# Preclinical evaluation of the efficacy and mechanism of action for an alkylated polyamine analogue diethylnorspermine in treating pheochromocytoma/paraganglioma

> **NIH NIH R21** · UNIVERSITY OF FLORIDA · 2021 · $190,625

## Abstract

Abstract: Adrenal pheochromocytomas (PCC) and extra-adrenal pheochromocytomas (paragangliomas,
(PGL)) are rare neuroendocrine malignancies that carry high disease burden due to excessive hormone
secretion by tumor cells and high probability of metastasis [1]. Metastatic disease is especially prevalent in
carriers of deleterious mutations in the subunits of succinate dehydrogenase complex (SDHx), which makes
this patient group the highest treatment priority [2, 3]. The absence of effective treatment for this lethal disease
remains a major clinical challenge. Our preliminary analysis of the PCC/PGL metabolome in cell lines and
patient tumor samples demonstrated up-regulation of the polyamine pathway upon SDHx deficiency. N-
alkylated polyamine analogue N1, N11diethylnorspermine (DENSPM) offers an exciting and innovative
pharmacological approach to targeting over-reactive polyamine pathway. DENSPM has been FDA approved
for clinical trial use (Phase I [4, 5]), and was evaluated for treatment of breast cancer malignancies in Phase II
trial [6]. In agreement with the metabolomic analysis, our preliminary data demonstrate that DENSPM
polyamine analogue is highly effective at targeting PCC-derived cells, both in vitro and in the mouse xenograft
model. Importantly, DENSPM appears to be remarkably potent against PCC/PGL tumor cells with a loss of the
SDHx function that present the highest clinical concern. Based on our preliminary data and the follow-up work
outlined in this application, an opportunity would open for a Phase II clinical trial at the University of Florida
(UF) to treat patients with metastatic PCC/PGL using DENSPM as UF has an active patent on this drug. To
proceed to the clinical trial it is necessary to directly compare DENSPM to the current standard of care
treatment and to evaluate the relevant biomarkers, as is proposed here. We propose that augmented
polyamine metabolism that we now uncovered in SDHx-deficient tumors (tissue and cells) could be a
vulnerability point unique to these (and not other) tumors that could be successfully targeted pharmacologically
with DENSPM. This study will put forward the first safe and effective pharmacological treatment against
metastatic tumors with a loss of the SDHx function and transform the lives of many patients urgently needing
treatment.

## Key facts

- **NIH application ID:** 10188669
- **Project number:** 5R21TR003044-02
- **Recipient organization:** UNIVERSITY OF FLORIDA
- **Principal Investigator:** Hans K. Ghayee
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $190,625
- **Award type:** 5
- **Project period:** 2020-06-15 → 2023-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10188669

## Citation

> US National Institutes of Health, RePORTER application 10188669, Preclinical evaluation of the efficacy and mechanism of action for an alkylated polyamine analogue diethylnorspermine in treating pheochromocytoma/paraganglioma (5R21TR003044-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10188669. Licensed CC0.

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