Combination approach could overcome treatment resistance in deadly breast cancer

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There is an urgent need to develop new treatments for patients with metastatic breast cancer, which is highly aggressive and difficult to treat. QIMR Berghofer-led research in collaboration with Australian oncology company, Kazia Therapeutics, has found that combining the drug candidate paxalisib with immunotherapy triggered a molecular epigenetic process that prevented the spread of cancer cells and overcame treatment resistance in preclinical models of triple negative breast cancer.

Journal/conference: Molecular Cancer Therapeutics

Research: Paper

Organisation/s: QIMR Berghofer, The University of Queensland, The Australian National University, Griffith University

Funder: S. Rao is supported by an Inaugural Daniela Dwyer foundation fellowship. Funding was provided by collaborative agreement between Kazia Therapeutics Limited and QIMR Berghofer Medical Research Institute.

Media release

From: QIMR Berghofer

QIMR Berghofer-led research in collaboration with Australian oncology company, Kazia Therapeutics, has found that combining the drug candidate paxalisib with immunotherapy triggered a molecular epigenetic process that prevented the spread of cancer cells and overcame treatment resistance in preclinical models of triple negative breast cancer.

The research has been published in Molecular Cancer Therapeutics, a journal of the American Association for Cancer Research.

The study showed for the first time that inhibiting two key cancer signalling pathways at the same time, the PI3K and mTOR pathways, disrupted a molecule EZH2 which is known to be critical to the spread of cancer cells.

The research also found that the combination of paxalisib and immunotherapy in the preclinical models helped make the tumour cells more visible to immune cells, as well as reinvigorating the immune cells.

See video animation here.

There is an urgent need to develop new treatments for patients with metastatic breast cancer, which is highly aggressive and difficult to treat. Around half of all triple negative breast cancer patients develop metastatic disease where the cancer spreads to other parts of the body. Standard therapies such as chemotherapy and immunotherapy are only effective for a small number of patients at this advanced stage and, importantly, have not been effective in treating cancer stem cells.

The promising preclinical research findings just published have paved the way for a clinical trial which is recruiting 24 patients with triple negative or BRCA mutation-associated metastatic breast cancer at three sites in Queensland – the Royal Brisbane & Women’s Hospital, Gold Coast University Hospital, and Sunshine Coast University Hospital.

Sponsored by Kazia Therapeutics, the multi-centre, open-label phase 1b clinical trial is assessing the safety and efficacy of paxalisib given in combination with the standard of care approach of chemo-immunotherapy, or with the targeted PARP inhibitor olaparib.

In a first-of-its kind, QIMR Berghofer researchers are collaborating with the trial investigators to test a new liquid biopsy platform designed to track metastatic cancer cells in the blood of participants and monitor how they are responding to the treatment.

The study is available at this link https://aacrjournals.org/mct/article/doi/10.1158/1535-7163.MCT-24-0693 with DOI 10.1158/1535-7163.MCT-24-0693 in Molecular Cancer Therapeutics, a journal of the American Association for Cancer Research.

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    Professor Sudha Rao, QIMR Berghofer Gene Regulation and Translational Medicine Laboratory

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