Tumor functional profiling for personalizing therapy with bevacizumab, chemotherapy, and tyrosine kinase inhibitors

WHAT WE KNOW (and what we think we know):

The most effective systemic agent for poorly differentiated brain tumors (glioblastoma multiforme) is bevacizumab (Avastin).

Other anti-angiogenic agents have activity, as well.

In principle, combining different anti-angiogenics may improve outcomes.

In principle, adding traditional chemotherapeutic agents to anti-angiogenics may improve outcomes.

PROBLEM #1:

Individual tumors are different from one another.  The above treatments are very expensive and, more importantly, have a very high failure rate. When it comes to combining drugs, the potential number of combinations is very large.

POTENTIAL SOLUTION:

One would wish to have a robust, sensitive and specific test to determine which drug(s) would have the greatest probability of providing benefit on an individual basis.

PROBLEM #2:

Existing tests, based on genetic profiling, are virtually useless.  This includes whole genomic sequencing.  These are very elegant tests which are virtually worthless for the purpose of individualizing therapy.

BETTER SOLUTION:

Cell culture testing (functional profiling), with a unique, sensitive, specific endpoint.  Simultaneously test the ability of drugs to kill tumor cells and kill tumor-associated blood vessel (endothelial) cells.

GENERAL APPROACH AND PILOT DATA:

http://precedings.nature.com/documents/7069/version/1

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 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: 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.  http://precedings.nature.com/documents/4499/version/1.

5. Weisenthal, Larry . Endothelial Massive Calcium Accumulation Death (MCAD): Mechanism, Target, and Predictive Biomarker for Anti-Angiogenic Therapy. 13th international symposium on anti-angiogenic therapy: recent advances  and future directions in basic and clinical cancer research. LaJolla, CA. February 2011

Available from Nature Precedings  http://dx.doi.org/10.1038/npre.2011.6647.1

6. Weisenthal, L, Williamson, S, Ryan, K, Brunshwiler, C, and Rueff-Weisenthal, C.

    Massive calcium uptake in human endothelial cells, submitted for publication.

7.Bevacizumab-induced tumor calci?cations can be elicited in glioblastoma microspheroid culture and

represent massive calcium uptake death (MCAD) of tumor endothelial cells. Larry Weisenthal, Summer

Williamson, Cindy Brunschwiler, and Constance Rueff-Weisenthal, 14th International Anti-Angiogenesis

Symposium, LaJolla CA, Feb 2012. Available from Nature Precedings  http://dx.doi.org/10.1038/npre.2012.7069.1  (2012)

Sample report attached as a PDF file:

Ex_glioblastoma_L8106_sample_report

Larry Weisenthal MD

http://medpedia.com/users/110

http://weisenthalcancer.com