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 Biomarker
and Imaging Studies of
the Tumour Microenvironment
Anthony
Fyles, Mike Milosevic (Co-PI), M. Haider, A. Oza, and Ivan Yeung
Departments of Radiation Oncology, Diagnostic
Imaging, Medical Oncology and Clinical Physics, Princess
Margaret Hospital and University of Toronto
The microenvironment has profound effects on tumour progression and
metastasis in human tumours and animal models. Our work to date
in patients with cervix cancer has shown that hypoxia and IFP
independently predict for relapse and survival and can be used
to select groups of high-risk patients for intensified
treatment. However, a more thorough patient-specific
understanding of the dynamic nature of the microenvironment
prior to and during therapy is necessary to better predict
treatment outcome, individualize therapy to improve response,
and identify targets for novel biologically-targeted treatment.
We have also expanded our investigations to include patients
with prostate cancer as a companion project has demonstrated
significant hypoxia in nearly 200 patients, although follow-up
is not sufficient to allow evaluation of outcome. An intriguing
observation has been that androgen ablation appears to improve
oxygenation in these patients. Since androgen ablation increases
pelvic control and survival when added to radiotherapy, and has
been shown to cause regression of abnormal tumour vasculature,
we hypothesize that the mechanism may be related to reduction in
hypoxia.
Therefore, the goals of this project are to: evaluate dynamic functional MR
and CT imaging techniques in comparison with hypoxia and IFP
assays; determine the independent prognostic significance of
these imaging studies in a prospective study in patients with
cervix cancer; assess these biomarkers as predictors of response
in Phase I/II trials of innovative biologically-based treatments
(initially the hypoxic cytotoxin tirapazamine and the PDGF
inhibitor imatinib (Gleevecä)
in cervix cancer; and to assess the impact of neoadjuvant
androgen ablation on hypoxia in patients with prostate cancer.
The
proposed studies in cervix cancer will include 125 patients
evaluated at diagnosis with Eppendorf and IFP assays, multiple
biopsies for our tumour bank, serum samples, and dynamic MR and
CT imaging using novel methodologies developed by our group. A cohort of 75 of these patients will participate in Phase
I/II trials with repeat hypoxia and IFP assays, imaging, and
tumour and serum samples following two weeks of drug
administration alone, and two weeks of drug and radiation. These
trials will give us a comprehensive assessment of the temporal
changes in the microenvironment prior to and during treatment,
as well as in response to new drug therapy. The initial choice
of drugs to be used is based on the effect of tirapazamine on
hypoxic cells and its potentiation of chemotherapy, as well as
the promising preliminary results in head and neck cancer.
Gleevec is a multi-functional tyrosine kinase inhibitor that
blocks PDGF signalling, resulting in reductions in IFP and
increased drug uptake and potentiation of chemotherapy. PDGF
expression is associated with prognosis following radiation in
patients with cervix cancer, suggesting that its inhibition may
be beneficial and may be modulated by its effect on the
interstitium.
This project will capitalize on our existing strengths,
and add the expertise of our imaging and New Drug programs to
comprehensively investigate the prognostic and therapeutic
implications of hypoxia and interstitial hypertension in
patients with cervix and prostate cancer. The individualized
assessment of response to novel therapies in these studies will
lead to customized approaches that will improve outcome for our
patients.
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