Targeting DDR1 Aberrations in Metastatic ER+ Breast Cancer
Abstract
Background and Rationale: Despite the success of endocrine therapies that block estrogen receptor (ER) function in ER+ breast cancer, one-third of women will develop resistance. The causes of endocrine resistance in ER+ breast cancer are poorly understood. To identify the genes that are overexpressed in ER+ breast cancer and are associated with relapse and with poor outcome, we interrogated two independent datasets of ER+ breast cancers and found 20% overexpression of the Discoidin domain receptor (DDR1) strongly correlated with increased risk of metastasis and death. Our proposed work will identify associated molecular factors by using cell lines, animal models, and patient core biopsies. Additionally, we investigated the genes that can be found mutated in breast cancer cells as compared to normal cells, by sequencing over 625 breast tumor DNAs from patients who were treated by standard-of-care hormone therapy. They were followed for over 10 years, and we then identified mutations in the DDR1 gene as the mutations most strongly associated with increased risk of cancer death out of all the genes examined in our study. Our preliminary data thus strongly suggest that DDR1 gene mutations induce resistance to standard-of-care endocrine therapy and increase cell migration, perhaps explaining why mutations in DDR1 were so lethal in our sequenced patient cohort -- almost every patient with a DDR1 mutation had died. There are now no drugs that specifically target the lethal DDR1 aberrations, so our proposed work will also generate novel functional monoclonal antibodies that specifically inhibit the tumor growth of patients harboring DDR1 aberrations. Additionally, we aim to reposition drugs that are in common clinical use in other settings to target downstream DDR1 signaling. Finally, this study will screen relapsed patients who are progressing in spite of endocrine therapy for DDR1 mutations, using a non-invasive circulating tumor DNA (ctDNA) diagnostic approach. Objective and Aims: The objective of this proposed study is to investigate a role for DDR1 aberration (overexpression and mutations) in driving ER+ breast cancer progression, resistance to endocrine therapy, metastasis, and poor patient outcome, and is based on the hypothesis that, by targeting DDR1 overexpression/mutations and the key nodes of the DDR1 adaptive kinome response, we could expect to overcome treatment resistance and metastasis, and thus improve patient disease-specific survival. Who This Project Will Help: The results of this study will primarily help the >30,000 women harboring DDR1 aberrations in their ER+ breast cancers who are resistant to standard-of-care endocrine therapy every year in the US alone. Time to Patient-Related Outcomes: Our proposed work will reposition drugs already in common clinical use to target downstream components of the DDR1 signaling pathway, SRC1 and CDK4/6. Working with long-term collaborator Dr. Ellis, our projected time to patient-related outcomes is short (3 years). Additionally, we are also generating novel monoclonal antibodies directly targeting DDR1 itself, and our long-term goal for this aspect is to generate humanized DDR1 monoclonal antibodies. Translating these antibodies into the clinic will take a longer time (10 years). Impact on Ending Breast Cancer: At even a conservative estimate based on analysis of multiple clinical trial datasets, 20% of ER+ breast cancers have aberrant DDR1 overexpression and 1%-2% of clinical breast cancers carry DDR1 mutations. Therefore, we expect about 35,000 endocrine therapy resistant breast cancer patients every year to be responsive to drugs targeting DDR1, so that the results of this study could save the lives of as many as 175,000 women over 5 years in the US alone by preventing resistance and personalizing treatment strategies.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Oct 29, 2018
- Source ID
- W81XWH1810040
Entities
People
- Meghashyam Kavuri
Organizations
- Baylor College of Medicine
- United States Army