Study finds blocking angiogenesis signaling from inside cell may lead to serious heal

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A new story entry has been added:

Study finds blocking angiogenesis signaling from inside cell may lead to serious health problems

[B]'Extremely surprising' outcome may result in more caution in use of angiogenesis drugs[/B]

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 effects than traditional chemotherapy. 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 (VEGF), an important signaling protein that spurs growth of new blood vessels. Avastin, 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.

[gdpawel]

Targeted drugs are based on a variety of biological mechanisms (pathways) that essentially stop cancer from spreading. They interfere with specific molecules (receptors and enzymes inside and outside a cancer cell) involved in carcinogenesis (the process by which normal cells become cancer cells) and tumor growth.

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.

[gdpawel]

The human body has a remarkable ability to repair itself. It has countless mechanisms to fight viruses and bacteria, to recover from infections and fevers, and to heal cuts and punctures, but one mechanism we seldom think about is angiogenesis, or the body’s ability to grow new blood vessels.

All tissues need blood

All of the tissues of the body—including skin, cartilage, and bone—must have a constant supply of blood, which provides oxygen and nutrients essential to survival. Any time, from conception until death, that blood vessels are damaged, special proteins and molecules called growth factors go to work at the site of the damage to promote the development of new blood vessels.

Ironically, angiogenesis, which is essential to life itself, has become a primary target in the fight against cancer. Tumors also need a reliable blood supply to survive, and the same angiogenic factors that help maintain vital tissues also help maintain cancerous tissues.

Understanding the process

Scientists have been working for years to understand the mechanisms that control angiogenesis. They have discovered that both healthy tissues and tumors naturally produce proteins and molecules that either promote or inhibit angiogenesis. Experiments on mice have been performed to determine whether angiogenesis is triggered by the tumor itself or by the surrounding host tissue. The findings proved that tumors initiate angiogenesis by releasing growth factors into the surrounding tissue, in a sense ordering the tissue to start making blood vessels. For a tumor to grow, it must release more angiogenesis-promoting factors than inhibiting factors into the surrounding tissue.

The fact that tumors also produce angiogenesis inhibitors happens to be very important in explaining metastasis, which is the spread of cancer to other parts of the body and the main reason for cancer-related deaths. Frequently, tiny, microscopic metastases in areas of the body far away from the primary tumor will remain inactive for years and begin to grow only after the primary tumor is removed. This happens because the primary tumor has been releasing angiogenesis inhibitors into the bloodstream, and when these inhibitors are gone, the microscopic tumors begin to grow. Cancer researchers hope that by preventing angiogenesis, they can prevent these microscopic metastases from growing. Furthermore, if a tumor has not metastasized, or spread to other areas, and has been effectively treated with antiangiogenesis agents, metastasis is much less likely to occur because fewer blood vessels are available to spread cancer cells from the tumor.

Fighting angiogenesis

The almost two dozen angiogenesis inhibitors currently being tested work in many different ways. Some block the growth of vascular endothelial cells, which are the primary cells in blood vessels. Another category of angiogenesis inhibitors indirectly attacks endothelial cell growth. Others are designed to interfere with the signaling that takes place between tumor cells and cells in the surrounding tissue, preventing a tumor’s order to produce blood vessels from ever reaching the host tissue. Yet another category includes angiogenesis inhibitors with different mechanisms of action that are not completely understood.

Looking to the future

The science of stopping tumor angiogenesis is relatively new, and there are many unanswered questions. What are the short-term and long-term side effects of antiangiogenesis therapies? Will cancer cells adapt to render antiangiogenesis drugs ineffective? How long will these treatments last? These questions and others are now being addressed in clinical trials, which you can read about on the National Cancer Institute Web site ([url]http://www.nci.nih.gov/clinicaltrials/developments/anti-angio-table[/url]) .

Source: OncoLog, June 2004, Vol. 49, No. 6

[gdpawel]

Angiogenesis is essential for the growth and metastasis (spread) of cancer. A growing tumor requires nutrients and oxygen, which helps it grow, invade nearby tissue, and metastasize. To reach these nutrients, the tumor builds new blood vessels. In fact, growing tumors can become inactive if they can't find a new supply of nutrients.

Because angiogenesis is necessary in the growth and spread of cancer, each part of the angiogenesis process is a potential target for new cancer therapies. The assumption is that if a drug can stop the tumor from receiving the supply of nutrients, the tumor will "starve" and die.

However, there are multiple ways by which tumors can evolve that are independent of angiogenesis.

There are some scientists that believe the realization of Dr. Judah Folkman's brilliant dream of inhibition of angiogenesis, or new blood vessel formation, and starving tumors by shutting off their blood flow, is not sufficient to consistently control cancer.

Tumors can acquire a blood supply by angiogenesis, but some say also by co-option of existing blood vessels, and vasculogenic mimicry. All must be inhibited to consistently starve tumors of oxygen.

Vascular co-option is the invasion of malignant cells along blood vessels. Instead of growing new blood vessels, tumor cells can just grow along existing blood vessels. This process cannot be stopped with drugs that inhibit new blood vessel formation.

Vasculogeneic mimicry is where some types of cancers form channels that carry blood, but are not actual blood vessels. Drugs that target new blood vessel formation also cannot stop this process.

All three of these processes involve the use of normal cellular machinery to carry out proliferation and invasiveness.

The consistent and specific control of cancer requires therapy that can target the set of "all" malignant cells that could evolve. It is critical that each drug be given at a dose sufficient to kill "all" cells that express the pattern targeted by the individual drug. That requires that all three mechanisms be addressed.

These new targeted drugs mostly need to be combined with active chemotherapy to provide any benefit and the need for predictive tests allowing for a rational and economical use of them for individualized therapy selection has increased.

Abnormal angiogenesis occurs during the development of solid tumors and their metastases. Tumors require blood vessels to supply nutrients and oxygen to their cells. With access to a blood supply cancer is free to grow and spread. Without it the tumor cannot grow larger than a pea and is non lethal.

To allow them to keep growing, cancer cells release substances which induce angiogenesis and cause the formation of new capillaries. Researchers have develop angiogenesis inhibitors which starve the tumor cells to death. The Microvascularity Viability Assay will greatly facilitate the development of new anti-angiogenesis drugs.

According to Harrison's Principles of Internal Medicine, for ever 1.3 million new cases of cancer diagnosed, 500,000 will be cured by surgery and radiation, and only 40,000 will actually be cured by chemotherapy. Considering the widespread use of chemotherapy, its results are extremely disappointing.

Sources:
Eur J Clin Invest, Volume 37(suppl. 1):60, April 2007
Cure: Scientific, Social and Organizational Requirements for the Specific Cure of Cancer,"