Abstract CT144: Development of GMI-1359, a novel agent targeting tumor-microenvironment cross-talk in bone metastatic cancer
Authors: Marcom P. Kelly , Price Trevor T. , Murray Andrew S. , Fogler William E. , Magnani John L. , Thackray Helen , Feldman Eric , Sipkins Dorothy 
Published: July 2021

Abstract
Pre-clinical and clinical data suggest that the bone marrow (BM) environment provides breast cancer (BC) cells a protective haven against chemotherapeutic insult, endocrine therapies, and immune recognition. Novel agents that intercept cross-talk between BC cells and the host could therefore improve the depth of response to therapies and potentially increase overall survival in metastatic BC. We have previously shown that bone metastatic BC cells reside in perivascular niches expressing high levels of SDF-1α (CXCL12) and E-selectin, two molecules for which emerging data have demonstrated a significant role in metastatic BC progression. Our prior pre-clinical studies have shown that E-selectin inhibition specifically prevents circulating BC cells from homing to the BM, whereas CXCR4 blockade mobilizes micrometastases from the marrow into circulation, where they may be sensitized to chemotherapeutic cell kill. Given the normal role of these molecules in host immune responses, E-selectin/CXCR4 blockade has additional potential to impact the tumor immune microenvironment.
GMI-1359 is a small molecule, glycomimetic compound with dual inhibitory activity against E-selectin and CXCR4. We hypothesize that GMI-1359 can block E-selectin and CXCR4 binding to E-selectin ligands and SDF-1, disrupting the protective effects of the bone microenvironment on tumor cells. A single-center, phase 1b, open-label, single and multiple ascending dose study (NCT04197999) is therefore evaluating GMI-1359 in patients with HR+ metastatic breast cancer with bony metastases who are stable or minimally progressive on endocrine therapy, with or without a CDK4/6 inhibitor. To date, 2 patients have been enrolled and received single monthly doses of 3.5, 5.0 and 7.0 mg/kg followed by 3 daily doses of 7 mg/kg. Both patients have completed treatment with no dose limiting toxicities observed. Coincident with GMI-1359 administration at all dose levels, we observed mobilization of CD34+ cells coupled with a reduction in elevated serum sE-selectin levels, demonstrating the dual functionality of the compound. Initial peripheral blood immunophenotype data on one patient revealed a redistribution of myeloid derived suppressor cells and a shift in macrophage polarization from M2 to M1. Notably, we observed similar immune alterations in ongoing preclinical studies in the E0771 syngeneic BC mouse model. We found that orthotopically-engrafted mice treated with single agent 1359 had a significant increase in the ratio of CD8/Tregulatory cells isolated from the primary tumor and BM. We also observed a decrease in primary tumor M-MDSCs and lung metastasis-associated macrophages.
In summary, our preliminary clinical data suggest that GMI-1359 is well-tolerated and elicits on-target effects expected from disruption of the host microenvironment. Ongoing clinical and preclinical work will define the efficacy of this strategy to enhance responses to chemo and immune therapies.
Citation Format: P. Kelly Marcom, Trevor T. Price, Andrew S. Murray, William E. Fogler, John L. Magnani, Helen Thackray, Eric Feldman, Dorothy Sipkins. Development of GMI-1359, a novel agent targeting tumor-microenvironment cross-talk in bone metastatic cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr CT144.