Myelodysplastic syndromes (MDS) are a collection of clonal diseases of dysfunctional hematopoietic stem cells, characterized by ineffective hematopoiesis, cytopenias, and dysplasia. Limited conventional treatment options exist for these patients, with hypomethylating agents remaining the standard of care for higher-risk MDS patients.
Publication
Molecular pathophysiology of the myelodysplastic syndromes: insights for targeted therapy
The clinical heterogeneity of the myelodysplastic syndromes (MDSs) relates to the recently discerned panoply of molecular abnormalities extant within this disease spectrum. Despite increasing recognition of these biologic abnormalities, very limited therapeutic options exist to exploit our increasing understanding of the molecular pathophysiology of MDS.
Publication
Ex Vivo Drug Sensitivity Profiling In Myelodysplastic Syndrome (MDS) Patients Defines Novel Drug Sensitivity Patterns For Predicting Clinical Therapeutic Outcomes
We performed drug sensitivity profiling on 60 patient samples in both newly diagnosed and treatment-refractory myeloid neoplasms (46 MDS, 4 CMML, 10 AML). Fresh bone marrow aspirates and/or peripheral blood specimens were RBC-lysed and re-suspended in serum-free media with cytokines.
Publication
A Feasibility Study of Biologically Focused Therapy for Myelodysplastic Syndrome Patients Refractory to Hypomethylating Agents
We performed a prospective feasibility study in 21 patients with HMA-refractory MDS enrolled at Stanford University from April 2018 through March 2019. All patients had a baseline bone marrow (BM) biopsy with BM aspirate and peripheral blood (PB) samples sent for mutation testing (596-gene panel, Tempus, Chicago, IL) and ex vivo DSS (Notable Labs, Foster City, CA).
Publication
Comprehensive Transcriptome Profiling of Cryptic CBFA2T3-GLIS2 Fusion-Positive AML Defines Novel Therapeutic Options – a COG and Target Pediatric AML Study
A cryptic inv(16)(p13.3q24.3) encoding the CBFA2T3-GLIS2 fusion is associated with poor outcome in infants with acute megakaryocytic leukemia. We aimed to broaden our understanding of the pathogenesis of this fusion through transcriptome profiling. Experimental Design: Available RNA from children and young adults with de novo AML (N=1,049) underwent transcriptome sequencing (mRNA and miRNA).
Scientific Poster
SY-1425, A Potent and Selective RARA Agonist, Reprograms AML Cells for Differentiation Along Distinct Lineages Uncovering PD Markers for Clinical Studies
A subgroup of the patient samples was defined by an SE driving RARA, which co-occurred with SEs driving FOS and JUNB, or IRF8. FOS and JUNB form the AP-1 heterodimeric TF known to promote an immature cell state and the interferon regulatory factor 8 (IRF8) pathway has been implicated in AML pathogenesis.
Scientific Poster
Pharmacodynamic and pharmacokinetic evaluation of SY-1425 (tamibarotene) in biomarker-selected acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) patients
SY-1425 (tamibarotene) is an oral, potent and selective synthetic RARα agonist previously approved for the treatment of relapsed/refractory acute promyelocytic leukemia (APL) in Japan. Given preclinical evidence of SY-1425 sensitive AML cell lines and patient samples with RARA pathway activation defined by elevated RARA or IRF8, SY-1425 is being...
Scientific Poster
RARA Pathway Activation Biomarkers in Study SY-1425-201 Define a New Subset of AML and MDS Patients and Correlate with Myeloid Differentiation Following Ex Vivo SY 1425 Treatment
We developed an epigenetic approach to profile the gene regulatory landscape of primary AML/MDS patient samples. A novel patient subset defined by RARA pathway activation was identified by super-enhancers (SEs) at the RARA and IRF8 gene loci.
Scientific Poster
Early Results from a Biomarker-Directed Phase 2 Trial of SY-1425 in Acute Myeloid Leukemia (AML) and Myelodysplastic Syndrome (MDS) Demonstrate DHRS3 Induction and Myeloid Differentiation Following SY-1425 Treatment
Bone marrow biopsies (H&E) at 40x from screening (A) and C3D1 (B). Bone marrow aspirate (WG stain) at 100x from screening (C) and C3D1 (D). (A) Blasts (black arrows) occur in many small groups. Maturing myeloid cells (yellow arrows), erythroid precursors (red arrows) and megakaryocytes (blue arrows) are also present.
Scientific Poster
Successful Treatment with Bortezomib, Panobinostat, and Dexamethasone of Acute Myeloid Leukemia (AML) in 2nd Relapse After Allogeneic Stem Cell Transplantation (SCT): Therapy Selected Based Upon Results of a Personalized Flow Cytometric Screen for Drug
Notable Labs uses a flow cytometric-based assay to test a panel of FDA-approved chemotherapy and targeted agents—singly and in combinations using a custom robotic platform—to determine anti-cancer effect against individual patient’s tumor cells.