Highlighted Publications

  • A Phase 1 Dose Escalation Study of the Pyruvate Kinase Activator Mitapivat (AG-348) in Sickle Cell Disease. In this Phase 1 single-center, open-label study of the novel red-cell pyruvate kinase (PKR) activator mitapivat (AG-348) for the treatment of sickle cell disease (SCD), led by Dr. Julia Xu and published in the journal Blood, the team evaluated the safety, tolerability, pharmacokinetics, and pharmacodynamics of multiple ascending doses of mitapivat in 17 adults with HbSS disease. The study found that mivapivat was overall safe and well tolerated, with no drug discontinuations for treatment-related adverse events. Of the 16 subjects completing at least 3 ascending dose levels of mitapivat, 9/16 (56.3%) subjects achieved a hemoglobin response of ≥ 1 g/dL increase compared to baseline. Mean reductions in hemolytic markers and dose-dependent decreases in mean 2,3-DPG and increases in mean ATP levels were observed, in line with mitapivat’s mechanism of action. This study provides proof of concept that mitapivat has disease-modifying potential in patients with SCD. (Xu JZ, …, Thein SL. Blood. 2022 Nov 10;140(19):2053-2062. PMID: 35576529.)
  • Hematopoietic stem cell regeneration through paracrine regulation of the Wnt5a/Prox1 signaling axisA recent publication in the Journal of Clinical Investigation from Dr Wei Du’s lab investigates the crosstalk between the bone marrow (BM) niche and hematopoietic stem cells (HSCs) in HSC regeneration. Dr. Du’s team identified a paracrine Wnt5a/Prox1 Signaling axis as a regulator of HSCs regeneration under conditions of injury and aging, therefore suggesting a potential target for improving HSC function under stressed conditions. (Lin Q, Wu L, Chatla S, Chowdhury FA, Atale N, Joseph J, Du W. J Clin Invest. 2022 Jun 15;132(12):e155914. PMID: 35703178)
  • Differential responses to immune checkpoint inhibitor dictated by pre-existing differential immune profiles in squamous cell carcinomas caused by same initial oncogenic drivers. New Research published in the Journal of Experimental & Clinical Cancer Research from Dr. Jing Hong Wang‘s lab has uncovered tumor-intrinsic differences between two SCC tumor lines (TAb2 and TCh3), both of which harbor TP53 deletion and PIK3CA hyperactivation, and their differential response to anti-PD-L1 therapy. The study demonstrates that stratifying cancers according to their genetic alterations alone is not sufficient in determining immune checkpoint inhibitor (ICI) efficacy. In addition, the findings suggest that evaluating HNSCC tumor-intrinsic cues along with immune profiles in the TME may help better predict ICI responses in individual hosts. The experimental models used may provide a platform for pinpointing tumor-intrinsic differences underlying an immunosuppressive TME in HNSCCs and for testing combined immunotherapies targeting either tumor-specific or TAM-specific players to improve ICI efficacy. These findings may be translatable to individual HNSCC patients with unique TMEs (e.g., higher expression of CSF1/VEGF-C), and determine if these multi-factorial profiles will help identify patients who may benefit from ICI therapy or other personalized therapies. (Chen SMY, …. , Wang JH. J Exp Clin Cancer Res. 2022 Apr 2;41(1):123. PMID: 35366939)

NIH Funding

Scientific Presentations

  • Dr. Dawar Diwakar will present the following talks at the upcoming SITC meeting in Boston: “Neoadjuvant nivo/vidu in high-risk resectable melanoma” and “Phase I study of TLR7/8 agonist TC TLR 7/8 in advanced solid tumors.”