Scientists at VCU Massey Cancer Center found that a novel combination of drugs is effective against acute myeloid leukemia (AML) in preclinical models. The findings, recently published in the Journal of Cancer Research, could lead to new and improved treatments for AML and other hematologic malignancies.
Massey Cancer Center reports on research attempting to improve AML treatments. AML represents a group of related cancers that start in the bone marrow and move into the blood. The American Cancer Society estimates over 19,000 new diagnoses of the disease would occur in 2018 alone among older adults in the United States, which will lead to over 10,000 deaths.
The Study: New Combination Disrupts Leukemia Cells in Preclinical Studies
Led by Massey investigator Steven Grant, MD, they found combining the existing drug venetoclax (Genentech/Roche & AbbVie) with a class of agents known as P13K inhibitors led to a synergistic set of interactions in AML cells stemming from interruption the function of BCL-2 proteins and triggering cell death. BCL-2 proteins help regulate a form of cell suicide known as apoptosis.
Massey researchers sought to investigate the efficacy of combining venetoclax with clinically relevant agents that interfere with the P13 kinase pathway, which is essential for cellular replication and often mutated in AML cells. They found that P13K inhibitors altered the balance of BCL-2 proteins, making venetoclax more effective against AML cells.
Venetoclax was paired with the P13K inhibitors GDC-0980 (apitolisib) and taselisib (and experimental Roche cancer drug) an agent currently in clinical trials. Both combinations exhibited robust and broad activity against AML cells, including those with multiple forms of venetoclax resistance. It should be noted that both GDC-0980 and taselisib are Genentech/Roche related investigational cancer therapies.
Steven Grant, MD associate director for translational research, co-leader of the Developmental Therapeutics research program and Shirley Carter and Sture Gordon Olsson Chair in Cancer Research at Massey noted, “This study could provide a foundation for a new, clinically relevant strategy for the treatment of AML; employing novel targeted agents that may cooperate to kill leukemia cells.”
Grant continued “These findings build upon our previous studies, which demonstrated that other, less clinically relevant P13K inhibitors and BCL-2 inhibitors interact synergistically to kill leukemia and other malignant hematopoietic cells. The earlier findings set the stage for the development of this therapeutic strategy.”
Grant and the investigative team will expand the study to include other hematologic malignancies, such as non-Hodgkin’s lymphoma. Additional studies are being performed with the goal of translating these findings into a clinical trial that will combine venetoclax with P13 kinase inhibitors in patients with relapsed/refractory AML, a disease that lacks effective treatment options.
Collaborative Investigative Team
- Steven Grant, MD associate director for translational research, coleader of the Developmental Therapeutics research program
- Ferreira-Gonzalez, Ph.D., associate professor and chair of the Division of Molecular Diagnostics in the Department of Pathology at the VCU School of Medicine
- Xinyan Pei, M.D., Ph.D., of the VCU Department of Internal Medicine
- Jewel Nkwocha, Lab Specialist, Massey
- Elisa Hawkins, Lab Specialist, Massey
- Rebecca E. Parker, Lab Specialist, Massey
- Joel D. Leverson, AbbVie
- Mohamed Rahmani, Ph.D., currently of the University of Sharjah
- National Cancer Institute
- NIH-NCI Cancer Center Support
- Leukemia and Lymphoma Society of America