The long-term goals of my laboratory are to understand how cancers arise and to develop better approaches for their diagnosis and treatment. Our focus is on the regulation of apoptosis by the Bcl-2 family.
In collaboration with other scientists at the institute, members of my laboratory are unravelling the mechanisms by which members of the Bcl-2 family determine whether a cell lives or dies. Precisely how Bcl-2 restrains essential cell death mediators Bax and Bak is unclear and how Bax and Bak become activated to drive apoptosis is also uncertain. Elucidating the key steps in cell death signalling is essential for understanding how cell death is regulated physiologically.
We are actively translating the knowledge we have gained so far into efforts to target Bcl-2 or its pro-survival relatives for treating patients with cancers (e.g. leukaemias, lymphomas) and identifying potential mechanisms why such small molecule inhibitors might fail.
Khaw SL, Merino D, Anderson MA, Glaser SP, Bouillet P, Roberts AW, Huang DC. Both leukaemic and normal peripheral B lymphoid cells are highly sensitive to the selective pharmacological inhibition of prosurvival Bcl-2 with ABT-199. Leukemia. 2014 Jun;28(6):1207-15. PMID: 24402163.
Okamoto T, Coultas L, Metcalf D, van Delft MF, Glaser SP, Takiguchi M, Strasser A, Bouillet P, Adams JM, Huang DC. Enhanced stability of Mcl1, a prosurvival Bcl2 relative, blunts stress-induced apoptosis, causes male sterility, and promotes tumorigenesis. Proc Natl Acad Sci U S A. 2014 Jan 7;111(1):261-6. PMID: 24363325.
Lessene G, Czabotar PE, Sleebs BE, Zobel K, Lowes KN, Adams JM, Baell JB, Colman PM, Deshayes K, Fairbrother WJ, Flygare JA, Gibbons P, Kersten WJ, Kulasegaram S, Moss RM, Parisot JP, Smith BJ, Street IP, Yang H, Huang DC, Watson KG. Structure-guided design of a selective BCL-X(L) inhibitor. Nat Chem Biol. 2013 Jun;9(6):390-7. PMID: 23603658.
Souers AJ, Leverson JD, Boghaert ER, Ackler SL, Catron ND, Chen J, Dayton BD, Ding H, Enschede SH, Fairbrother WJ, Huang DC, Hymowitz SG, Jin S, Khaw SL, Kovar PJ, Lam LT, Lee J, Maecker HL, Marsh KC, Mason KD, Mitten MJ, Nimmer PM, Oleksijew A, Park CH, Park CM, Phillips DC, Roberts AW, Sampath D, Seymour JF, Smith ML, Sullivan GM, Tahir SK, Tse C, Wendt MD, Xiao Y, Xue JC, Zhang H, Humerickhouse RA, Rosenberg SH, Elmore SW. ABT-199, a potent and selective BCL-2 inhibitor, achieves antitumor activity while sparing platelets. Nat Med. 2013 Feb;19(2):202-8. PMID: 23291630.
Roberts AW, Seymour JF, Brown JR, Wierda WG, Kipps TJ, Khaw SL, Carney DA, He SZ, Huang DC, Xiong H, Cui Y, Busman TA, McKeegan EM, Krivoshik AP, Enschede SH, Humerickhouse R. Substantial susceptibility of chronic lymphocytic leukemia to BCL2 inhibition: results of a phase I study of navitoclax in patients with relapsed or refractory disease. J Clin Oncol. 2012 Feb 10;30(5):488-96. PMID: 22184378.
Mason KD, Carpinelli MR, Fletcher JI, Collinge JE, Hilton AA, Ellis S, Kelly PN, Ekert PG, Metcalf D, Roberts AW, Huang DC, Kile BT. Programmed anuclear cell death delimits platelet life span. Cell. 2007 Mar 23;128(6):1173-86. PMID: 17382885.
van Delft MF, Wei AH, Mason KD, Vandenberg CJ, Chen L, Czabotar PE, Willis SN, Scott CL, Day CL, Cory S, Adams JM, Roberts AW, Huang DC. The BH3 mimetic ABT-737 targets selective Bcl-2 proteins and efficiently induces apoptosis via Bak/Bax if Mcl-1 is neutralized. Cancer Cell. 2006 Nov;10(5):389-99. PMID: 17097561.
Willis SN, Chen L, Dewson G, Wei A, Naik E, Fletcher JI, Adams JM, Huang DC. Proapoptotic Bak is sequestered by Mcl-1 and Bcl-xL, but not Bcl-2, until displaced by BH3-only proteins. Genes Dev. 2005 Jun 1;19(11):1294-305. PMID: 15901672.
Chen L, Willis SN, Wei A, Smith BJ, Fletcher JI, Hinds MG, Colman PM, Day CL, Adams JM, Huang DC. Differential targeting of prosurvival Bcl-2 proteins by their BH3-only ligands allows complementary apoptotic function. Mol Cell. 2005 Feb 4;17(3):393-403. PMID: 15694340.
O’Connor L, Strasser A, O’Reilly LA, Hausmann G, Adams JM, Cory S, Huang DC. Bim: a novel member of the Bcl-2 family that promotes apoptosis. EMBO J. 1998 Jan 15;17(2):384-95. PMID: 9430630.
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.