Molecular Targeted Therapy for Cancer
Moderators: Dr. Robert Yoshiyuki Osamura and Dr. Allen M. Gown
Section 4 -
Molecular Diagnostics in the Development and the Use of Novel Cancer Therapeutics
Chair, McGill University Department of Oncology & Director, Segal Cancer
Jewish General Hospital
The identification and validation of molecular targets has been the focus of new treatment research in
cancer. This spawned the development of pathology platforms that provide higher throughout capacity,
especially tissue microarrays. Techniques continue to be developed to easily and quickly identify
particular DNA sequence variants in small tissue samples, or protein biomarkers in tissue or even blood.
More and more specific DNA polymorphisms or mutations and protein biomarkers identified in experimental
research labs are being validated as effective predictors of response to a particular treatment.
Important examples of molecular targets that are used in cancer therapeutics include nuclear hormone
receptors such as estrogen (ER) and androgen (AR) in breast and prostate cancer.
The ErbB family of receptors is being developed or are approved for use as targeted therapies in
breast, lung, head and neck and possibly other tumor types. In each case, there is a continuing
evolution of the understanding of the potentially critical features of the target molecule, and this
requires ongoing research capacity, intimately tied to clinical diagnostics, in order to stay abreast of
the optimal molecular context for the therapy in question. Level of gene expression, protein content,
specific mutations are amongst the molecular diagnostic questions that have become clinical vital in
diagnosis, prognosis and therapeutic options.
- While the current standard for measurement of
ER is immunohistochemistry, with pathologist rating of number of tumor cells staining and intensity of
staining, a recent PCR-based panel of gene expression that predicts response to anti-estrogen therapy in
breast cancer, appears to be heavily weighted by the ER. It is suggested that more quantitative
measurement of ER represents a more reliable predictor of response.
androgen receptor is generally not assayed as a part of clinical pathology, since most, though not all
prostate cancer cells are initially hormone dependent and therefore responsive to anti-androgen
therapies. Furthermore, hormone-independence is not accompanied by the loss of expression of androgen
receptor protein. The phenomenon of the "antagonist-agonist switch" provides some insights, since it
appears that a specific mutation at a site remote from the AR ligand binding domain creates a change in
the 3-D conformation of the receptor, such that a drug that is usually an antagonist has the opposite
effect; it acts as an agonist. It may be that the molecular diagnosis of prostate cancer should include
examination for some key DNA sequence variants.
Furthermore, as patients are treated with targeted agents, we have seen the emergence of novel
mutations in the therapeutic molecular target. These too are recognized and studied in research
- For Erb-B2 (Her-2 neu), the amount of protein,
as expressed either by immunohistochemistry, or where equivocal, by FISH analysis of gene copy number, is
the benchmark in selecting Bevacizumab or other targeted agents.
- ErbB-2 (EGFr)
represents a still-evolving target from a molecular diagnostics standpoint. Multiple studies failed to
show a correlation between efficacy of EGFr inhibitors and levels of the receptor protein as measured by
immunohistochemistry. This was followed by the revelation that specific mutations in the ATP binding
site of the EGFr were associated with responses to these targeted agents. Although attractive, this has
been challenged by large clinical correlative studies, which have instead indicated that gene copy
number, as measured by FISH analysis, is the real predictor. Part of the solution to this puzzle is
undoubtedly technologic: improved antibodies for IHC, improved sequencing techniques to identify
mutations in small tissue samples, etc. This is an excellent example of why the pathologist's molecular
diagnostic lab should be closely linked to the evolving world of molecular target research.
Some mutations in target genes have been unequivocally shown to be central to the tumor's response to
a targeted agent. The best example is the c-kit tyrosine kinase recptor in Gastrointestinal stromal
tumors (GIST). Only the tumors with particular activating mutations in c-kit are dramatically responsive
to Imatinib (Gleevac).
Computational biology and dynamic modeling of protein targets that incorporates these mutations can be
used to predict response, or resistance, to a given therapeutic agent, and this data is fed back to drug
development programs that can either alter the therapeutic model to better bind the altered target
pharmacophore, or aim therapeutic targeting at another submolecular site.
This talk will provide a few examples of targeted agents in use and in development where molecular
diagnostics is as critical as morphology in the diagnosis, prognosis and guide for therapy. The
importance of interfacing of the experimental research laboratory, with the molecular diagnostics lab and
the pathology department will be highlighted. While it may seem that in many ways the weight of the
molecular target is approaching that of the tumor morphology, the pathologist is the focal point of these
activities, who can integrate these various components with the morphologic data to arrive at a more
powerful diagnostic and prognostic determination.