Cancer Drug Resistance

Group Head: Dr John Allen

The Cancer Drug Resistance Group works to improve the scientific basis of chemotherapy by understanding the cellular and molecular processes underlying drug resistance and related problems of drug toxicity and variable drug pharmacokinetics. We aim to identify new mechanisms of anti-cancer drug resistance, to evaluate their clinical significance, and to find ways of overcoming them or at least predicting them in advance. We focus on resistance to new and promising anti-cancer drugs that are being applied to treating common, recalcitrant tumours, including melanoma and multiple myeloma.

Research focus

Interactions of new anti-cancer drugs with multi-drug transporter proteins
Multi-drug transporter proteins remove toxins encountered in the diet or produced by normal metabolism, from cells, from tissues, organs and the body as a whole. Many anti-cancer drugs resemble such toxins, so the multi-drug transporter proteins interfere with their uptake into the body and into cancer cells. The Cancer Drug Resistance Group is systematically investigating how the multi-drug transporter proteins affect the efficacy of promising new anti-cancer drugs.

In specific types of cancer the presence of multi-drug transporter proteins predicts poor outcomes for chemotherapy. A good example is paediatric neuroblastoma, where high levels of the MRP1 and MRP4 transporters and the NMYC oncogene all indicate a poor prognosis. Cellular and molecular work suggests that the MRP4 transporter is directly upregulated by MYC oncogenes, which are frequently activated in common adult cancers. In addition, MRP4 is a marker of progression in prostate cancer, possibly because its expression turns out to be an androgen-regulated.

Drug resistance in melanoma
Australia is the skin cancer capital of the world with the highest incidence of melanoma, one of the cancers most resistant to chemotherapy. Left too long untreated, melanoma is invariably fatal. The Cancer Drug Resistance group is interested in the reticence of melanoma cells to undergo apoptosis when damaged by anticancer drugs. It is an open question how important this resistance is in relation to others forms of drug resistance that operate in melanoma cells. Analysis of resistance to apoptosis is technically challenging because propagation of melanoma cells in vitro invariably alters their properties in this respect. Hence, the focus is on pursuing genetically manipulated mouse models of human melanoma, where melanomas develop and can be treated in their natural sites of origin, in the presence of a normal immune system.

Drug resistance in multiple myeloma
Multiple myeloma is an incurable cancer of the blood plasma cells that secrete large quantities of antibodies to fight infection. The production of antibodies is known to depend on the unfolded protein response, a system that ensures correct folding and assembly of proteins and the disposal of incorrectly folded or damaged ones. The Cancer Drug Resistance group suspects that dependence on this system is what makes myelomas resistant to many drugs but, conversely, susceptible to a new class of new drugs, the proteasome inhibitors. Initial results indicate that a simple marker of the unfolded protein response can predict the sensitivity of myelomas to the proteasome inhibitor Bortezomib both in vitro and in myeloma patients.