Repurposing a psychoactive drug for children with cancer: p27Kip1-dependent inhibition of metastatic neuroblastomas by Prozac.,Oncogenesis

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Repurposing a psychoactive drug for children with cancer: p27Kip1-dependent inhibition of metastatic neuroblastomas by Prozac.
Oncogenesis ( IF 5.9 ) Pub Date : 2020-01-02 , DOI: 10.1038/s41389-019-0186-3
Sandra Bibbo' _{1,

2} , Alessia Lamolinara _{2,

3} , Emily Capone _{2,

4} , Stefania Purgato ₅ , Alexia Tsakaneli ₆ , Valeria Panella _{1,

2} , Michele Sallese _{2,

4} , Cosmo Rossi ₂ , Paolo Ciufici _{1,

2} , Valentina Nieddu _{1,

7} , Vincenzo De Laurenzi _{2,

4} , Manuela Iezzi _{2,

3} , Giovanni Perini ₅ , Gianluca Sala _{2,

4} , Arturo Sala _{1,

2,

6}

Affiliation

The MYC family of transcription factors is a major driver of human cancer and potential therapeutic target. However, no clinically viable drugs have been yet developed that are able to directly tackle MYC oncoproteins. In our laboratory, we are exploring alternative approaches aiming to disturb signalling downstream of MYC. MYCN is frequently activated in neuroblastoma, a paediatric solid malignancy that, in its metastatic form, has a very poor prognosis. An important pathway regulated by MYC is the CKS1/SKP2/p27kip1 axis. In this study, we have repurposed the anti-psychotic drug Prozac to disrupt CKS1/SKP2/p27Kip1 signalling and assess its potential as an anti-neuroblastoma agent in vitro and in vivo. Using DNA editing technology, we show that stabilisation of p27Kip1 operated by Prozac in MYC-activated cells is essential for the anti-neuroblastoma activity of the drug. Furthermore, dosing mice with a concentration of Prozac equivalent to that used in long-term clinical trials in children with psychiatric disorders caused a significant reduction of metastatic disease in two models of high-risk neuroblastoma. The favourable toxicity profile of Prozac suggests that long-term treatments might be implemented in children with MYC/CKS1high neuroblastomas.

中文翻译：

为患癌症的儿童改用精神活性药物：Prozac对p27Kip1的转移性神经母细胞瘤的抑制作用。

MYC转录因子家族是人类癌症和潜在治疗靶标的主要驱动力。但是，尚未开发出能够直接解决MYC癌蛋白的临床上可行的药物。在我们的实验室中，我们正在探索旨在干扰MYC下游信号的替代方法。MYCN常在神经母细胞瘤中激活，神经母细胞瘤是一种儿童实体恶性肿瘤，其转移形式预后很差。MYC调节的重要途径是CKS1 / SKP2 / p27kip1轴。在这项研究中，我们将抗精神病药物Prozac重新用于破坏CKS1 / SKP2 / p27Kip1信号传导，并评估其在体外和体内作为抗神经母细胞瘤药物的潜力。使用DNA编辑技术，我们表明，由Prozac在MYC激活的细胞中稳定的p27Kip1对于该药物的抗神经母细胞瘤活性至关重要。此外，在两种高风险神经母细胞瘤模型中，给小鼠服用Prozac的浓度与长期用于精神疾病儿童的长期临床试验所用的浓度相同，会导致转移性疾病的明显减少。百忧解具有良好的毒性，提示对患有MYC / CKS1高神经母细胞瘤的儿童可能需要长期治疗。

更新日期：2020-01-02

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