Strategies to Enhance Virotherapy for Breast Cancer

描述(申请人提供)：溶瘤病毒是治疗乳腺癌等恶性疾病的一种有价值的新方法，因为它们可以选择性地在肿瘤细胞中复制，而不影响正常细胞。与典型的基于基因的癌症治疗不同，溶瘤病毒通过选择性复制/细胞溶解直接杀死肿瘤细胞，然后扩散到周围的肿瘤组织。这些特性提供了一个主要的优势，而不是基因传递的固有低效，因此有限的肿瘤细胞杀伤力通常与基因介导性治疗相比。在上一个资助期进行的研究表明，将细胞膜融合活性整合到溶瘤单纯疱疹病毒(HSV)中可以显著增强该病毒对乳腺癌的杀瘤效果。此外，双融合溶瘤HSV(Synco-2D)可诱导有效的抗肿瘤免疫反应。目前的方案建立在这些先前进展的基础上，并研究了能够最大化Synco-2D的抗肿瘤效果的策略，从而增加了其临床成功的可能性。我们提出的研究的目标1将检验是否可以通过合理设计的组合策略来进一步增强Synco-2D的抗肿瘤活性，包括在病毒中加入血栓诱导因子和改变肿瘤微环境以利于病毒复制。目的2将探索能够改善Synco-2D介导的肿瘤分解所诱导的抗肿瘤免疫反应的功能的策略。特别是，我们将研究共刺激分子的表观遗传上调是否可以显著改善诱导的抗肿瘤免疫的功能。我们还将确定酸性肿瘤微环境是否影响免疫效应细胞的抗肿瘤活性，并探索逆转不利影响的策略。AIM 3将寻求开发使Synco-2D能够摧毁肿瘤干细胞以获得长期治疗效果的策略。该项目的长期目标是开发一种有效的病毒疗法，能够对晚期乳腺癌产生显著的治疗效果，并有可能在不久的将来转化为临床使用。公共卫生相关性：尽管最近在早期诊断和治疗方面取得了进展，但乳腺癌患者的预后仍然非常差。这项建议旨在开发一种新的病毒疗法来治疗晚期乳腺癌患者，拟议研究的成功将极大地造福于这种恶性疾病的患者。

DESCRIPTION (provided by applicant): Oncolytic viruses represent a valuable new modality for the treatment of malignant diseases such as breast cancer, as they can selectively replicate in tumor cells while sparing normal cells. Unlike typical gene-based forms of cancer therapy, oncolytic viruses kill tumor cells directly through their selective replication/cytolysis and consequent spread to surrounding tumor tissues. These properties offer a major advantage over the inherent inefficiency of gene delivery and thus the limited tumor cell killing often seen with gene-mediated therapy. Work conducted during the previous funding period has demonstrated that incorporation of cell membrane fusion activity into an oncolytic herpes simplex virus (HSV) can significantly enhance the tumor killing effect of the virus against breast cancer. Moreover, tumor destruction by a doubly fusogenic oncolytic HSV (Synco-2D) can elicit effective antitumor immune responses. The current proposal builds upon these prior advances and investigates strategies that can maximize the antitumor effect of Synco-2D, thus increasing the likelihood of its clinical success. The Aim 1 of our proposed studies will examine if the antitumor activity of Synco-2D can be further enhanced by rationally designed combinatorial strategies, including incorporation of a thrombosis-inducing factor into the virus and alteration of tumor microenvironment to favor the virus replication. Aim 2 will explore strategies that can improve the functionality of antitumor immune responses elicited by Synco-2D-mediated oncolysis. In particular, we will investigate if epigenetic upregulation of costimulatory molecules can significantly improve the functionality of the induced antitumor immunity. We will also determine if the acidic tumor microenvironment affects the antitumor activity of immune effector cells, and explore strategies that can reverse the adverse effect. Aim 3 will seek to develop strategies that enable Synco-2D to destroy tumor stem cells for a long-lasting therapeutic effect. The long-term goal of this project is to develop a potent virotherapy capable of producing significant therapeutic effects against advanced-stage breast cancer, with the potential to be translated into clinical use in the near future. PUBLIC HEALTH RELEVANCE: Despite recent progresses in early diagnosis and treatment, patients with breast cancer still have very poor prognoses. This proposal seeks to develop a novel virotherapy to treat patients with late stage breast cancer and success of the proposed studies will greatly benefit patients suffering from this malignant disease.