Following the Right Path(way)
This is a story about an important cancer pathway that is one of the most elusive to target. But first, a quick refresher on the fundamentals: cells communicate with each other and coordinate their internal machinery through what are called signaling pathways. Some of these pathways control how cells survive and move. If the pathways go haywire, it can lead to uncontrolled growth and cancer.
Diving deeper, one of the most important signaling pathways inside cells involves a protein called phosphoinositide-3 kinase, or PI3K. About a decade ago, it was discovered that mutations in PI3K are commonly found in human cancers and drive cancer growth. Since then there’s been an all-out race to develop medicines that target this protein.
PI3K has proven to be a difficult target. In fact we still don’t have any FDA-approved medicines that target the mutations. Fortunately, we have learned why PI3K is such a difficult target. Simply put, it has multiple functions and intersects with other important pathways. Using this knowledge, we are developing an arsenal of inhibitors designed to shut down this important pathway when it becomes over-active in cancer.
A Central Player
We know that PI3K is a central pathway that can accept signals from other pathways or generate signals on its own. In a way, it is similar to a star player on a soccer team who can assist other players or shoot on his or her own.
To carry our soccer analogy further, when another player on the ‘team’ is blocked, cell growth signals can be passed through PI3K instead. You can imagine how cancer could exploit that ability. Not surprisingly, existing data would suggest that the PI3K pathway works in different ways to promote how cancers grow and survive. In some cases, specific mutations cause PI3K signaling to become overactive and constantly pass along signals. In other cases, activity of the PI3K pathway may increase in response to treatment.
PI3K may be why some cancers become resistant to targeted medicines or chemotherapy.
For example, pre-clinical studies in breast cancer show that the activity of the PI3K pathway increases in response to a commonly used class of chemotherapy called taxanes. And, PI3K may also play a role in how hormone-driven breast cancer growth evades hormone therapy. We have ongoing clinical trials that test both of these hypotheses.
Blocking the Assist
Pre-clinical research from Genentech and others suggests that PI3K works alongside another important cancer signaling pathway, called RAS-RAF. The PI3K and RAS-RAF pathways have distinct functions, but they also regulate many of the same proteins. Our preclinical models of cancer have shown that inhibiting both pathways simultaneously can potentially achieve better results than only targeting one. In addition, preclinical studies have also shown that inhibiting one pathway at two different points could be more effective than using a single drug.
Importantly, we have taken these approaches into clinical trials, and are studying both PI3K pathway inhibition and RAF inhibition in combination with MEK inhibitors. It is our hope that this type of combination strategy may reduce the possibility of resistance and relapse.
A Diverse Skill Set
Another level of complexity with PI3K is that there are actually several versions of this protein, called isoforms. There are four isoforms of PI3K with distinct but possibly overlapping functions, called PI3K-alpha, beta, gamma, and delta. PI3K-alpha in particular is mutated in some of the most common tumor types, while PI3K-delta influences immune related processes.
In certain types of cancer, the ability to selectively target PI3K-alpha could avoid potential side effects. In other cancer types, however, the ability to target all four isoforms at once could be the most effective strategy. To address this, we relied on our medicinal chemists to develop a suite of PI3K inhibitors that are selective for one or all isoforms, as well as investigational medicines that inhibit other proteins in this pathway.
Our approach is to examine multiple combinations of drugs with new biomarkers in clinical trials, and pinpoint early which set of investigational medicines may be most promising for any given disease.
Defending Against the PI3K Playbook
To see these pathways in action and to learn more about the proteins and inhibitors, please scroll over the individual players.
Receptor Tyrosine Kinases (RTKs) are proteins that sit on the cell surface and are activated, or turned on, when growth factors bind to them. They generate a signal that can be passed to either PI3K or RAS proteins.
PI3K is a protein that is a central player in the signaling pathway which is important for cell growth and survival. The protein receives signals generated from the cell surface or from other signaling pathways and passes them to proteins inside the cell. There are four isoforms of PI3K, called alpha, beta, gamma and delta, which have similar but distinct roles. Mutations in specific isoforms can lead to overactive PI3K signaling.
Akt is protein in the cell that receives signals from PI3K and can pass on the signal other proteins in the pathway. Studies have shown that some tumors are associated with increased Akt activity.
mTOR is a protein that can receive signals from proteins in the PI3K pathway and relay those signals to other players. Similar to other proteins in this pathway, studies have shown that it is associated with increased activity in some tumor types.
RAS is a protein that has many different forms, such as KRAS which is found mutated in different tumor types. It receives signals from the cell surface and can activate both the RAS-RAF and PI3K signaling pathway.
RAF can receive signals from RAS and relay them to other proteins in the pathway. RAF has several forms, including BRAF, which can be mutated and lead to overactive signaling in some tumor types.
MEK & ERK
MEK and ERK are proteins activated by many signaling pathways, including RAS-RAF. Defects in MEK-ERK signaling lead to uncontrolled growth and the formation of tumors.
There are many ways to target PI3K. The ability to target one or all isoforms of PI3K could help treat different types of cancer. We are studying several different inhibitors to identify the most promising strategy in specific types of cancer. "Pan-inhibitors" are designed to target all four isoforms.
PI3Kα (alpha) mutations are among the most common mutations found in many types of cancer. Inhibitors that target the mutated form of PI3Kalpha, but not PI3Kbeta, are referred to as beta-sparing.
These inhibitors may block signaling through Akt, and can be combined with other inhibitors to potentially reduce the chance of tumors evolving a resistance to them.
Inhibitors designed to target the PI3K pathway at multiple nodes can offer a more complete signaling blockade and potentially reduce the chance of drug resistance. This is also important because mTOR can be activated by other pathways.
Medicines designed to target the BRAF protein, a key component of the RAS-RAF pathway, have been shown to help people with certain types of cancer. Overactive forms of BRAF can lead to uncontrolled cell growth and survival, making it an important target in cancer cells.
These small molecules can selectively inhibit MEK, which may disrupt the activation of ERK and prevents uncontrolled cell growth.
Blocking ERK may prevent it from activating proteins in the nucleus that regulate cell growth and cell death.
Overcoming the Odds
We know that PI3K is elusive, as it's found in many different forms and can interact with other pathways. These facts have presented challenges to developing medicines that effectively target the PI3K protein.
Nevertheless, the science tells us that the answers to important problems like relapse and resistance may lie within the PI3K pathway, and we follow the science. The solutions may be difficult, but with five investigational medicines that target the PI3K pathway in many ongoing clinical studies, we are well on our way to potentially finding them.
Lori Friedman was trained in Molecular and Cell Biology, having received her PhD from the University of California, Berkeley in 1995, and then completing postdoctoral research at Cambridge University, UK in 1998. Lori joined the biotech company Exelixis, Inc. as a research scientist, where she led multiple oncology research projects and advanced to become the Director of the Signal Transduction Research department. In 2004 Lori joined Genentech where she has continued to build her scientific expertise in targeting key cancer pathways using small molecule drug discovery. The research in her department includes validation/invalidation of new oncology targets, understanding mechanism of action and mechanism of resistance of compounds, in vitro and in vivo pharmacology, discovery and validation of preclinical PD assays, and using preclinical cancer models to predict which patients will respond to new agents. She was attracted to Genentech because of the palpable commitment to helping patients by drawing on scientific insights. Lori has 70 peer-reviewed scientific publications and is an inventor on 20 issued patents. She is a Sr. Director in Research and oversees the Translational Oncology department.