Breast cancer virotherapy

乳腺癌是全世界妇女最常诊断的癌症。 尽管在早期发现和治疗方面取得了进展，但仍有一部分患者进展 到无法治愈的转移性疾病因此，迫切需要 有效的治疗策略。乳腺癌的发生主要是由于遗传或表观遗传 异常调节癌基因、肿瘤抑制基因或免疫基因的改变。 虽然有利于癌细胞增殖或免疫逃逸，但这些变化通常 使恶性细胞易受溶瘤性单纯疱疹（HSV）的攻击。有 现在越来越多的人认识到，动态病毒-宿主相互作用决定了 细胞破坏或释放免疫原性因子。初步研究表明， 缺乏所选基因基序的重组HSV有效地复制并裂解 癌细胞此外，它激活了树突细胞，这是必要的调解 适应性抗肿瘤免疫我们假设选择性工程HSV可能 作为一种独特的抗癌平台，在破坏恶性细胞的同时， 引发上级抗肿瘤免疫。凭借最先进的技术，我们将确定 溶瘤HSV在临床前模型中的治疗效力。因此，我们将 系统地检测了遗传修饰的HSV所发挥的抗肿瘤活性。到 实现治疗协同作用，我们将整合环GAMP合酶，一个关键因素， 先天免疫，进入溶瘤病毒骨架。此外，我们将描述其 溶瘤功效与免疫检查点阻断组合。最后，我们将 研究溶瘤HSV重塑肿瘤微环境的性质， 抗肿瘤反应。总的来说，这些研究可以促进小说的发展 用于乳腺癌治疗的药剂。

Breast cancer is the most frequently diagnosed cancer in women worldwide. Despite advances in early detection and treatment, a notable fraction of patients progress to metastatic disease where no cure exists. Accordingly, there is a pressing need for effective therapeutic strategies. Breast cancer arises primarily due to genetic or epigenetic alterations that aberrantly regulate oncogenes, tumor-suppressor genes or immune genes. While advantageous for cancer cell proliferation or immune-escape, these changes often make malignant cells vulnerable to attack by oncolytic herpes simplex (HSV). There is now increased recognition that dynamic virus-host interplay determines the magnitude of cell destruction or release of immunogenic factors. Preliminary studies suggest that recombinant HSV that lacks selected gene motifs efficiently replicates in and lyses cancer cells. Furthermore, it activates dendritic cells that are necessary to mediate adaptive antitumor immunity. We hypothesize that selectively engineered HSV may serve as a distinct anticancer platform, which destructs malignant cells meanwhile primes superior antitumor immunity. With state of the art technology, we will determine the therapeutic potency of oncolytic HSV in preclinical models. As such, we will systematically examine the antitumor activities exerted by genetically modified HSV. To achieve therapeutic synergy, we will integrate cyclic GAMP synthase, a key factor of innate immunity, into the oncolytic virus backbone. In addition, we will characterize its oncolytic efficacy in combination with an immune checkpoint blockade. Lastly, we will investigate the nature by which oncolytic HSV remodels the tumor microenvironment for antitumor responses. Collectively, these studies may facilitate the development of novel agents for breast cancer therapy.