Breast Cancer

Overcoming ADC Resistance Through Mechanistic Combinations

Project Summary

This SPORE project aims to find new treatments for metastatic triple-negative breast cancer (mTNBC) that are more effective and cause fewer side effects. Our team of HCC researchers have led the development of several antibody-drug conjugates (ADCs) for advanced breast cancer, including the drug Sacituzumab govitecan (SG). These treatments have shown better response rates, longer progression-free survival, and longer overall survival compared to standard chemotherapy.

Cancer can be difficult to treat when it shows resistance to therapy, either by not responding to the treatment from the beginning (initial resistance) or by becoming less responsive over time (acquired resistance).  Our clinical and translational research program focuses on finding treatment combinations with ADCs that can overcome both initial and acquired resistance to therapy. We recently completed a phase 1b/2 clinical trial of SG and the PARP inhibitor talazoparib for mTNBC. The drugs were given in a sequential dosing schedule, meaning one after the other, based on our hypothesis that this schedule might reduce side effects and improve effectiveness. While giving the drugs sequentially lowered the risk of severe bone marrow suppression, compared to giving the drugs at the same time, the sequential combination still caused significant blood-related (hematologic) side effects. In this project, our team will explore the best ways to use newer ADC/PARP inhibitor combinations and test new combination treatments with ADCs.

• In Aim 1 we will carry out pre-clinical studies leading to the design and launch of a phase 1b/2 clinical trial combining a TROP-2 targeted, TOP1 inhibitor-based ADC with a new PARP1-selective inhibitor, since PARP1 inhibition is known to have a hematopoietic stem/progenitor-(blood-related) sparing effect. We will also study how treatment response relates to biomarkers of DNA damage and repair by analyzing samples from the trial and other patients, comparing the ADC/PARP1i combination to ADC alone.
• In Aim 2, we will test a new combination of an ADC with a targeted therapy, identified through CRISPR screens, that may improve effectiveness by both impacting the repair of TOP1-related damage and increasing TROP2 expression.

Together, these studies will support innovative, mechanism-based clinical trials using ADC combination therapies for patients with mTNBC.

Rational Approaches to Improve Treatment Outcomes of Patients With Breast Cancer Brain Metastases

Project Summary

Brain metastases occur when cancer spreads to the brain, a serious and often life-threatening development for people with advanced cancer. These tumors are especially challenging to treat because many therapies can't reach the brain due to the protective blood-brain barrier (BBB). However, when cancer spreads, this barrier can become disrupted, creating what's called a blood-tumor barrier (BTB). Brain metastases are a devastating complication, and treatment options remain limited. 

Recently, antibody-drug conjugates (ADCs), a type of targeted cancer therapy, have significantly improved outcomes for patients with metastatic breast cancer. However, most ADC trials have excluded patients with active brain metastases. Encouragingly, both laboratory and early clinical studies suggest that ADCs may be effective in treating brain metastases, likely because they can cross the BTB and reach the tumor. 

Our research team recently discovered that blocking a protein called PI3Kβ can boost the immune system’s ability to fight tumors that are missing another protein called PTEN. Since PTEN loss is common in BCBM, we aim to explore whether combining PI3Kβ inhibitors with immunotherapy can help overcome immune resistance in these tumors. To test this, we’ll use advanced research models, including patient-derived xenografts (PDXs) and genetically engineered mouse models (GEMMs), to develop and evaluate ADC-based combination therapies that could lead to better outcomes for patients with BCBM.

• Aim 1: Improve the effectiveness of the HER2-targeted therapy trastuzumab deruxtecan (T-DXd) in BCBM that are HER2-positive or HER2-low. We will test combination treatments, including adding PI3Kβ inhibitors to help the immune system fight the cancer. These strategies will be studied both in the lab and through clinical trials in patients.
• Aim 2: Study the TROP2-targeted ADC therapy, datopotamab deruxtecan (Dato-DXd), in triple-negative breast cancer brain metastases, especially in cases where PTEN is lost. We will test whether combining Dato-DXd with PI3Kβ inhibitors improves treatment response and will also begin translating these findings into clinical trials for patients.

