Approximately 18-45 patients with Hepatocellular Carcinoma (HCC) will be treated with DENSPM at approximately 5 centers in the United States. First, we will be trying to determine the highest dose that can be given safely and is well tolerated (this is called the maximally tolerated dose, or the MTD, for short). Once that is established, we will enroll additional patients to learn more about potential side effects and to see whether DENSPM can slow the growth of HCC tumors. We also want to learn about the safety of DENSPM. Many medications used to treat cancer cause side effects (discomforts or illness). In this study, we want to understand what side effects occur in patients with HCC who are treated with DENSPM.Study was terminated after initial assessment of insufficient data to support clinical benefit in this population.

Start Date01 Mar 2004

Sponsor / Collaborator

Genzyme Corp.

100 Clinical Results associated with Diethylnorspermine

100 Translational Medicine associated with Diethylnorspermine

100 Patents (Medical) associated with Diethylnorspermine

221

Literatures (Medical) associated with Diethylnorspermine

16 Jan 2024·Endocrinology

Discordant Effects of Polyamine Depletion by DENSpm and DFMO on β-cell Cytokine Stress and Diabetes Outcomes in Mice

Article

Author: Mirmira, Raghavendra G ; May, Sarah C ; Nelson, Jennifer B ; Hammoud, Batoul ; Tersey, Sarah A

AbstractType 1 diabetes (T1D) is an autoimmune disease leading to dysfunction and loss of insulin-secreting β cells. In β cells, polyamines have been implicated in causing cellular stress and dysfunction. An inhibitor of polyamine biosynthesis, difluoromethylornithine (DFMO), has been shown to delay T1D in mouse models and preserve β-cell function in humans with recent-onset T1D. Another small molecule, N1,N11-diethylnorspermine (DENSpm), both inhibits polyamine biosynthesis and accelerates polyamine metabolism and is being tested for efficacy in cancer clinical trials. In this study, we show that DENSpm depletes intracellular polyamines as effectively as DFMO in mouse β cells. RNA-sequencing analysis, however, suggests that the cellular responses to DENSpm and DFMO differ, with both showing effects on cellular proliferation but the latter showing additional effects on mRNA translation and protein-folding pathways. In the low-dose streptozotocin-induced mouse model of T1D, DENSpm, unlike DFMO, did not prevent or delay diabetes outcomes but did result in improvements in glucose tolerance and reductions in islet oxidative stress. In nonobese diabetic (NOD) mice, short-term DENSpm administration resulted in a slight reduction in insulitis and proinflammatory Th1 cells in the pancreatic lymph nodes. Longer term treatment resulted in a dose-dependent increase in mortality. Notwithstanding the efficacy of both DFMO and DENSpm in reducing potentially toxic polyamine levels in β cells, our results highlight the discordant T1D outcomes that result from differing mechanisms of polyamine depletion and, more importantly, that toxic effects of DENSpm may limit its utility in T1D treatment.

03 Jan 2023·Molecular Cancer Research

JAZF1: A Metabolic Regulator of Sensitivity to a Polyamine-Targeted Therapy

Article

Author: Rowsam, Aryn M. ; Smiraglia, Dominic J. ; Rosario, Spencer R. ; Jacobi, Justine J. ; Affronti, Hayley C. ; Long, Mark D.

AbstractIdentifying and leveraging unique points of metabolic dysregulation in different disease settings is vital for safe and effective incorporation of metabolism-targeted therapies in the clinic. In addition, it has been shown identification of master metabolic transcriptional regulators (MMTR) of individual metabolic pathways, and how they relate to the disease in question, may offer the key to understanding therapeutic response. In prostate cancer, we have previously demonstrated polyamine biosynthesis and the methionine cycle were targetable metabolic vulnerabilities. However, the MMTRs of these pathways, and how they affect treatment, have yet to be explored. We sought to characterize differential sensitivity of prostate cancer to polyamine- and methionine-targeted therapies by identifying novel MMTRs. We began by developing a gene signature from patient samples, which can predict response to metabolic therapy, and further uncovered a MMTR, JAZF1. We characterized the effects of JAZF1 overexpression on prostate cancer cells, basally and in the context of treatment, by assessing mRNA levels, proliferation, colony formation capability, and key metabolic processes. Lastly, we confirmed the relevance of our findings in large publicly available cohorts of prostate cancer patient samples. We demonstrated differential sensitivity to polyamine and methionine therapies and identified JAZF1 as a MMTR of this response.Implications:We have shown JAZF1 can alter sensitivity of cells and its expression can segregate patient populations into those that do, or do not highly express polyamine genes, leading to better prediction of response to a polyamine targeting therapy.

