Project title: Epigenetic dysregulation of transposons in pancreatic neuroendocrine tumors

Description 

Senapati is researching whether defects in the ATRX and DAXX genes activate certain sequences in DNA that cause pancreatic NETs to form. She is also studying changes in DNA methylation to find elements that may be activated in the formation of tumors. 

What question will you try to answer through your research?

My study will address which genetic components, called retrotransposons, are expressed in pancreatic NETs (PNETs) that have mutations in the ATRX and DAXX genes, and whether an abnormal expression of retrotransposon proteins can help predict outcomes for patients. My team and I will also explore how the ATRX/DAXX mutation in PNETs leads to dysregulation of retrotransposons that are silenced and tightly regulated in normal cells.

Why is this important?

ATRX/DAXX mutations in PNETs are associated with a worse prognosis for patients. If we better understand which retrotransposons are abnormally regulated in PNETs and how they lead to cancer progression, we may be able to identify markers that may affect prognosis and develop new treatment strategies for PNETs.

What will you do as part of this research project?

We will analyze the abnormal genomes of PNETs and the aberrant regulation of their genetic components that contribute to the formation of PNETs. We will explore the role and contribution of the ATRX and DAXX genetic mutations in causing pancreatic NETs. 

How might your research improve the treatment of NETs?

This study will help us identify genes and genetic pathways that may be used to develop diagnostic or prognostic markers and immunotherapeutic strategies to target PNETs. 

What is your next step?

Our study will explore whether the expression of retrotransposon proteins is associated with poorer clinical outcomes. The results may point to possible therapeutic strategies that target these proteins in PNETs.

Outcomes:

In this study, we investigated side effects of a medical treatment called radioligand therapy (PRRT), which is used for treating metastatic neuroendocrine tumors by delivering radioisotopes to tumor cells. Recently, second generation radioligands targeting the NET biomarker SSTR2, have entered clinical evaluation. Those ligands can achieve better treatment effects due to higher tumor accumulation. However, during the initial clinical study, this treatment unexpectedly caused severe side effects and led to a toxic reduction of blood cells.

In this study, we investigated our hypothesis that the harmful effects were not simply due to the treatment circulating through the bloodstream but were instead caused by the radioligand specifically binding to hematopoietic stem cells. These stem cells are responsible for producing various blood cells in the bone marrow. To investigate this hypothesis, we developed fluorescent analogs of clinically used first (agonists) and second (antagonists) generation SSTR2-targeting radioligands, which enable characterization of their binding properties on a single cell basis. We created five different versions of the fluorescent compounds to select a lead candidate, which had similar characteristics to the clinical radioligands. We then proceed to characterize the binding of agonists and antagonists to bone marrow stem cells, which reside in very low number in the bone marrow. We found that the ligands specifically bound to very small subpopulations (0.1%) of mononuclear cells in the bone marrow niche. Since the antagonist exhibited higher binding level, it can be assumed that the clinical treatment leads to a higher-than-calculated exposure of these stem cells to the cytotoxic irradiation. Since these stem cells are very sensitive to irradiation, this could lead to the clinically observed bone marrow toxicity. Understanding the binding characteristics of these new compounds to bone marrow stem cell subpopulations is crucial for assessing potential risks associated with PRRT, particularly for hematological toxicities.

Our findings will hopefully contribute to increasing patient safety and the development of personalized treatment protocols for cancer patients. In conclusion, we successfully created multimodal variants of PRRT agents and identified a possible mechanism of the unexpected bone marrow toxicity of the antagonist 177Lu-DOTA-JR11. This knowledge will aid in improving cancer therapies and minimizing potential adverse effects.

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