Antivascular activity of lapatinib (Tykerb) and bevacizumab (Avastin) in primary microcluster cultures of breast cancer and other human neoplasms

Sub-category: New Systemic Agents - New drugs and targets (includes anti-angiogenics) - Other

Category: Treatment

Meeting: 2008 Breast Cancer Symposium

Abstract No: 166

Author(s): L. Weisenthal, D. J. Lee, N. Patel

Abstract:

Background:

The following tyrosine kinase inhibitors (TKI) have been shown to have antivascular (AV) activity: sunitinib (Su), sorafenib (So), gefitinib (G), erlotinib (E), and imatinib (I). To date, AV activity has not been reported for lapatinib (LAP).

Methods:

We studied the ability of TKI to induce tumor cell death (TCD) and also endothelial cell death (ECD) in primary human tumor cultures, using a novel functional profiling assay system, which detects TCD vs ECD in floating cell microclusters derived with > 90% success rate from fresh human tumor biopsies (Weisenthal, 2007 ASCO GI Symposium Abst 439; http://tinyurl.com/ywfnsy; Weisenthal, et al. J Intern Med, In Press).

Results:

LAP (15 µg/ml) induced significantly greater tumor cell death (TCD) in breast cancer biopsy specimens (n=25) than in specimens from cancers other than breast (n=42). However, there was no average difference between the degree of LAP-induced endothelial cell death (ECD) in breast cancer specimens vs. non-breast cancer specimens. At drug concentrations which were equitoxic to tumor cells, LAP induced significantly greater ECD than did sorafenib (So). At concentrations (2.5 and 1.25 mg/ml) of bevacizumab (BEV) which reduced VEGF in the culture media supernatant to levels below detection by commercial ELISA assay, BEV-induced ECD was not significantly enhanced by So, Su, G, E, or I; however, BEV-induced ECD was significantly enhanced by LAP.

Conclusions:

1. LAP has AV activity superior to that of sorafenib. 2. BEV + LAP may be the first clinically-exploitable AV drug combination. 3. Our functional profiling assay system may be used to individualize AV therapy. 4. High dose, intermittent 'bolus' schedules of LAP to coincide with BEV administration may be clinically advantageous, even in HER2-negative tumors.

Source: Presentation at the American Society of Clinical Oncology Breast Cancer Symposium September 5, 2008

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

Direct anti-tumor and anti-vascular effects were studied of Tykerb, Nexavar and Avastin in fresh biopsy specimens. 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.

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.

It can accurately sort drugs into categories of above average probability of providing clinical benefit on one hand and below average probability of providing clinical benefit on the other hand, based both on tumor response and patient survival.