LSD1 Inhibition to Treat T-cell Acute Lymphoblastic Leukemia/Lymphoma
Background
T-cell lymphoblastic leukemia/lymphoma (T-AL/L) is a life-threatening cancer that afflicts children of all ages. Current therapy enables about 85% of pediatric T-AL/L patients to survive, but with life-limiting consequences. For those patients whose disease returns, survival is unlikely. If we are to do better, we need treatments that target the specific mechanisms of T-AL/L cell survival. We have discovered that two proteins, GFI1 and LSD1, work together to enable T-AL/L cell survival. Inhibiting either one of these proteins triggers T-AL/L cell death. We have also found that the GFI1--LSD1 partnership is enhanced by NOTCH, which is the most common driver of T-AL/L development. Our findings suggest the GFI1--LSD1 axis may be an "Achilles' heel" for T-AL/L cells. To test this, we have developed a new drug, SP-2577, that blocks LSD1 function. Our initial studies indicate that T-AL/L cells, even those isolated from patients whose T-AL/L has relapsed, are exquisitely sensitive to SP-2577.
Project Goal
With our proposed experiments, we will confirm that SP-2577 kills T-AL/L cells isolated from patients and transplanted into mice. We will also devise tests that show SP-2577 "hits its target" (LSD1) and may predict which patients will respond to the drug.
Project Update 2020
As often happens in biomedical science, our initial experiments generate findings that pull back the curtain to reveal much more complex biology. That has certainly been true for our work. We started with the knowledge that GFI1 was critical to the survival of T-AL/L cells, that its partnership with LSD1 was pivotal to that role, and that an inhibitor of LSD1 (SP-2577) could trigger T-AL/L cell death. Since then, we have learned that our LSD1 inhibitor blocks the binding between GFI1 and LSD1 and disrupts interactions with other GFI1 partners important for leukemia development. Insofar as successful new drug development depends upon a thorough understanding of the biology underlying its target, we feel it is extremely important to expand our studies to address these unexpected but exciting findings. We hope they will increase the probability of successfully targeting the GFI1—LSD1 relationship for therapeutic benefit.
Project Update 2018
Since our project began, we have laid the groundwork for deploying a new drug to treat leukemia. Unlike current drugs that act non-specifically to kill leukemia cells, our drug targets two proteins, GFI1 and LSD1, that leukemia cells need to stay alive. By targeting leukemia’s Achilles’ heel, we hope to achieve better outcomes for patients but fewer immediate and long term side effects. Along the way, we have discovered new details about how this partnership between GFI1 and LSD1 works, which not only reveals new insights about how our drug might be working, but also suggests how our drug might be combined with others to work even better. We are really excited by both the treatment opportunity that lies right in front of us and perhaps an even brighter future.
Project Update 2017
“I thought you might be interested to know that we recently presented our work at an international workshop on T-ALL in Leuven, Belgium. This was a gathering of world leaders in this area of inquiry and it was an honor to be asked to participate. The work engendered a lot of enthusiasm and even forged a new collaboration with (Dr.)Tom Look (an ALSF Grantee at Dana-Farber Cancer Institute). Overall, it was a great experience and a terrific opportunity to showcase work supported by ALSF. Thanks so much!"