Our overall goal is to develop and advance new ADC-based therapies that work in the brain, helping address a critical treatment gap for patients with BCBM.

BET Bromodomain Inhibitor Combinations in Breast Cancer

Project Summary

Current treatments for advanced breast cancer, such as immune checkpoint inhibitors (ICIs) for triple-negative breast cancer (TNBC) and CDK4/6 inhibitors for estrogen receptor-positive (ER+) breast cancer, have shown some success however many patients still don’t respond or eventually develop resistance to these treatments. This project explores whether a newer class of drugs, called BET bromodomain inhibitors (BBDIs), can improve outcomes when used in combination with existing therapies.

Our lab data show that BBDIs can make chemotherapy and CDK4/6 inhibitors work better, even in resistant tumors, and may also enhance the immune system’s ability to fight cancer. We plan to test these promising combinations in both lab models and clinical trials.

• Aim 1: Test whether combining a BBDI with paclitaxel (a chemotherapy drug) and anti-PD-1 (an immune therapy) improves treatment response in models of metastatic and drug-resistant TNBC. We will look at how the tumor environment changes, including the role of immune cells like B cells and signs of tumor cell aging (senescence). A Phase 1 trial will test this combination in patients, using tumor biopsies to look for immune activity and PD-L1 expression.
• Aim 2: Test the combination of a BBDI with CDK4/6 inhibitors in ER+ breast cancer models that have developed resistance. We’ll also study this in a rat model of ER+ tumors. A Phase 2 clinical trial will assess how well this combination works and how safe it is in patients with ER+/HER2- metastatic breast cancer that no longer responds to hormonal therapy or CDK4/6 inhibitors.

Our goal is to find better combination therapies for advanced breast cancer and identify biomarkers that can help match patients to the treatments most likely to work for them.
 

Combined targeting of DNA repair and macrophage-mediated immunosuppression in BRCA-associated breast cancer 

Project Summary

PARP inhibitors are standard treatment for breast cancers with BRCA mutations. They work by targeting a specific DNA repair weakness in these tumors and can also help activate the immune system. However, studies show that adding immune checkpoint inhibitors (like PD-1/PD-L1 blockers) hasn’t made PARP inhibitors more effective.

Our recent research suggests that this may be because PARP inhibitors also attract immune-suppressing cells called tumor-associated macrophages (TAMs), especially those with a marker called CSF-1R. Blocking CSF-1R reduces these TAMs and makes PARP inhibitors work better, especially when CD8+ T-cells are active. This project will explore this new strategy.

• Aim 1: Study tumor samples from patients with BRCA-associated breast cancer who were treated in clinical trials with PARP inhibitors, alone or in combination with immune therapies. We will use RNA sequencing and advanced imaging (CyCIF) to examine immune cells in the tumor, especially T-cells and TAMs, to understand how they interact and change during treatment.
• Aim 2: Run a Phase 1 clinical trial combining the CSF-1R-blocking drug axatilimab with the PARP inhibitor olaparib in patients with BRCA-related metastatic breast cancer who have not yet received PARP inhibitors or responded well to them. Tumor biopsies will help determine whether the treatment depletes harmful TAMs and improves immune activity.
• Aim 3: Use lab models of BRCA1-deficient breast cancer that have become resistant to PARP inhibitors to test whether adding CSF-1R blockers can overcome resistance. Since resistant tumors often have more TAMs and immune checkpoint activity, we will also test combinations with immune therapies (anti-PD-1 and anti-TIM-3).

Our goal is to understand how the tumor immune environment changes during PARP inhibitor treatment and to develop more effective combination strategies, especially for patients whose tumors are resistant to current therapies.