Anti-angiogenic Therapies

[gpawelski]

Giving low doses of several drugs every day by mouth. There would be no needles and the side effects are expected to be mild. Unlike standard chemotherapy, which is given in high doses to kill as many cancer cells as possible, the lower-dose regimen is meant to attack the blood vessels that feed the tumor. Tumors create their own supply lines by secreting substances that stimulate the formation of new blood vessels and researchers suspect that frequent low doses of certain drugs may disrupt the growth of those new vessels, starving the tumor.

The treatment includes small daily doses of standard chemotherapy drugs and two other drugs that have been found to inhibit the formation of new blood vessels, called angiogenesis. One is Celebrex and the other is Thalidomide. It is offered only to people who have no other options, who have advanced tumors that standard treatment cannot cure or those for whom standard chemotherapy has quit working.

Women with advanced breast or ovarian cancer are being given smaller, more frequent doses of chemotherapy to reduce side effects. It is hoped that low-dose treatment may help other cancer patients, not just those who are considered terminal. It may work just as well or even better, maybe through this ability to cause an anti-angiogenesis effect.

This approach to treatment is based on something that can frequently occur in people, when a tumor becomes resistant to chemotherapy and high doses stop working. It is believed that angiogenesis plays a role. Angiogenesis is essential to the survival of many tumors. Many chemotherapy drugs, in addition to killing tumor cells, also fight angiogenesis. But, if these medicines stop angiogenesis, chemotherapy should work better than it does. Blood vessel cells are less likely than tumor cells to become resistant to chemotherapy, so if cancer cells become drug resistant, these medicines should still be able to shrink tumors by destroying their blood supply.

The reason chemotherapy was not stopping angiogenesis was that chemotherapy is usually given in big doses, with breaks of several weeks between doses to let the body recover. During the breaks, the tumor's blood vessels could grow back. By giving chemotherapy more often, at lower doses, it might prevent the regrowth of blood vessels and kill the tumor or at least slow its growth.

It is especially important to study low-dose therapies now because they are being used increasingly in clinics. Doses, timing and combinations all need to be worked out. Doctors need to find out whether the treatments can make patients live longer and whether tumors will eventually outsmart the drugs and find ways to survive even without angiogenesis.

For further information about clinical trials, refer to the National Cancer Institute's website: http://cancertrials.nci.nih.gov

The October 2005 issue of Ultrasound in Medicine and Biology reports that researchers at the University of Pennsylvania School of Medicine are studying the use of ultrasound to disrupt the vessels supplying blood and nutrition to tumors, much like cancer treatment utilizing anti-angiogenic therapies. After all, cutting-edge techniques can often provide superior results over tried-and-true methods that have been around for many years.

This approach is in keeping with the latest studies of cancer treatment utilizing antiangiogenic therapies, in which they look for ways to stop the growth of vessels supplying blood and nutrition to tumors, rather than develop methods to kill tumor cells themselves. In the future, treatments with ultrasound either alone or in combination with chemotherapeutic agents could be used to treat cancers.

Nobody believed Judah Folkman when, in the 1960s, he claimed that the growth of cancers could be stopped, even reversed, by blocking the tiny vessels that feed them blood. Over the years, however, he has survived peer rejection of his theory, and gone on to develop drugs that did what he predicted they would do. The angiogenesis-blocker boom is on.

[Jyoung20]

Sounds great!!! Thanks for the info.

GOD BLESS!!

Jamie

[gpawelski]

A microvascular viability assay for anti-angiogenesis-related drugs

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.

Angiogenesis starts when cancer cells produce a variety of growth factors and other activators (biologic molecules that begin a process). Growth factors cause endothelial cells (the cells that line blood vessels) to produce chemicals that break down the nearby tissue and the extracellular matrix (the spaces between cells). Then, the endothelial cells divide into more cells and begin building new blood vessels. Other elements, such as stromal cells (cells that form connective tissue), provide structural support for the new blood vessels.

