Combining Therapies to Overcome Treatment Resistance in Aggressive Breast Cancer

Recent groundbreaking research led by QIMR Berghofer, in partnership with Australian oncology company Kazia Therapeutics, has unveiled a promising new approach for tackling one of the most challenging forms of breast cancer—triple-negative breast cancer (TNBC). The study demonstrates that combining the experimental drug paxalisib with immunotherapy triggers a critical molecular epigenetic process that prevents cancer cell dissemination and overcomes resistance to standard treatments in preclinical models.

The research, published in the journal Molecular Cancer Therapeutics, reveals for the first time that simultaneously inhibiting two key cancer signaling pathways—the PI3K and mTOR pathways—disrupts EZH2, a molecule integral to cancer spread. This dual pathway inhibition not only halts tumor progression but also enhances the visibility of tumor cells to the immune system, effectively reinvigorating immune cell activity.

This approach addresses a major unmet need in metastatic breast cancer, a highly aggressive disease where conventional therapies like chemotherapy and immunotherapy achieve limited success, especially in advanced stages containing cancer stem cells. Nearly half of all TNBC patients develop metastasis, making treatment particularly challenging.

Building on these promising preclinical findings, a Phase 1b clinical trial has been initiated across three sites in Queensland—Royal Brisbane & Women’s Hospital, Gold Coast University Hospital, and Sunshine Coast University Hospital. The trial aims to assess the safety and efficacy of paxalisib in combination with either chemo-immunotherapy or the targeted PARP inhibitor olaparib in 24 patients with metastatic TNBC or BRCA mutation-associated breast cancer.

In addition, researchers are developing a novel liquid biopsy platform to monitor metastatic cancer cells in the bloodstream, providing real-time insights into how patients respond to treatment. This innovative strategy could pave the way for more effective, personalized therapies against metastatic breast cancer.

This research underscores a critical shift towards multi-targeted therapies capable of overcoming resistance mechanisms in deadly cancer types, offering hope for improved clinical outcomes in the future.