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
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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.
Late last year, data from several papers (here, here, and here) finally helped answer the question behind this apparent paradox. It turns out that hormone receptor-positive breast cancer is so addicted to estrogen signaling that the receptor will actually change (or mutate) so it doesn’t need the hormone to work; it could become active even without estrogen binding to it.
We learned that we needed a new way to stop the estrogen receptor.
Eliminating the Estrogen Receptor
Through our planned acquisition of Seragon (more on that here), we will add a class of oral, investigational medicines called Selective Estrogen Receptor Degraders (SERDs) to our pipeline. SERDs are designed to work in two main ways.
SERDs are designed to work by throwing the key driver of disease into what is essentially a cellular garbage can
First, they are designed to bind to the estrogen receptor to limit its function.
Second, when SERDs bind to the estrogen receptor, they can also change its shape. This may seem trivial, but SERDs may be able to change the shape of the receptor so the cell treats it like “cellular junk” and eliminates it. The ability to eliminate the estrogen receptor from the cell may help address the source of the problem.
Opening up a new avenue for research
Breast cancer is a disease that can strike any woman at any time; whether she’s starting a career or enjoying her retirement. It’s also one where we’ve made tremendous progress, but need better medicines, especially for those who will see it return.
We believe these investigational next-generation oral SERDs developed by Seragon could one day potentially redefine the standard of care for hormone receptor-positive breast cancer. The discovery of these types of molecules is a much-needed advance in the field.
At the same time, we recognize that cancer is tricky, and we will be looking into combination studies. Our hope is that one of the many medicines in our pipeline will be able to overcome a potential SERD resistance - if one exists.