New data presented at the AACR-NCI-EORTC Molecular Targets and Cancer Therapeutics Meeting, in Philadelphia, demonstrated that using alisertib along with TAK-228, two of Takeda‘s investigational therapies, was more effective in patients with triple-negative breast cancer and solid tumors than either treatment individually.
The data come from two different studies conducted at the University of Colorado Cancer Center. The first, “Rational combination of mTOR and Aurora kinase A inhibition in preclinical models of triple-negative breast cancer,” was a laboratory study.
It provided the basis for the second study, “A phase Ib study of the combination of MLN0128 (dual TORC1/2 inhibitor) and MLN8237 (Aurora A inhibitor, alisertib) in patients with advanced solid tumors,” a Phase 1 dose-escalation trial in patients with advanced solid tumors.
Prior studies have shown that a protein called Aurora A plays a role in the development of breast cancer. Thus, a treatment called alisertib, which inhibits this protein, was developed to fight the disease. In some cancers, alisertib has the ability to kill cells. But in the case of triple-negative breast cancer, it causes a sleep-like state called senescence. In senescence, cancer cells stop growing quickly but don’t die. While achieving senescence in tumor cells can be good, killing the cancer cells is better.
In the first study, researchers have shown that when treated with alisertib, the triple-negative breast cancer cells increase a pathway called mTOR, which allows these cells to survive.
“Unfortunately, even in this senescent state, triple-negative breast cancer cells can signal their neighbors to grow,” Jennifer Diamond, MD, who presented both studies at the meeting, said in a press release. “The first study we presented shows that mTOR is important for these cells to maintain senescence.”
Along with alisertib, researchers then used the treatment TAK-228, which is known to block mTOR signaling. This actually led to the death of triple-negative breast cancer cells. Thus, a combination of the two treatments blocked the different pathways the cells were using to stay alive.
Researchers confirmed this by showing that treating the cells with each individual drug results in cell cycle arrest, causing senescence. However, when treated together, the cells entered into a phase called apoptosis, which is a programmed cell death.
Once Diamond’s group had a scientific basis for this combination, they submitted their findings to the company Takeda, which produces both alisertib and TAK-228.
“We were approved,” said Diamond, referring to the collaboration. “They would provide the drug and we would run the study.” In 2016, this led to the Phase 1 clinical trial (NCT02719691) of alisertib in combination with TAK-228 in patients with advanced solid tumors.
Results presented at the conference showed that among 16 patients treated with this combination, the treatments were well-tolerated, with the most common adverse effect being fatigue and reduced neutrophil count. This has led to the establishment of a maximum tolerated dose of 30 mg alisertib per day for a week, with two weeks off, in combination with 2 mg of TAK-228 every day.
“We had multiple patients that were on the trial for a long time – a breast cancer patient who was on treatment for over a year and a prostate cancer patient whose disease continues to be under control for almost a year, both good results for a phase 1 study,” Diamond said.
These promising data led to the expansion of the trial to an additional 20 patients, which will help further determine the correct dose and the dose timings. The trial also will help to determine the types of patients most likely to benefit from the combination of the two therapies.