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Old 11-24-2011, 09:07 PM
gdpawel gdpawel is offline
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Default Biomarker for Avastin

For some time, clinicians have been grumbling about not having a biomarker for Avastin or any other anti-angiogenesis compound to better help choose which patients would be most likely to respond, thereby avoiding the need to treat everyone to gain a benefit in a few.

One of the biggest challenges with Vascular Endothelial Growth Factor (VEGF) therapy has been the lack of a predictive biomarker.

There is no idea which patients would most likely respond to therapy when selecting a number of new classes of drugs that target VEGF, at the protein level (Avastin, Zaltrap), at the tyrosine kinase level (Iressa, Nexavar, Tarceva, Sutent) or at the intracelluar metabolic pathway mTOR (Afinitor, Torisel).

Suppose there was a biomarker that was relative to Avastin and could be helpful for predictive purposes? Then you could actually make better use of the drug based on the biomarker. You would be able to predetermine and monitor therapy for specific subtypes and avoid exposing patients to the effects and costs of a drug that may not work for them.

A private cell-based assay lab came along with a smart idea, a rational approach to the problem and some creative thinking to develop a biomarker for anti-angiogenesis compounds.

The Journal of Internal Medicine reported the discovery of the first practical laboratory test to guide the use of new-generation drugs that kill cancer cells by cutting off their blood supply. The new test, called AngioRx, is an anti-ngiogenesis microvascular viability (MVV) assay, was developed by Larry Weisenthal, MD, PhD., a medical oncologist who operates a cancer testing laboratory in Huntington Beach, California. The test works by measuring drug effects upon endothelial cells which make up blood vessels. Its use could prolong lives, save money, and spare patients exposure to harmful side-effects of ineffective chemotherapy treatments.

The MVV test also could streamline development of new anti-cancer cancer drugs and identify effective and sometimes unexpected new drug combinations, such as one reported in the Journal. Used today principally by cancer physicians, to choose effective therapies on a patient-by-patient basis, the assay also has potential for use as an early-warning screen for a variety of illnesses ranging from heart disease, cancer, diabetes, autoimmune disorders, and many others. Patents have been filed.

Dr. Weisenthal invented his new test after making the discovery that endothelial cells are present in cancer biopsy specimens even after the specimens are reduced to clusters of living cancer cells in order to make them suitable for testing in the laboratory. Endothelial cells form capillaries which carry oxygen and nutrients to cancer cells. Dr. Weisenthal noted that the effects of various drugs upon endothelial cells can be measured separately from the effects of those same drugs upon cancer cells within the same biopsy specimen. Dr. Weisenthal describes this as "anti-vascular effect versus anti-tumor effect." Using this discriminatory property of his new test, Dr. Weisenthal has published several, original and often unexpected observations about the ways in which various drugs work.

Dr. Weisenthal further describes a logical extension of the test, in which the ability to identify and characterize endothelial cells in mixed-cell populations could lead to early diagnosis and thereby more successful treatment of a broad spectrum of illnesses for which elevated numbers of circulating endothelial cells can be a feature. Potentially included are cancer, heart disease, diabetes, macular degeneration and others. Dr. Weisenthal envisions an accurate and inexpensive test, performed annually and based upon a simple blood draw, which would warn of the possible presence of a medical condition for which additional tests were warranted. The result would be earlier diagnosis of disease and also avoidance of much of the expensive and often unnecessary medical testing which occurs today.

The most immediate application of the assay focuses upon cancer and specifically upon the much-heralded angiogenesis-inhibiting drugs, which work by attacking tumor vasculature and thereby starving cancer cells. A recent NIH listing contained over 800 active clinical trials involving angiogenesis-inhibiting agents.

One problem with these drugs, in addition to their high cost, is determining in advance who will benefit from them. The other problem is learning how to make the drugs more effective by using them in combination. The new MVV test could help on both fronts.

Dr Weisenthal expresses his belief that cancer can become a chronic and controllable illness through the use of combinations of anti-angiogenesis drugs. He says, "The long-awaited magic-bullet cure for cancer hasn't materialized. Now we're thinking more in terms of long-term control such as is the case with high blood pressure or diabetes. The way to make that happen sooner is to use our current ammunition more affectively."

