Trial to test new strategy for aggresive breast cancer to begin soon

Researchers are recruiting volunteers for a clinical trial that will use a new therapy to target a ‘defence switch’ on cancer cells that alerts cancer to the threat of chemotherapy.

The new strategy hopes to improve survival rates for patients with triple negative breast cancer — a treatment-resistant form of cancer that can quickly adapt against chemotherapy — that affects about 1500 women each year in New South Wales.

Set to commence in August, the trial will be led by Associate Professor Christine Chaffer and Dr Beatriz San Juan from the Garvan Institute of Medical Research, and Senior Staff Specialist in medical oncology Dr Rachel Dear of St Vincent’s Hospital Sydney. It will be conducted at The Kinghorn Cancer Centre in Darlinghurst.

“Triple negative breast cancer is an aggressive disease with a greater likelihood of spreading around the body and recurring within five years than other breast cancers,” Chaffer said.

“In preclinical studies, we found that an experimental drug, seviteronel, combined with chemotherapy, could be twice as effective in reducing the size of tumours than chemotherapy alone,” Chaffer said.

Androgen hormones tell triple negative breast cancer to adapt against chemotherapy and to behave aggressively. Seviteronel works by blocking these warning signals and potentially makes other treatments more effective.

Dr Dear said, “This is an exciting opportunity to test a new treatment option for metastatic triple negative breast cancer, for which there is currently a gap in effective drug treatments.”

Seviteronel is not currently approved for clinical use. If this trial is successful, it will be followed by a larger safety study within a year.

The research leading to the trial has been supported by the NELUNE Foundation, which awarded Chaffer with the Rebecca Wilson Fellowship in Cancer Research in 2017 enabling her to bring her research back to Sydney from the USA. The Fellowship is a lasting legacy to sports journalist the late Rebecca Wilson.

New approach for triple negative breast cancer

About 10–15% of breast cancer cases are diagnosed as triple negative breast cancer, which means the cancer cells lack all three receptors that doctors can target with cancer-treating medications. As there are currently no effective targeted therapies, triple negative breast cancers have a poorer prognosis compared to other forms of breast cancer.

Research from Chaffer’s team revealed that triple negative cancer cells ‘switch’ their cell state in response to chemotherapy, which not only makes the cancer cells more aggressive, but also allows them to evade treatment.

“We found that chemotherapy triggers a cell change in cancer cells that enables them to build a defence against the chemotherapy. This means that a different type of cancer cell emerges after treatment, which has become resistant to the chemotherapy and is a major cause of cancer relapse,” Chaffer explained.

“We aim to put a stop to this cancer resistance strategy to improve the effectiveness of chemotherapy for triple negative breast tumours.”

Dr Beatriz Perez San Juan, the postdoctoral researcher in Associate Professor Chaffer’s lab who led the preclinical study, discovered that activation of androgen receptors in breast cancer cells triggers the cell state switching. Androgens are commonly thought of as male sex hormones but are also found at lower levels in women.

In preclinical models of triple negative breast cancer, the researchers administered chemotherapy together with seviteronel, an experimental treatment that blocks androgen production. The combination approach caused a 70% to 100% greater reduction in tumour size, compared to chemotherapy alone. This strategy prevented the emergence of chemotherapy-resistant cells and reduced the spread of the cancer around the body.

Repurposing an experimental treatment

Seviteronel was originally developed as a standalone therapy for breast and prostate cancers that carry the androgen receptor and was proven safe for patients in Phase II clinical trials.

“Our research has revealed that seviteronel may be far more beneficial as an adjunct therapy. We found that androgen inhibition blocks cancer cell state switching, ‘locking’ cancer cells in a chemotherapy-sensitive state. This is why chemotherapy plus seviteronel treatment was more effective than chemotherapy alone at targeting cancer in our preclinical studies,” Perez San Juan said.

“We hope that this new combination treatment approach will drastically reduce drug resistance to improve the effectiveness of standard-of-care chemotherapy and, ultimately, improve outcomes for patients.”

Those interested in registering interest in the 4CAST clinical trial can contact the St Vincent’s Hospital Sydney Research Office, SVHS.cancerresearch@svha.org.au.

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