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