Understanding the role of SAMHD1 in response to immune checkpoint inhibition in triple negative breast cancer
Active Project Grant Awarded Last action
- Award ID
- F31CA301888
- Recipient
-
Emory University UEI S352L5PJLMP8
- Awarding agency
-
National Cancer Institute
National Institutes of Health, Department of Health and Human Services
- Obligated
- $50,114
Award facts
- Assistance listing
- 93.398 Cancer Research Manpower
- Completion date 0% complete
- Place of performance
- Atlanta, GA 30322, USA
Award details come from USAspending.gov.
Description
- Abstract
- Triple negative breast cancer (TNBC) is an aggressive breast cancer subtype with the inability to respond to more conventional therapies, and a five-year survival rate of only 10% once metastasized. The addition of the immune checkpoint inhibitor (ICI), pembrolizumab, to standard-of-care treatment for TNBC has shown great promise for improving patient outcomes. However, >35-50%, of patients still fail to respond to combination chemotherapy and ICI treatment with poor outcomes. Thus, there is an urgent need to understand the mechanisms that underly ICI response to improve survival outcomes of TNBC patients. Sterile alpha motif (SAM) and histidine-aspartic acid (HD) domain containing-protein 1 (SAMHD1) is an enzyme known to be dysregulated in many cancers, including overexpressed in up to 27% of breast cancers, which we have shown to be specific to TNBC and significantly lower survival. SAMHD1 is most known for preventing the induction of type-I IFN (IFN- I) during HIV-1 replication and when mutated, causing the autoimmune disease associated with chronic IFN, aicardi goutières syndrome. However, our team has discovered an additional function for SAMHD1 in facilitating DNA repair in cancer by stimulating MRE11 exonuclease activity. Not only could this role help promote resistance to DNA break inducing chemotherapeutics used in the treatment of TNBC, but IT may also act to impede important immune-stimulating inflammation by preventing the accumulation of cytosolic DNA that would otherwise activate the cyclic GMP-AMP synthase (CGAS)-stimulator of interferon genes (STING) pathway of IFN-I expression, important for the anti-tumor immune response. Therefore, we hypothesize that SAMHD1 is a key regulator of anti-tumor immunity in TNBC, and that inhibition of SAMHD1 will enhance response to ICI treatment through increased IFN-I signaling, stimulation and infiltration of ICI responsive immune cells that will fuel the anti-cancer immune response. To investigate this, we first plan to define the relationship between SAMHD1 expression, IFN- I, and response to combination chemotherapy and ICI treatment in TNBC cell lines and patient samples using elisa and spatial transcriptomics. Following this, we plan to establish proof of concept that targeting SAMHD1 in vivo sensitizes resistant TNBC tumors to ICI treatment using an innovative bioengineered murine model of TNBC and a novel therapeutic treatment method to target SAMHD1. This project will be done with the goal of ultimately assessing the efficacy of this novel combination treatment method in the form of a clinical trial, with the hopes of one day greatly improving outcomes for patients burdened with TNBC.
Quick answers
Who received award F31CA301888?
F31CA301888 was awarded to Emory University by National Cancer Institute (National Institutes of Health) on December 1, 2026.
How much is award F31CA301888 worth?
$50,114 has been obligated on F31CA301888.
On GovTribe
See this award's full record
- Every transaction and subaward
- The recipient's other awards and teaming partners
- Similar grant awards
- Ask GovTribe AI about this award