Preclinical Assessment of the Combination of PSMA-Targeting Radionuclide Therapy with PARP Inhibitors for Prostate Cancer Treatment.
Preclinical Assessment of the Combination of PSMA-Targeting Radionuclide Therapy with PARP Inhibitors for Prostate Cancer Treatment.
复制标题
DOI：
10.3390/ijms23148037
复制
发表时间：
2022-07-21
影响因子：
5.6
通讯作者：
中科院分区：
文献类型：
--
作者：
前列腺特异性膜抗原靶向放射性核素治疗（PSMA-TRT）是前列腺癌（PCa）患者的一种有前途的新型治疗方法。然而，PSMA-TRT 尚不能用于治疗目的，因此有必要进一步研究如何提高治疗效果。实现这一目标的一种潜在方法是将 TRT 与聚 ADP-核糖基化抑制剂 (PARPi) 相结合，该抑制剂在神经内分泌肿瘤细胞的 TRT 方面显示出有希望的结果。目前，该组合治疗 PCa 的多项临床试验已启动，但迄今为止，尚无针对 PCa 的协同作用证据。因此，我们在临床前 PCa 模型中评估了 PSMA-TRT 与三类 PARPi 的组合。使用表达 PSMA 的 PCa 细胞系 PC3-PIP 和 LNCaP 进行体外活力和存活测定，以评估与单次 PARPi 治疗相比，增加 PARPi veliparib、olaparib 或 talazoparib 浓度与 PSMA-TRT 组合的效果。接下来，通过免疫荧光染色定量 DNA 断裂数量来进行 DNA 损伤分析。最后，在携带 PC3-PIP 异种移植物的小鼠体内研究了联合治疗的潜力。我们的结果表明，PSMA-TRT 与 PARPi 组合不会协同影响体外克隆存活或细胞活力。 DNA 损伤分析显示，当 PSMA-TRT 与 veliparib 联合治疗时，DNA 断裂仅显着增加，而其他联合治疗则没有。此外，与 PSMA-TRT 单一疗法相比，PSMA-TRT 联合 PARPi 治疗并没有改善肿瘤控制。总体而言，所提供的数据并不支持将 PSMA-TRT 与 PARPi 相结合可在 PCa 中产生协同抗肿瘤作用的假设。这些结果强调，与其他癌症类型一样，必须使用各种 PCa 模型进行广泛的临床前研究，以验证组合策略对 PCa 的适用性。
Prostate specific membrane antigen targeted radionuclide therapy (PSMA-TRT) is a promising novel treatment for prostate cancer (PCa) patients. However, PSMA-TRT cannot be used for curative intent yet, thus additional research on how to improve the therapeutic efficacy is warranted. A potential way of achieving this, is combining TRT with poly ADP-ribosylation inhibitors (PARPi), which has shown promising results for TRT of neuroendocrine tumor cells. Currently, several clinical trials have been initiated for this combination for PCa, however so far, no evidence of synergism is available for PCa. Therefore, we evaluated the combination of PSMA-TRT with three classes of PARPi in preclinical PCa models. In vitro viability and survival assays were performed using PSMA-expressing PCa cell lines PC3-PIP and LNCaP to assess the effect of increasing concentrations of PARPi veliparib, olaparib or talazoparib in combination with PSMA-TRT compared to single PARPi treatment. Next, DNA damage analyses were performed by quantifying the number of DNA breaks by immunofluorescent stainings. Lastly, the potential of the combination treatments was studied in vivo in mice bearing PC3-PIP xenografts. Our results show that combining PSMA-TRT with PARPi did not synergistically affect the in vitro clonogenic survival or cell viability. DNA-damage analysis revealed only a significant increase in DNA breaks when combining PSMA-TRT with veliparib and not in the other combination treatments. Moreover, PSMA-TRT with PARPi treatment did not improve tumor control compared to PSMA-TRT monotherapy. Overall, the data presented do not support the assumption that combining PSMA-TRT with PARPi leads to a synergistic antitumor effect in PCa. These results underline that extensive preclinical research using various PCa models is imperative to validate the applicability of the combination strategy for PCa, as it is for other cancer types.
登录
查看更多内容
DOI：
10.1007/s00259-019-04345-0
发表时间：
2019-08-01
影响因子：
9.1
作者：
Muller, Cristina;Umbricht, Christoph A.;van der Meulen, Nicholas P.
通讯作者：
van der Meulen, Nicholas P.
影响因子：
9.3
作者：
Kratochwil, Clemens;Bruchertseifer, Frank;Morgenstern, Alfred
通讯作者：
Morgenstern, Alfred
影响因子：
5.7
作者：
Murai J;Huang SY;Renaud A;Zhang Y;Ji J;Takeda S;Morris J;Teicher B;Doroshow JH;Pommier Y
通讯作者：
Pommier Y
DOI：
10.1158/1078-0432.ccr-14-2572
发表时间：
2015-02-15
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
--
作者：
Smith MA;Reynolds CP;Kang MH;Kolb EA;Gorlick R;Carol H;Lock RB;Keir ST;Maris JM;Billups CA;Lyalin D;Kurmasheva RT;Houghton PJ
通讯作者：
Houghton PJ
影响因子：
--
作者：
Purohit, Nupur K;Shah, Rashmi G;Beauregard, Jean-Mathieu
通讯作者：
Beauregard, Jean-Mathieu