Targeting signal transduction in hematologic malignancies:
Cytokines play important roles in the regulation of normal hematopoiesis and a balance between the actions of hematopoietic growth factors and myelosuppressive factors is required for optimal production of different hematopoietic cell lineages. The myelodysplastic syndromes (MDS) are collections of heterogeneous hematologic diseases characterized by refractory cytopenias due to ineffective hematopoiesis. These preleukemic disorders are common causes of anemia in the elderly and are rapidly increasing in incidence. We have also demonstrated that the TGF-beta superfamily/smad, IRAK and MAP kinase pathways is overactivated in MDS. Our work has led to clinical trials with Luspatercept, Galunisertib, CA4948, ARRY-614 and various other promising agents in MDS. We are trying to study the molecular mechanisms that lead to the activation of these pathways in MDS and are using small molecule inhibitors in mouse models to target these pathways.
Targeting aberrant stem and progenitor cells in myelodysplastic neoplasms:
We have demonstrated that aberrant stem cells persist during morphological remissions and are involved in relapse. We have identified novel targets against MDS/AML stem cells that are being tested in various studies. We are also conducting sequencing/epigenetic analysis of highly purified human stem cells and evaluating the role of these alterations in transformation of MDS to AML.
Epigenomic analysis of tumors:
We are using high throughput assays to analyze DNA methylation across the genome and have optimized these assays to work with low amounts of DNA. We have successfully used these assays in conducting an integrative analysis of epigenetic and genetic alterations in various tumor models, including MDS, esophageal cancer, pancreatic cancer and renal cell cancer.
Clinical studies in Myelodysplastic syndromes:
We have a “center of excellence” clinic for patients with Myelodysplatic syndromes. We offer a variety of clinical trials for these patients (www.mdstreatment.com).