Preclinical studies reveal MLN4924 is a promising new retinoblastoma therapy

Aubry, Arthur; Tao, Yu; Bremner, Rod

doi:10.1038/s41420-020-0237-8

Cited by 41 publications

(25 citation statements)

References 44 publications

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“…Functional loss of SKP2 has a synthetic lethal effect in RB1 -deficient tumors including retinoblastoma [ 71 , 76 , 77 , 156 ]. SKP2 inhibitors that prevent SKP2 binding to the SCF (Skp1-Cullin1-F-box) core subunit inhibit proliferation of retinoblastoma cells, but the potency of currently synthesized inhibitors is poor [ 157 ]. Pevonedistat (MLN4924) suppresses NEDD8-activating enzyme E1 activity in neddylation of Cullin1, thereby dampening SCF activity [ 158 ].…”

Section: Treatmentsmentioning

confidence: 99%

“…Pevonedistat (MLN4924) suppresses NEDD8-activating enzyme E1 activity in neddylation of Cullin1, thereby dampening SCF activity [ 158 ]. Pevonedistat tested in clinical trials for treatment of many cancers potently suppresses the growth of retinoblastoma with minimal off-target effects via intravitreal delivery in orthotopic xenograft models [ 157 , 158 ]. The drug exerts a broad range of activities from cytostatic to lethal in multiple retinoblastoma cell lines, regardless of the RB1 or MYCN status [ 157 ].…”

Section: Treatmentsmentioning

confidence: 99%

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Retinoblastoma: Etiology, Modeling, and Treatment

Kaewkhaw

Rojanaporn

2020

Cancers

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Retinoblastoma is a retinal cancer that is initiated in response to biallelic loss of RB1 in almost all cases, together with other genetic/epigenetic changes culminating in the development of cancer. RB1 deficiency makes the retinoblastoma cell-of-origin extremely susceptible to cancerous transformation, and the tumor cell-of-origin appears to depend on the developmental stage and species. These are important to establish reliable preclinical models to study the disease and develop therapies. Although retinoblastoma is the most curable pediatric cancer with a high survival rate, advanced tumors limit globe salvage and are often associated with high-risk histopathological features predictive of dissemination. The advent of chemotherapy has improved treatment outcomes, which is effective for globe preservation with new routes of targeted drug delivery. However, molecularly targeted therapeutics with more effectiveness and less toxicity are needed. Here, we review the current knowledge concerning retinoblastoma genesis with particular attention to the genomic and transcriptomic landscapes with correlations to clinicopathological characteristics, as well as the retinoblastoma cell-of-origin and current disease models. We further discuss current treatments, clinicopathological correlations, which assist in guiding treatment and may facilitate globe preservation, and finally we discuss targeted therapeutics for future treatments.

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Section: Treatmentsmentioning

confidence: 99%

Section: Treatmentsmentioning

confidence: 99%

Retinoblastoma: Etiology, Modeling, and Treatment

Kaewkhaw

Rojanaporn

2020

Cancers

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“…SKP2, a component of the SCF SKP2 ubiquitylating complex, is another promising hub as its loss is synthetic lethal in many RB1 null contexts, including RB [ 16 ]. Indeed, blocking activation of the SCF SKP2 complex with the neddylation inhibitor MLN4924 (Pevonedistat) shows promise as a new RB therapy [ 17 ]. Such studies illustrate the value in dissecting networks that drive RB cell growth and survival to identify novel therapeutic strategies.…”

Section: Introductionmentioning

confidence: 99%

Functional genomics identifies new synergistic therapies for retinoblastoma

et al. 2020

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Local intravitreal or intra-arterial chemotherapy has improved therapeutic success for the pediatric cancer retinoblastoma (RB), but toxicity remains a major caveat. RB initiates primarily with RB1 loss or, rarely, MYCN amplification, but the critical downstream networks are incompletely understood. We set out to uncover perturbed molecular hubs, identify synergistic drug combinations to target these vulnerabilities, and expose and overcome drug resistance. We applied dynamic transcriptomic analysis to identify network hubs perturbed in RB versus normal fetal retina, and performed in vivo RNAi screens in RB1 null and RB1 wt ; MYCN amp orthotopic xenografts to pinpoint essential hubs. We employed in vitro and in vivo studies to validate hits, define mechanism, develop new therapeutic modalities, and understand drug resistance. We identified BRCA1 and RAD51 as essential for RB cell survival. Their oncogenic activity was independent of BRCA1 functions in centrosome, heterochromatin, or ROS regulation, and instead linked to DNA repair. RAD51 depletion or inhibition with the small molecule inhibitor, B02, killed RB cells in a Chk1/Chk2/p53-dependent manner. B02 further synergized with clinically relevant topotecan (TPT) to engage this pathway, activating p53–BAX mediated killing of RB but not human retinal progenitor cells. Paradoxically, a B02/TPT-resistant tumor exhibited more DNA damage than sensitive RB cells. Resistance reflected dominance of the p53–p21 axis, which mediated cell cycle arrest instead of death. Deleting p21 or applying the BCL2/BCL2L1 inhibitor Navitoclax re-engaged the p53–BAX axis, and synergized with B02, TPT or both to override resistance. These data expose new synergistic therapies to trigger p53-induced killing in diverse RB subtypes.

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“…This small molecule is an adenosine sulfamate analog that covalently binds to NAE to create a NEDD8-MLN4924 adduct, consequently blocking neddylation of all cullin-RING ligases (CRLs), which regulate the destruction of many intracellular proteins. Inhibition of CRL neddylation suppresses cancer cell growth by increasing the levels of their substrates, which in turn triggers the DNA damage response, cell-cycle arrest, apoptosis and autophagy (Aubry et al 2020 ). MLN4924 has been applied in several phase I clinical trials for certain solid tumors and hematologic malignancies and showed clinical activity in a phase I clinical trial of acute myelogenous leukemia (AML) (Swords et al 2010 ).…”

Section: Inhibitors Of Ubiquitinating Enzymes-clinical Trialsmentioning

confidence: 99%