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PI3K cell-signaling pathway on verge of clinical trials

For more than two decades, DF/HCC laboratory researchers have been homing in on a signaling network that genes and cells use to talk to each other — the phosphoinositide 3-kinase (PI3K) pathway. This signaling pathway relates to a wide range of disease-based solid tumors: breast, colon, glioma, melanoma, prostate, ovarian, head and neck.

It is an opportune pathway for pharmaceutical intervention in cancer, offering a target for drug companies to develop inhibitors. Cancer medicine is now at the cusp of an exciting new era as these findings evolve into clinical studies using “smart” drugs that target specific elements in the pathway.

Among scientists leading this effort are Lewis Cantley, PhD, chief of the BIDMC Division of Signal Transduction and DF/HCC deputy associate director of Basic Science, and Thomas Roberts, PhD, chair of the DFCI Department of Cancer Biology. Together, they discovered the PI3K enzyme and its role in cancer in the mid-1980s. Although the scientific community initially considered their early work an aberration, Cantley and Roberts persevered. The PI3K pathway is now known as a key player in cancer and is being studied from every angle by research teams around the globe. Within DF/HCC, intense research efforts are underway — including several collaborative NCI program project grants in solid tumors involving the PI3K pathway.

The PI3K pathway is multi-stepped and complicated. It involves genes and proteins that cascade along chains of biochemical events. But the underlying premise is straightforward. PI3K adds phosphates onto a lipid in the cell membrane. Once phosphorylated, these lipids act as “messengers” — recruiting cellular machinery needed to communicate growth and survival signals to the cell.

When the genetic blueprint for PI3K is normal, it helps cells perform normally — absorbing nutrients and oxygen and performing other functions needed for metabolism, growth, survival and duplication — all at appropriate rates and times.

But if there’s a genetic mutation in the activation of PI3K, the “accelerator” gets stuck to the floor. It stimulates cell growth and survival under conditions that ordinarily would have been unsuitable, such as low oxygen or nutrient depletion. In essence, the abnormal cells gain a huge advantage over normal cells and proceed to grow uncontrollably.

“Our strategy is to find the catalytic pocket, or active region, for each PI3K mutation in various cancers and work with pharmaceutical companies to develop drugs that dock in that pocket to block its activation,” says Cantley, who recently co-authored a PI3K overview article (Nature 441, 424-30 (May 25 2006); published online 24 May 2006).

There’s a checkpoint in the PI3K network — a natural “brake” called PTEN. The job of this tumor suppressor is to remove the phosphates that PI3K has inappropriately added. DF/HCC researchers and others have found that this brake is frequently mutated or absent in human cancers. Repairing the brake would provide another novel treatment tactic.

Scientists now know PI3K “activating” mutations are present in colon cancer (32%), breast cancer (30%), brain cancer (27%) and gastric cancer (25%). The PTEN “brake” is deleted or mutated in about 50% of gliblastomas and gastric cancers, and about 30% of prostate cancers and melanomas.

Within a few months, clinical trials will begin for some of the newly developed drugs that target various components along the PI3K signaling network. “We are excited about the possibilities, but it’s not a slam dunk,” says Roberts. “These drugs may have side effects that will need to be considered and managed. For example, because the PI3K pathway is a key part of the body’s metabolic processes, an effort to treat cancer by inhibiting PI3K may also affect the patient’s response to insulin. As always, we must proceed with cautious optimism.”

Investigators at DF/HCC have forged highly interactive relationships with pharmaceutical firms. “There’s been a paradigm shift in the way drug companies think about the business side of research and development,” says Cantley. “Because pathways such as PI3K have potential applications for so many different cancers, even rare ones, pharmaceutical firms are now saying that no cancer is too small for us.”

