Targeting ornithine decarboxylase reverses the LIN28/Let-7 axis and inhibits glycolytic metabolism in neuroblastoma

Lozier, Ann; Rich, Maria; Grawe, Anissa Pedersen; Peck, Anderson; Zhao, Pingping; Chang, Anthony; Bond, Jeffrey P.; Sholler, Giselle L. Saulnier

doi:10.18632/oncotarget.2768

Cited by 58 publications

(44 citation statements)

References 34 publications

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“…Combination drug therapies offered several advantages such as better efficacy, Interestingly, sensitivities of NB cells to DFMO and bortezomib were correlated with LIN28B transcript levels. Previously, we reported that BE(2)-C cells expressed high levels of LIN28B and MYCN whereas SMS-KCNR cells expressed high MYCN but low LIN28B transcripts [25]. We observed that combination therapy of DFMO and bortezomib produced higher synergistic effect in BE(2)-C cells as compared to SMS-KCNR cells, which correlated with their LIN28 expression levels.…”

Section: Discussionsupporting

confidence: 52%

“…These results also suggest that although DFMO and bortezomib act on different targets, they may mediate their actions, at least partly, through a common mechanism involving LIN28. DFMO works by irreversibly binding to and inhibiting ODC, the rate limiting enzyme in polyamine biosynthesis and the upstream regulator of LIN28 expression [25] [40]. Polyamines are also shown to regulate NF-kB pathway [41].…”

Section: Discussionmentioning

confidence: 99%

“…Furthermore, three different NB patients enrolled in a DFMO clinical trial had reduced tumor metabolic activity as measured by Positron Emission Tomography (PET) scans after starting DFMO treatment with prolonged stabilization of disease [24]. Recent preclinical studies have shown that DFMO treatment reduced polyamine levels, reversed the LIN28/Let-7 axis, reduced glycolytic metabolism both in vitro and in vivo, and suggested that DFMO may be targeting CSCs in NB [22] [25]. Used in combination with other agents that also target CSC pathways, DFMO could offer a novel chemotherapeutic approach to increase long-term survival for patients with NB, as well as several other cancers associated with overexpression of LIN28.…”

Section: Introductionmentioning

confidence: 99%

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Inhibition of Neuroblastoma Cell Growth by Difluoromethylornithine (DFMO) and Bortezomib through Suppression of LIN28 and MYCN

Rich¹,

Zhao²,

Nagulapally³

et al. 2017

JCT

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Neuroblastoma (NB) is the most common childhood cancer arising from the nervous system. Many high-risk neuroblastoma (HRNB) patients develop relapse after initial response to induction treatment and overall long term survival remains poor (less than 60%), emphasizing the need for new therapeutic approaches and more effective treatments. Combination therapies present a favorable approach to improve efficacy, decrease toxicity, and reduce development of drug resistance. Difluoromethylornithine (DFMO) has shown promise in recent clinical trials as a therapeutic agent in treating HRNB. Proteasomes are known to play an important role in tumor cell growth. Bortezomib was the first proteasome inhibitor shown to have anticancer activity clinically. In this study we explore the mechanistic and therapeutic effects of the novel drug combination of DFMO and bortezomib in NB. Cell proliferation studies demonstrated synergistic inhibition of NB cell growth. Bortezomib induced cleaved caspase-3 apoptotic pathway whereas DFMO induced a cytostatic effect on NB cells. Western blot analyses demonstrated down regulation of MYCN, LIN28 and NF-kB in response to DFMO and bortezomib, pathways that are important in cancer stem cells. A decrease in ATP-per-cell when treated with combination therapy suggests inhibition of glycolytic metabolism in NB cells. DFMO as a single agent or in combination with bortezomib significantly reduced tumor growth in xenograft mice. Given the lack of effective treatments, DFMO coupled with bortezomib offers a potential new therapeutic treatment for children with NB.

