It’s necessary to recollect, Shagisultanova says, that HER2 and PI3K are crucial for cell growth and development – the form of development that takes place in regular tissue. However, “when it becomes abnormally activated, all systems of checks and balances get unbalanced, and that’s when cancer starts.”
HER2 is a protein current in about 20% of breast cancers. HER2-positive breast cancers are typically extra aggressive than different breast cancers, although therapies designed to particularly goal HER2 have been proven to be very efficient. Many of these therapies contain blocking HER2 development indicators.
“Since we discovered HER2 inhibitors, life expectancy for patients with HER2-positive breast cancer has improved tremendously, because we’re able to block one of the main drivers of this cancer,” Shagisultanova says. “If we just use chemotherapy and don’t block HER2, cancer cells divide faster than we can kill them, even with a powerful chemotherapy. But once we block HER2 growth signals, the combination of that HER2 blocker and chemotherapy can kill tumor cells and cure patients with early stage HER2-positive breast cancer or prolong the life of patients with metastatic HER2-positive tumors.”
However, about 30% of HER2-positive sufferers even have PIK3CA mutations. Because the PI3K protein is immediately related to the HER2 receptor, “if it is mutated and has been activated, it doesn’t matter how much you block HER2 growth signals upstream, PI3K will still send the growth signal downstream and make our blockade futile, Shagisultanova explains. “PI3K will inform the tumor cells to develop.”
Developing a PIK3CA inhibitor
Now that proof exhibits PI3K drives therapeutic resistance in HER2-positive breast most cancers, one of many subsequent necessary focuses of analysis shall be creating inhibitors for PI3K.
“It’s been very difficult to develop effective inhibitors to this molecule because PI3K is connected to many growth factor receptors,” Shagisultanova says. “In initial trials we saw that when you block PI3K, insulin signaling tries to counteract this block and blood sugar goes up. So, one of the side-effects has been diabetes, and we don’t want to make cancer patients unnecessarily sick from other conditions while treating cancer.”
In 2019, a second-generation PI3K inhibitor that does not have excessive ranges of toxicity was developed. Through cell line and animal modeling executed in her lab, Shagisultanova has been capable of present that the not too long ago accepted PI3K blocker mixed with a HER2 blocker made tumors regress, “which is very, very encouraging,” she says. “We were seeing that it resulted in the prevention of tumor growth.”
“What we’re trying to do is cut off all the pathways for the tumor cells to grow” Shagisultanova explains. “We’re hopeful that this combination of PI3K and HER2 inhibitors will show significant results for patients with this aggressive type of breast cancer.”