Disrupting Polyamine Homeostasis as a Therapeutic Strategy for Neuroblastoma

Abstract

MYC genes are deregulated in a plurality of human cancers. Through direct and indirect mechanisms, the MYC network regulates the expression of > 15% of the human genome, including both protein-coding and noncoding RNAs. This complexity has complicated efforts to define the principal pathways mediating MYC's oncogenic activity. MYC plays a central role in providing for the bioenergetic and biomass needs of proliferating cells, and polyamines are essential cell constituents supporting many of these functions. The rate-limiting enzyme in polyamine biosynthesis, ODC, is a bona fide MYC target, as are other regulatory enzymes in this pathway. A wealth of data link enhanced polyamine biosynthesis to cancer progression, and polyamine depletion may limit the malignant transformation of preneoplastic lesions. Studies with transgenic cancer models also support the finding that the effect of MYC on tumor initiation and progression can be attenuated through the repression of polyamine production. Highrisk neuroblastomas (an often lethal embryonal tumor in which MYC activation is paramount) deregulate numerous polyamine enzymes to promote the expansion of intracellular polyamine pools. Selective inhibition of key enzymes in this pathway, e.g., using DFMO and/or SAM486, reduces tumorigenesis and synergizes with chemotherapy to regress tumors in preclinical models. Here, we review the potential clinical application of these and additional polyamine depletion agents to neuroblastoma and other advanced cancers in which MYC is operative. (Clin Cancer Res 2009;15(19):5956-61)

Neuroblastoma: Molecular Pathogenesis and Therapy

“…Thus, it is not surprising to find high levels of MYCN in a subset of poorly differentiated aggressive neuroblastomas (7). This has translated to clinical approaches targeting MYCN and other downstream pathways such as MDM2 (RG3788, Roche Pharmaceuticals) (41, 42), ODC1 (difluoromethylornithine -DFMO) (43) and mTOR (Temazolamide) (44, 45). However, many high-risk cases have minimal MYCN expression, suggesting additional mechanisms for tumorigenesis independent of MYCN deregulation (46).…”

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 .…”

Consumption of Red/Processed Meat and Colorectal Carcinoma: Possible Mechanisms Underlying the Significant Association

“…the action of Myc on tumor initiation and progression can be weakened through intercepting endogenous polyamine production (Evageliou and Hogarty, 2009). Further, recent molecular findings link polyamines to the LIN28/let-7 pathway, i.e.…”