A/Prof Gemma Kelly, Lab Head | WEHI Researcher Profile

Q: Identifying potential resistance factors to BH3 mimetic drugs targeting MCL-1 for cancer therapy

BH3 mimetic drugs aim to trigger cell death for cancer therapy through inhibiting cellular pro-survival proteins of the BCL-2 family.In earlier work we found that expression of the pro-survival protein MCL-1 was required for the continued growth of MYC-driven lymphomas. We have been working with the pharmaceutical company Servier to test novel BH3 mimetic drugs targeting MCL-1 for cancer therapy and related drugs entered clinical trials in 2018.We are currently seeking to identify factors that could confer resistance, either primary or acquired, to these MCL-1 targeting drugs with the aim to find strategies that could overcome resistance. Project resources:Survival protein a potential new target for many cancers [https://www.wehi.edu.au/news/survival-protein-potential-new-target-many-cancers]New compound shows promise in treating multiple human cancers [https://www.wehi.edu.au/news/new-compound-shows-promise-treating-multiple-human-cancers]

Q: Investigating mutant p53 in cancer

Approximately 50 per cent of human cancers harbor mutations in the tumour suppressor p53 that result in reduced sensitivity to many conventional chemotherapeutics and a poor prognosis for the patients. We seek to understand how exactly these mutations in p53 contribute to the growth of cancer cells, in particular we are interested to know if there are neomorphic gain-of-function effects of mutant p53. Additionally, we aim to determine if mutant p53 contributes to the growth of established tumours, thereby identifying it as a therapeutic target. For these experiments we have generated novel and sophisticated pre-clinical models of mutant p53 cancers.Project resources:Mutant protein tackles DNA guardian to promote cancer development [https://www.wehi.edu.au/news/mutant-protein-tackles-dna-guardian-promote-cancer-development]

Q: Investigating the role of the Epstein-Barr virus in lymphomas

Approximately 200,000 cancers annually are associated with the Epstein-Barr virus (EBV). We are researching the role of EBV in two types of lymphoma – Burkitt’s lymphoma (an aggressive B cell lymphoma), and T/NK cell lymphoma.In a subset of Burkitt’s lymphomas, EBV expresses a viral homologue of the cellular pro-survival BCL-2 proteins, called BHRF1. We seek to understand how BHRF1 interacts with the cellular apoptotic machinery to block cancer cell death. In the setting of EBV-associated T/NK cell lymphomas we aim to understand how viral proteins contribute to tumour growth and to find alternative therapeutic options since these patients currently have a very poor prognosis.

Q: Is there therapeutic potential in targeting the BCL-2 pro-survival proteins BCL-W and BFL-1/A1 for cancer therapy?

BH3 mimetic drugs targeting the pro-survival protein BCL-2 have shown efficacy in the clinic for the treatment of patients with chronic lymphocytic leukemia (CLL).More recently, BH3 mimetics targeting the related BCL-2 family protein, MCL-1, have shown promise for the treatment of certain blood cancers in pre-clinical models and entered clinical trials for these cancers in 2018.Two of the other BCL-2 pro-survival proteins, BCL-W and BFL-1/A1, are by comparison relatively understudied. We are using genetically engineered pre-clinical lymphoma models and CRISPR/Cas9 genome editing of blood cancer cells to determine if drugs targeting BCL-W and BFL-1/A1 would have therapeutic potential.

About

My laboratory uses cutting edge molecular and cellular biology techniques to identify vulnerabilities in leukaemia and lymphoma cells that could be exploited for cancer therapy.

Through our research projects we investigate the contribution of key cellular genes that control proliferation and cell death for the growth and chemosensitivity of both normal and malignant cells.

My laboratory also has a strong interest in virus-associated cancers, in particular in Epstein-Barr virus-associated lymphomas. We aim to understand how viral proteins can manipulate host cell proliferation and death to contribute to cancer development, growth and chemoresistance.

