MedicalResearch.com Interview with:
Dr. Uras
Dr. Iris Z Uras and Univ.-Prof. Dr. Veronika Sexl
Dr. Sexl
Institute of Pharmacology and Toxicology
University of Veterinary Medicine
Vienna
MedicalResearch.com: Exactly what is the background for this study? Exactly what are the main findings?
Response: Acute myeloid leukemia (AML) is the a lot of common form of acute leukemia in adults. Patients suffering from AML have actually inadequate prognosis and higher mortality fee despite substantial advances in chemotherapy and hematopoietic stem cell transplantations. Up to 30% of patients along with AML harbor an activating mutation in the FLT3 receptor tyrosine kinase (FLT3-ITD). Such mutations are associated along with a higher predisposition to relapse after remission. In a simplified method we can easily say that these tumor cells depend on FLT3: Is FLT3 blocked, cells die. Hence, FLT3 inhibitors are being produced as targeted therapy for FLT3-mutant AML; however, clinical responses are short-lived and their usage is confusing by rapid progression of resistance. This emphasizes the demand for extra therapeutic targets.
Our study represents a novel therapeutic window to specifically target and kill AML cells along with FLT3-ITD mutations. We discovered that the tumor-promoting enzyme CDK6 however not its close relative CDK4 straight regulates and initiates the production/transcription of FLT3 and thus lead to disease. The FDA-approved kinase inhibitor Palbociclib not just blocks the activity of CDK6 however in turn impairs FLT3 expression: Mutant AML cells die immediately. The treatment does not affect cells free of the mutation.
The electricity of CDK6 inhibition in AML cells goes beyond FLT3: Palbociclib additionally stops production of the PIM1 kinase and thus overcomes the potential activation of survival pathways counteracting the effects of FLT3 inhibition.
MedicalResearch.com: Exactly what must readers take away from your report?
Response: In 2015, Palbociclib has actually received complete FDA approval to handle breast cancer. We now reveal that Palbociclib additionally offers a therapeutic breakthrough in patients suffering from FLT3-steered AML. Leukemic cells are attacked in a dual way: CDK6 inhibition impairs the production of FLT3 and PIM1, and thus deprive cells of “nutrients”.
MedicalResearch.com: Exactly what suggestions do you have actually for future research as a result of this study?
Response: This study has actually immediate clinical relevance: A clinical trial in FLT3-steered AML must be initiated. Furthermore, this is the initial study that shows that the transcriptional activity of CDK6 depends on its kinase activity. In this method the CDK6 inhibitor attacks two birds along with one stone: It not just lessens cell proliferation however additionally destroys the Achilles’ heel of a cancer cell. Kinase-dependent and -independent functions of CDK6 should be carefully dissected additionally in various other cancer entities to a higher extent which shall offer rise to further efficacious target-personal agents for leukemia.
MedicalResearch.com: Is there anything else you would certainly adore to add?
Response: Our study could additionally supply a direct influence for clinical decisions in various other diseases: FLT3 mutations are not restricted to AML however are additionally detected in patients suffering from chronic myeloid leukemia (CML), chronic lymphocytic leukemia (CLL) and acute lymphoid leukemia (ALL). Furthermore, lots of patients along with AML and every one of express higher levels of wildtype FLT3. We showed that simultaneously targeting CDK6 and FLT3 is highly efficient in killing the FLT3-wildtype leukemic cells while respective mono-therapies fall short to do so. Such a synergy could be the vital get rid of potential resistance to treatment and permit reduced doses of the drugs to be used, minimizing toxicities while preserving therapeutic efficacy.
MedicalResearch.com: Thank you for your supplement to the MedicalResearch.com community.
Citation:
Iris Z. Uras, Gina J. Walter, Ruth Scheicher, Florian Bellutti, Michaela Prchal-Murphy, Anca S. Tigan, Peter Valent, Florian H. Heidel, Stefan Kubicek, Claudia Scholl, Stefan Fröhling, and Veronika Sexl. Palbociclib treatment of FLT3-ITD AML cells uncovers a kinase-dependent transcriptional regulation of FLT3 and PIM1 by CDK6. Blood, 2016
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