Polyamine pathway inhibition as a novel therapeutic approach to treating neuroblastoma

Abstract

Polyamines are highly regulated essential cations that are elevated in rapidly proliferating tissues, including diverse cancers. Expression analyses in neuroblastomas suggest that up-regulation of polyamine pro-synthetic enzymes and down-regulation of catabolic enzymes is associated with poor prognosis. Polyamine sufficiency may be required for MYCN oncogenicity in MYCN amplified neuroblastoma, and targeting polyamine homeostasis may therefore provide an attractive therapeutic approach. ODC1, an oncogenic MYCN target, is rate-limiting for polyamine synthesis, and is overexpressed in many cancers including neuroblastoma. Inhibition of ODC1 by difluoromethylornithine (DFMO) decreased tumor penetrance in TH-MYCN mice treated pre-emptively, and extended survival and synergized with chemotherapy in treating established tumors in both TH-MYCN and xenograft models. Efforts to augment DFMO activity, or otherwise maximally reduce polyamine levels, are focused on antagonizing polyamine uptake or augmenting polyamine export or catabolism. Since polyamine inhibition appears to be clinically well tolerated, these approaches, particularly when combined with chemotherapy, have great potential for improving neuroblastoma outcome in both MYCN amplified and non-MYCN amplified neuroblastomas.

Coupling of the polyamine and iron metabolism pathways in the regulation of proliferation: Mechanistic links to alterations in key polyamine biosynthetic and catabolic enzymes

“…These metabolic differences are modulated by the different molecular phenotypes frequently observed in cancer cells [1, 10, 20, 68]. Indeed, this is demonstrated herein for c-Myc and p53, which are regulated by iron levels and act antagonistically to affect the expression of key polyamine pathway proteins (Figs.…”

Novel Interaction of Ornithine Decarboxylase with Sepiapterin Reductase Regulates Neuroblastoma Cell Proliferation

“…ODC is a direct target of the transcription factor Myc and is required for Myc-induced lymphoma development 5 . Research investigating the role of ODC and ODC-associated proteins as oncogenic factors in neuroblastoma (NB), a pediatric malignancy that arises in neural crest-derived cells of the sympathetic nervous system, has gained significant momentum 6; 7; 8; 9; 10; 11; 12; 13; 14; 15; 16; 17 . Evidence exists that ODC is a direct transcriptional target of the Myc-related MYCN transcription factor 18; 19 , and it is therefore not surprising that the role of ODC and ODC-associated proteins is especially clear in the aggressive NB tumors that show amplification of the MYCN gene 20; 21; 22 .…”

Genetic variants in RUNX3, AMD1 and MSRA in the methionine metabolic pathway and survival in nonsmall cell lung cancer patients

“…AMD1 , located on chromosome 6, encodes the S-adenosylmethionine decarboxylase 1, an enzyme that catalyzes the conversion of S-adenosyl methionine to S-adenosylmethioninamine, controlling the second rate-limiting step in the polyamine biosynthetic pathway 42 . Polyamines are highly regulated essential cations that are elevated in rapidly proliferating tissues of diverse cancers.…”

“…Polyamines are highly regulated essential cations that are elevated in rapidly proliferating tissues of diverse cancers. Reduced levels of intracellular polyamines activate checkpoints that constrain proliferation, as seen in senescent and post-mitotic cells, while enhanced polyamine synthesis accompanies oncogenic proliferation 42, 43 . Recent studies demonstrated that rapamycin complex 1 (mTORC1)-dependent AMD1 upregulation sustains polyamine metabolism in prostate cancer 44 .…”