Appendix BCase Study:
Biospecimens for Validation of a Biological Target
and Discovery of Alternative Therapeutic Uses
Imatinib mesylate (STI-571, Gleevec®; Novartis, Basel, Switzerland), a small molecule
developed originally for the treatment of chronic myeloid leukemia (CML), has become a model
drug for the validation of molecular targets. Although designed to inhibit the tyrosine kinase
(TK) activity associated with the CML-specific protein, BCR-ABL, imatinib mesylate
demonstrated a similar effect on the activity of the proto-oncogenic TK, KIT (also called stem
cell factor receptor). In 1998, Hirota and coworkers used immunohistochemistry to identify KIT
expression in 49 gastrointestinal stromal tumors (GIST).1
DNA analysis on a subset of these
samples using reverse transcriptase-polymerase chain reaction (RT-PCR) revealed that KIT
expression often correlated with specific mutations in c-kit, the gene that codes for KIT.
Activation of KIT was then hypothesized as a critical step in the pathogenesis of GIST,
suggesting another possible use for imatinib mesylate.
Clinical use of imatinib mesylate in patients with GIST proved dramatic, as 60-70 percent of
appropriately selected GIST patients responded to the therapy. These results were all the more
remarkable, given the difficulty of treating GIST, a cancer that is essentially completely resistant
to other systemic therapies. Based on a rapid series of highly successful clinical trials, the FDA
approved imatinib mesylate for GIST in 2001, less than 1 year after the agency approved the
drug as therapy for CML. As with the case of trastuzumab (Herceptin®), successful treatment
with imatinib mesylate is predicated upon identifying those patients whose tumors indicate the
appropriate biologic aberrations.
Standardizing the collection and analysis of tissue samples is a key factor for selecting
appropriate GIST patients for treatment. Samples are assayed for the presence of several specific
mutations in c-kit that are linked with uncontrolled TK activity. Yet the percentage of GISTs
reported to have the appropriate c-kit mutations varies widely. Differences in assay techniques
and the type of tissues used for DNA extraction (e.g., paraffin-fixed samples versus frozen
samples) affect the specificity and sensitivity of mutation detection, thereby affecting patient
selection for therapy. The unqualified success of imatinib mesylate as therapy for GIST has been
established. Delivering this therapy to every patient who will benefit requires a standardized
methodology, the development of which will be greatly facilitated by a central repository of
tissues.
The Gleevec story proves the concept of validation of a drug target and demonstrates that a
cancer drug approved for one indication may find a “second career” as an agent for other cancers
with similar etiologies. The success of imatinib mesylate is spurring the development of many
novel agents with activity against cell lines that express KIT and BCR-ABL, many of which
ultimately will be tested in combination with imatinib mesylate in clinical trials. However, as
researchers unravel links between molecular pathways and specific cancers and treatments,
thereby discovering yet untold uses for many existing therapies, standardization of tissue
collection and analysis will become increasingly important for linking various independent
observations. Imatinib mesylate has demonstrated that a therapeutic agent may have multiple
specific applications, validating molecular targets along the causal pathway and leading to the
development of more specific and more potent therapies in the future. As with the case of
imatinib mesylate, the systematic use of a variety of tissue samples will serve a pivotal role in
translating observations from the laboratory into benefits for the cancer patient.
|