Dr. Weisenthal's observations are reinforced by early studies of angiogenesis-inhibiting drugs in animal tumor models. In these studies, single agents produced only sporadic and temporary benefits. However, the effectiveness of these drugs increased substantially when they were administered in combination with other angiogenesis-inhibiting drugs. According to Dr. Weisenthal, the MVV test is the first practical tool that allows for design and testing of new anti-angiogenic drug combinations in human cancer.

Using his new MVV test, Dr. Weisenthal says that he often finds strong synergies among new combinations of different types of angiogenesis-inhibiting drugs, including drugs which were not previously known to have anti-angiogenic properties. One observation, which he reported in the Journal of Internal Medicine article, is that dimethylsulfoxide and ethanol are two compounds which often enhance the activity of anti-angiogenesis drugs in the laboratory. According to Dr. Weisenthal, therapeutic levels of ethanol in the bloodstream theoretically could be achieved simply by drinking wine or another alcoholic beverages in prescribed doses concurrent with receiving angiogenesis-inhibiting drugs. The concept might please some patients and alarm others but Dr. Weisenthal finds support in actual case studies reported in the medical literature. However, he warns that further clinical studies are required.

The MVV test is applicable to cancer patients whose bodies harbor cancer cells which are obtainable though biopsy. Currently, the test is available only through Dr. Weisenthal's laboratory, the Weisenthal Cancer Group. Dr. Weisenthal says that he provides his testing services more like a medical practice and less like a typical reference laboratory. Although he regularly performs testing for cancer patients in the U.S. and also from several foreign countries, he intends to to stick to medicine and leave marketing of the MVV test to others. Dr. Weisenthal says that he would like to see the test become available to patients worldwide through service agreements with larger laboratory companies or with a biotechnology company which might develop a testing kit for sale to hospitals and laboratories. He also would like to license the test to pharmaceutical companies for use in new drug development.

About Weisenthal Cancer Group

Weisenthal Cancer Group is a privately-held commercial cancer testing laboratory and research facility headquartered in Huntington Beach, California. The company was founded in 1992 by Larry Weisenthal, MD, PhD, a medical oncologist and Associate Clinical Professor of Medicine at the University of California Irvine. Dr. Weisenthal trained at the NCI and has served in a variety of advisory and review capacities. Dr. Weisenthal is widely published and has been a keynote speaker at numerous meetings and symposia presented by oncology societies in Europe and Asia. Weisenthal Cancer Group provides functional tumor cell profiling studies and medical consultation to physicians and patients worldwide in connection with chemotherapy treatment.

The laboratory also provides contract and collaborative research services to biotech and pharmaceutical companies and to cancer researchers.

Bibliography relevant to AngioRx/Microvascular Viability assay (MVVA)

1. Weisenthal, L. M. Patel,N., Rueff-Weisenthal, C. (2008). "Cell culture detection of microvascular cell death in clinical specimens of human neoplasms and peripheral blood." J Intern Med 264(3): 275-287. [url]http://onlinelibrary.wiley.com/doi/10.1111/j.1365-2796.2008.01955.x/full

2. Weisenthal, L., Lee,DJ, and Patel,N. (2008). Antivascular activity of lapatinib and bevacizumab in primary microcluster cultures of breast cancer and other human neoplasms. ASCO 2008 Breast Cancer Symposium. Washington, D.C.: Abstract # 166. Slide presentation at: [url]http://tinyurl.com/weisenthal-breast-lapatinib

3. Weisenthal, L. M. (2010). Antitumor and anti-microvascular effects of sorafenib in fresh human tumor culture in comparison with other putative tyrosine kinase inhibitors. J Clin Oncol 28, 2010 (suppl; abstr e13617)

4. Weisenthal, L., H. Liu, Rueff-Weisenthal, C. (2010). "Death of human tumor endothelial cells in vitro through a probable calcium-associated mechanism induced by bevacizumab and detected via a novel method." Nature Precedings 28 May 2010. from [url]http://precedings.nature.com/documents/4499/version/1
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Last edited by gdpawel : 04-01-2013 at 11:35 AM. Reason: corrected url address
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  #2  
Old 11-24-2011, 09:11 PM
gdpawel gdpawel is offline
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Default Anti-Vascular Drugs - Who Can Benefit?