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.

Anti-angiogenesis drugs work by blocking the activity of vascular endothelial growth factor (VEGF) to prevent the growth of new capillaries into the tumor and thereby sustain tumor growth. In addition to VEGF, researchers have identified a dozen other activators of angiogenesis, some of which are similar to VEGF.

VEGF causes angiogenesis by attaching to special receptors (proteins on the outside of cancer cells that act like doorways), and this action starts a series of chemical reactons inside the cell. Because VEGF is so important to angiogenesis, it is a target of new cancer treatments.

Since tumor growth is dependent on angiogenesis, and angiogenesis is dependent on VEGF, a drug like Avastin directly binds to VEGF to directly inhibit angiogenesis. Within 24 hours of VEGF inhibition, endothelial cells have been shown to shrivel, retract, fragment and die by apoptosis. Tumors which secrete relatively low levels of VEGF might be more susceptible to an agent like Avastin which works by blocking VEGF (Avastin "sensitive" tumors). It potently inhibits the formation of new blood vessels.

Vatalanib (PTK/ZK) is a small molecule tyrosine kinase inhibitor with broad specificity that targets all VEGF receptors (VEGFR), the platelet-derived growth factor receptor, and c-KIT. It is a multi-VEGFR inhibitor designed to block angiogenesis and lymphangiogenesis by binding the intracellular kinase domain of all three VEGFRs, VEGFR-1 (Flt-1), VEGFR-2 (KDR/Flk-1), and VEGFR-3 (Flt-4). Vatalanib is a targeted drug that inhibits the activity of all known receptors that bind VEGF. The drug potently inhibits the formation of new blood vessels (angiogenesis).

In some cases, these and other drugs, kill tumor cells without killing microvascular cells in the same time frame. In other cases they kill microvascular cells without killing tumor cells. In yet other cases they kill both types of cells or neither type of cells. The ability of these agents to kill tumor and/or microvascular cells in the same tumor specimen is highly variable among the different agents.

A major modification of the DISC (cell death) assay allows for the study of anti-microvascular drug effects of standard and targeted agents, such as Avastin, Nexavar and vatalanib. The Microvascularity Viability Assay is based upon the principle that microvascular (endothelial and associated) cells are present in tumor cell microclusters obtained from solid tumor specimens. The assay which has a morphological endpoint, allows for visualization of both tumor and microvascular cells and direct assessment of both anti-tumor and anti-microvascular drug effect. CD31 cytoplasmic staining confirms morphological identification of microcapillary cells in a tumor microcluster.

The principles and methods used in the Microvascularity Viability Assay include: 1. Obtaining a tissue, blood, bone marrow or malignant fluid specimen from an individual cancer patient. 2. Exposing viable tumor cells to anti-neoplastic drugs. 3. Measuring absolute in vitro drug effect. 4. Finding a statistical comparision of in vitro drug effect to an index standard, yielding an individualized pattern of relative drug activity. 5. Information obtained is used to aid in selecting from among otherwise qualified candidate drugs.

It is the only assay which involves direct visualization of the cancer cells at endpoint, allowing for accurate assessment of drug activity, discriminating tumor from non-tumor cells, and providing a permanent archival record, which improves quality, serves as control, and assesses dose response in vitro.

Photomicrographs (below) of the assay can show that some clones of tumor cells don't accumulate the drug. These cells won't get killed by it. The Assay measures the net effect of everything which goes on (Whole Cell Profiling methodology). Are the cells ultimately killed, or aren't they?

This kind of technique exists today and might be very valuable, especially when active chemoagents are limited in a particular disease, giving more credence to testing the tumor first. After all, cutting-edge techniques can often provide superior results over tried-and true methods that have been around for many years.

Source: Eur J Clin Invest, Volume 37(suppl. 1):60, April 2007

http://weisenthal.org:80/slide.057.jpg

http://weisenthal.org:80/slide.058.jpg

[Bill]

Giving low doses of several drugs every day by mouth...

