Genomic Instability as a Therapeutic Target in Breast and Colorectal Cancer
Lead Research Organisation:
CANCER RESEARCH UK
Department Name: London Research Institute (LIF)
Abstract
Genetic information is contained in units of DNA in a cell called chromosomes. Normal cells rely upon checkpoints to control the passage of genetic information contained in chromosomes to daughter cells. The mitotic checkpoint, regulates the passage of genetic information before the formation of daughter cells and if this fails, cancers become resistant to death induced by the taxane breast cancer drug and develop resistance to other cancer drugs in the laboratory. Failure of the same checkpoint promotes gain or loss of whole chromosomes (called chromosomal instability, CIN cancers) associated with worse prognosis in cancer patients.
Many patients with breast cancer experience side effects but derive limited or no benefit from taxane treatment. A CR-UK team will analyse breast cancer tissue from patients treated with taxanes within clinical trials to assess whether CIN is associated with taxane resistance. This may identify which patients may benefit from this treatment in the future.
The CRUK team will identify how to selectively target CIN cancers to promote new approaches for anticancer drug discovery. These drugs may eventually limit the evolution of tumour drug resistance and have greater cancer-specificity, reducing side effects to normal tissue (skin, hair and white blood cells) with normal chromosome number.
Many patients with breast cancer experience side effects but derive limited or no benefit from taxane treatment. A CR-UK team will analyse breast cancer tissue from patients treated with taxanes within clinical trials to assess whether CIN is associated with taxane resistance. This may identify which patients may benefit from this treatment in the future.
The CRUK team will identify how to selectively target CIN cancers to promote new approaches for anticancer drug discovery. These drugs may eventually limit the evolution of tumour drug resistance and have greater cancer-specificity, reducing side effects to normal tissue (skin, hair and white blood cells) with normal chromosome number.
Technical Summary
Chromosomal instability (CIN) is associated with the acquisition of drug resistance and poorer prognosis in many solid tumours. Our work has focussed on the association of CIN with taxane resistance. We have identified several genes which when silenced by RNA interference (RNAi), impair a taxane induced mitotic arrest and promote paclitaxel resistance. Many of these genes promote centrosomal amplification, multinucleation and endoreduplication without drug exposure, indicating that aberrations in chromosomal segregation may serve as a marker of intrinsic taxane resistance. In agreement, we have established a correlation between increasing numerical-CIN (known as Chromosomal Numerical Heterogeneity or CNH) in breast and colorectal cancer cell lines and resistance to microtubule stabilising agents such as paclitaxel. The polygenic nature of multi-drug resistance, supported by our work, may explain the evolution of resistance to non-cross resistant cytotoxics in human tumours driven by genomic instability mechanisms such as CIN. Identifying vulnerable pathways within tumours harbouring specific patterns of genomic instability such as CNH may reveal novel oncogenic targets, enhance taxane sensitivity and limit the acquisition of multi-drug resistant disease.
Aims and Objectives
1. Assess the relationship between CNH and microtubule stabiliser response in breast and colorectal cancer.
2. Elucidate mechanisms of cancer cell survival in the presence of specific patterns of genomic instability (chromosomal or microsatellite instability) to:
provide therapeutic cancer-specific targets
limit acquisition of taxane and multi-drug resistant disease.
Design and Methodology
Using established clinical trial samples in primary breast cancer (NeoTango) and FISH expertise, the association of CNH status with paclitaxel response will be assessed in vivo and a gene expression signature associated with CNH derived.
A high throughput whole genome RNAi screen and an automated Acumen laser scanning cytometer will identify genomic instability-specific survival regulators in isogenic cancer cell lines deficient in mismatch repair or spindle assembly checkpoint components.
Expression of validated candidates will be assessed in breast and colorectal cancer trial samples (CINATRA, TACT, NeoTANGO) for which genomic instability data will be available. Live cell microscopy will elucidate the mechanisms of death following silencing of CIN-survival candidate genes.
Scientific and Medical Opportunities
Validated candidates may further understanding of mitotic deregulation and chromosome segregation in colorectal and breast cancer and provide suitable leads for future drug discovery programmes to delay multi-drug resistance by targeting specific mechanisms of genomic instability. This work may optimise the selection of patients with disease sensitive to microtubule inhibitors and provide therapeutic targets in taxane-resistant disease.
Aims and Objectives
1. Assess the relationship between CNH and microtubule stabiliser response in breast and colorectal cancer.
2. Elucidate mechanisms of cancer cell survival in the presence of specific patterns of genomic instability (chromosomal or microsatellite instability) to:
provide therapeutic cancer-specific targets
limit acquisition of taxane and multi-drug resistant disease.
Design and Methodology
Using established clinical trial samples in primary breast cancer (NeoTango) and FISH expertise, the association of CNH status with paclitaxel response will be assessed in vivo and a gene expression signature associated with CNH derived.
A high throughput whole genome RNAi screen and an automated Acumen laser scanning cytometer will identify genomic instability-specific survival regulators in isogenic cancer cell lines deficient in mismatch repair or spindle assembly checkpoint components.
Expression of validated candidates will be assessed in breast and colorectal cancer trial samples (CINATRA, TACT, NeoTANGO) for which genomic instability data will be available. Live cell microscopy will elucidate the mechanisms of death following silencing of CIN-survival candidate genes.
Scientific and Medical Opportunities
Validated candidates may further understanding of mitotic deregulation and chromosome segregation in colorectal and breast cancer and provide suitable leads for future drug discovery programmes to delay multi-drug resistance by targeting specific mechanisms of genomic instability. This work may optimise the selection of patients with disease sensitive to microtubule inhibitors and provide therapeutic targets in taxane-resistant disease.