THE PROMISE

One of the most promising areas of cancer treatment today is also among the most perplexing. A new class of anti-cancer drugs works by interfering with the formation of capillaries which deliver blood to the tumor mass. Eliminating the blood supply to the tumor starves cancer cells of oxygen and nutrients, interferes with the elimination of cellular wastes, shuts-down routes of tumor metastasis, and potentially aids in the delivery of other types of anti-cancer drugs to the tumor mass.

THE PROBLEM

The problem is that the new drugs – called anti-angiogenesis drugs – work for only a small percentage of patients. Moreover, they can cause serious side effects in some patients and they are extremely expensive – well over $100,000 per year of treatment. Anti-angiogenesis drugs are being used more and more frequently in a widening range of cancer types and so the cost to the healthcare system and to individual patients who must pay for insurance co-payments threatens to be staggering. In fact, several new drugs have now shown anti-angiogenesis activity and these are being combined with standard drugs and with other targeted drugs to produce the maximum therapeutic benefit. A critical but previously-elusive challenge, therefore, has been to develop methods to identify exactly which patients could benefit from anti-angiogenesis therapy, which anti-angiogenesis drugs are best for these patients, and precisely which additional drugs, if any, should be administered concurrently in order to achieve the best result for each patient.

THE SOLUTION

Using a laboratory test which he invented, Dr. Weisenthal made the discovery that endothelial cells are present in disaggregated tumor micro-clusters. Previously, this was unknown in the medical literature. Endothelial cells form the capillaries which supply blood to tumor cells. Building on this discovery, Dr. Weisenthal developed the AngioRx microvascular viability assay. To date, the AngioRx assay is the only laboratory test which appears to be capable of identifying anti-angiogenic drug activity in live tumor micro-clusters. Other capabilities exclusive to Dr. Weisenthal’s AngioRx assay are:

•Discriminates anti-tumor effect from anti-angiogenic effect within mixed-populations of tumor, endothelial, and other cell types. It is extremely important to understand the mechanism by which treatment works for each patient.

•Measures the effects of different anti-angiogenic drugs within the same drug class. This is essential for pin-pointing which specific anti-angiogenic drug will work best for each patient - several such drugs are available.

•Measures the single-agent activity of specific anti-angiogenic drugs, standard cytotoxic drugs, and EGFR-targeted drugs. This can be the key to identifying potentially-beneficial drug combinations for each patient.

•Identifies synergistic effects which can occur among specific anti-angiogenic and non-anti-angiogenic drugs in rationally-selected drug combinations. This exclusive capability becomes particularly critical when combining cytotoxic drugs with anti-vascular drugs

Weisenthal Cancer Group
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  #3  
Old 01-04-2012, 10:47 PM
gdpawel gdpawel is offline
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Default Biologic therapy is on the ascendancy

The possibility of eradicating cancer by selective destructon of tumor blood vessels may represent an attractive therapeutic avenue. It's going to take combination antivascular therapy to make a difference. The AngioRx Assay is the most promising technology on the therapeutic horizon. And, on top of that, putting a vascular disrupting agent in combination with an antiangiogenesis agent.

In general, four strategies are being used by investigators to design anti angiogenesis agents: 1. Block the factors that stimulate the formation of blood vessels, 2. Use natural inhibitors of angiogenesis, 3. Block molecules that allow newly forming blood vessels to invade surrounding tissue, 4. Incapacitate newly dividing endothelial cells

Drug resistance is a major problem with conventional cytotoxic chemotherapy agents. This is because most cancer cells are genetically unstable, are more prone to mutations and are therefore likely to produce drug resistant cells. Since angiogenic drugs target normal endothelial cells which are not genetically unstable, drug resistance may not develop. So far, resistance has not been a major problem in long-term animal studies or in clinical trials, and neither has it with cell-based functional profiling assay-directed therapy.

