistance. What the theory would predict,” he suggested, “is that once you start to give therapy with an anti-angiogenic drug, if you get a positive clinical response to the drug, that antitumor effect would be maintained virtually indefinitely. In other words, you wouldn’t get a relapse or at least not a rapid relapse.”
Kerbel pointed out, “There are other examples where what you get is a kind of tumor-growth delay not necessarily a dormancy effect. You simply slow down the tumor growth, but it’s still growing relentlessly. Eventually the therapy may no longer be effective. So we’re trying to address why this happens. Then hopefully we can provide more effective therapeutic strategies.
“That’s really the rationale behind our Science paper,” he noted, “so we decided to consider whether there might be some instances in which an anti-angiogenic type of therapy works at first, but then eventually loses some or all of its effects over time as a result of genetic selection for mutant tumor-cell populations. Maybe if we’re lucky, even shrink the tumor, and induce a state of dormancy. How can we get the maximum state of tumor dormancy? Can we make it indefinite, and achieve really long-term stable disease?
“That meant,” Kerbel went on, “understanding why sometimes anti-angiogenic therapy may work for a while, then gradually begin to lose its effectiveness. One way this could occur is that by shutting down the angiogenesis lifelines over time, you create hypoxia an oxygen-deprived environment. It’s long known that tumors can survive under certain conditions of oxygen deprivation that normal cells can’t survive. They develop a relative hypoxia resistance not completely independent of oxygen but creating a partial hypoxia, as opposed to total anoxia.
“We knew that one of the main genetic changes that could lead to hypoxia resistance was mutation loss of p53 tumor suppressor genes. So we asked: If we had a tumor-cell population that lacked p53, but in every other way was identical to another tumor-cell population, would the population that had the inactivated, disrupted p53 be less responsive to anti-angiogenic therapy?’ And the answer indeed yes’ is in the Science paper.”
Kerbel made the point, “The p53 tumor suppressor gene is inactivated in half of human cancers. Tumor cells deficient in p53 display a diminished rate of apoptosis under hypoxic conditions, a circumstance that might reduce their reliance on vascular supply, and hence their responsiveness to anti-angiogenic therapy.”
He and his co-authors seeded SCID mice (lacking immune defenses) subcutaneously with colorectal tumors lacking p53 genes. They proved less responsive to anti-angiogenic therapy than mice carrying genetically matched cells, but with p53-positive tumors.
Antibody Beards Angiogenesis Master Molecule
A factor that creates and proliferates blood vessels in the body is VEGF vascular endothelial growth factor. Its angiogenesis is the major bull’s eye of anti-angiogenesis. “It’s considered to be the most important of all pro-angiogenic growth factors made by tumors,” Kerbel observed. “So VEGF has been a hot target for anti-angiogenic therapy for a decade. The DC 101 antibody is a drug that targets one of VEGF’s two receptors.
“As an anti-angiogenic compound,” he said, “DC101 is very good. We’ve been working with it in vivo for about four years. The results we get are impressive. We can give it twice a week to tumor-bearing mice for extremely long periods of time, and often obtain long-term if not permanent growth control. So now we’re asking: Is there a way to take this promising new antibody and combine it with cancer chemotherapy drugs?’ We won’t have all the usual horrendous side effects, yet counterintuitively achieve better antitumor effects with continuous, low-dose metronomic protocols: regular, frequent beats or cycles of chemotherapy maybe even every day combined with DC101 or its equivalent.”