Repurposing Antiestrogens to Prime the Immune System for Breast Cancer Immunotherapy
Abstract
Rationale, Objective, Aims, and Ultimate Applicability: Endocrine therapies that target estrogen receptor (ER) in breast cancer (BC) are successfully used to treat ER-positive (ER+) tumors and are an effective targeted treatment for metastatic ER+ BC. However, substantial numbers of patients with localized disease, and almost all patients with metastatic BC, become resistant to endocrine therapies. In the absence of options to current treatments such as tamoxifen or aromatase inhibitors, cytotoxic chemotherapy is often the only alternative. Similarly, chemotherapies are often used for patients with triple-negative breast cancer (TNBC). The TNBC subtype occurs in 15%-20% of BC patients and can’t be managed with endocrine or HER2-targeted therapies as TNBCs lack ER, PR, and HER2 overexpression. However, recent trials reveal that 20%-30% of TNBC patients respond to immunotherapy (IMT) such as immune checkpoint inhibitors (ICI). Despite this advance, the majority of patients with TNBC and other BC subtypes do not benefit from IMT. Many cancers express signaling molecules (“checkpoints”) that act as a “shield” to stop recognition and killing by the natural immune system. In this context, it is important to note that estrogen does not only act directly on BC cells – estrogen also regulates many immune cells that express ER. Notably, sex hormone-induced immune cells termed “myeloid-derived suppressor cells” (MDSCs) are proposed to support maternal-fetal immune tolerance by blocking certain maternal immune functions in pregnancy. Emerging data from our laboratory show that MDSCs similarly inhibit the adaptive immune response in BCs by blocking activity of specialized immune cells (T-cells) that would normally recognize and eliminate BC cells. These MDSC-mediated actions allow BCs to escape immune attack and also interfere with antitumor activity of ICIs. We propose that BC escape from immune attack can be blocked by powerful antiestrogens that exert antitumor activity particularly when used together with ICIs. Of note, a large difference in responses to IMT between males and females is reported, with ICIs showing more benefit for men with advanced cancers than for women. Despite known sex-related differences in immune responses in some autoimmune diseases, little is known about effects of sex hormones or antiestrogens on immune cell functions in BC. Depending on results of this work, use of antiestrogens with ICIs could lead to timely use of endocrine therapies in both ER+ and potentially ER-negative or treatment-resistant BCs, thus expanding application of these drugs in the clinic and promoting patient survival. Overarching Challenges: The proposed research project will address the following overarching challenges: (1) Revolutionize treatment regimens by replacing them with ones that are more effective, less toxic, and improve patient survival. (2) Eliminate the mortality associated with metastatic breast cancer. What types of patients will it help and how will it help them? Development of treatment resistance is one reason that BC is the second most frequent cause of cancer death in women. We aim to devise a translational strategy to address challenges of endocrine resistance. We have developed a new antiestrogen that enables downregulation of ER (termed “SERDs”) and stops BC progression. SERD fulvestrant was the first drug in this class of antiestrogens, and it has significant clinical benefit; yet optimal antitumor effects of fulvestrant are limited by its poor bioavailability. Our new, more bioavailable SERD is designed to target endocrine-sensitive and -resistant BCs. Further, SERDs stop BC indirectly by inhibiting tumor-associated cells with immune suppressive activity, thus allowing BCs to escape immune surveillance. Research on such antiestrogens can lead to timely trials of dual therapy with ICIs to overcome treatment resistance and improve the survival of greater numbers of BC patients. W
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Nov 19, 2019
- Source ID
- W81XWH1910814
Entities
People
- Richard Pietras
Organizations
- United States Army
- University of California, Los Angeles