Department of Biochemistry and Molecular Biology, Mayo Clinic Florida, 4500 San Pablo Road S, Jacksonville, FL, 32224, USA.
PolyARNA Therapeutics, One Kendal Square, Cambridge, MA, 01329, USA.
J Exp Clin Cancer Res. 2024 Jun 6;43(1):159. doi: 10.1186/s13046-024-03079-8.
Renal cell carcinoma (RCC) was historically considered to be less responsive to radiation therapy (RT) compared to other cancer indications. However, advancements in precision high-dose radiation delivery through single-fraction and multi-fraction stereotactic ablative radiotherapy (SABR) have led to better outcomes and reduced treatment-related toxicities, sparking renewed interest in using RT to treat RCC. Moreover, numerous studies have revealed that certain therapeutic agents including chemotherapies can increase the sensitivity of tumors to RT, leading to a growing interest in combining these treatments. Here, we developed a rational combination of two radiosensitizers in a tumor-targeted liposomal formulation for augmenting RT in RCC. The objective of this study is to assess the efficacy of a tumor-targeted liposomal formulation combining the mTOR inhibitor everolimus (E) with the survivin inhibitor YM155 (Y) in enhancing the sensitivity of RCC tumors to radiation.
We slightly modified our previously published tumor-targeted liposomal formulation to develop a rational combination of E and Y in a single liposomal formulation (EY-L) and assessed its efficacy in RCC cell lines in vitro and in RCC tumors in vivo. We further investigated how well EY-L sensitizes RCC cell lines and tumors toward radiation and explored the underlying mechanism of radiosensitization.
EY-L outperformed the corresponding single drug-loaded formulations E-L and Y-L in terms of containing primary tumor growth and improving survival in an immunocompetent syngeneic mouse model of RCC. EY-L also exhibited significantly higher sensitization of RCC cells towards radiation in vitro than E-L and Y-L. Additionally, EY-L sensitized RCC tumors towards radiation therapy in xenograft and murine RCC models. EY-L mediated induction of mitotic catastrophe via downregulation of multiple cell cycle checkpoints and DNA damage repair pathways could be responsible for the augmentation of radiation therapy.
Taken together, our study demonstrated the efficacy of a strategic combination therapy in sensitizing RCC to radiation therapy via inhibition of DNA damage repair and a substantial increase in mitotic catastrophe. This combination therapy may find its use in the augmentation of radiation therapy during the treatment of RCC patients.
与其他癌症适应症相比，肾细胞癌（RCC）在历史上被认为对放射治疗（RT）的反应性较低。然而，通过单次分割和多分割立体定向消融放疗（SABR）实现的精准高剂量放射递送来治疗 RCC。此外，许多研究表明，某些治疗剂，包括化疗药物，可以提高肿瘤对 RT 的敏感性，这使得人们对联合使用这些治疗方法的兴趣日益增加。在这里，我们开发了一种将两种放射增敏剂靶向包封在脂质体中的合理组合，以增强 RCC 的 RT 效果。本研究的目的是评估靶向肿瘤的脂质体制剂联合 mTOR 抑制剂依维莫司（E）和存活素抑制剂 YM155（Y）增强 RCC 肿瘤对辐射敏感性的疗效。
我们对之前发表的靶向肿瘤的脂质体制剂进行了轻微修改，开发了一种将 E 和 Y 靶向包封在单一脂质体制剂（EY-L）中的合理组合，并在体外评估了其对 RCC 细胞系的疗效，以及体内 RCC 肿瘤的疗效。我们进一步研究了 EY-L 对 RCC 细胞系和肿瘤对辐射的增敏作用，并探讨了放射增敏的潜在机制。
与相应的单药负载制剂 E-L 和 Y-L 相比，EY-L 在抑制原发肿瘤生长和提高免疫活性同种异体 RCC 小鼠模型存活率方面表现更好。体外实验结果显示，EY-L 对 RCC 细胞的辐射增敏作用明显高于 E-L 和 Y-L。此外，EY-L 在异种移植和小鼠 RCC 模型中增强了 RCC 肿瘤对放射治疗的敏感性。EY-L 通过下调多个细胞周期检查点和 DNA 损伤修复途径诱导有丝分裂灾难，这可能是增强放射治疗的原因。
综上所述，我们的研究表明，通过抑制 DNA 损伤修复和有丝分裂灾难的大量增加，一种策略性联合治疗可以有效地使 RCC 对放射治疗敏感。这种联合治疗方法可能会在治疗 RCC 患者时用于增强放射治疗。
