Chemotherapy drug resistance in solid tumours results in treatment failure and the rapid deterioration in patient quality of life. Tailoring cytotoxic chemotherapy schedules to those patients most likely to benefit based on tumour molecular phenotype and the identification of patients who should be considered for clinical trials with novel therapeutic agents due to intrinsically drug resistant disease, may help to improve patient outcome and maximise the survival benefit associated with chemotherapy schedules. Our work is focused on identifying drug resistance pathways to common cytotoxics and targeted therapies used in medical oncology practice in order to support clinical strategies directed towards the more effective delivery of these agents (Swanton et al, Breast Cancer Res 2008; 10:214).
Quantification and relevance of CIN to microtubule stabiliser resistance in solid tumours
Functional genomic screening data from our laboratory has revealed several genes that simultaneously regulate chromosomal instability (CIN) and response to microtubule stabilising agents such as paclitaxel (Swanton et al, Cancer Cell 2007; 11: 498 -512). We are currently exploring the frequency of numerical chromosomal instability in primary breast cancer in collaboration with Dr Rebecca Roylance (Institute of Cancer) and the TRANS-TACT consortium. The consortium is analysing tumour samples from the phase III TACT clinical trial where patients were randomised to treatment with a taxane/anthracycline schedule or standard anthracycline based chemotherapy alone. We are investigating the expression of proteins known to be involved in CIN in these tumours and the relationship of CIN to clinical outcome following taxane therapy. CINATRA (hromosomal INstability and Anti-Tubulin Response Assessment) is a phase II clinical trial deriving from our laboratory programme that has recently opened at the Royal Marsden Hospital. We are investigating whether near diploid colorectal cancers display intrinsic sensitivity to the microtubule stabilising agent, Epothilone 906 compared to colorectal cancers with CIN.
Relevance of the multi-drug resistance protein CERT to drug resistance and clinical outcome
The response rates to successive 'non-cross resistant' chemotherapy schedules decline as the cancer advances and lines of treatment progress. Expression of the ABC family of multi-drug efflux transporters does not fully explain the clinical phenomenon of multi-drug resistance in vivo. Through an RNA interference drug sensitivity screen we have identified a ceramide transporter, CERT, the silencing of which results in sensitisation to multiple cytotoxics (Swanton et al, Cancer Cell 2007; 11: 498 -512). We have found that CERT is over-expressed in drug resistant cell lines and cytotoxic resistance can be attenuated by CERT depletion in these cells. Ceramide, termed a 'pro-apoptotic lipid', is generated through de novo synthesis or sphingomyelin hydrolysis. Ionising radiation and cancer cytotoxics induce many of the enzymes required for ceramide synthesis resulting in cell death through diverse mechanisms including the inactivation of AKT. In keeping with the importance of the ceramide pathway in the regulation of drug response, several enzymes in the ceramide biosynthetic pathway have been proposed to play a role in drug resistance both in vitro and in vivo (Figure 1).
Figure 1. Activation of enzymes required ceramide synthesis occurs following cancer cytotoxic exposure (blue). Proteins implicated in drug resistance are highlighted in red. The lipid transporter CERT and beta-glucosidase were identified by our laboratory as novel drug resistance molecules.
We are attempting to understand how disruption of ceramide transport to the golgi apparatus promotes cell death following exposure to chemotherapeutic agents and the relevance of CERT expression to cytotoxic sensitivity in breast cancer. We have found that depletion of CERT in cells exposed to paclitaxel results in the induction of endoplasmic reticulum (ER) stress as measured by an increase in phosphorylated PERK. We are investigating the role of the ER stress pathway and ceramide generation within the endoplasmic reticulum in the initiation of cell death following cytotoxic chemotherapy exposure. Work in collaboration with Cancer Research Technology is investigating whether CERT could present a novel drug target to optimise drug sensitivity in cancer.
Genome instability and drug resistance
Patterns of genomic instability contribute to chemotherapy resistance and represent a common feature of malignancy. Aneuploid tumour cell lines that have acquired resistance to one chemotherapy agent have been shown to demonstrate resistance to non-cross resistant cytotoxic agents. This has led to the hypothesis that tumour aneuploidy may catalyse drug resistance through spontaneous chromosome reassortments, such that tumour cell selection for drug resistance to one chemotherapy agent is often associated with resistance to multiple unselected chemotherapy agents. We have shown that multi-drug resistance is a more frequent phenotype associated with gene silencing than resistance to single cytotoxics (Swanton et al, Cell Cycle 2007; 6:2001-2004). This implies that non-cross resistant cytotoxic agents depend on the activation of similar cell survival pathways to promote drug resistance and may further explain the relative ease through which patterns of genomic instability may initiate resistance to common cytotoxic agents. We are using bioinformatics and whole genome functional approaches to attempt to identify common survival pathways in aneuploid tumour cells that may enable the more efficient and specific targeting of tumours to limit the rapid acquisition of drug resistance in vivo.
For a list of refereed research papers, see Publications (in navigation on left).
