Targeting the Rac GTPase Pathway to Sabotage RAS Signaling in RAS-mutated Leukemia
The development of novel targeted therapies for cancer is a crucial priority in the field of oncology. This is particularly true for some types of leukemias that are characterized by a high risk of relapse and poor response to conventional therapies. For these diseases, it is imperative to identify and act on the essential signals that drive the malignant transformation and the survival of cancer cells.
Our laboratory, directed by Dr. David Williams, has previously identified Rac (a protein that controls many cellular functions including cell growth and survival) as a promising therapeutic target in refractory leukemias. Our group has extensive expertise and a long-standing interest in the biology of this protein. In recent years, the Williams Lab has partnered with Evotec AG, a drug discovery company based in Germany, to use novel platforms and techniques to identify and develop new inhibitors of Rac. The endpoint of this partnership is to obtain a drug that can be used in a clinical setting for high-risk leukemias and that can improve the prognosis of these aggressive diseases. We have identified a small chemical compound that acts on Rac protein activity and has a good antileukemic action on resistant leukemia cells, in a laboratory setting. Further characterization of this compound could pave the way for new targeted therapy approaches and sustain the preclinical and clinical development of selected compounds already identified by our laboratory for the treatment of aggressive leukemias.
Our main compound DW0254 indirectly inhibits the activation of Rac protein through binding to another protein called PDE6D and shows very promising antileukemic activity in refractory and resistant acute leukemias in a laboratory setting. The goal of this project is to study the importance of PDE6D in resistant leukemias and understand its role in modulating Rac activity and the survival of cancer cells to ultimately validate the use of our compound as a targeted therapeutic for clinical use. The use of samples derived from acute lymphocytic and myelocytic leukemia patients in the proposed study will give results that are closer to the clinical reality of these diseases. Validating the use of such compounds in this setting has the potential to revolutionize the treatment of aggressive leukemias. We anticipate that consequent clinical-grade compounds could be used in combination with other currently used therapies to boost their antileukemic effect.