The Story of PIK3CA

A young scientist studying insulin signaling uncovered a key to cancer growth in cells, opening a flood of research into the PIK 3CA gene and other mutations.

In 1985, a young scientist named Dr. Lewis Cantley and his colleagues at Tufts University discovered an enzyme called PI3K. Finding a new enzyme is an achievement for any academic. But this particular enzyme turned out to influence decades of future cancer and diabetes research. Thirty years later, scientists are still working with PI3K to find ways to treat cancer with PIK3CA mutations.

From an enzyme to cancer

PI3K turned out to be not just one enzyme, but a family of enzymes that play a crucial role in cellular
functions such as insulin signaling, cell growth, proliferation, and differentiation. Together, the actions and effects of the various PI3K enzymes are called the PI3K pathway. Before Cantley discovered the PI3K pathway, he had an idea that the way cells use insulin and blood sugar (glucose) was in some way linked to cancer. For one, he noticed tyrosine kinases (another enzyme family) were a factor in some cancer studies and so was insulin signaling.

“I was really interested in both cancer and insulin, and until that observation (of PI3K) no one really suspected that they were connected. Now we know there are very strong links,” said Cantley. For instance, doctors now know that people who become insulin resistant (a risk for type 2 diabetes) from an unhealthy diet and lifestyle have a higher risk for cancer. Researchers have also located specific genes such as PIK3CA which, when altered, encode faulty PI3K enzymes. These faulty PI3K enzymes promote cancerous growth by changing how a cell uses insulin. The PIK3CA gene codes for a protein that becomes a building block of the PI3K enzyme. When PIK3CA mutates in a certain way, malformed PI3K enzymes result and begin to wreak havoc in the cell.

“Insulin makes your muscle take up glucose and it can make your muscles grow,” said Cantley.

PIK3CA and P13K

Within a decade after Cantley and colleagues first published about PI3K, a team of scientists cloned the PIK3CA gene from a cow, and found its specific location on chromosome 3.

A healthy PIK3CA gene codes for a protein called p100-alpha. By itself, the p100-alpha protein doesn’t
do anything within the cell. But it forms a duo with another protein called p85 to make up one type of P13K enzyme.

Imaging the PI3K enzyme as a simple car. The part of the protein encoded by PIK3CA (p100-alpha) would be the gas pedal, jump starting the action of PI3K, while the p85 part of the protein would act as a brake, keeping the action of the enzyme in check. A PIK3CA mutation results in a PI3K enzyme with its foot on the gas.

Although by the early 1990s, it was clear that the PI3K pathway could influence cell growth and cancer,
researchers had yet to find to connect all the dots between PI3K, PIK3CA and cancer.

Connecting PIK3CA and Pl3K to cancer

In 1998, Jack Dixon, then of the University of Michigan, and colleagues made the connection that a newly-discovered tumor suppressor called PTEN worked by stopping PI3K activity. PTEN codes for a protein (also called PTEN) that plays an important role in controlling the pace of cell division. Since several types of cancer were discovered to have a mutated PTEN gene, Dixon’s work indirectly made one more link between PI3K and cancer.

A mutated PIK3CA gene isn’t behind every cancer, of course. But as the 1990s continued, more
experiments on tumor samples from various cancers found PI3KCA to be a contributing gene. By 1999,
research teams had linked PIK3CA mutations to ovarian cancer and squamous cell lung cancer. By the
mid-2000s, large-scale cancer sequencing projects that catalogued oncogenes in various tumors were underway.

In 1999, a researcher named Laleh Shayesteh suggested that PIK3CA mutations in ovarian cancer were
likely linked to an overactive PI3K pathway. In the next five years, several more papers identified PIK3CA mutations in cancers – including colorectal, gastric, breast, and certain brain tumors.

At John Hopkins, researchers then found that PIK3CA mutations contributed to cancer growth by slowing
the death of sick cancer cells and facilitating tumor invasion of healthy tissue. Their study also found that a known PI3K inhibitor slowed the growth of cancer cells with PIK3CA mutations.

Today, PIK3CA mutations have now been flagged in a large fraction of tumors in breast, breast, endometrial, prostate, brain, thyroid, head, neck, and stomach cancers, among others.

A PIK3CA mutation can be a treatment target

From early experiments in the early 1980s, Cantley and hordes of other researchers set in motion a wave of discovery about how healthy cells work, and some of the ways healthy cells become cancerous. But the jump from oncogene to treatment is a difficult one.

“It’s hard to target the gene, what you really target is the enzyme
encoded by that gene,” said Cantley. If a person has an oncogene that is producing an over-active enzyme, it’s possible to take a drug that binds to that enzyme and prevent it from functioning, Cantley explained.

Scientists from various fields started testing drugs that target the PI3K pathway and mutated PIK3CA
genes in the mid-2000s, and Cantley was among them. He showed how PIK3CA mutations in breast cancer
contributed to the growth and proliferation of tumors and in 2008, started testing anti-PIK3CA drugs
in mice with induced lung cancer.

These initial experiments were effective and soon a dozen PI3K-targeted drugs were in the works for initial tests. In 2009, Cantley and a team of renowned researchers received a $15 million dollar research grant from StandUp 2 Cancer to study PI3K-related cancers in women. The research funded by that grant helped move along research into drugs that may treat PIK3CA-related tumors. Since then, PIC3CA inhibitors – including buparlisib (BKM120) and BYL719 from Novartis – have shown promise in clinical trials.

One PI3K inhibitor used to treat B-Cell lymphoma already has FDA approval. However, this drug does not target PIK3CA mutations. PIK3CA mutations proved to be especially difficult target because of the
link between insulin, blood sugar and cancer. Taking a PI3K inhibitor to treat cancer with a PIK3CA
mutation would then also interfere with how cells use insulin and take up glucose from the bloodstream.
Blocking PI3K with a drug could then lead to a buildup of blood sugar, which can cause damage to the body over time.

“That can be limiting because that causes hyperglycemia, so one has to use other drugs to compensate,” said Cantley. Today, if you found your tumor had a PIK3CA mutation, your doctor couldn’t prescribe a
drug, but your doctor can help put you into a clinical trial, Cantley said.

“There are 15 maybe more, (PI3K inhibitor) drugs in clinical trials. Almost every pharmaceutical company has at least one,” said Cantley. “I expect within the next year or less, one of those will be approved.”

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