5 Questions for Josep Tabernero, MD

Josep Tabernero, MD

Josep Tabernero, MD, is head of the Medical Oncology Department at Vall d’Hebron University Hospital and director of Clinical Research at Vall d’Hebron Institute of Oncology in Barcelona, Spain. He is also the head of the Gastrointestinal Tumors Unit and is actively involved in clinical research with molecular targeted therapies, with a focus on EGFR-family and PI3K-Akt-mTOR pathway inhibitors, in phase II and III studies with new chemotherapy agents in gastrointestinal tumors.

1

What role does PI3K/Akt signaling play in normal cells?

The primary biochemical function of the PI3Ks is to phosphorylate the 3-hydroxyl group of phosphoinositides, which results in activation of second messengers, the most important one being the serine/threonine kinase Akt. The activation of Akt stimulates a variety of critical physiological cellular metabolic and survival functions.

2

How important is it in cancer development?

With the exception of the p53 tumor suppressor pathway, the PI3K pathway is the most highly perturbed in human cancer. Deregulation of this cascade can be due to a host of genetic aberrations, resulting in either decreased expression of PTEN, amplification or mutation of PIK3CA, amplification or mutation of Akt, and other less frequent events. This pathway is not only activated in a myriad of human cancers, but it also has prognostic and predictive relevance in many human tumors.

3

What PI3K/Akt-targeted treatments are currently available?

The first compounds targeting this pathway were the rapalogs, which include temsirolimus and everolimus, and target the downstream effector mTOR. Although clearly active in some selected tumors, rapalogs have been considered less efficacious than initially expected in most of the tumor types. More recently, significant advances in our understanding of the PI3K pathway and its complex downstream signaling, interactions, and crosstalk have led to the development of pure PI3K inhibitors (both pan-PI3K and isoform-specific), dual PI3K/mTOR inhibitors, and Akt inhibitors. Most of these compounds are in phase II clinical development, either as single agents or in combination with cytotoxics or other targeted agents.

4

What has been the key discovery in cancer in recent years?

It has been very elegantly demonstrated that the PI3K/Akt pathway is one of the most exciting targets for cancer therapeutics, and therefore development of inhibitors has become an area of intense interest in both academic and pharmaceutical industry [settings] in recent years. One of the more challenging aspects has been to optimize the chemical structure of these compounds so as to find candidates with acceptable pharmacological, pharmacokinetic, and selectivity profiles. Novel therapeutics targeting different components of this pathway are demonstrating efficacy in an array of human cancer types in preclinical studies, and many of these drugs are being carried forward into clinical trials.

5

What is the main unanswered question with regard to PI3K/Akt signaling in cancer research or targeted treatments?

There are several unanswered questions related to the PI3K pathway. The first is how to characterize which tumors are dependent on the PI3K pathway for tumor growth and proliferation. A huge effort is underway to molecularly characterize tumors that are “addicted” to PI3K/Akt signaling. A second important question to be answered is which treatment strategies will have the most impact in inhibiting this pathway. This question may not have a unique answer, as different tumor types with specific molecular perturbations of the pathway may have differential activity with each specific compound or combination of compounds.