01 May 2022·Biomaterials Advances

Hyaluronate-coated perfluoroalkyl polyamine prodrugs as bioactive siRNA delivery systems for the treatment of peritoneal cancers

Article

Author: Sil, Diptesh ; Oupický, David ; Stewart, Tracy Murray ; Panja, Sudipta ; Foley, Jackson ; Ding, Ling ; Jia, Huizhen ; Tang, Weimin ; Yu, Ao ; Tang, Siyuan ; Casero, Robert A ; Smith, Lynette M ; Hang, Yu ; Holbert, Cassandra E

RNA interference (RNAi) is an emerging therapeutic modality for cancer, which remains in critical need of effective delivery vectors due to the unfavorable biopharmaceutical properties of small RNAs. Polyamines are essential for functioning of mammalian cells. Dysregulated polyamine metabolism is found in many cancers and has been an attractive therapeutic target in combination therapies. Combination therapies based on drugs that affect polyamine metabolism and nucleic acids promise to enhance anticancer activity due to a cooperative effect on multiple oncogenic pathways. Here, we report bioactive polycationic prodrug (F-PaP) based on an anticancer polyamine analog bisethylnorspermine (BENSpm) modified with perfluoroalkyl moieties. Following encapsulation of siRNA, F-PaP/siRNA nanoparticles were coated with hyaluronic acid (HA) to form ternary nanoparticles HA@F-PaP/siRNA. The presence of perfluoroalkyl moieties and HA reduced cell membrane toxicity and improved stability of the particles with cooperatively enhanced siRNA delivery in pancreatic and colon cancer cell lines. We then tested a therapeutic hypothesis that combining BENSpm with siRNA silencing of polo-like kinase 1 (PLK1) would result in cooperative cancer cell killing. HA@F-PaP/siPLK1 induced polyamine catabolism and cell cycle arrest, leading to enhanced apoptosis in the tested cell lines. The HA-coated nanoparticles facilitated tumor accumulation and contributed to strong tumor inhibition and favorable modulation of the immune tumor microenvironment in orthotopic pancreatic cancer model. Combination anticancer therapy with polyamine prodrug-mediated delivery of siRNA. Hyaluronate coating of the siRNA nanoparticles facilitates selective accumulation in orthotopic pancreatic tumors. Perfluoroalkyl conjugation reduces toxicity and improves gene silencing effect. Nanoparticle treatment induces polyamine catabolism and cell cycle arrest leading to strong tumor inhibition and favorable modulation of immune tumor microenvironment.

100 Deals associated with Diethylnorspermine

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Indication	Highest Phase	Country/Location	Organization	Date
Alzheimer Disease	Phase 2	-	Pfizer Inc.	-
Alzheimer Disease	Phase 2	-	Sanofi	-
Alzheimer Disease	Phase 2	-	Nippon Kayaku Co., Ltd.	-
Liver Cancer	Phase 2	-	Pfizer Inc.	-
Liver Cancer	Phase 2	-	Nippon Kayaku Co., Ltd.	-
Liver Cancer	Phase 2	-	Sanofi	-
Pancreatic Cancer	Phase 2	-	Sanofi	-
Pancreatic Cancer	Phase 2	-	Pfizer Inc.	-
Pancreatic Cancer	Phase 2	-	Nippon Kayaku Co., Ltd.	-
Renal Cell Carcinoma	Phase 2	-	Nippon Kayaku Co., Ltd.	-

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