Autophagosome-Lysosome Fusion Inhibition Enhances Flavopiridol Efficacy in Cancer
T2011-012 A novel method to increase the effectiveness and practicality of the cancer treatment drug Flavopiridol.
Chronic lymphocytic leukemia (CLL) is the most common adult leukemia and the current therapies are not curative. High-risk genetic modifications are associated with poor response to traditional therapies. Flavopiridol, a broad-spectrum cyclin-dependent kinase inhibitor, activates significant clinical activity in CLL patients who are in relapse after long and complex treatment regimens and who carry high-risk genetic mutations. Although flavopiridol has been shown to be effective in treatment of CLL, other hematologic malignancies (lymphoma, AML, ALL and solid tumors) are relatively less responsive to this therapy. In addition, in one study, only 53% of high-risk patients receiving flavopiridol treatment showed a partial/complete response (Byrd et al. 2009). Therefore, flavopiridol alone is not the best option for CLL patients or others with hematologic malignancies.
The Ohio State University researchers, led by Drs. John Byrd and Dr. Michael Grever, have discovered that autophagy plays an important role in treatment for patients with CLL. Flavopiridol is a broad-spectrum cyclin-dependent kinase inhibitor and induces autophagy in CLL patients. Adding in chloroquine, which also inhibits autophagy, enhances the efficiency of the flavopiridol and extends the treatment to non-responsive tumors to flavopiridol as well as enhancing the clinical activity of flavopiridol in other cancer types.
- Chronic Lymphocytic Leukemia Treatment
- Solid Tumor and Hematologic Malignancy Treatment
- Chloroquine increases the autophagy in cells and treats tumors resistant to flavopiridol alone.
- Additionally, the compounds can increase intracellular calcium in CLL cells and cause an increase in endoplasmic reticulum stress response that is linked to autophagy stimulation.