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In the lab and in the clinic, alisertib with TAK-228 excels against solid tumors, including triple-n

November 1, 2017


Two University of Colorado Cancer Center studies were presented this weekend at the AACR-NCI-EORTC Molecular Targets and Cancer Therapeutics Meeting in Philadelphia, PA showing that using the drug alisertib along with the drug TAK-228 is more effective against triple-negative breast cancer and solid tumors than either drug alone. The first study details the scientific work that forms the basis for the second study, which presents results of an ongoing phase 1 dose-escalation clinical trial of this combination in patients with advanced solid tumors.


Previous work implicates a kinase called Aurora A in the development and growth of breast cancer. The drug alisertib inhibits this kinase. This drug has the ability to kill many types of cancer cells; however, rather than dying in response to aurora A kinase inhibition, some triple-negative breast cancer cells enter a sleep-like state known as senescence. Senescence may be good – cells stop dividing quickly – but cell death is better.                                                                                                                                                   Jennifer Diamond, MD

“Unfortunately, even in this senescent state, triple-negative breast cancer cells can signal their neighbors to grow,” says Jennifer Diamond, MD, investigator at CU Cancer Center and the study’s first author. In fact, work in the Diamond lab and elsewhere shows that when triple-negative breast cancer cells become senescent, the cancer can, in fact, continue to grow.

The Diamond lab has also shown that when triple-negative breast cancer cells are treated with aurora A kinase inhibitors, they increase their signaling through a pathway known as mTOR.

“The first study we presented shows that mTOR is important for these cells to maintain senescence,” Diamond says.

When the group used TAK-228 to block mTOR signaling, instead of becoming senescent, triple-negative breast cancer cells died. In other words, it seemed as if these cells were using mTOR to escape alisertib. And using TAK-228 to block mTOR nixed this escape.

To confirm this effect, the group collaborated with James Orth, PhD, assistant research professor at CU Boulder, to apply a fluorescent labeling system to show where cells treated with each drug alone and in combination were in
     S. Lindsey Davis, MD                                   their cycle of replication. Alone, alisertib and TAK-228 each resulted in cell                                                                              cycle arrest – the cells stopped partway through the cell cycle to become senescent. When the group combined alisertib with TAK-228, instead of cell cycle arrest, cancer cells entered the cell death known as apoptosis.

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