Targeting NOTCH Activation in Small Cell Lung Cancer through LSD1 Inhibition
This week we profile a recent publication in Science Signaling from Dr. David MacPherson
(second from right) at Fred Hutchinson Cancer Research Center.
Can you provide a brief overview of your lab’s current research focus?
My lab is focused on understanding small cell lung cancer (SCLC), an extremely aggressive and highly metastatic cancer type. We study genes mutated in SCLC to try to understand how these genetic changes contribute to SCLC and we seek to identify new therapeutic approaches. We employ genetically engineered mouse models, patient derived xenograft models and functional screens in our research program. One area of particular interest is in the high number of mutations in genes that regulate transcription by modifying histone proteins. We are also interested in histone modifying enzymes as therapeutic targets.
What is the significance of the findings in this publication?
Our recent study tested an inhibitor of a histone demethylase, LSD1, in patient derived xenograft models of SCLC. Out of the seven models tested, one exhibited an exceptional response to the LSD1 inhibitor, which included complete tumor regression. We probed the molecular basis for response to LSD1 inhibition in SCLC and found that LSD1 inhibition activated the NOTCH signaling pathway which suppressed a key transcription factor, ASCL1, that SCLC cells rely on for survival. The exceptional responder hyperactivated the NOTCH pathway and strongly suppressed ASCL1 to drive tumor regression. The results are significant as while we previously knew that NOTCH activation can suppress SCLC, we did not have a good druggable target to achieve this.
What are the next steps for this research?
One key direction is to better understand features associated with strong response to LSD1 inhibition in SCLC. We would like to understand whether specific genetic alterations lead to hyperactivation of NOTCH signaling in response to LSD1 inhibition. In doing so, perhaps we can direct this treatment towards patients most likely to respond strongly. We are also interested in whether LSD1 inhibition might synergize with other treatments, including therapies directed towards increasing immunes responses in these tumors.