Project title: Targeting the Epigenetic Landscape of GEP-NETs through Menin-MLL Inhibition

What critical problem/question will researchers try to answer?
Epigenetic alterations in GEP-NETs are widespread and can influence their response to therapy. Yet, current strategies to target these deregulated epigenetic signals are limited. Our team will investigate a new class of drug compounds, called Menin-MLL inhibitors, that carry the potential to restore normal epigenetic regulation in GEP-NETs. Our prior work showed that Menin-MLL inhibition can potentially rescue the function of a tumor suppressor protein whose expression and function are frequently lost in GEP-NETs. We aim to elucidate an underlying epigenetic mechanism for these events and determine whether Menin-MLL inhibitors can be applied as a menin-restorative therapy for these cancers.

Why is this important?
Neuroendocrine tumors that develop in the gastrointestinal tract and pancreas present with epigenetic alterations that drive tumor growth and pose a significant challenge to improving patient outcomes. Therapies that restore normal epigenetic regulation in GEP-NETs carry strong potential to improve the standard of care. This project investigates how the delivery of a novel therapy, compounds known as Menin-MLL inhibitors, can restore the normal epigenetic landscape in these cancers by rescuing the function of a tumor suppressor protein known as Menin. This work will increase our understanding of how these cancers develop and test the effect of blocking Menin-MLL as a potential new treatment for patients with GEP-NETs.

What will the researchers do?
Our research team will define how Menin-MLL inhibition in GEP-NETs alters the epigenetic landscape through restoration of Menin. We will apply a combination of sequencing and biochemical approaches to determine how Menin-MLL inhibition modifies tumor-promoting epigenetic signals and impacts the physical interaction of Menin with epigenetic proteins. Next, we will decipher the therapeutic impact of Menin-MLL inhibition using patient and mouse derived GEP-NET organoids. 

How might this improve treatment of neuroendocrine cancer?
Menin is a tumor suppressor protein that interacts with epigenetic proteins that contribute to altered epigenetic signaling in GEP-NETs. Prior studies showed that a majority of these tumors display abnormal Menin protein expression, suggesting the potential of using Menin-restorative compounds as a novel therapeutic strategy to modulate the tumor-promoting epigenetic landscape. We previously discovered that a new class of drug compounds, known as Menin-MLL inhibitors, can potentially rescue Menin expression and block NET cell growth. Our goal is to inform the potential delivery of these compounds in the clinic by defining the underlying epigenetic mechanism of Menin-MLL inhibition and evaluating its therapeutic application in preclinical GEP-NET models.

What is the next step?
From this work, we will generate a list of epigenetic proteins and downstream molecular targets that are impacted by Menin-MLL inhibition. In the next steps, we will evaluate how alterations in these signaling pathways contribute to NET development and therapy resistance. Future studies by our team will aim to validate these results using Menin-MLL inhibitors that are currently being tested in Phase 2 clinical trials. Ultimately, we hope to inform the delivery of these compounds in the adjuvant setting as a novel treatment strategy for patients with GEP-NETs.

 

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