We have recently launched a novel personalised therapy clinical trial to treat patients with late-stage colorectal cancer
at George Mason University's Center for Applied Proteomics and Molecular Medicine (CAPMM). This is one of the most cutting-edge
personalised therapy clinical trials in the world for several reasons including:
- it uses protein information rather than genomic information to guide therapy
- the activation state of the protein, not its total amounts, is used to guide therapy
- therapy is tailored to the molecular signature of the metastatic lesion rather than the primary tumour
- the input to the analysis is tumour cells isolated from the metastatic lesion itself using a technique we invented called
laser capture microdissection (LCM)
- it uses a novel protein microarray, the reverse phase array (RPMA), to map the activation state of the protein network. This
is the first trial in the world where functional protein pathway network mapping is used to guide and tailor therapy.
In particular, the trial will be testing Novartis's Gleevec, which is FDA-approved for chronic myelogenous leukemia and gastrointestinal
tumours. According to research conducted at CAPMM, Gleevec targets disease pathways in tumour cells that are among those found
in typically fatal liver metastasis in colorectal cancer patients.
Unravelling the human genome
For our, trial, a patient's metastasis is sampled using a needle biopsy and the pure tumour cells are isolated using laser
capture microdissection. They are then solubilised and analysed with the reverse phase protein microarray, and the activation
states of the Gleevec drug targets (ckit, cabl and PDGFr) are assessed. Gleevec is then given to patients with highly activated
signatures while patients whose network is not activated are given the standard care therapy.
Gleevec would not normally have been considered for treatment in these cases. In the new paradigm of personalised therapy,
however, the site of the cancer does not matter because it is the molecular signature that drives selection — true personalised
The primary objectives of the trial are to see if we can implement this workflow and generate a Gleevec drug target activation
score for each patient, see how that score changes before and after therapy, and determine the safety of Gleevec combined
with an anti-EGFR therapy. The primary therapy endpoint is disease stabilisation as per RECIST (response evaluation criteria
in solid tumours). We hope to have results on a statistically significant number of patients by the end of the year.