LONDON – Azeria Therapeutics Ltd. has raised £32 million (US$41.3 million) in a series B round to take forward small-molecule inhibitors of FOXA1, a transcription factor that is pivotal to the growth and progression of estrogen receptor (ER)-positive breast cancer.

The money will enable the company to take the lead program into the clinic and build a pipeline of other products, including drugs targeting FOXA1 in prostate cancer.

FOXA1 (Forkhead Box protein A1) belongs to a family of specialized transcription factors, known as pioneer factors, that have the ability to open up condensed chromatin, setting in train gene expression patterns that have been shown to drive progression of certain cancers.

Stephen Myatt, CEO, Azeria

This is “a completely new target,” said Stephen Myatt, CEO of Azeria. Although pioneer factors were identified as far back as 2002, Azeria claims to be the first company to be dedicated to the discovery of inhibitors.

“It has taken a long time from an oncology perspective,” Myatt said. The initial research revolved around the role of pioneer factors in development. “It took time for the field to appreciate their role in cancer,” he told BioWorld.

Much of that understanding rests on the research of Jason Carroll, professor of molecular oncology at Cancer Research UK’s Cambridge Institute and Azeria’s scientific founder. He has spent 10 years investigating the genomic and molecular features of ER-mediated transcription in breast cancer cells.

ER previously was thought to be a standalone transcription factor which interacted directly with DNA in response to estrogen. Carroll has shown ER activity hangs on a number of co-factors, including FOXA1, which acts by opening up chromatin, making DNA accessible for ER to bind.

FOXA1 is required for all interactions between ER and DNA, and in the absence of FOXA1, ER does not associate with DNA.

As a transcription factor that can bind to compacted chromatin independent of other factors, and initiate chromatin opening, FOXA1 plays a central role in driving ER-positive breast cancer. “It creates the foundation for opening up chromatin and letting in other factors,” said Myatt.

Existing treatments for ER-positive breast cancer, such as tamoxifen and aromatase inhibitors, work by disarming ER. While those have delivered significant clinical benefit, 30% of patients progress to late-stage endocrine-resistant disease.

In that context, FOXA1 looks to be an important target because it is required for the growth of cancer cells that have become resistant to standard therapies, including tamoxifen.

“The focus has been targeting ER directly, or interfering with downstream genes. What we are doing is very different,” Myatt said. “It’s a new approach to tackling resistance, by pulling away the foundational platform.”

There is now a large body of data validating the importance of FOXA1 in the growth and development of breast cancer and it is suggested inhibiting that factor would circumvent many of the known mechanisms of resistance to marketed drugs.

FOXA1 has also been shown to be important for activating the androgen receptor in prostate cancer. Cell models of castration-resistant prostate cancer are dependent on FOXA1 for cell growth.

Azeria’s approach to FOXA1 inhibition does not involve drugging it directly. However, Myatt declined to elaborate. “There is not a lot in the public domain about how we are going about it. This is clearly a competitive area and breast cancer is a large market, so we are not revealing details at this point.”

The majority of the money in the series B, £29.5 million, came from Syncona Investment Management Ltd., the quoted fund set up by the research charity Wellcome Trust in 2013. Syncona is an evergreen fund that takes a long-term view and supports technologies all the way through to market. The fund is prepared to invest for 10 to 12 years if necessary, giving Azeria a stable foundation.

In effect, Syncona is following on from the £4 million series A round Azeria raised in September 2018. That money came from Cancer Research UK’s Pioneer fund, in which Syncona is the largest investor.

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