In breast cancer, estrogen and its receptor (ER) are common accomplices warped to serve tumor growth. Since this connection was first identified in the 1960s, treatments have aimed to block estrogen’s role in promoting breast cancer, as well as other key signaling pathways that drive malignancy. At the 2024 San Antonio Breast Cancer Symposium (SABCS), the “Unlocking New Targets with Molecular Degraders” session illustrated how far we’ve come, both in our understanding of breast cancer biology and our ability to target breast cancer with precision.
Presenters put our progress in perspective, pondering the latest clinical implications for selective estrogen receptor degrader (SERDs) and providing a glimpse into promising preclinical approaches, like proteolysis- and lysosome-targeting chimeras (PROTACs and LYTACs) and biparatopic antibodies, with the potential to help more patients.
Selective Estrogen Receptor Degraders (SERDs)
Before SERDs, we modulated ER activity with selective estrogen receptor modulators (SERMs) like tamoxifen, explained Rinath M. Jeselsohn, MD, the director for ER+ Breast Cancer Translational and Discovery Research, and a medical oncologist and assistant professor, at Dana-Farber Cancer Institute. However, SERMs only partially block ER, allowing cancer to adapt. Mutations in ESR1, the gene encoding ER, occur in over 50% of ER-positive metastatic breast cancers, enabling cancer cells to evade SERMs and sustain estrogen-driven proliferation.
SERDs, like fulvestrant, are “pure” ER blockers that destabilize and degrade the receptor. Elacestrant became the first FDA-approved oral SERD last year, and this year’s SABCS highlighted imlunestrant, another oral SERD. Both improved recurrence-free survival in pretreated patients with advanced ER-positive, HER2-negative, and ESR1-mutated tumors. Imlunestrant combined with CDK4/6 inhibition extended these benefits to patients regardless of ESR1 mutation status or prior CDK4/6 therapy.
This effectiveness may stem from how oral SERDs target mutated ER. Latest research from Jeselsohn’s group shows both fulvestrant and imlunestrant degrade normal ER similarly. However, against mutated ER, fulvestrant’s degradation ability—and tumor elimination in mice—was compromised, unlike imlunestrant’s. In support of this, molecular docking studies indicated stark differences in binding to the mutated ER, explaining imlunestrant’s superior efficacy.
Jeselsohn closed her talk by pointing to several phase III trials examining SERDs as standard of care for metastatic breast cancer. One study is evaluating an even more cutting-edge SERD that is a PROTAC, which takes ER degradation to the next level.
Proteolysis-Targeting Chimeras (PROTACs)
Traditional SERDs promote ER degradation through proteasome-mediated proteolysis, achieved by passively destabilizing the receptor. In contrast, PROTACs actively promote ER degradation, explained Stephen M. Hinshaw, PhD, a senior research scientist in the Center for Therapeutics Discovery and at the Stanford Cancer Institute. Vepdegestrant, an ER-specific PROTAC with FDA fast-track designation in breast cancer, exemplifies this approach.
PROTACs use a linker molecule to connect two small molecules: one binds the target protein (e.g., ER), and the other binds an E3 ubiquitin ligase within the proteasome degradation complex, facilitating efficient degradation.
Hinshaw’s preclinical research with PROTACs targeting CDK4/6 in breast cancer revealed durable pharmacological effects. “[PROTACs] may initially degrade only a small portion of the target, but over time, the target is cleared, resulting in effects that outlast the compound itself,” he explained.
To expand PROTAC pharmacology, Hinshaw’s team identified 20 new degradation pathways using less-common E3 ubiquitin ligases like KLHDC2. This bodes well for the feasibility of more rapid progression from proof of concept to drug candidate, Hinshaw said.
In addition to bivalent PROTACs, which bind both the target protein and E3 ubiquitin ligase, monovalent PROTACs target only the E3 ubiquitin ligase, creating new binding pockets that recruit proteins of interest. Both approaches provide high specificity and prolonged therapeutic effects. Here, Hinshaw highlighted ongoing efforts to develop covalent PROTACs with applications in breast cancer, malignant rhabdoid tumors, and acute myeloid leukemia.
