Malignant rhabdoid tumors (MRTs) are among the most aggressive and treatment-resistant malignancies affecting infants, originating in the kidney, brain, liver, and soft tissues. The 5-year event-free survival rate for these cancers is a mere 20%. In nearly all cases of MRT, theSMARCB1gene (occasionallySMARCA4)—a pivotal component of the SWI/SNF chromatin remodeling complex—is homozygously deleted, although the precise etiology of these tumors remains unknown. While young patients with localized MRT generally show improved outcomes, especially those who are older and have early-stage disease, the overall prognosis remains poor despite optimal standard treatments. This highlights the urgent need for more effective treatment strategies. We investigated the antitumor activity of a PARP1 inhibitor (talazoparib, TLZ) combined with a DNA alkylating agent (temozolomide, TMZ) in MRT xenograft models. PARP1 is a widely targeted molecule in cancer treatment and, beyond its role in DNA repair, it participates in transcriptional regulation by recruiting chromatin remodeling complexes to modulate DNA accessibility for RNA polymerases. To widen the therapeutic window of the drug combination, we employed PEGylated TLZ (PEG~TLZ), which has been reported to reduce systemic toxicity through slow drug release. Remarkably, our findings indicate that five out of six MRT xenografts exhibited an objective response to PEG~TLZ+TMZ therapy. Significantly, the loss ofSMARCB1was found to confer a protective effect, correlating with higher expression levels of DNA damage and repair proteins inSMARCB1-deficient MRT cells. Additionally, we identified MGMT as a potential biomarker indicative of in vivo MRT response to PEG~TLZ+TMZ therapy. Moreover, our analysis revealed alterations in signaling pathways associated with the observed antitumor efficacy. This study presents a novel and efficacious therapeutic approach for MRT, along with a promising candidate biomarker for predicting tumor response.
恶性横纹肌样瘤（MRTs）是影响婴幼儿最具侵袭性和治疗抵抗性的恶性肿瘤之一，起源于肾脏、大脑、肝脏及软组织。这类癌症的5年无事件生存率仅为20%。几乎所有MRT病例都存在SWI/SNF染色质重塑复合体关键组分SMARCB1基因（少数为SMARCA4）的纯合性缺失，但其确切病因仍不明确。虽然局限性MRT的年轻患者（尤其是年龄较大且处于疾病早期者）预后相对改善，但即使接受最佳标准治疗，总体预后仍然较差，这凸显了开发更有效治疗策略的迫切需求。本研究在MRT异种移植模型中探讨了PARP1抑制剂（他拉唑帕利，TLZ）联合DNA烷化剂（替莫唑胺，TMZ）的抗肿瘤活性。PARP1是癌症治疗中广泛靶向的分子，除参与DNA修复外，还能通过招募染色质重塑复合体调节RNA聚合酶的DNA可及性，从而参与转录调控。为拓宽联合用药的治疗窗口，我们采用聚乙二醇化TLZ（PEG~TLZ），该剂型可通过缓慢释放药物降低全身毒性。值得注意的是，研究发现六种MRT异种移植模型中有五种对PEG~TLZ+TMZ治疗产生客观反应。特别重要的是，SMARCB1缺失被发现具有保护效应，这与SMARCB1缺陷型MRT细胞中DNA损伤修复蛋白的高表达水平相关。此外，我们鉴定出MGMT可作为预测MRT体内对PEG~TLZ+TMZ治疗反应的潜在生物标志物。进一步分析揭示了与观察到的抗肿瘤疗效相关的信号通路改变。本研究为MRT提供了一种新型有效治疗策略，并提出了具有前景的肿瘤反应预测生物标志物。
Synergistic Antitumor Activity of Talazoparib and Temozolomide in Malignant Rhabdoid Tumors
肿瘤(癌症)患者之家