Among the many DF/HCC investigative teams focusing on the PI3K pathway are the following:

  • The Cantley laboratory (BIDMC) is investigating the roles of a variety of proteins that have evolved domains that specifically interact with PI3K’s lipid products and recruit biological complexes to cell membranes. In addition, his laboratory has knocked out genes for PI3K subunits in the mouse to better understand the importance of this enzyme in development, immunity and cancers. Another major focus is the structural basis for specificity in protein-protein interactions in the signal cascades, in particular, the mechanism by which protein phosphorylation can control the assembly of signaling complexes.

  • The Roberts laboratory (DFCI) is creating genetically engineered “knockout” animal models to study the various catalytic subunits involved in the PI3K pathway. These humanized tumor systems, which are available to other researchers, allow scientists to study inhibitors of the pathway in realistic tumor models such as mice and zebrafish. Among cancers his lab is studying are human cells involved in breast cancer. He also is developing yeast systems that serve as good models for studying PI3K.

  • The laboratory of Charles Stiles, PhD (DFCI), focuses on brain cancer. Primary cancers of the brain account for less than 2 percent of new cancer cases in the United States each year. However the majority of these cancers are malignant gliomas and these tumors are, for all practical purposes, incurable.  High morbidity of malignant glioma converts these relatively infrequent cancers into a significant cause of cancer related death among middle-aged adults. Research shows that about one-fourth of brain cancers involve PI3K activation and another fourth involve loss of the PTEN brake.  Thus brain cancers are plausible targets for drugs that antagonize PI3K signaling events.

  • The laboratory of Joan Brugge (HMS) is using a special cell culture model to understand the mechanisms whereby activation of the PI3K pathway leads to aberrations in cell proliferation and survival. In this model, cells are cultured in a gel containing proteins that are naturally found in the breast environment. Under these conditions, the breast cells organize into small, hollow, gland-like structures that resemble those found in the normal breast.  When an activated mutant form of PI3K from human breast tumors is introduced into these cells, they proliferate uncontrollably and create large, filled structures that resemble human tumors. The goal is to identify targets for therapeutic intervention in human tumors that contain mutant PI3Ks.

  • The laboratory of Ronald DePinho, MD (DFCI), focuses on pancreatic cancer, which is highly lethal. Gaining an understanding of its biological mechanisms offers a greater chance to find subsets of patients who may respond to targeted drugs. DePinho is developing animal models to study mutations involved in pancreatic cancer. Although no direct PI3K mutation has been identified, the pathway is so key to cell survival that turning it off somewhere along the line may be a way to combat it. [adding DePinho’s work on glioblastoma involving PTEN signaling]

  • Massimo Loda, MD (DFCI), is a pathologist whose efforts focus on identifying the genetic “signature” of mutations involved in all forms of cancer. This information would identify subtypes that are good candidates for targeted therapies. With Phil Kantoff, MD, his lab is specifically studying prostate cancer, in which about 30 percent show a loss of PTEN. Other research shows that a loss of p27, another powerful tumor suppressor, occurs in other cases. By identifying the underlying biological mechanism behind each patient’s disease, treatment can be selected to specifically target that mechanism, greatly improving the chance of survival and cure.

  • J. Dirk Iglehart, MD (DFCI/BWH), directs the DF/HCC Specialized Program of Research Excellence (SPORE) in Breast Cancer, which maintains a large repository of tissues from women with breast cancer, DNA samples from women with an elevated risk, and treatment and outcome data on several thousand women. These resources are being applied to understand the role of PI3K and its conspirators in the initiation and progression of breast cancer, with the goal of finding a useful drug to inhibit the pathway. Iglehart’s own research concerns signal traffic coming into the cancer cell from the epidermal growth factor receptor (EGFR) family of receptors, including the HER2 receptor commonly amplified in breast cancer. This traffic flows through PI3K and activates nuclear factor kappa B (NF-kB). Blocking NF-kB activation may provide a strategy to block signals coming from PI3K. Iglehart is also collaborating with other research centers on the discovery and development of biomarkers of PI3K activation.

Image of prostate cancer (provided by Massimo Loda): tumor suppressor gene PTEN in the normal mucosa (brown, left) and complete loss in the tumor glands (right). Loss of PTEN results in PI3K activation.