Alan C. Sartorelli, Ph.D.
Yale University School of Medicine
New Haven, Connecticut
"The role of trascription factor Scl in leukemia cell resistance to all trans-retinoic acid induced differentiation"
Background:
Cellular differentiation refers to the process by which new cells obtain their individual structural and functional identity. When differentiation ends prematurely, the development of many critical cellular processes, such as cell cycle arrest, are left incomplete. Cell cycle arrest is a type of breaking mechanism and the lack of such activities result in uncontrolled proliferation of defective cells, leading to cancer.
In the late 1980s, NFCR supported scientist, Dr. Leo Sachs at Weitzmann Institute, Israel , was the very first to demonstrate the reversibility of tumor cells. His pioneering research showed that it is possible to make a cancer cell healthy again by treating them with cellular differentiation agent, molecules that induce a cell to complete its differentiation process. His groundbreaking basic cancer research has since then progressed into a brand new field of curative cancer treatment that is known today as the differentiation therapy.
Project Director and Research:
As a professor of the pharmacology department in the School of Medicine at Yale University, Dr. Alan Sartorelli is currently investigating different approaches to overcome drug resistance against all-trans retinoic acid (ATRA). ATRA, a differentiation agent and a derivative of vitamin A, is generally used in combination with chemotherapy, bringing complete remissions to patients with acute promyelocytic leukemia (APL). Although extremely effective, drug resistance often develops quickly and the therapeutic impact of this treatment is usually short lived.
Many different proteins are associated with cellular replication. One such protein is Scl, a protein associated with cellular replication, is present in an abnormal amount in patients with stem cell leukemia and acute lymphoblastic leukemia. It has been demonstrated in vitro that Scl has the capability to render ATRA susceptible leukemia cells resistant. It was also found that APL patients expressing Scl had lower rates of complete remission and overall poorer prognosis than patients whose leukemic cells did not express Scl. Thus the hypothesis that Scl plays a critical role in rendering ATRA inactive was formed.
As one of his research objectives for next year, Dr. Sartorelli plans to access the mechanism of action of Scl in leukemia. He also plans to combine lithium chloride (LiCl) a chemical that can disrupt Scl activity, with ATRA to maximize the therapeutic value of this novel differentiation therapy agent.
Impact on Cancer Prevention, Treatment, or Cure:
The introduction of differentiation therapy as a new therapeutic method has been an important advance in the treatment of cancer. As a differentiation drug, ATRA has proven to be extremely effective. Unfortunately, incomplete terminal differentiation and rapid development of ATRA resistance are factors that contribute to the short remission duration for APL patients. The determination of the mode of action of Scl combined with the synergistic effects of LiCl has the potential to negate these factors and offer APL patients a more effective method of treatment.