Our data in this mouse CKD model add new insights to the role of hepcidin in the development of CKD anemia over time. Furthermore, the results are promising and support further mechanistic and clinical studies to elucidate the therapeutic role for sevuparin as a treatment in anemia of inflammatory and/or chronic diseases in monotherapy or in combination with EPO and to explore its role in kidney protection.

No abstract available

No abstract available

The year 2017 marks a cornerstone in the treatment landscape of AML with the approval of midostaurin in the United States for newly diagnosed fit adults with FLT3 mutated AML. Subsequently, the therapeutic armamentarium of AML considerably expanded with the approval of enasidenib, ivosidenib, gilteritinib, and venetoclax in combination with hypomethylating agents and others...As a result, AML therapy is constantly evolving and so are the escape mechanisms leading to disease relapse. Therefore, it is of paramount importance to sequentially evaluate the patient during the course of AML treatment and intervene at the right time.

P2, N=51, Completed, Washington University School of Medicine | Active, not recruiting --> Completed

Preliminary results from this Phase I study reveals a tolerable safety profile of UPRO with AZA/VEN in pts with untreated AML ineligible for IC. No DLTs were observed, and the most common Grade 3-4 AE and SAE were hematologic. The combination shows promising preliminary efficacy, including a 50% rate of MRD-ve CR/CRi.

The combination produced an ORR of 62% in a high-risk, refractory population whose prognosis is very dismal. The relationship of E-selectin ligand expression, response to treatment, and outcomes is being analyzed.

P2, N=51, Active, not recruiting, Washington University School of Medicine | Recruiting --> Active, not recruiting

P1/2, N=28, Recruiting, John Horan, MD | Not yet recruiting --> Recruiting

P1/2, N=28, Not yet recruiting, John Horan, MD

P1, N=18, Suspended, National Cancer Institute (NCI) | Recruiting --> Suspended

P1, N=18, Recruiting, National Cancer Institute (NCI) | Not yet recruiting --> Recruiting | N=51 --> 18 | Trial completion date: Nov 2025 --> Nov 2024

P1b, N=4, Terminated, GlycoMimetics Incorporated | Trial completion date: Mar 2022 --> Aug 2021 | Recruiting --> Terminated | Trial primary completion date: Dec 2021 --> Aug 2021; After demonstrating the on target effect of GMI-1359 via pharmacodynamic markers (CXCR4 and E-selectin), Sponsor terminated the trial due to COVID-related slow enrollment.

P1, N=51, Not yet recruiting, Children's Oncology Group

P3, N=140, Recruiting, Apollomics Inc. | Not yet recruiting --> Recruiting

P2, N=50, Recruiting, Washington University School of Medicine | Trial completion date: Jun 2022 --> Dec 2022 | Trial primary completion date: Jun 2022 --> Dec 2022

We previously demonstrated (Chang et al., ASH 2020) that E-selectin blockade by the pharmacological antagonist, GMI-1271 (uproleselan; GlycoMimetics, Inc) sensitized therapy-resistant LSC to Bcl-2 targeted therapy...Hence, we hypothesized that co-targeting E-selectin/CXCR4 more efficiently mobilizes AML cells from BM niches and synergizes with the anti-leukemia activity of venetoclax/hypomethylating agent (Ven/HMA)...We also observed upregulated pro-survival signaling pathways such as phosphorylation of AKT-MAPK-ERK along with increased Bcl-xL, Bcl-2, and Idu expression in MSC from the GMI-1359 + Ven/HMA treated PDX mice compared to Ven/HMA single treatment cohorts. Collectively, our results provide strong evidence that co-targeting E-selectin/CXCR4 with GMI-1359 profoundly reduces BM retention of LSC as well as protects BM niche component cells from apoptosis induced by targeted therapy, resulting in improving the anti-leukemia activity of Ven/HMA therapy in AML.