The treatment includes small daily doses of standard chemotherapy drugs ...

G :

I don't understand how these standard chemotherapeutic agents would be formulated for oral use in lung cancer chemotherapy. Most of these agents are not available orally and are ineffective orally. Breast cancer has a better selection of oral meds. I am aware of attempts to formulate navelbine into a targeted-therapy drug but I have seen no follow-up on it's success or failure. And, I'm not sure what type of dosage form is being tested but I don't recall it being oral. IMO, the current popular tx modality for NSCLC is targeted-tx drugs such as Tarceva combined with lower dosage standard chemotherapeutic agents. Chemotherapeutic agents are then dropped and added into the mix over time depending on results.

B

[gpawelski]

Bill

When I talk about oral chemotherapy, I am not just talking about the new, high renumerative targeted drugs. I'm talking about the tried and true generics also. There are many cancer drug regimens, all of which have approximately the same probability of working. The tumors of different patients have different responses to chemotherapy.

There are over one hundred different therapeutic drug regimens, and some four hundred are in the pipeline. Any one or combination of them can help cancer patients. The system is overloaded with drugs and under loaded with wisdom and expertise for using them.

Cancers that can be treated with oral chemotherapy include, breast cancer, colon and colorectal cancer, leukemia, chronic myeloid leukemia, chronic lymphocytic leukemia, acute promyelocytic leukemia, acute non-lymphocytic leukemia, lymphoma, cutaneous T-cell lymphoma, small cell lung cancer, non-small cell lung cancer, Kaposi's sarcoma, prostate cancer, multiple myeloma, ovarian cancer, brain tumours.

Just some of the oral-dose cancer drugs:

Drug (Brand Name) & Specific Cancer Indication

Imatinib mesylate (Gleevec) -- for chronic myelogenous leukemia and gastrointestinal stromal tumor

Bexarotene (Targretin) -- for cutaneous T-cell lymphoma

Altretamine (Hexalen) -- for epithelial ovarian cancer

Thalidomide (Thalomid) -- for multiple myeloma

Gefitinib (Iressa) -- for non-small cell lung cancer

Letrozole (Femara) -- for stages 2-4 breast cancer

Exemestane (Aromasin) -- for stages 2-4 breast cancer

Anastrozole (Arimidex) -- for stages 2-4 breast cancer

Tamoxifen (Nolvadex) -- for stages 2-4 breast cancer

Toremifene (Fareston) -- for stages 2-4 breast cancer

Mesna (Mesnex) -- for people receiving ifosfamide

Temozolomide (Temodar) -- for anaplastic astrocytoma

Xeloda (Capecitabine) -- for mestastatic breast cancer

Cyclophosphamide (Cytoxan) -- for several types of cancer

Methotrexate (Rheumatrex) -- for several types of cancer

Busulfan (Myleran) -- for blood cancers

Etoposide (VePesid) -- for small cell lung cancer

Melphalan (Alkeran) -- for several types of cancer

Chlorambucil (Leukeran) -- for several types of cancer

Erlotinib (Tarceva) -- for non-small cell lung cancer

Oral-dose drugs are equally efficacious as infusional therapy with better adverse event profiles and easier administration.

Oncologists prescribe patients one standard empiric chemotherapy regimen after another, until they find one that works. This often can expose patients to the side effects of chemotherapy, without showing any cancer-killing results. You know how I feel about the tactic of using biopsied cells to predict which cancer treatments will work best for the patient, by taking pieces of tumor tissue, apply different chemotherapy treatments to it and examine the results to see which drug or combination of drugs do the best job killing the tumor cells.

Researchers have tested how well women with relapsed ovarian cancer would respond to a combination of a pancreatic cancer drug and an ovarian cancer drug. They found the combination worked on a number of women, and testing cells in petri dishes predicted which women would respond to this combination and which wouldn't. A metastatic pancreatic cancer patient can be treated successfully with a combination of drugs commonly used to fight lung, pancreatic, breast and colorectal cancers. How would anyone know this if they hadn't tested the tumor first?