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Section: Discussionsupporting

confidence: 52%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Inhibition of Neuroblastoma Cell Growth by Difluoromethylornithine (DFMO) and Bortezomib through Suppression of LIN28 and MYCN

Rich¹,

Zhao²,

Nagulapally³

et al. 2017

JCT

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“…Targeting LIN28B is currently under extensive investigation in a variety of cancers, with promising results in neuroblastoma and pediatric brain tumors. 36,37 It thus will be of great interest to evaluate whether treatment with LIN28B-targeting agents can enhance survival rates in this novel fetal-like subgroup of JMML.…”

Section: Lin28b Defines a Fetal-like Stem Cell Signature In Jmml Patimentioning

confidence: 99%

LIN28B overexpression defines a novel fetal-like subgroup of juvenile myelomonocytic leukemia

Helsmoortel

Bresolin

Lammens

et al. 2016

Blood

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Key Points• LIN28B is overexpressed in about half of juvenile myelomonocytic leukemia patients and defines a novel fetal-like disease subgroup. • LIN28B expression is correlated with high fetal hemoglobin levels and the absence of monosomy 7.Juvenile myelomonocytic leukemia (JMML) is a rare and aggressive stem cell disease of early childhood. RAS activation constitutes the core component of oncogenic signaling. In addition, leukemic blasts in one-fourth of JMML patients present with monosomy 7, and more than half of patients show elevated age-adjusted fetal hemoglobin (HbF) levels. Hematopoietic stem cell transplantation is the current standard of care and results in an event-free survival rate of 50% to 60%, indicating that novel molecular-driven therapeutic options are urgently needed. Using gene expression profiling in a series of 82 patient samples, we aimed at understanding the molecular biology behind JMML and identified a previously unrecognized molecular subgroup characterized by high LIN28B expression. LIN28B overexpression was significantly correlated with higher HbF levels, whereas patients with monosomy 7 seldom showed enhanced LIN28B expression. This finding gives a biological explanation of why patients with monosomy 7 are rarely diagnosed with high age-adjusted HbF levels. In addition, this new fetal-like JMML subgroup presented with reduced levels of most members of the let-7 microRNA family and showed characteristic overexpression of genes involved in fetal hematopoiesis and stem cell self-renewal. Lastly, high LIN28B expression was associated with poor clinical outcome in our JMML patient series but was not independent from other prognostic factors such as age and age-adjusted HbF levels. In conclusion, we identified elevated LIN28B expression as a hallmark of a novel fetal-like subgroup in

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“…In vitro and xenograft models have demonstrated decreased neurosphere and tumor formation as a result of decreased LIN28 and increased Let7 after DFMO treatment. 17,18 DFMO has been clinically studied through the Beat Childhood Patients with HRNB who completed standard upfront therapy without progression were eligible for enrollment. DFMO was initiated within 120 days of the completion of therapy at a dose of 750 ± 250 mg/m 2 /dose, twice daily.…”

mentioning

confidence: 99%

A subset analysis of a phase II trial evaluating the use of DFMO as maintenance therapy for high‐risk neuroblastoma

Lewis

Kraveka

Ferguson

et al. 2020

Intl Journal of Cancer

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Neuroblastoma is a sympathetic nervous system tumor, primarily presenting in children under 6 years of age. The long-term prognosis for patients with high-risk neuroblastoma (HRNB) remains poor despite aggressive multimodal therapy. This report provides an update to a phase II trial evaluating DFMO as maintenance therapy in HRNB. Event-free survival (EFS) and overall survival (OS) of 81 subjects with HRNB treated with standard COG induction, consolidation and immunotherapy followed by 2 years of DFMO on the NMTRC003/003b Phase II trial were compared to a historical cohort of 76 HRNB patients treated at Beat Childhood Cancer Research Consortium (BCC) hospitals who were disease-free after completion of standard upfront therapy and did not receive DFMO. The 2-and 5-year EFS were 86.4%

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Targeting ornithine decarboxylase reverses the LIN28/Let-7 axis and inhibits glycolytic metabolism in neuroblastoma

Cited by 58 publications

References 34 publications

Inhibition of Neuroblastoma Cell Growth by Difluoromethylornithine (DFMO) and Bortezomib through Suppression of LIN28 and MYCN

Inhibition of Neuroblastoma Cell Growth by Difluoromethylornithine (DFMO) and Bortezomib through Suppression of LIN28 and MYCN

LIN28B overexpression defines a novel fetal-like subgroup of juvenile myelomonocytic leukemia

A subset analysis of a phase II trial evaluating the use of DFMO as maintenance therapy for high‐risk neuroblastoma

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