Unexpectedly, 72-h suppression of MEK/ERK signaling with selumetinib or pimasertib also upregulated CXCR4 in MOLM14 cells. No effects in this regard were observed by suppressing AKT/mTOR or Stat5 with AZD8055 or STAT5-IN-1, respectively. Additionally, in Dox-inducible NRAS (G12D)-mutated MOLM13 AML cells which also harbor FLT3 ITD mutations, ERK activation by doxycycline downregulated CXCR4 levels implying the MEK/ERK signaling pathway was associated with the suppression of CXCR4. Furthermore, under BM microenvironment-mimicking, co-culture using human MSCs/ECs and MOLM14 cells, blockade of CXCR4 and/or E-selectin signaling using the CXCR4 antagonist plerixafor, the E-selectin antagonist GMI-1271, or the CXCR4 and E-selectin dual inhibitor GMI-1359 showed that GMI-1359 markedly abrogated BM protection and sensitized MOLM14 cells to quizartinib-induced apoptosis. We further validated the effect of GMI-1359 in a PDX model of AML which were from a patient who relapsed from sorafenib+E6201+DAC in clinic and showed resistant to quizartinib ex vivo...GMI-1359 sensitized AML cells to quizartinib-induced apoptosis in vitro and statistically significantly extended AML PDX mouse survival in vivo . These findings provide a pre-clinical rational for using GMI-1359 to prevent or overcome FLT3i resistance when treating FLT3-mutant AML patients.

P3, N=140, Not yet recruiting, Apollomics Inc.

A phase 1/2 study (NCT02306291) evaluated the safety, tolerability, and anti-leukemic activity of uproleselan (5-20 mg/kg) with MEC (mitoxantrone, etoposide, cytarabine) among patients with relapsed/refractory (R/R) acute myeloid leukemia (AML)...In a separate cohort, 25 newly diagnosed patients aged ≥60 years received uproleselan at the RP2D plus cytarabine and idarubicin (7+3)...In the R/R cohort, E‑selectin expression above 10% was associated with a higher response rate and improved survival. The addition of uproleselan to chemotherapy was well tolerated with high remission rates, low-induction mortality, and low rates of mucositis, providing strong rationale for phase 3 randomized confirmatory studies.

P1, N=12, Recruiting, Apollomics Inc. | Trial completion date: Dec 2021 --> Feb 2023 | Trial primary completion date: Aug 2021 --> Dec 2022

In addition, expression of CD44 in CD15sCSC and CD15sCSC was determined. Compound 1 significantly decreased the percentage of CD15sCSC, CD15sCD44CD24, and CD15sCD44 subpopulations, as well as the expression of CD15s in CD44CD24 and CD44 cells, and therefore shows potential as a treatment for TNBC.

Furthermore, the cell surface localization of P-selectin and the subsequent production of other critical cell adhesion molecules (such as E-selectin, ICAM-1 and VCAM-1) that recruit immune cells required endothelial TLR2. Our findings demonstrate that endothelial cells actively contribute to innate immune pathways and propose that endothelial TLR2 has a pathological role in proinflammatory conditions.

P2, N=50, Recruiting, Washington University School of Medicine | Not yet recruiting --> Recruiting

CircRSF1 regulated ox-LDL-induced vascular endothelial cell proliferation, apoptosis and inflammation through modulating miR-135b-5p/HDAC1 axis in AS, providing new perspectives and methods for the treatment and diagnosis of AS.

Thus, these proteins are candidates as drivers for sustaining the tumorigenic process. More studies with small-molecule inhibitors or silencing RNAs are fully justified and need to be undertaken to better evaluate the cancer-driving role of the targets herewith identified.

P1b, N=6, Recruiting, GlycoMimetics Incorporated | Trial completion date: Aug 2020 --> Mar 2022 | Trial primary completion date: Aug 2020 --> Dec 2021

Most importantly, our data revealed that cimetidine, an E-selectin inhibitor, was able to block cell adhesion, extravasation, and metastasis formation in ESDN-null mice, underlying a major role of ESDN in E-selectin transcription upregulation, which according to our data may presumably be linked to STAT3. Based on our results, we propose a protective role for ESDN during the spread of melanoma and reveal its therapeutic potential.

