Why do you think your paper is highly cited?

We believe there are several reasons for this: first, it puts forward a simple, yet unifying and general principle for oncogenic conversion of protein kinases.  Simply stated, we argue that oncogenic conversion of kinases results from perturbation or obstruction of the normal autoinhibitory and regulatory constraints on kinase activity.  In other words, rather than looking at oncogenic mutations as activating per se, we favor the view, supported by numerous structural studies, that kinases are normally kept in an inactive state, quite distinct from their activated "on-state".  The gain-of-function mutations or other activating alterations present in these dominant oncoproteins in effect remove these constraints.  We showed that this general principle applies in each of the three major types of oncogenic conversions: activating fusions, activating point mutations, and amplifications.  Second, we provided a comprehensive and updated compendium of the reported connections between all the known oncogenic alterations in each and every tyrosine kinase in the genome and the associated human tumors and malignancies.  Clearly, there was a need for this, and to our knowledge, it was the first of its kind.  Third, we summarized the accumulating evidence that pointed to the importance of oncogenic alterations in the phosphatidylinositide 3' kinase (PI3'K) and ribosomal S6 kinase/mTOR signaling pathways for the development of many types of cancer.  We believe that this has sparked an interest in several companies and academic laboratories in pursuing targets within this particular pathway.  For all these reasons, it has become a crucial resource paper for pharmaceutical and biotechnology companies.   The table listing all the potential drug targets and the associated cancer types, with the general biochemical activating mechanism, acts as a guide in selecting a target for a particular cancer type, and provides insights into the best way to inhibit the target kinase's deregulated activity in vivo.   In that sense the review has facilitated translational research.  In fact, that quickly became our mission from the outset: rather than writing yet another detailed review on kinase regulation, we wanted to make a compendium-type of review, linking molecular alterations with disease insight.  In addition, due to the fact that our paper is rather comprehensive and detailed, yet provides simplifying and general principles with translational implications, this review has broad appeal.  We have been pleased to see that it is being used in graduate biology courses, as well as by clinical oncologists and molecular pathologists worldwide.

  Does it describe a new discovery or a new methodology that's useful to others?

In the review we described many very recent findings, trying to unify these findings into general conclusions.   We also tried to look ahead, and this is probably the main guiding principle behind the writing of the review.   Again, while it is not a surprise today that deregulated kinases in the PI3'K and p70S6K/mTOR pathway are involved in a vast number of human malignancies, that was not so obvious at the time of writing.   That is reflected in a simple PubMed search of 'Akt and cancer'.   Very few references and reviews appeared before our review came out, while the number of citations has exploded over the last year, or so.  Also, based on a thorough knowledge of the specificity of the first clinically approved and marketed small molecule kinase inhibitor, Gleevec from Novartis that inhibits not only Bcr-Abl, but also c-Kit and PDGF receptors, we could predict that Gleevec might be useful in several new therapeutic areas, including treatment of c-Kit-induced gastrointestinal stromal tumors.

  What were some of the circumstances that led you to do this research?

This area has been a major interest for both authors for many years.   As most people are aware, Tony Hunter has been instrumental in the development of the whole protein tyrosine kinase field, and was one of the co-discoverers of protein tyrosine phosphorylation in the late 1970s.  Many of the general protein tyrosine kinase signaling mechanisms were originally elucidated through his and others' studies of the cytoplasmic tyrosine kinase Src and the EGF receptor tyrosine kinase.  Peter Blume-Jensen obtained his MD in Copenhagen , Denmark , where early on he became interested in oncology.   The obvious need for better and rational treatments led him into molecular research, and he spent the last 12 years studying oncogenic kinase signaling.   After obtaining his Ph.D. in Dr. Carl-Henrik Heldin's laboratory in Uppsala , Sweden , he was a post-doctoral fellow in Tony Hunter's laboratory, before taking up my current position at Serono Reproductive Biology Institute in Boston , MA .   There, he has established a molecular oncology research program and is heading several small molecule kinase inhibitor programs with the goal of developing new cancer therapeutics.

  Could you summarize the significance of your paper in layman's terms?

The paper describes the strong association between mutations in a certain class of enzymes, called protein kinases, and the resulting associated diseases, in particular cancers.   We describe for each of these proteins the many types of changes they can undergo, and the cancer types that result.  This provides direct insight into specific ways to treat the associated cancers.

Peter Blume-Jensen, M.D., Ph.D.
Associate Director Molecular Oncology and Reproduction
Head Cancer and Germ Cell Biology
Serono Reproductive Biology Institute
Rockland , MA