Our laboratory studies how cell death is regulated, with a particular interest in how errors in the control of apoptotic cell death contribute to cancer.
Our research is focused on discovering and developing novel anti-cancer therapies that restore the ability of cancer cells to undergo apoptosis, and how these can be used for treating patients with cancer.
The BH3 mimetic compounds are small molecules that mimic the action of the BH3-only proteins that act to antagonize Bcl-2 and its pro-survival relatives. Some of these compounds (e.g. ABT-199) are now in clinical trials.
In collaboration with the Roberts lab, we are undertaking laboratory studies associated with the trials and actively identifying which cancers are most susceptible to which BH3 mimetic. While targeted therapies are often effective, treatment can fail because of resistance and we are characterising potential mechanisms why therapy with BH3 mimetics fail so that we might be able to circumvent these barriers to improved treatment responses.
Mcl-1 is a pro-survival relative of Bcl-2 and its over-activity is implicated in tumorigenesis as well as resistance to standard-of-care agents used to treat cancer patients. It is a very labile protein with a half-life of less than 30 minutes. Interestingly, stabilisation of Mcl-1 can promote tumour formation.
Thus, we are interested in elucidating mechanisms that promote Mcl-1 turnover especially those that might be subverted in cancer cells. We are actively investigating ways that might promote Mcl-1 degradation as a means to indirectly target Mcl-1 for the treatment of cancers.
Precisely how the essential cell death mediators Bax and Bak become activated to drive permeabilisation of the outer mitochondrial membrane and hence, apoptosis, is unclear. To identify the key events in their activation, we are developing novel reagents that block apoptosis at critical steps. In collaboration with the Czabator laboratory, we are characterising novel antibodies that interfere with the activation of Bax.
By taking a phenotypic screening approach and in collaboration with the Kile and Lessene laboratories, we have also developed small molecule inhibitors of these cell death mediators which may also be useful to prevent excessive apoptosis.
We are generating novel tools and reagents to identify, characterize and target novel cancer cell susceptibilities. Improvements in screening technology, availability of improved compound libraries combined with the power of genetic engineering using CRSIPR/Cas9 technology allow us to undertake screens for novel cancer cell susceptibilities, such as to screen for genes that modulate the sensitivity of a specific leukaemia to a Bcl-2 inhibitor.
Members of our team work closely with one another, although each student or post-doctoral fellow is responsible for their own project. We collaborate extensively with the Roberts laboratory on projects relating to the BH3 mimetics and with other colleagues in the Institute.