Lysosome-Targeting Chimeras (LYTACs)
PROTACs can help promote proteasome-mediated degradation of proteins inside cells, but they can’t target proteins outside or on the surface of cells, which make up around 40% of the proteome, according to Weiping Tang, PhD, the Janis Apinis Professor of Pharmaceutical Sciences and director of Medicinal Chemistry Center at the University of Wisconsin-Madison School of Pharmacy, and Vilas Distinguished Achievement Professor of UW-Madison.
Enter LYTACs, which employ lysosomes to degrade proteins internalized into cells via endocytosis. And because LYTACs target surface and secreted proteins and consequently aren’t as limited by size, they can incorporate components of antibodies, peptides, and small molecules, offering more design flexibility.
LYTACs trigger endocytosis by binding surface lysosome-targeting receptors (LTRs). By targeting specific LTRs expressed only by certain cells, LYTACs can be designed to home to certain tissues, including tumors.
Tang’s team demonstrated this with LYTACs targeting the asialoglycoprotein receptor in liver cells and explored a more therapeutically valuable receptor: the folate receptor overexpressed in cancers such as lung, ovarian, and triple-negative breast cancer.
Using a linker to attach folic acid (which binds the folate receptor) to existing antibodies against epidermal growth factor receptor (EGFR) or the immune checkpoint ligand PD-L1, the team generated two LYTACs that triggered the degradation of EGFR and PD-L1. This degradation occurred to a greater extent in cancer cells, likely due to their elevated expression of the folate receptor.
“In most cases, we observed much more significant degradation of either EGFR or PD-L1 in the cancer cells that overexpress folate receptor compared to normal cells,” Tang shared.
Most notably, the PD-L1-targeting LYTAC enhanced CD8-positive T-cell tumor infiltration and protected against tumor growth in mice, outperforming the unmodified PD-L1 antibody.
Biparatopic Antibodies
Some cancer targets are particularly challenging because their malignant transformation can take several paths. In the lab of William Sellers, MD, the director of the Cancer Program at the Broad Institute of MIT and Harvard, scientists are taking LYTAC technology one step further to tackle such challenges.
As noted by Saireudee Chaturantabut, PhD, a staff scientist in Sellers’ lab, fibroblast growth factor receptor 2 (FGFR2) is frequently implicated in cancers such as breast and gastric. FGFR2 alterations, including amplifications, mutations, and fusions, drive oncogenesis by promoting malignancy through distinct mechanisms. And despite the availability of FGFR inhibitors, their clinical efficacy is limited by resistance mutations and off-target effects, leaving a significant therapeutic gap, she said.
To address this, their team adapted LYTAC principles and used destabilizing mutations to develop biparatopic antibodies designed to target aberrant FGFR2 in these different oncogenic contexts. By binding FGFR2 complexes at two distinct sites, these biparatopic antibodies led to enhanced receptor internalization and lysosomal degradation.
In addition to biparatopic constructs that suppressed the growth of FGFR2 fusion-driven tumors in mice, they also developed constructs with promising degradation capabilities for amplifications and mutated versions of FGFR2 associated with resistance. Interestingly, the distinct pharmacology of these biparatopic constructs were not predicted by mixtures of antibodies targeting the two epitopes, which weren’t as effective despite the same epitopic coverage.
Lastly, Chaturantabut unveiled data from biparatopic FGFR2-targeting antibodies conjugated with a cancer-killing drug. This approach was also effective at addressing tumor heterogeneity, inducing bystander effects to eliminate FGFR2-negative cancer cells adjacent to FGFR2-positive ones. This capability not only enhances efficacy in diverse tumor environments but also highlights the promise of biparatopic antibodies as a transformative tool for targeting complex oncogenic drivers like FGFR2.
Hope for a Brighter Future
The advancements highlighted at the 2024 SABCS represent the immense potential power of innovative molecular degrader therapies like SERDs, PROTACs, LYTACs, and biparatopic antibodies. Building on the progress achieved thus far, these approaches are poised to improve how we target resistant and complex breast cancers moving forward, offering new hope for improved outcomes for more patients. While challenges remain, these breakthroughs mark a pivotal step toward more effective, personalized treatments, bringing us closer to a future where even the most aggressive breast cancers can be controlled.
