Alexander Dobrovic, Ph.D. Peter MacCallum Cancer Centre (Australia)

THERAPY/ PROGNOSTIC

Identifying Therapeutic Targets by Profiling DNA repair in CLL

Grant awarded 2006

Abstract:

DNA repair genes are involved in the detection, response to and repair of DNA damage. The knowledge of which DNA repair genes are abnormal in a patient's leukemic cell population can be used to guide the appropriate choice of therapy for CLL patients.

We will use a new high throughput methodology that will allow an unprecedented view of the repair status of the leukemic cells. We further seek to use this information to choose appropriate DNA damaging therapy to target CLL.

Our underlying hypotheses are:

" defects in DNA repair occur in many cases of CLL
" identifying specific DNA repair defects may guide the choice of appropriate therapy.

SPECIFIC AIMS:

1. To identify alterations of DNA repair genes in CLL.
2. To identify DNA repair genes which are switched off in CLL.
3. To relate specific repair deficiencies with response to therapy.

EXPERIMENTAL DESIGN:
This proposal uses a new methodology based on accurately measuring the level of messages for all known DNA repair genes at one time to profile DNA repair in tumors. Model systems will be used to evaluate the therapeutic implications of any repair deficiencies identified.

POTENTIAL OUTCOMES AND BENEFITS OF THE RESEARCH:
This is the first systematic study of DNA repair gene deficiencies in any cancer. These studies are targeted towards discoveries that will allow us to improve the appropriateness and effectiveness of DNA damaging therapies in CLL. Knowing which repair pathways are altered specifically in the CLL cells can allow us to target the CLL while leaving normal cells comparatively unscathed.