P1, N=12, Recruiting, Apollomics Inc.

GMI-1070 (rivipansel) was designed to inhibit E, P, and L-selectins by incorporating a mimic of sialyl Lex together with that of the tri-sulfated domain of PSGL-1...In animal models of VOC, GMI-1687 blocked occlusion and normalized blood flow at 0.04 mg/kg BID...Based on positive phase 2 data, the FDA granted uproleselan “Breakthrough Therapy Designation”...Animal models of bone metastasis treated with GMI-1359 and chemotherapy show reduction of tumor volume and significant improvement in survival. GMI-1359 is now being studied in breast cancer patients at Duke University.

Expression of E-selectin•IgM-binding functional E-selectin ligand carbohydrates can serve as a reliable and potentially superior prognostic biomarker of patients with ccRCC.

Taken together, xanthorrhizol inhibits VEGF-induced angiogenesis of endothelial cells by blocking the activation of the PI3K/Akt/eNOS axis and subsequent upregulation of adhesion molecules induced by the transcriptional activation of NF-[Formula: see text]B. Xanthorrhizol is a promising anti-angiogenic agent and can serve as a beneficial agent to enhance anticancer treatments.

We report that cell-autonomous sialofucosylation (sLeX display) steadily increases in culture- and in vivo-expanded CAR T cells, and that, the cytokines used during T-cell activation influence both the degree of such endogenous sialofucosylation and the CD19-CAR T-cell efficacy and persistence in vivo. However, glycoengineered enforced sialofucosylation of E-selectin ligands was dispensable for CD19-CAR T-cell activity and BM homing in multiple xenograft models regardless the cytokines employed for T-cell expansion, thus, representing a dispensable strategy for CD19-CAR T-cell therapy.

Moreover, polyphenols were detected at the intracellular level or membrane-bound to cells, with evidence for breast cancer resistance protein (BCRP) efflux transporter role. Altogether, these findings emphasize the ability of polyphenols to protect cerebral endothelial cells in hyperglycemic condition and their relevance for pharmacological strategies aiming to limit cerebrovascular disorders in diabetes.

No significant association between the BHI and any of the endothelial markers was found in the control group, while in the hepatitis group, the scatter plot of ICAM-1 vs BHI suggested that the association might be present. In conclusion, the results of this study confirm an association between a chronic HCV infection and altered cerebrovascular reactivity as well as higher levels of markers of endothelial activation (ICAM-1, VCAM-1) as possible indicators of an increased CVD risk.

The dual-functionalized cells resulted in the efficient suppression of B lymphoma in a xenograft model. Our results suggest that nature killer cells modified with glycan ligands to CD22 and selectins promote both targeted killing of B lymphoma cells and improved trafficking to sites where the cancer cells reside, respectively.

Embelin accelerates TIL infiltration and the antitumor immune response by recovering VCAM-1 expression in TECs. Our strategy may be a therapeutic approach for accelerating the immunotherapeutic response in immune-quiescent tumors, leading to clinical trials' success.

Up-regulation of adhesion molecules, but not HGF/c-Met signaling, may contribute to the lung metastasis enhanced by local infection/inflammation.

To delineate the mechanism of E-sel at the onset of drug mediated changes in AML signaling signatures, we employed another PDX model (Flt3-ITD and WT1 mutations, sorafenib-resistant). Other oncogenic signaling pathways including MAPK, p-S6, and STAT3, were all inhibited by the addition of GMI-1271 to Ven/HMA. Collectively, our results provide first evidence that an E-sel targeting strategy with GMI-1271 can overcome microenvironmental resistance to Ven/HMA-based therapy in AML by cancer cell autonomous and non-cell autonomous mechanisms in the BM vascular niche.

Changes in levels of selected CAFs were associated with response/resistance to pazopanib in mRCC patients.