Study the membrane density of somatostatin receptors in neuroendocrine tumors to see if membrane trafficking (the process by which somatostatin receptors are distributed throughout the cell) can be modulated to enhance the efficacy of LUTATHERA.
What question will the researchers try to answer?
Somatostatin receptor 2 (SSTR2)-targeting radiolabeled peptides have high clinical potential for imaging and systemic radiotherapy of NETs. However, tumor heterogeneity contributes to inadequate tumor targeting and low drug delivery that contributes to disease progression. In this context, a homogeneous expression of tumoral SSTR2 is necessary for LUTATHERA to bind tumor cells. This project aims to modulate SSTR2 heterogeneity in ways that enhance LUTATHERA systemic radiotherapeutic efficacy.
Why is this important?
LUTATHERA has revolutionized the treatment of patients with neuroendocrine tumors that are positive for somatostatin receptors. However, not all tumors respond to LUTATHERA and tumor heterogeneity contributes to inadequate LUTATHERA delivery, ultimately leading to disease progression. By overcoming the heterogeneity of SSTR2 that characterizes non-responder NETs, LUTATHERA-tumor binding and endoradiotherapeutic efficacy can improve.
What will researchers do?
We have generated preclinical imaging data indicating that the temporal modulation of endocytosis increases tumor targeting of antibodies and other small molecules. In this proposal, we will temporally modulate endocytosis to increase the efficacy of LUTATHERA and extend the therapeutic benefit to neuroendocrine tumors of heterogeneous expression of SSTR2 (including SSTR2-low tumors). We will perform pharmacokinetic studies to define the dose of endocytic modulators necessary to temporally modulate membrane levels of SSTR2 for human translation and determine the potential dosimetric impact of endocytic modulation on clinical imaging and LUTATHERA endoradiotherapy.
How might this improve the treatment of NETs?
These preclinical studies will provide proof of concept for an innovative approach to increase the effectiveness of peptide receptor radionuclide therapy in NETs. In addition, it is likely that the results will contribute to the understanding of the mechanisms of SSTR2 in NETs molecular imaging and response to endoradiotherapy, thereby fundamentally advancing the fields of theranostics. These studies provide a basis for the next steps toward clinical translation that can impact many patients with NETs.
What is the next step?
The next important step is to establish a foundation for a clinical trial combining endocytic modulators of SSTR2 with LUTATHERA peptide receptor radionuclide therapy to prevent or delay the emergence of drug resistance in patients with NETs.