Trashing A Common Cancer Driver

Not all breast cancers are the same. They differ based on their molecular features and the types of signals that tell them to grow and spread. Along with early detection, classifying breast cancers based on their underlying biology has no doubt led to important advances. Depending on the type of breast cancer, women may be eligible for treatments that target those underlying causes of the disease.

However, we still have a long way to go. Breast cancer will claim the lives of nearly 40,000 women in the United States this year. A new class of investigational medicines called Selective Estrogen Receptor Degraders, or SERDs, could represent an important avenue of research for half of these women.

Hijacking a Hormone

Hormones, like estrogen, are critical for breast tissue growth during puberty, pregnancy and nursing. Unfortunately, they also drive the growth of a majority of breast cancers. This type of disease is called hormone receptor-positive breast cancer, and it occurs when the cancer hijacks this natural hormone to fuel its growth and spread.

This type of breast cancer essentially becomes “addicted” to estrogen signaling, which is activated when the estrogen hormone goes inside the cell and attaches to a protein called the estrogen receptor. The estrogen receptor then turns on genes that cause the cell to multiply. In order to treat this type of cancer, two main types of medicines were developed to stop estrogen signaling.

One commonly used class of medicine is called tamoxifen, which binds to the estrogen receptor and thereby prevents it from binding to estrogen and turning on cell growth genes.

The other class of medicines that target estrogen signaling do so by blocking estrogen production. These medicines include aromatase inhibitors and luteinizing-hormone- releasing hormone (LHRH) agonists, which work by blocking the production of estrogen itself, decreasing the amount of estrogen available to activate the receptor.

Hormone receptor-positive breast cancer essentially becomes “addicted” to estrogen signaling, and we need new ways to stop the estrogen receptor.

These classes of medicines have made an enormous impact on hormone receptor-positive breast cancer, and in some cases have helped prevent relapse. But not in all cases.

The Estrogen Receptor Paradox

Unfortunately, many women who are prescribed these anti-hormonal medicines will see their disease come back. For years, doctors and scientists couldn’t understand why these anti-hormone therapies stopped working against hormone receptor-positive disease when it returned. If the estrogen receptor is still present and active in the tumor, why wouldn’t anti-hormonal treatments be able to block it?

One in two women who die of breast cancer have ER positive disease that no longer responds to current anti-hormonal medicines.

Small Molecule, Big Effects

SERDs are a beautiful family of molecules for many reasons. They're small molecules that have been rationally designed to enter the cell, change the shape of the estrogen receptor, and mark it for elimination.

Although other molecules have shown similar effects, their chemical structure makes them “oily” (chemists call this hydrophobic). That means that they have to be administered through injections into the muscle tissue and not in a pill form. To achieve the concentrations needed to eliminate most of the estrogen receptor, a woman with hormone-positive breast cancer would need to endure more injections than clinically feasible.

SERDs represent a class of small molecules that may exert a big effect on a key driver of the disease and can be administered as a pill. Recent research tells us that the estrogen receptor remains the Goliath of hormone-positive breast cancer, and we’re hopeful that we’ve found a David.

*While Mike Varney was an employee at the time this article was published, he has since retired from Genentech.