The old office-based oncology practice has served as an incentive to overtreat with infusion chemotherapy and to encourage the patient to receive 2nd, 3rd, and 4th line chemotherapy, regardless of the likelihood of meaningful benefit.

If an oncologist is not thinking of giving a patient oral chemotherapy, instead of infusional therapy, I wonder if the extended demonstration project in oncology, which is an extra $130 paid per infusional-chemotherapy recipient per treatment day, helps them to make that decision?

My wife had chemotherapy in 1972. The postoperative drug she took was Chlorambucil (Leukeren) which is among the slowest acting and least toxic of the alkylating agents (well tolerated oral drugs). Depression of the immune system was slow and reversible, allowing it to regenerate and contribute to recovery. A malfunctioning immune system can fail to stop the growth of cancer cells. Imagine if she was taking an immune-suppressing toxic infusional regimen which is trying to stop the growth of cancer cells? It would virtually cancel it out.

She went twenty-four years before she had a recurrence to her lung. The effectiveness of the combination regimen for her recurrence was limited because of the late stages of the cancer and most patients develop resistance. Most cancer patients have the drug bounce off their tumors, doing little if any good.

I look forward to the day that infusion therapy goes by the way of the Neanderthal.

[Bill]

G :

Generally speaking, I don't disagree with much of your theoretical opinion about cancer tx. My point is that whether we're talking new or old, targeted-tx or traditional chemotherapy, the list of oral agents available for tx of lung cancer is next to nil. The list that you included in your last post clearly illustrates that. IMO, multi-tasking with targeted tx agents in various combinations with traditional chemotherapeutic agents will be the preferred approach in the tx of late stage lung cancer for the forseeable future.

B

[gpawelski]

Bill

Researchers can easily test how well patients with relapsed lung cancer would respond to a combination of a pancreatic cancer drug and an ovarian cancer drug. They found a combination that worked on a number of women with ovarian cancer, and testing cells in petri dishes predicted which women would respond to this combination and which wouldn't. A metastatic lung cancer patient could be treated successfully with a combination of drugs commonly used to fight lung, pancreatic, breast, colorectal, or whatever cancers.

Wouldn’t it be better to experiment in the petri dish rather than the human body?

You give a patient drugs and wait three weeks and then give more drugs and then wait three weeks and then repeat tumor measurements (exam, scans, markers). Using biological markers, which would apparently be found via analysis of blood and tissue samples, or even imaging scans, and could potentially predict which cancer patients will respond to certain therapies, and hopefully reduce the “shotgun” approach to cancer treatment that many oncologists practice today. However, you have the patient getting potentially toxic and ineffective treatment and then you still have to wait weeks until you can then try Plan B.

That’s conceptually the same thing drug sensitivity tests are doing. They give drugs and then measure effects on tumors a few days later. That’s what assay tests do, only they do it in the laboratory, rather than in the patient. And they can only try one or two treatments at a time. Assay tests can try up to twenty treatments at the same time and see which one works best. The key to improving drug sensitivity tests is related to the number and types of drugs tested. The more anti-cancer drug types there are in the selective arsenal, the more likely the system is to prove beneficial. In order to acquire sufficient data, tumors should be tested with at least two assay endpoints, and most often three, for sensitivity tests in any one patient. On average, up to twenty drugs and combinations at two concentrations in three different assay systems, is an effective way to avoid false-positive or false-negative data. Careful choice of drug doses and administration intervals also improves outcomes.

Every cancer patient should have his/her own unique chemotherapy trial based on consultation of pathogenic profiles and drug sensitivity testing data. Research and application of drug sensitivity assays are being encouraged by growing patient demands, scientific advances and medical ethics. Drug sensitivity tests are not a luxury but an absolute necessity, and a powerful strategy that cannot be overlooked.