Investigators at the Dana-Farber Cancer Institute found that certain types of myeloid and lymphoid leukemias rely on a molecular complex known as PI3Kgamma for their survival. Their study offers both mechanistic and preclinical evidence to support the prompt start of clinical trials for patients with acute myeloid leukemia (AML) to evaluate an existing drug that inhibits the complex, called eganelisib. This includes testing the drug alone and in combination with the most commonly used AML chemotherapy, cytarabine.The research study provides evidence to support the rapid start of clinical trials for patients with acute myeloid leukemia (AML) to test eganelisib, an existing medicine that inhibits a complex. The study suggests testing eganelisib alone and in combination with the most commonly used AML chemotherapy, cytarabine. Principal investigator Andrew Lane, MD, PhD, states, “Given what we’ve observed, we can move very quickly to take these medicines, which appear to be safe and well tolerated, to patients with AML.” The study was published in Nature.at Dana-Farber. “We are planning clinical trials to start hopefully within the next year.”
In the past 10 years, there have been advancements in the treatment of AML. However, most patients end up relapsing after treatment. Although therapies targeting AML-related mutations have been beneficial for some patients, the cancer eventually adapts to resist the treatment.
The team at Dana-Farber took a different approach in their search for therapeutic targets. Rather than focusing on mutations, first author Qingyu Luo, MD, PhD, a research fellow in Lane’s lab, used genome wide CRISPR interference to search for genes that AML cells rely on to grow.
Through this method, he discovered A promising discovery was made when it was found that a specific gene, known as PI3KR5, was essential for the survival of a subset of leukemia cells. This gene is responsible for producing a crucial component of the PI3Kgamma complex.
What made this discovery even more compelling was the fact that the PI3Kgamma complex had been previously studied, although not in relation to AML. Furthermore, there was already an existing drug, eganelisib, that could inhibit it. This drug had been undergoing trials for certain solid tumors in order to improve cancer immunotherapy.
However, what Luo and Lane had uncovered was a whole new way in which the drug could potentially work directly on leukemia cells to halt their growth.
rnrnTo test this theory, the team used eganelisib to treat animal models with patient-derived leukemia xenografts. They discovered that the leukemia xenografts, which were expected to rely heavily on PI3Kgamma, decreased in size, and the animal models lived longer after being treated with eganelisib.
When analyzing data from The Cancer Genome Atlas (TCGA), the team noticed that patients with AML who were expected to respond well to eganelisib did not have as favorable outcomes when undergoing existing therapies compared to those with negative biomarkers. This indicates that patients with high levels of PI3KR5 expression, identified as a result, may have a specific need.
There is potential for new medications that may benefit from treatment with eganelisib for patients with AML,” says Lane. “This drug has already undergone clinical trials for patients with solid tumors and is now ready for testing in AML patients.”
Luo, the researcher behind this study aimed at improving current AML therapies, conducted experiments on animal models of leukemia using cytarabine alone and in combination with eganelisib. The results showed that those treated with eganelisib and cytarabine together lived longer than those treated with cytarabine alone, regardless of the leukemia’s sensitivity to PI3Kgamma inhibition alone.
The obserLuo’s observations indicated that the two medications worked together in a beneficial way. Upon further investigation, Luo determined that inhibiting PI3Kgamma also led to the suppression of a metabolic process in leukemia cells known as oxidative phosphorylation (OXPHOS). Leukemia cells rely on OXPHOS for energy, and inhibiting this process can lead to their destruction.
Luo also found that leukemia cells that survive standard treatment with cytarabine become more reliant on PI3Kgamma than they were before treatment. These surviving leukemia cells, which are responsible for AML relapse, could potentially be susceptible to combination therapy with eganelisib and cytarabine. < blockquote>
According to Luo, the goal is to create synergy between two drugs. He explains that eganelisib, by inhibiting PI3Kgamma, can suppress an energy pathway that is important in AML relapse.
Now, the team is focused on creating clinical trials for patients.
Lane adds, “This research provides the scientific basis for clinical use and also helps us understand how our discoveries can meet the needs of our patients. Dana-Farber is a unique place where we can seamlessly transition from molecular biology in the lab to testing in models using patient samples, and then quickly initiating a clinical trial.”
