Cancer Research - Europa

Keywords | Cancer chemotherapy | drug resistance | toxicity | lung cancer | melanoma |
CHEMORES
Molecular mechanisms underlying
chemotherapy resistance, therapeutic
escape, effi cacy and toxicity
Summary
The CHEMORES project aims to improve the outcome of
cancer chemotherapy by developing novel tools to predict
tumour response to treatment as well as individual toxicity
to chemotherapy. The project will thus seek to identify and
validate mechanisms of intrinsic and acquired chemotherapy
resistance, as well as predictors of effi cacy and of individual
toxicity.
This is achieved by integrating the work of groups conducting
large clinical trials with preclinical research groups, as
well as with state-of-the-art platforms for genomic and proteomic
analyses and bioinformatics. The participants have
chosen to focus on melanoma and lung cancer as model
tumours of separate histogenetic types exhibiting intrinsic
resistance and/or a high degree of acquired resistance to
chemotherapy.
Candidate mechanisms of drug resistance and therapeutic
effi cacy will be identifi ed using genomic and proteomic
analyses of sequential tumour samples and paired sera
obtained before and after chemotherapy, as well as experimental
systems, including in vitro studies of tumuor cell
lines, transplanted human tumours and novel animal tumour
models. These putative mechanisms will then be validated
in further analyses of larger sets of tumour biopsies from
patients. Functional studies of novel mechanisms and pathways
will be also performed using in vitro systems and
animal models. The result of these activities will thus be
a set of clinically and functionally validated mechanisms of
chemotherapy resistance and therapeutic effi cacy.
Likewise, large-scale genomic analyses of patients receiving
chemotherapy as part of clinical trials will be performed, in
order to validate novel markers of individual toxicity following
chemotherapy.
Problem
Resistance to systemic chemotherapy still remains one of
the greatest problems in clinical oncology, and contributes
to the death of a large number of cancer patients. Despite
extensive eff orts, no signifi cant prog ress has been made in
solving this fundamental problem during the last decades.
Not only have effi cient means to overcome chemotherapy
TREATMENT
resistance not been identifi ed, but also the development of
clinically useful tools to predict response to chemotherapy
has been largely unsuccessful.
The diff erent aspects of the chemoresistance problem are
well illustrated in the two model tumours that will be studied.
The two main subtypes of lung cancer are small cell lung cancer
(SCLC) which is highly chemosensitive with response
rates of 80 % to chemotherapy; and non-small cell lung cancer
(NSCLC) that is moderately chemosensitive with response
rates of 30-60 %. For all stages and types of lung cancer
(NSCLC/SCLC), relapse after primary therapy is common, at
which stage most patients have developed an acquired resistance
to chemotherapy and seldom respond to second line
treatment. In lung cancer, a therapeutic plateau has thus been
reached with existing cytotoxic drugs and further improvements
in survival are dependent on our understanding of the
molecular mechanisms of chemoresistance.
There is no eff ective systemic therapy for metastatic
melanoma and only a small minority of patients with
melanoma respond to chemotherapy, which also has no discernible
impact upon median overall survival. In the adjuvant
setting interferon-alfa (IFN) is the only agent that has demonstrated
a consistent eff ect on relapse-free survival, but
without a signifi cant impact on overall survival. We have as
yet no tools to identify the patient population that benefi ts
from treatment with IFN. Thus, improved knowledge regarding
mechanisms of resistance is needed in order both to
develop predictive tests and to modulate resistance and
thus improve the therapeutic outcome in melanoma.
Cancer chemotherapy is frequently associated with severe
toxic side-eff ects. Novel tools to identify individuals with an
increased risk of developing severe side-eff ects are required
in order to avoid such adverse events.
Aim
The overall aim of CHEMORES is to improve the outcome of
cancer chemotherapy by developing novel tools to predict
tumour response to treatment as well as individual toxicity
to chemotherapy.
Expected results
The novel knowledge obtained through the project will lead
to new tools for prediction of treatment outcome as well as
toxicity of chemotherapy. This knowledge may also be used
to identify and prepare for pre-clinical development of
potential novel modulators of drug resistance based on validated
mechanisms and pathways. The new information
obtained in CHEMORES will be disseminated to the medical
profession and other key stakeholders, such as health care
providers, patient organisations and policy-makers.
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