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Novel Drug May Reverse Breast Cancer Hormone Therapy Resistance

Novel Drug May Reverse Breast Cancer Hormone Therapy Resistance content piece image
Breast cancer cell. Credit: Anne Weston, Francis Crick Institute via the Wellcome Collection

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A novel drug based on a natural compound found in broccoli, kale and other cruciferous vegetables could hold the key to reversing or even preventing resistance to breast cancer hormone therapy, new research has found.

Scientists from the University of Manchester found that drug SFX-01 – which has shown promise in a phase II trial (STEM) as a treatment for secondary breast cancer that is already resistant to hormone therapy – could reverse or even prevent resistance to hormone therapy by blocking a key cancer signaling pathway (a chain of reactions within cancer cells) called STAT3.

Breast cancer is the UK’s most common cancer, with around 55,000 women and approximately 370 men being diagnosed throughout the country each year.

Up to 80% of breast cancers are encouraged to grow by the hormone estrogen and are known as estrogen receptor (ER) positive breast cancer, which accounts for up to 44,000 cases each year in the UK.

While hormone therapy (which blocks the effect of estrogen) is very effective in reducing the risk of recurrence for most, around a third of patients with ER positive breast cancer see their disease return within 15 years, and some of these are due to the cancer developing resistance to treatment.

SFX-01 – inspired by a natural plant-derived compound called sulforaphane, which was first discovered in cruciferous vegetables such as rocket, broccoli and kale – has recently been shown in a clinical trial to delay the progression of incurable secondary breast cancer in women whose disease has already developed resistance to hormone therapy.

In a new study led by Dr Bruno Simões, Dr Sacha Howell and Professor Rob Clarke at the University of Manchester, researchers investigated the effect of SFX-01 alone, or in combination with tamoxifen or fulvestrant, in patient samples and in mice to understand how the drug works and how it can be best used to treat breast cancer.

They found that SFX-01 reduced the ability of specialized cells called breast cancer stem cells to form tumors in mice, with the drug also reducing the ability of breast cancer cells to form secondary tumors in the mice’s lungs.

The researchers then looked at the gene activity levels within the breast cancer stem cells from hormone therapy-resistant tumor samples from patients, finding that the cancer stem cells relied heavily on the STAT3 signaling pathway, which can become active in response to hormone therapy and lead to treatment resistance.

SFX-01 blocked the STAT3 signaling pathway and reversed the effects that may lead to hormone therapy resistance.

In a recent phase II trial (STEM) in patients with ER positive secondary breast cancer that had already started becoming resistant to hormone therapy, 25% of participants benefitted from the addition of SFX-01 to hormone therapy  but the mechanism of why this worked was not known until now.

Further research is now focusing on understanding why certain patients’ tumors are sensitive to SFX-01 and whether an accompanying diagnostic test for activity of the STAT3 signaling pathway could be used to identify the patients that would benefit the most from this treatment.

It is also hoped that SFX-01 could in future be added to hormone therapies such as tamoxifen or aromatase inhibitors from the outset of treatment to increase their effectiveness in patients with primary breast cancer.

Co-author Dr Bruno Simões, Research Fellow at the University of Manchester, said:

“Estrogen receptor positive breast cancer is the most common breast cancer. These cancers frequently develop resistance to hormone therapies, which is a major clinical problem that we are working to address.

“We are excited by our findings that combining standard hormone therapies with SFX-01 could improve treatment of some breast cancer patients by reversing resistance driven by the STAT3 signaling pathway.

“With the success of the recent clinical trial in secondary breast cancer, we hope that further studies will now help to identify which patients may benefit the most from this drug so that it could soon reach the clinic.”

Dr Simon Vincent, Director of Research at Breast Cancer Now, which helped to fund the study, said:

“It’s really exciting that SFX-01 could in future help to improve the effectiveness of hormone therapies and prevent or treat the return of breast cancer. While hormone therapy is effective for most women, around a third still see their breast cancer return and we urgently need to find new ways to tackle and prevent drug resistance.

“This important discovery reveals exactly how SFX-01 can help overcome hormone therapy resistance and we hope it could now open the door to it being used from the outset of treatment, to prevent resistance from developing in the first place.

“We look forward to results of further trials to fully understand who is likely to benefit most and at what stage of treatment it should be added to hormone therapy to give patients the best chance of survival.”

The study is being presented at the UK Interdisciplinary Breast Cancer Symposium, hosted by Breast Cancer Now.