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'Extremely surprising' outcome may result in more caution in use of angiogenesis drugs
Angiogenesis inhibitors that block a tumor’s development of an independent blood supply have been touted as effective cancer fighters that result in fewer side effectsterm than traditional chemotherapyterm. However, a new study by researchers at UCLA’s Jonsson Cancer Center showed that one method of blocking blood supply development could result in serious and potentially deadly side effects.
Several newly developed angiogenesis inhibitors work by blocking vascular endothelial growth factor (VEGFterm), an important signaling protein that spurs growth of new blood vessels. Avastinterm, an approved angiogenesis inhibitor for colon and lung cancers, inhibits angiogenesis by blocking VEGF signaling from outside of the cell. UCLA researchers wanted to know what happened when VEGF signaling was blocked from within endothelial cells, a mechanism used by some small molecule drugs currently being tested in late phase clinical trials.
The result was unexpected, and sobering. More than half of the mice in the study suffered heart attacks and fatal strokes, while those that remained alive developed serious systemic vascular illness, said Luisa Iruela-Arispe, a professor of molecular, cell and developmental biology and director of the Cancer Cell Biology program at UCLA’s Jonsson Cancer Center.
The study appears in Aug. 24, 2007 in the prestigious, peer-reviewed journal Cell.
“This was an extremely surprising result,†said Iruela-Arispe, past president of the North American Vascular Biology Organization and a national expert on angiogenesis. “I think this study is cause for some caution in the use of angiogenesis inhibitors in patients for very long periods of time and in particular for use of those inhibitors that block VEGF signaling from inside the cell.â€
About 5 percent of patients taking Avastin develop blood clot-related side effects, Iruela-Arispe said. But because Avastin was approved only three years ago, it is unclear what side effects may occur when patients remain on the drug for many years, she said.
In the three-year study, Iruela-Arispe created mice that were missing VEGF in the endothelial cells, the cells that line the inside of blood vessels and form an interface between circulating blood and the vessel wall. Endothelial cells line the circulatory system from the heart to the smallest capillary and reduce friction of the flow of blood. Iruela-Arispe and her team didn’t expect to see much of an effect because the amount of VEGF made inside endothelial cells was miniscule compared to the levels of VEGF created outside the cells.
However, 55 percent of the mice in the study died by 25 weeks of age, the equivalent of age 30 in humans. The other mice that were followed into old age were very ill.
“Some side effects have already been identified in people taking angiogenesis inhibitors,†Iruela-Arispe said. “And they’ve been along the lines of what we’re seeing in the lab.â€
Iruela-Arispe and her team were surprised that the higher levels of VEGF found outside the endothelial cells did not compensate for the absence of the very tiny amounts inside the cells. The miniscule amount of VEGF missing had “a tremendous biological significance,†she said.
“Clearly there is signaling from inside the cell that is different from signaling initiated outside the cell,†Iruela-Arispe said. “When there is no VEGF signaling inside the cell, the endothelial cells die. The intracellular part of the VEGF signaling loop is required for cell survival. This is the first demonstration that intracellular signaling is an important event.â€
It had been unclear why some patients on angiogenesis inhibitors developed problems with blood clots. Iruela-Arispe said her study sheds light on one possible cause.
“There is enough smoke in the sky here to make me feel there may be a fire,†she said. “I believe the survival function of VEGF signaling is mediated from both outside and inside the cell. When we block it from the inside, the outside signaling cannot compensate. But when we block it from the outside, maybe the inside signaling can compensate. That would explain the lesser side effects found when using drugs such as Avastin, which block the extra cellular signaling.â€
Iruela-Arispe believes angiogenesis inhibitors will continue to be effective weapons in the cancer arsenal. However, a more targeted approach to drug delivery should be explored. Avastin, as well as most angiogenesis inhibitors, are infused systemically now. If the drugs could be targeted more directly to the new vessels being formed by the tumor, they might not result in the side effects seen now.
