In silico discovery of a FOXM1 driven embryonal signaling pathway in therapy resistant neuroblastoma tumors

Herman

Expert Opinion on Therapeutic Targets

2020

Introduction: Neuroblastoma (NB) is the prime cancer of infancy, and accounts for 9% of pediatric cancer deaths. While children diagnosed with clinically stable NB experience a complete cure, those with high-risk disease (HR-NB) do not recover, despite intensive therapeutic strategies. Development of novel and effective targeted therapies is needed to counter disease progression, and to benefit long-term survival of children with HR-NB. Areas covered:Recent studies (2017-2020) pertinent to NB evolution are selectively reviewed to recognize novel and effective therapeutic targets. The prospective and promising therapeutic targets/strategies for HR-NB are categorized into (a) targeting oncogene-like and/or reinforcing tumor suppressor (TS)-like lncRNAs; (b) targeting oncogene-like microRNAs (miRs) and/or mimicking TS-miRs; (c) targets for immunotherapy; (d) targeting epithelial-to-mesenchymal transition and cancer stem cells; (e) novel and beneficial combination approaches; and (f) repurposing drugs and other strategies in development.Expert opinion: It is highly unlikely that agents targeting a single candidate or signaling will be beneficial for an HR-NB cure. We must develop efficient drug deliverables for functional targets, which could be integrated and advance clinical therapy. Fittingly, the looming evidence indicated an aggressive evolution of promising novel and integrative targets, development of efficient drugs, and improvised strategies for HR-NB treatment.

Section: Targeting Mirnasmentioning

confidence: 99%

Emerging therapeutic targets for neuroblastoma

Herman

Expert Opinion on Therapeutic Targets

2020

“…Although this focus is still in its infancy, researchers are attempting to understand the basics. On that note, with an in silico approach, studies have listed a panel of ESC miRs along with mRNA signatures that are associated with poor NB patient outcomes, specifically for the N-MYC-amplified and N-MYC non-amplified high-risk subsets [171] . In addition, the findings indicated that the ESC signature is majorly driven by FOXM1 and could be useful to inhibit tumor progression and therapy resistance.…”

Section: Role Of Mirs In Nb Therapy Resistancementioning

confidence: 99%

MicroRNAs in neuroblastoma tumorigenesis, therapy resistance, and disease evolution

Aravindan¹,

Karthikeyan²,

Somasundaram³

et al. 2019

CDR

Neuroblastoma (NB) deriving from neural crest cells is the most common extra-cranial solid cancer at infancy. NB originates within the peripheral sympathetic ganglia in adrenal medulla and along the midline of the body. Clinically, NB exhibits significant heterogeneity stretching from spontaneous regression to rapid progression to therapy resistance. MicroRNAs (miRNAs, miRs) are small (19-22 nt in length) non-coding RNAs that regulate human gene expression at the post-transcriptional level and are known to regulate cellular signaling, growth, differentiation, death, stemness, and maintenance. Consequently, the function of miRs in tumorigenesis, progression and resistance is of utmost importance for the understanding of dysfunctional cellular pathways that lead to disease evolution, therapy resistance, and poor clinical outcomes. Over the last two decades, much attention has been devoted to understanding the functional roles of miRs in NB biology. This review focuses on highlighting the important implications of miRs within the context of NB disease progression, particularly miRs' influences on NB disease evolution and therapy resistance. In this review, we discuss the functions of both the "oncomiRs" and "tumor suppressor miRs" in NB progression/therapy resistance. These are the critical components to be considered during the development of novel miR-based therapeutic strategies to counter therapy resistance.

Genes Chromosomes & Cancer

“…This is of interest given that 17q gains and amplifications are a recurrent finding in cancers including embryonic malignancies such as neuroblastoma and medulloblastoma. In neuroblastoma, we recently reported an elevated ESC‐derived stemness gene signature activity in ultra‐high‐risk patients 7 . In view of the above, we investigated the selective growth advantage of segmental chromosomal aberrations (with primary focus on 17q+) in hESCs under controlled replicative stress conditions as this may also provide insights into the functional significance of recurrent 17q + in cancer cells.…”

Section: Introductionmentioning

confidence: 99%

Recurrent chromosomal imbalances provide selective advantage to human embryonic stem cells under enhanced replicative stress conditions

Mus

Haver

Popovic

et al. 2021

Self Cite

Human embryonic stem cells (hESCs) and embryonal tumors share a number of common features, including a compromised G1/S checkpoint. Consequently, these rapidly dividing hESCs and cancer cells undergo elevated levels of replicative stress, inducing genomic instability that drives chromosomal imbalances. In this context, it is of interest that long‐term in vitro cultured hESCs exhibit a remarkable high incidence of segmental DNA copy number gains, some of which are also highly recurrent in certain malignancies such as 17q gain (17q+). The selective advantage of DNA copy number changes in these cells has been attributed to several underlying processes including enhanced proliferation. We hypothesized that these recurrent chromosomal imbalances become rapidly embedded in the cultured hESCs through a replicative stress driven Darwinian selection process. To this end, we compared the effect of hydroxyurea‐induced replicative stress vs normal growth conditions in an equally mixed cell population of isogenic euploid and 17q + hESCs. We could show that 17q + hESCs rapidly overtook normal hESCs. Our data suggest that recurrent chromosomal segmental gains provide a proliferative advantage to hESCs under increased replicative stress, a process that may also explain the highly recurrent nature of certain imbalances in cancer.