New drug combination disrupts leukemia cells in preclinical studies
Research conducted by 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 Cancer Research, could lead to new and improved treatments for AML and other hematologic malignancies.
AML represents a group of related cancers that begin in the bone marrow and move into the blood. The American Cancer Society estimates that over 19,000 new diagnoses of the disease will occur in 2018 among older adults in the United States and lead to over 10,000 deaths.
The study, led by Massey physician-researcher Steven Grant, M.D., found that combining the existing drug venetoclax with a class of agents known as PI3K inhibitors led to synergistic interactions in AML cells stemming from interruption of the function of BCL-2 proteins and triggering of cell death. BCL-2 proteins help regulate a form of cell suicide known as apoptosis.
While venetoclax alone has shown evidence of activity against AML, it is generally thought that single-agent therapy is unlikely to be effective in the broad spectrum of AML treatment. This prompted Massey researchers to investigate the efficacy of combining venetoclax with clinically relevant agents that interfere with the PI3 kinase pathway, which is essential for cellular replication and often mutated in AML cells. They found that PI3K inhibitors altered the balance of BCL-2 proteins, making venetoclax more effective against AML cells.
“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,” said Grant, 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. He is also a professor of hematology-oncology at the VCU School of Medicine.
“These findings build upon our previous studies, which demonstrated that other, less clinically relevant PI3K inhibitors and BCL-2 inhibitors interact synergistically to kill leukemia and other malignant hematopoietic cells,” said Grant. “The earlier findings set the stage for the development of this therapeutic strategy.”
For the study, venetoclax was paired with the PI3K inhibitors GDC-0980 and taselisib, an agent currently in clinical trials. Both combinations exhibited robust and broad activity against AML cells, including those with multiple forms of venetoclax resistance.
Venetoclax caused disruption of BCL-2 function in AML cells, and PI3K inhibitors synergized with this agent to significantly extend survival in mouse models of patient-derived AML.
“This is the first demonstration of venetoclax/PI3K inhibitor activity in primary patient-derived AML cells,” said Grant. “It is also a first for clinically relevant PI3K inhibitors in patient-derived xenograft models.”
Moving forward, Grant is expanding on 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 PI3 kinase inhibitors in patients with relapsed/refractory AML, a disease that currently lacks effective treatment options.
Grant collaborated on this research with Maciej Kmieciak, Ph.D., assistant director of translational and clinical research at Massey; Andrea 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, Elisa Hawkins and Rebecca E. Parker, all laboratory specialists at Massey; Joel D. Leverson of AbbVie; and Deepak Sampath of Genentech. Mohamed Rahmani, Ph.D., currently of the University of Sharjah, was the lead author of the study.
This work was supported by grants from the National Cancer Institute (UH2TR001373, CA205607, CA167708), an award from the Leukemia and Lymphoma Society of America and, in part, by funding from the NIH-NCI Cancer Center Support Grant (P30 CA016059).
The published manuscript of the study is available at: http://cancerres.aacrjournals.org/content/78/11/3075.