Dasatinib (synergizes with chemo)

[Rich66]

October 5, 2009 | Research

New Chemo Cocktail Blocks Breast Cancer Like a Fence


Drug aimed at preventing spread of breast cancer to organs
By Marla Paul

CHICAGO --- Think of a protective fence that blocks the neighbor's dog from charging into your backyard. The body, too, has fences -- physical and biochemical barriers that keep cells in their place. When breast cancer spreads or metastasizes, it crashes through the body's protective fences. The disease becomes fatal when it travels outside the mammary ducts, enters the bloodstream and spreads to the bones, liver or brain. Currently, there are only drugs that try to stem the uncontrolled division of cancer cells within the ducts. Until now, no drugs specifically targeted the invasion and spread of breast cancer to the organs.
A researcher from Northwestern University Feinberg School of Medicine has found a way to strengthen the breast's "fence" to prevent cancer from metastasizing. Researcher Seth Corey, M.D., has discovered that when a drug normally used to treat leukemia is added to a commonly used breast cancer drug, the potent new chemotherapy cocktail helps prevent breast cancer cells from invading.
"This is an entirely new way of targeting a cancer cell," said Corey, the Sharon B. Murphy-Steven T. Rosen Research Professor of Cancer Biology and Chemotherapy at the Feinberg School and director of the pediatric oncology program at the Robert H. Lurie Comprehensive Cancer Center of Northwestern University.
Working in the lab with women's breast cancer cells, Corey found that when the leukemia drug dasatinib is combined with the breast cancer drug doxorubicin, the potent mix inhibits breast cancer cell invasion by half. Corey is the principal investigator of the study, which recently was reported in the British Journal of Cancer.
Dasatinib targets an enzyme called the Src kinase, which is believed to play a key role in breast cancer invasion and metastases.
"Perhaps this drug could be given to prevent invasion from happening in the first place," said Corey, who also is a pediatric oncologist at Children's Memorial Hospital. "This might keep the disease in check and prevent it from progressing."

Marla Paul is the health sciences editor. Contact her at marla-paul@northwestern.edu




British Journal of Cancer (2009) 101, 38–47. doi:10.1038/sj.bjc.6605101 www.bjcancer.com
Published online 9 June 2009
Dasatinib synergizes with doxorubicin to block growth, migration, and invasion of breast cancer cells

C S Pichot¹, S M Hartig², L Xia³, C Arvanitis⁴, D Monisvais⁴, F Y Lee⁵, J A Frost¹ and S J Corey⁴

1. ¹Department of Integrative Biology and Pharmacology, University of Texas Health Science Center, Houston, Texas, USA
2. ²Department of Cell Biology, Baylor College of Medicine, Houston, Texas, USA
3. ³Department of Surgical Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas, USA
4. ⁴Departments of Pediatrics and Cellular and Molecular Biology, Children's Memorial Hospital and Robert H. Lurie Comprehensive Cancer Center, Northwestern University, Chicago, Illinois, USA
5. ⁵Bristol-Myers Squibb Pharmaceutical Research Institute, Princeton, New Jersey, USA

Correspondence: Dr SJ Corey, Robert H. Lurie Comprehensive Cancer Center, Northwestern University, Lurie 5-107, 303 East Superior Street, Chicago, Illinois 60611, USA; E-mail: s-corey@northwestern.edu
Revised 22 April 2009; Accepted 27 April 2009; Published online 9 June 2009.

Top of pageAbstract

Background:

Src family kinases control multiple cancer cell properties including cell cycle progression, survival, and metastasis. Recent studies suggest that the Src inhibitor dasatinib blocks these critical cancer cell functions.

Methods:

Because the molecular mechanism of action of dasatinib in breast cancers has not been investigated, we evaluated the effects of dasatinib as a single agent and in combination with the commonly used chemotherapeutic doxorubicin, on the proliferation, viability, and invasive capacity of breast cancer cells lines earlier categorised as dasatinib-sensitive (MDA-MB-231) and moderately resistant (MCF7 and T47D). We also tested the effects of these drugs on the actin cytoskeleton and associated signalling pathways.

Results:

The cell lines tested varied widely in sensitivity to growth inhibition (IC₅₀=0.16–12.3 M), despite comparable Src kinase inhibition by dasatinib (IC₅₀=17–37 nM). In the most sensitive cell line, MDA-MB-231, dasatinib treatment induced significant G₁ accumulation with little apoptosis, disrupted cellular morphology, blocked migration, inhibited invasion through Matrigel (P<0.01), and blocked the formation of invadopodia (P<0.001). Importantly, combination treatment with doxorubicin resulted in synergistic growth inhibition in all cell lines and blocked the migration and invasion of the highly metastatic, triple-negative MDA-MB-231 cell line.

Conclusion:

The observed synergy between dasatinib and doxorubicin warrants the re-evaluation of dasatinib as an effective agent in multi-drug regimens for the treatment of invasive breast cancers.

[Rich66]

Dasatinib is available and marketed as Sprycel:
http://www.sprycel.com/Index.aspx

So..available off label for cancer?