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Stopping Cancer From Rebounding After Treatment
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WEDNESDAY, Sept. 10 (HealthDay News) — Tumors often rebound rapidly following chemotherapy, and oncologists may now understand why: Blame the body.
They may also have found a new way to prevent that rebound effect, at least in their mouse model.
Robert Kerbel, of the Sunnybrook Health Sciences Centre, Toronto, and the University of Toronto, led an international team of researchers that discovered that some — but not all — chemotherapeutic agents damage not only cancerous tissue, but also the blood vessels that supply that tissue with oxygen and nutrients.
That damage, in turn, induces the body to mobilize so-called "circulating endothelial progenitor" (CEP) cells, blood vessel precursors that home to and repopulate the damaged tumor, enabling it to regenerate.
That effect appeared to be mediated by a cellular growth factor called SDF-1alpha. Fortunately, co-administration of drugs that either block SDF-1alpha or directly block blood vessel development appears to blunt that response — making the chemotherapy regimen more effective.
"We view this as a yin-yang, action-reaction situation," Kerbel said. "The primary action is the effect of the drug on the tumor. The reaction is the host response, which compromises part of the action, and you want to blunt that with an anti-angiogenic drug and/or something targeting this [protein] SDF-1. That's what this paper is all about."
Should these findings be validated in human subjects, they could potentially explain why anti-angiogenic therapies such as bevacizumab (Avastin) work better with some chemotherapeutics (such as paclitaxel, also called Taxol) than others. They may also explain why tumors seem to rebound so rapidly following chemotherapy treatment, as well as offering up a novel drug target (SDF-1) to suppress this effect. On a more practical level, the findings could help researchers decide which combination therapies to test in clinical trials, and which to put on the back burner.
"These data give a potential explanation for why some [drug] combinations have given much better bang for the buck than others," said Dr. Kathy Miller of the Indiana University School of Medicine in Indianapolis, who co-authored an editorial on Kerbel's study.
The findings were published in the September issue of the journal Cancer Cell.
The question at the heart of this study involves a relatively new class of anticancer drugs called anti-angiogenesis therapies. Angiogenesis is the process of new blood vessel growth, and it is critical to tumor development. That's because the growing tumor mass requires ever-increasing amounts of nutrients and oxygen to survive. Anti-angiogenic therapies target this process to choke off the tumor's supply lines.
Oncologists rarely if ever prescribe anti-angiogenic therapies in isolation; they almost always are paired with a traditional chemotherapy. Yet it turns out that only in certain cases does the anti-angiogenic drug provide a benefit above that of the standard cytotoxic agent. In other cases, the combination was no better than the chemotherapeutic agent alone. Kerbel wanted to understand why.
In earlier work, his team found that when mice are given certain cytotoxic agents, CEP cell levels in the bloodstream spiked rapidly, within three or four hours, and then migrated to the damaged tumor, where they began repairing the damage.
As Kerbel explained, this was a departure from conventional oncology wisdom.
"The ability to recover from cytotoxic chemotherapy has often been viewed as an intrinsic property of the tumor — they are Hercules, they have the property to survive and rebound very quickly after therapy," he said. "What we say in the [earlier] paper is, perhaps a part of the ability to repopulate is not just a function of the tumor cell population, but also of the host."
The current study was a follow-up in which Kerbel and his team systematically analyzed different chemotherapeutics for their ability to induce this host CEP response.
"We found there are some chemotherapy drugs — for instance, taxanes — that are very, very effective in inducing in mice this bone marrow response. There are other drugs like gemcitabine that are not very effective at all in inducing this response," Kerbel said.
In other words, some drugs cause CEP levels to spike, while others do not. "We don't know why there are these differences," he adds, "but there are these differences."
Importantly, the researchers also showed that co-administration of traditional chemotherapeutics with anti-angiogenic agents could blunt this CEP response. And, they implicated the body's own growth factor SDF-1alpha in mounting that response.
"We put forward the notion that drugs that target SDF-1 or its receptor, CXCR4, maybe they might be useful anticancer agents, not on their own, but combined with certain cytotoxic agents," said Kerbel.
"I think [this study] is very exciting, looking at it from a potential impact on how we use different drugs in the clinic," added Miller.
Not only can the data potentially explain why some drug combinations work better than others, she said, "it also gives a much better way to screen potential combinations in the lab."
Preliminary clinical data presented in the paper suggests the mouse findings will be replicated in human patients, said Kerbel.
Yet that doesn't mean doctors can now change clinical practice, said Dr. Alan Sandler, Medical Director of Thoracic Oncology at Vanderbilt-Ingram Cancer Center in Nashville, Tenn.
"This is really early preclinical stuff," he said. "There's already data out there showing that anti-angiogenic agents work. This is helping to explain perhaps why it may work."
SOURCES: Robert Kerbel, Ph.D., senior scientist, Sunnybrook Health Sciences Centre, Toronto, and professor and Canada Research Chair, University of Toronto; Alan Sandler, M.D., associate professor, medicine, and medical director, Thoracic Oncology, Vanderbilt-Ingram Cancer Center, Nashville, Tenn.; Kathy Miller, M.D., associate professor, medicine, Indiana University School of Medicine, Indianapolis; September 2008 Cancer Cell
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