The Acute Myeloid Leukemia (AML)/ Myelodysplastic Syndromes (MDS) Moon Shot has opened two clinical trials to address a crucial problem for MDS patients: swift progression when their disease resists a crucial class of drugs called hypomethylating agents. Both trials are based on research into resistant MDS by physician-scientist and moon shot leader Guillermo Garcia-Manero, M.D., professor in Leukemia.
One trial is the first conducted in leukemia of a rising type of cancer immunotherapy called immune checkpoint blockade.
Garcia-Manero and colleagues implicated several immune checkpoint molecules, which stop the immune system’s natural attack on cancer cells, in the development of MDS resistance. In solid tumors, these checkpoints have been successfully blocked by antibody-based drugs, unleashing the immune system to attack, an approach invented by James Allison, Ph.D., executive director of the immunotherapy platform and chair of Immunology.
The clinical trial tests a drug that blocks the PD1 checkpoint.
The team also identified the receptor 2 protein (TLR2) as a potential target and connected with an Irish biotech company to test an antibody to TLR2 in the second clinical trial.
Tracking down the details
Intensive research continues to identify other sources of resistance, Garcia-Manero says. Three pairs of drug-resistant and drug-sensitive MDS cell lines have been generated, as well as the first mouse model of MDS.
Moon shots investigators have also identified faulty molecular signaling pathways that lead to drug resistance in some MDS patients.
In molecular signaling, a group of molecules in a cell work together to control one or more cell functions. After the first molecule in a pathway receives a signal, it activates another molecule.
This process is repeated until the last molecule is activated and the cell function is carried out. Abnormal activation of signaling pathways can cause cancer, drug resistance or other problems.
Parallel DNA and RNA sequencing, which reduces costs and speeds results by sequencing both at the same time, and DNA methylation analyses, which identifies a common signaling tool that cells use to turn off genes that suppress cancer cells, are also underway.
There are also similar research efforts targeting AML cell lines resistant to hypomethylating agents.
Under the auspices of the APOLLO platform (Adaptive Patient-Oriented Longitudinal Learning Optimization), more than 3,500 AML and MDS samples gathered repeatedly from patients over time have been genomically sequenced.
“We expect to achieve full genomic and proteomic understanding of AML and MDS within five years,” Garcia-Manero says.
