Targeting the GRM/MAPK1/ESRRG Axis in Endocrine-Resistant Invasive Lobular Carcinoma of the Breast
Abstract
Molecular classification of breast cancer has changed clinical practice, allowing women to be treated with therapies that work best for their particular form of breast cancer. However, one area in which we have lagged unacceptably behind is in recognizing that histological differences in breast cancer also have a profound effect on tumor behavior and response to therapy. Invasive lobular breast cancer (ILC) is the second most common type of breast cancer (affecting 10%-15% of women diagnosed each year) and has unique clinical features that distinguish it from the more common invasive ductal breast cancer (IDC). It forms a long, thin mass that is frequently missed by screening mammograms, is more often found in both breasts, and metastatic ILC tends to spread to different sites than IDC (e.g., peritoneum, gastrointestinal tract, orbital cavity). The vast majority of ILC is molecularly classified as Luminal A -- estrogen receptor positive and slow growing -- for which endocrine therapy with Tamoxifen, Fulvestrant, or an aromatase inhibitor is recommended. Because estrogen receptor-positive breast cancers like ILC are managed by endocrine therapy long term (>10 years), it is essential to treat this breast cancer subtype with therapies that properly balance efficacy and quality of life while taking into account its unique biology. However, today most women with ILC are treated no differently than those with the more common IDC. This needs to change, since multiple studies now show that women with ILC have significantly worse response to multiple endocrine therapies than those with IDC. Our proposal will specifically address the needs of women with recurrent, endocrine-resistant ILC by testing whether we can target a signaling network that our data show is more commonly activated in these tumors. This signaling network links cell surface proteins, metabotropic glutamate receptors (GRMs), to estrogen-related receptor gamma (ESRRG) -- which we already established can drive Tamoxifen resistance in ILC -- through mitogen activated protein kinase (MAPK). Our new preliminary data show that two existing drugs -- Tosedostat and Riluzole -- are strong candidates to be repurposed for treating endocrine resistant ILC with activation of this GRM/MAPK/ESRRG signaling network. Tosedostat is an aminopeptidase inhibitor that has shown success in clinical trials for myelodysplastic syndromes and certain leukemias, and it has been well tolerated by elderly patients for whom harsh chemotherapy regimens would have too many dose-limiting toxicities. Riluzole is a glutamate release inhibitor that is Food and Drug Administration-approved for long-term use to slow disease progression in patients with amyotrophic lateral sclerosis (ALS), a devastating neurodegenerative disorder. Riluzole is also being tested in a clinical trial of breast cancer survivors to determine whether it can improve cognitive function and reduce fatigue. We are excited by the potential for Riluzole, in particular, to have both anti-cancer activity and quality-of-life improvement for women with ILC. The specific aims of our proposal will identify the best combinations of Riluzole or Tosedostat with specific endocrine therapies in laboratory and small animal models of ILC and establish what percentage of ILC patients may benefit from these approaches. By keeping our focus on what we can do to help women with ILC in the near future, our proposal efficiently addresses two Fiscal Year 2016 Breast Cancer Research Program Overarching Challenges: identify what drives breast cancer growth and determine how to stop it (addressing a major unmet need for women with endocrine resistant ILC); and revolutionizing treatment regimens by replacing interventions that have life-threatening toxicities with ones that are safe and effective (Riluzole or Tosedostat in combination with the right endocrine therapy). We have a strong, integrated team that brings together expertise in ILC-
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Oct 29, 2018
- Source ID
- W81XWH1710615
Entities
People
- Rebecca B Riggins
Organizations
- Georgetown University
- United States Army