Prof David Huang, Lab Head | WEHI Researcher Profile

Q: BH3 mimetics for treating haematological cancers

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.

Q: Regulation of Mcl-1 protein stability

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.

Q: How do Bax and Bak become activated?

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.

Q: Identifying novel cancer cell susceptibilities

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.

About

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.

Publications

Selected publications from Prof David Huang

Peng H, Jabbari JS, Tian L, Wang C, You Y, Chua CC, Anstee NS, Amin N, Wei AH, Davidson N, Roberts AW, Huang D, Ritchie ME, Thijssen R. Single-cell Rapid Capture Hybridization sequencing to reliably detect isoform usage and coding mutations in targeted genes. Genome Research. 2025;35(4):10.1101/gr.279322.124

Gong J-N, Djajawi TM, Moujalled DM, Pomilio G, Khong T, Zhang L-P, Fedele PL, Low MS, Anderson MA, Riffkin CD, White CA, Lan P, Lessene G, Herold MJ, Strasser A, Spencer A, Grigoriadis G, Wei AH, van Delft MF, Roberts AW, Huang DCS. Re-appraising assays on permeabilized blood cancer cells testing venetoclax or other BH3 mimetic agents selectively targeting pro-survival BCL2 proteins. Cell Death & Differentiation. 2025;:10.1038/s41418-025-01487-7

Li K, Yap YQ, Moujalled DM, Sumardy F, Khakham Y, Georgiou A, Jahja M, Lew TE, De Silva M, Luo M-X, Gong J-N, Yuan Z, Birkinshaw RW, Czabotar PE, Lowes K, Huang DCS, Kile BT, Wei AH, Dewson G, van Delft MF, Lessene G. Differential regulation of BAX and BAK apoptotic activity revealed by small molecules. Science Advances. 2025;11(10):10.1126/sciadv.adr8146

Brown FC, Wang X, Birkinshaw R, Chua CC, Morley T, Kasapgil S, Pomilio G, Blombery P, Huang DCS, Czabotar P, Priore SF, Yang G, Carroll M, Wei AH, Perl AE. Acquired BCL2 variants associated with venetoclax resistance in acute myeloid leukemia. Blood Advances. 2025;9(1):10.1182/bloodadvances.2024014446

Luo M-X, Tan T, Trussart M, Poch A, Nguyen TMH, Speed TP, Hicks DG, Bandala-Sanchez E, Peng H, Chappaz S, Slade C, Utzschneider DT, Koldej RM, Ritchie D, Strasser A, Thijssen R, Ritchie ME, Tam CS, Lindeman GJ, Huang DCS, Lew TE, Anderson MA, Roberts AW, Teh CE, Gray DHD. Venetoclax dose escalation rapidly activates a BAFF/BCL-2 survival axis in chronic lymphocytic leukemia. Blood. 2024;144(26):10.1182/blood.2024024341

Gao M, Georgiou A, Lin VS, Jahja M, White CA, Anderson MA, McCormack MP, Roberts AW, Huang DCS, Thijssen R. Potential impact of NOTCH1 activation on venetoclax sensitivity in chronic lymphocytic Leukaemia: In vitro insights and clinical implications. British Journal of Haematology. 2024;205(4):10.1111/bjh.19604

Yuan Z, van Delft MF, Li MX, Sumardy F, Smith BJ, Huang DCS, Lessene G, Khakam Y, Jin R, He S, Smith NA, Birkinshaw RW, Czabotar PE, Dewson G. Key residues in the VDAC2-BAK complex can be targeted to modulate apoptosis. PLOS Biology. 2024;22(5):10.1371/journal.pbio.3002617

Wang Z, Burigotto M, Ghetti S, Vaillant F, Tan T, Capaldo BD, Palmieri M, Hirokawa Y, Tai L, Simpson DS, Chang C, Huang AS, Lieschke E, Diepstraten ST, Kaloni D, Riffkin C, Huang DCS, Suen CSNLW, Garnham AL, Gibbs P, Visvader JE, Sieber OM, Herold MJ, Fava LL, Kelly GL, Strasser A. Loss-of-Function but Not Gain-of-Function Properties of Mutant TP53 Are Critical for the Proliferation, Survival, and Metastasis of a Broad Range of Cancer Cells. Cancer Discovery. 2024;14(2):10.1158/2159-8290.cd-23-0402

Galas-Filipowicz D, Chavda SJ, Gong J-N, Huang DCS, Khwaja A, Yong K. Co-operation of MCL-1 and BCL-XL anti-apoptotic proteins in stromal protection of MM cells from carfilzomib mediated cytotoxicity. Frontiers in Oncology. 2024;14:10.3389/fonc.2024.1394393

Yang D, Li Q, Lu P, Wu D, Li W, Meng X, Xing M, Shangguan W, Chen B, Yang J, Zhang Z, Wang Z, Huang DCS, Zhao Q. FOXA2 activates HIF2α expression to promote tumor progression and is regulated by the E3 ubiquitin ligase VHL in renal cell carcinoma. Journal of Biological Chemistry. 2024;300(1):10.1016/j.jbc.2023.105535

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Lab research projects

BH3 mimetics for treating haematological cancers

Regulation of Mcl-1 protein stability

How do Bax and Bak become activated?

Identifying novel cancer cell susceptibilities

Student research projects

Overcoming treatment resistance in blood cancers

Honours

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Overcoming treatment resistance in blood cancers

Honours

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Prof David Huang

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