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Old 08-25-2007, 02:14 PM
Dross Dross is offline
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Default Study finds blocking angiogenesis signaling from inside cell may lead to serious heal

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

'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 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.

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.¯

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.¯

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 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.¯

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.

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.

Last edited by gdpawel : 09-24-2013 at 06:34 PM. Reason: posted full article in forum board
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Old 08-29-2007, 11:09 PM
gdpawel gdpawel is offline
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Default Large Molecule vs Small Molecule

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.

Last edited by gdpawel : 01-08-2009 at 04:17 AM.
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Old 01-20-2008, 05:29 PM
gdpawel gdpawel is offline
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Default Understanding Angiogenesis

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][/url]) .

Source: OncoLog, June 2004, Vol. 49, No. 6
Gregory D. Pawelski

Last edited by gdpawel : 08-12-2010 at 09:57 PM. Reason: revision
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Old 08-12-2010, 10:07 PM
gdpawel gdpawel is offline
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Default Angiogenesis and Cancer Growth

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.

Eur J Clin Invest, Volume 37(suppl. 1):60, April 2007
Cure: Scientific, Social and Organizational Requirements for the Specific Cure of Cancer,"
Gregory D. Pawelski
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Old 09-24-2013, 06:26 PM
gdpawel gdpawel is offline
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Default Hedgehog Signaling is a Potent Regulator of Angiogenesis

Blocking the embryonic signalling pathway, known as Hedgehog (Hh), could form a basis of new treatments. By using drugs to inhibit the Hedgehog signalling, they should be able to increase the effectiveness of chemotherapy and reduce the risk of cancer relapse.

Erivedge (vismodegib) is such a drug that inhibits Hh signaling by targeting the serpentine receptor Smoothened (SMO), and has produced promising anti-tumor responses in clinical studies of cancers driven by mutations in this pathway.

Cancer stem cells (CSCs), are aggressive cells thought to be resistant to current anti-cancer therapies and which promote metastasis, are stimulated via a pathway that mirrors normal stem cell development. Disrupting the pathway, researchers are able to halt expansion of CSCs.

One approach is to force the CSCs into a differentiated state, thereby impairing stem characteristics, such as self-renewal. Interference with the Notch, Wnt, or Hedgehog pathways that are thought to regulate differentiation, are strategies that have been proposed.

Cell-based functional profiling labs have recognized the interplay between cells, stroma, vascular elements, cytokines, macrophages, lymphocytes and other environmental factors. This lead to their focus on the human tumor primary culture microspheroid (microclusters), which contains all of these elements.

In their earlier work, they endeavored to isolate tumor cells from their benign constituents so as to study "pure" tumor cells. As time went on, however, they found that these disaggregated cells were artificially sensitized to the effects of chemotherapy and provided false positive results in vitro.

Early work by Beverly Teicher and Robert Kerbel that examined cells alone and in three-dimensional (3D) structures, lead to the realization that cancer cells inhabit a microenvironment. Functional profiling labs now study cancer response to drugs within this microenvironment, enabling them to provide clinically relevant predictions to cancer patients.

It is their capacity to study human tumor microenvironments that distinguishes them from other lab platforms in the field. And, it is this capacity that enables them to conduct discovery work on the most sophisticated classes of compounds that influence cell signaling at the level of Notch, Hedgehog and Wnt, among others (Gonsalves, F, et al. (2011).

An RNAi-based chemical genetic screen identifies three small-molecule inhibitors of Wnt/wingless signaling pathway (PNAS vol. 108, no. 15, pp. 5954-5963). With this clinically validated platform they are now positioned to streamline drug development and advance experimental therapeutics.

Source: Dr. Robert Nagourney; Rational Therapeutics, Inc.

Gregory D. Pawelski
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