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Targeting Estrogen Receptors in Metastatic Breast Cancer

Article published on November 25, 2019, updated on July 2021

Oncology researchers at Sanofi are investigating a compound that takes aim at ER+ breast cancer.

Around 75% of breast cancers are classified as "estrogen-receptor-positive" (ER+). To tackle these cancers, Sanofi researchers are investigating an oral selective estrogen receptor degrader (SERD)—a type of molecule that, as the name implies, is designed to target and destroy estrogen receptors.

The idea of targeting estrogen receptors is not new: for decades, doctors have treated some breast cancers with therapeutics that reduce or block a receptor's ability to bind to estrogen. Often given in combination with chemotherapy, this approach keeps many cancers at bay for a time. 

But cancers are notorious evaders: in about 30–50% of people treated for ER+ breast cancer, tumor cells tinker with estrogen receptors, causing mutations that can interfere with treatments. 

Understanding the role of estrogen in breast cancer

How estrogen promotes tumor growth

Estrogen is a hormone with many important functions in healthy people. But in ER+ breast cancers, it promotes tumor growth. It does this by setting off a series of events:

  1. estrogen diffuses across the cell membrane; 
  2. once inside the cell, it binds to an estrogen receptor; 
  3. two activated estrogen receptors combine to form a dimer; 
  4. the estrogen-receptor dimer enters the nucleus, where it…
  5. … helps switch on genes involved in tumor growth, replication, and development of tumor cells.

Listening to breast cancer clinicians

“Over the years, clinicians kept coming to us, voicing their frustrations that there remains a significant treatment need in breast cancer care today. Specifically, they were asking for a SERD treatment that could be administered as an oral medication," said Youssef El-Ahmad, Group Leader, Medicinal Chemistry at Sanofi.

Sanofi R&D chemistry and pharmacology teams in France, Germany, and the US tackled the challenge together. Their approach was to first define their ideal oral SERD candidate, then search for a match using robotics to scan hundreds of thousands of chemical compounds. Once they found a candidate, they fine-tuned its properties until it met all the team's criteria. 

Rising to the challenge: optimizing SERDs in breast cancer therapeutics

"Medicines taken orally can be metabolized fairly quickly. The challenge we have taken on is to design a molecule that, if taken in pill form, would potentially be stable enough to reach the tumor in sufficient dose before being metabolized, bind to estrogen receptors, and degrade them," explained Sanofi scientist Maysoun Shomali, biology project lead.

“When you are hunting for a treatment with a specific therapeutic activity, you need to make sure that it has a chemical structure that can be processed easily by the body. Otherwise, you end up with a medicine that cannot fully reach its intended target and, therefore, cannot optimally do its job,” added El-Ahmad.

The team's resulting investigational compound appeared to balance metabolic stability and receptor binding potency. It also showed anti-tumor activity in metastatic breast-cancer models in the lab. All of this warranted further investigation in clinical trials. This research is ongoing–the molecule has not yet been evaluated for safety and efficacy in people by any regulatory authority. 

A great human adventure

As this important project continues to progress through development, the scientists who joined forces to make it a reality look on their invention with pride. 

“One of the most rewarding things is knowing that some of the same clinicians who asked us to take on this challenge in the first place are now leading the clinical trials that will determine if this oral SERD compound will make it to patients," said Monsif Bouaboula, the global project leader and Group Head, Molecular Oncology at Sanofi. "A lasting benefit of this work is that we have built valuable expertise across the teams, and refined our approach to selectively degrading protein receptors in cancer cells.”

“It is a great human adventure to see the spirit of collaboration, the passion of so many researchers working together across geographies, each making their unique contributions critical to creating something new that has the potential to benefit people with metastatic breast cancer,” added El-Ahmad.

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Source

  1. El-Ahmad Y, Tabart M, Halley F, et al. (2019) J Med Chem 63:512–528. DOI: 10.1021/acs.jmedchem.9b01293 
  2. Shomali M, Cheng J, Sun F, et al. (2021) Mol Cancer Ther 20:250-262. DOI: 10.1158/1535-7163.mct-20-0390