For some time, clinicians have been grumbling about not having a biomarker for Avastinterm
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 (VEGFterm) 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), at the tyrosine kinase level (Iressa, Nexavartermterm, Tarceva, Sutenttermterm) or at the intracelluar metabolic pathway mTOR (Afiinitor, 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 chemotherapyterm 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.
2. Weisenthal, L., Lee,DJ, and Patel,N. (2008). Antivascular activity of lapatinib and bevacizumabtermterm in primary microcluster cultures of breast cancer and other human neoplasms. ASCO 2008 Breast Cancer Symposium. Washington, D.C.: Abstract # 166. Slide presentation at: http://tinyurl.com/weisenthal-breast-lapatinib