Dr. Larry Weisenthal had a poster presenation at the 13th International Anti-Angiogenic Symposium in San Diego, CA on February 3, 2011. The theme of every single talk, in every signle disease was: (1) We need combination anti-angiogenic therapy, (2) We need some type of useful biomarker for predicting results of anti-angiogenic therapy, selecting best combinations, and individualizing treatment.

Information about Systems Biology Confronting the Complexity of Cancer states, one of the hallmarks of cancer is the complex interaction of genes, networks, and cells in order to initiate and maintain a cancerous state. This inherent complexity constantly challenges our ability to develop effective and specific treatments. A systems biology approach towards the understanding and treatment of cancer examines the many components of the disease simultaneously.

A vascular disrupting agent can go after the abnormal (sensitive) part of an established tumor vasculature (abnormal vs healthy). It already is higly fractured and architecturally disorded with fragile, immature blood vessels which lack external smoother muscle and pericyte support. The result is blocking blood flow to the tumor. With Avastin, tumor starves from the outside. With Zybrestat, the tumor starves from within.

Angiogenesis inhibitors target the formation of new blood vessels. Vascular disrupting agents target endothelial cells and pericytes (connective tissue) of the already established tumor vasculature, resulting in tumor ischemia (inadequate blood supply) and necrosis (death). So the thought here is to go after the formation of new blood vessels (Avastin) and go after the already established tumor vasculature (Zybrestat).

It's going to take combination antivascular therapy to make a big difference. If they can achieve this, then they may not need the other drugs, which really don't get into the tumor so well. Angiogenic attack provides true selective toxicity, something which is sorely lacking with all of our other treatments.

Source: The 13th International Symposium on Anti-Angiogenic Therapy: Recent Advances and Future Directions in Basic and Clinical Cancer Research, February 3-5, 2011

[url]http://www.mdanderson.org/education-and-research/education-and-training/schools-and-programs/cme-conference-management/conferences/2011-international-symposium-anti-angiogeneic-therapy.html
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Last edited by gdpawel : 07-17-2012 at 03:08 PM. Reason: added url address
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  #4  
Old 01-25-2012, 09:05 AM
gdpawel gdpawel is offline
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Default Predictive Biomarker for Anti-Angiogenic Therapy

Endothelial Massive Calcium Accumulation Death (MCAD): Mechanism, Target, and Predictive Biomarker for Anti-Angiogenic Therapy

Presented at the 13th international symposium on anti-angiogenic therapy: recent advances and future directions in basic and clinical cancer research. LaJolla, CA. Sponsor: MD Anderson Cancer Center; planning committee Robert S. Kerbel, Lee M Ellis, et al., 03 February 2011

Weisenthal Cancer Group

Abstract

We cultured human umbilical vein endothelial cells with bevacizumab, with tyrosine kinase inhibitors known to be AA, and with traditional cytotoxic drugs. The images below show that, in the presence of physiological saline and non-favorable culture conditions, the vast majority of the endothelial cells undergo a “non-specific” type of cell death (NSCD), not associated with calcium accumulation, but with loss of cell membrane integrity, allowing uptake of the Fast Green dye, staining these dead dells a pale blue green. In the presence of known AA agents (e.g. bevacizumab, some TK inhibitors) a large percentage of the endothelial cells undergo death associated with massive calcium accumulation (MCAD), with these cells staining hyperchromatic, refractile, blue-black, precisely as reported in

[url]http://www.ncbi.nlm.nih.gov/pubmed/18793333

and

[url]http://meeting.ascopubs.org/cgi/content/abstract/28/15_suppl/e13617

and

[url]http://tinyurl.com/weisenthal-breast-lapatinib

MCAD is strikingly demonstrated by Fast Green/Alizarin staining as reported in

[url]http://precedings.nature.com/documents/4499/version/1

Traditional cytotoxic drugs (e.g. cisplatin) produce only NSCD and inhibit MCAD. We propose that MCAD is a cell death mechanism unique to endothelial cells and provides a practical biomarker to predict for AA activity in clinical oncology and drug development, as well as a potential drug target.

[url]http://precedings.nature.com/documents/6647/version/1/files/npre20116647-1.pdf

Nature Precedings doi:10.1038/npre.2011.6647.1
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