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Large Molecule vs Small Molecule
The most common targets on the outside of a cancer cell are receptors, which are proteins that help relay chemical messages. Many targets on the inside of a cell are enzymes, which are proteins that help speed up chemical reactions in the body.
By focusing on these molecular and cellular changes, targeted cancer drugs go after the "target" in these cells, rather than just all cells. In other words, they focus on molecular and cellular changes that are specific to cancer.
Small molecule (enzyme) inhibitors of tyrosine kinase make biologic processes happen faster and are often key junctions in the signaling pathways. It is a key intermediary in the EGF cascade pathway.
Large molecule antibodies attach to specific proteins on the outside of cancer cells and do not have a convenient way of getting access to a large majority of the targeted cells on the inside, which are protected from the drug. Plus, there is multicellular resistance, the drugs affecting only the cells on the outside may not kill these cells if they are in contact with cells on the inside. The cells may pass small molecules back and forth.
Because many cancer cells use similar pathways, the same drug could be used to treat one person's breast cancer and another person's lung cancer, as long as each tumor contained similar targets. This is why many of these treatments are being used in a variety of cancer types.
Although targeted therapy is appealing, it is more complex than meets the eye. Cancer cells often have many mutations in many different pathways, so even if one route is shut down by a targeted treatment, the cancer cell may be able to use other routes.
In other words, cancer cells have "backup systems" that allow them to survive. The result is that the drug does not shrink the tumor as expected. One approach to this problem is to target multiple pathways in a cancer cell.
There has been a continuous parade of new targeted small and large molecule therapies that will continue to be introduced into the market virtually blind. Most of them have been developed for use in solid tumors but some have also emerged for hematological malignancies. These targeted drugs mostly need to be combined with active chemotherapy to provide any benefit and the need for predictive tests for individualized therapy selection has increased.
Multi-targeted drugs can be well-predicted by measuring the effect of the drugs on the "function" (is the cell being killed regardless of the mechansim) of live cells, as opposed to a "target" (does the cell express a particular target the the drug is supposed to be attacking).
While a "target" assay tells you whether or not to give "one" drug, a "functional" assay can find other compounds and combinations and can recommend them from the one assay.
Functional profiling can discriminate between the activity of different “targeted” drugs and identify situations in which it is advantageous to combine the “targeted” drugs with other types of cancer drugs. Because these new “smart” drugs will work for “some” but not “all” cancer patients who receive them, functional profiling can accurately identify patients who would benefit from treatment with molecularly-targeted anti-cancer therapies.
In regard to toxicities, cancer sufferers are taking doses of expensive and potentially toxic treatments that are possibly well in excess of what they need. Emerging evidence shows that many of the highly expensive targeted cancer drugs (Herceptin, Avastin and Rituximab) may be just as effective and produce fewer side effects if taken over shorter periods and in lower doses.
Pharmaceutical companies are attracted to studies looking at the maximum tolerated dose of any treatments. It is suggested that we make the search for minimum effective doses of these treatments one of the key goals of cancer research.
One example is Avastin, used to fight colon and lung cancers, the dose being tested is 15 milligrams per kilogram of body weight, despite other research showing it may work with 3 milligrams per kilogram.
The study of cell function analysis tells us that even when the disease is the same type, different patients' tumor respond differently to the same agents. A large molecule targeted drug may be more beneficial to some patients than a small molecule targeted drug (sometimes not).
Whatever the percentage of patients benefit from these drugs, the point is, targeted drugs are not for everybody. Pre-tests can help identify the individual cancer patient the drug works extremely well for, or it can tell that the drug is resistant. This could be Tykerb, Tarceva, Iressa, Sutent or Nexavar, because of being small molecule drugs. It is important to "personalize" cancer treatment, and this can be accomplished by "testing the tumor first."
There are huge economic problems here. Pharma cannot make drugs unless they can realize a profit. The ordinary trial system will not suffice if we are to encourage new drugs for restricted numbers of patients. More and more physicians and patients are turning to individualized therapies to treat cancers. Without individualized testing the efficacy of these drugs, it's difficult to determine which drugs are best for patients who don't respond to standard therapies.