Zeev Estrov, M.D. University of Texas MD Anderson Cancer Center

For the last 30 years, I have concentrated my efforts on studying hematopoietic stem and progenitor cells and their leukemic counterparts. My colleagues and I have used both cellular and molecular techniques to investigate the response of these cells to cytokines and growth factors, and explored the roles of signal transduction pathways and transcription factors in stimulating these cells and protecting them from apoptosis. One of my main interests has been finding better means for treatment of patients with chronic lymphocytic leukemia (CLL).

CLL is the most common leukemia among adults in the United States and Western Europe. CLL is a remarkably diverse neoplasm. In some patients, the disease is indolent and may never require treatment. In others the disease progresses rapidly and is fatal. We found that regardless of clinical characteristics or disease stage, in all patients with CLL signal transducer and activator of transcription (STAT) 1 and STAT-3 are constitutively phosphorylated on serine residues 727 in blood and marrow leukemic cells. Furthermore, we determined that inhibition of serine phosphorylated STAT-3 induces apoptosis of CLL cells. Traditionally, therapeutic interventions were aimed at palliation. Treatment of aggressive CLL yielded poor results.

In recent years, effective therapies such as combined antibody-chemotherapy and hematopoietic stem cell transplantation have been developed. In spite of significant improvements in clinical management only a few patients are cured, treatment-related complications are common, and patients with an aggressive course rapidly succumb to the disease. Targeting the molecular abnormality that is crucial for the survival of CLL cells provides a new direction of specific anti-CLL targeted therapy. While we are currently testing this concept in the clinic by treating CLL patients with a non-specific STAT-3 inhibitor (5-azacytidine), we intend to identify the molecular abnormality that induces STAT-3 activation in CLL cells and develop novel STAT-3 inhibitors for the future treatment of patients with CLL. Using laboratory observation to benefit our patients has been my lifelong goal. The current project I am working on explores the pathophysiology of CLL and will potentially provide new means for the treatment of CLL.