We have a wealth of accurate pre-clinical models of leukaemia and lymphoma that we utilise in our experiments, as well as expertise in the following techniques:

CRISPR/Cas9-mediated genome editing
lentiviral production and transduction of cells
drug screening
efficacy and toxicity testing of drugs in culture and in preclinical models
analysis of preclinical models of cancer

Education

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Publications

Selected publications from A/Prof Gemma Kelly

La Marca JE, Diepstraten ST, Kelly GL, Herold MJ. Awakening the Genome: CRISPR Activation to Unravel the Origin and Vulnerabilities of Cancer. Annual Review of Cancer Biology. 2025;9(1):10.1146/annurev-cancerbio-062624-104149

Thai AA, Young RJ, Bressel M, Kelly GL, Sejic N, Tsao SW, Trigos A, Rischin D, Solomon BJ. Characterizing and Targeting of BCL‐2 Family Members in Nasopharyngeal Carcinoma. Head & Neck. 2025;47(3):10.1002/hed.27973

Chen T, Ashwood LM, Kondrashova O, Strasser A, Kelly G, Sutherland KD. Breathing new insights into the role of mutant p53 in lung cancer. Oncogene. 2025;44(3):10.1038/s41388-024-03219-6

La Marca JE, Kelly GL, Strasser A, Diepstraten ST. Don’t fear the reaper: The role of regulated cell death in tumorigenesis and BH3-mimetics for cancer therapy. Developmental Cell. 2024;59(19):10.1016/j.devcel.2024.06.018

Lieschke E, Thomas AF, Kueh A, Atkin-Smith GK, Baldoni PL, La Marca JE, Young S, Huang AS, Ross AM, Whelan L, Kaloni D, Tai L, Smyth GK, Herold MJ, Hawkins ED, Strasser A, Kelly GL. Mouse models to investigate in situ cell fate decisions induced by p53. The EMBO Journal. 2024;43(19):10.1038/s44318-024-00189-z

Kelly G, Diepstraten S, Yuan Y, La Marca J, Young S, Chang C, Whelan L, Ross A, Fischer K, Pomilio G, Morris R, Georgiou A, Litalien V, Brown F, Roberts A, Strasser A, Wei A. 2007 – INFORMING THERAPEUTIC APPROACHES FOR P53 DEFECTIVE BLOOD CANCERS. Experimental Hematology. 2024;137:10.1016/j.exphem.2024.104564

Diepstraten ST, Yuan Y, La Marca JE, Young S, Chang C, Whelan L, Ross AM, Fischer KC, Pomilio G, Morris R, Georgiou A, Litalien V, Brown FC, Roberts AW, Strasser A, Wei AH, Kelly GL. Putting the STING back into BH3-mimetic drugs for TP53-mutant blood cancers. Cancer Cell. 2024;42(5):10.1016/j.ccell.2024.04.004

Chen T, Lieschke E, Scott L, Boyd D, Sutherland K, Strasser A, Kelly G. Abstract LT06: Understanding the Role of Mutant TP53 in Lung Cancer Using Novel Genetically Engineered Mouse Models. Cancer Research. 2024;84(8_Supplement):10.1158/1538-7445.fcs2023-lt06

Alcolea MP, Alonso-Curbelo D, Ambrogio C, Bullman S, Correia AL, Ernst A, Halbrook CJ, Kelly GL, Lund AW, Quail DF, Ruscetti M, Shema E, Stromnes IM, Tam WL. Cancer Hallmarks: Piecing the Puzzle Together. Cancer Discovery. 2024;14(4):10.1158/2159-8290.cd-24-0097

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

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Lab research projects

Identifying potential resistance factors to BH3 mimetic drugs targeting MCL-1 for cancer therapy

Investigating mutant p53 in cancer

Investigating the role of the Epstein-Barr virus in lymphomas

Is there therapeutic potential in targeting the BCL-2 pro-survival proteins BCL-W and BFL-1/A1 for cancer therapy?

Student research projects

Improving targeted therapies for hard-to-treat blood cancers

PhD

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Improving targeted therapies for hard-to-treat blood cancers

PhD

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View all student research projects

A/Prof Gemma Kelly

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