Antivascular activity of lapatinib and bevacizumab in primary microcluster cultures

[gdpawel]

Antivascular activity of lapatinib and bevacizumab 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