While the other clinically-available 'nib' drugs have been shown to have anti-vascular activity, anti-vascular activity of Tykerb has not been previously reported.

Angiogenesis studies are limited by the clinical relevance of laboratory model systems. They don't do "real world" studies under "real world" conditions. Patient outcomes need to be reported in real-time, so patients and cancer physicians can learn immediately if and how patients are benefiting from new drug therapies.

Cell culture detection of microvascular cell death in clinical specimens of human neoplasms and peripheral blood can identify the activity of both single drugs and combinations of drugs at the level of individual patients with individual cancers. It works by measuring drug effects (real-time) upon endothelial cells which make up blood vessels.

Drugs like Avastin had striking anti-microvascular effects but minimal anti-tumor effects. Tarceva and Gleevec had mixed antitumor and anti-microvascular effects. Anti-microvascular effects of Tarceva and Iressa were equal to those of Sutent and Nexavar. Anti-microvascular additivity was observed between Avastin and other drugs on an individual basis.

Conclusions of the study had shown that Tykerb has antivascular activity superior to that of Nexavar. Avastin + Tykerb may be the first clinically-exploitable antivascular drug combination. High dose, intermittent 'bolus' schedules of Tykerb to coincide with Avastin administration may be clinically advantageous, even in HER2-negative tumors.

The system utilized for the study was a functional profiling assay, which may be used to individualize antivascular therapy. It can be adapted for simple, inexpensive and sensitive/specific detection of tissue and circulating microvascular cells in a variety of neoplastic and non-neoplastic conditions, for drug development, and individualized cancer treatment.

Microaggregates (microscopic collection of platelets, leukocytes or fibrin particles that occurs in blood) which mimic the native environment of cells contained in biopsied tissue are used to assess and predict the effects of various treatments on the viability of cell types contained in the microaggregate.

There is a need for improved methods to predict the activity of treatments which target the microvasculature of tumors. Avastin is an anti-cancer drug which targets the microvasculature of tumors. The wholesale cost of Avastin is more than $40,000 for ten months of treatment for a relatively small percentage of patient that can derive substantial benefit from it.

The most commonly used in vitro methods involve isolating and culturing endothelial cells. Once the cells have been cultured, the effect of drugs are studied using cell death endpoints.

Normally, Avastin is administered to a patient on a trial basis and then early treatment effects are assessed by means of external diagnositc scanning (MRI) and/or post-treatment tumor biopsies, with histopathologic evaluation of treatment effects. This approach has many disadvantages, including expense of treatment, exposure of patient to potential toxicity of ultimately ineffective therapy, and the expense of diagnostic studies (MRI). Such studies also lack the ability to test multiple different treatments simultaneously without risk to the patient as is possible with in vitro methods.

In vitro methods are able to detect and/or quantify viability changes in the microvasculature of microaggregates of cells isolated from biopsied neoplastic tissues in response to treatments. The observed microvascular and other cellular changes serve as tests to predict the in vivo activity of the tested treatments, while able to detect specific effects on endothelial cells, and also permit the observation of effects of the same or concomitantly administered treatment on the surrounding cells (a particular drug may affect both endothelial cells and the surrounding cells).

Poster Presentation: http://www.weisenthal.org/Weisenthal_ASCO.pdf

*** Edited 11/5/2008 1:41:53 AM UTC by gdpawel***