Strategies to Enhance Virotherapy for Breast Cancer

描述（由申请人提供）：溶瘤病毒代表了治疗恶性疾病（如乳腺癌）的一种有价值的新模式，因为它们可以选择性地在肿瘤细胞中复制，同时保留正常细胞。与典型的基于基因的癌症治疗形式不同，溶瘤病毒通过其选择性复制/细胞溶解直接杀死肿瘤细胞，并随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，而不是固有的低效率的基因传递，因此有限的肿瘤细胞杀伤通常与基因介导治疗。在上一个资助期内进行的工作表明，将细胞膜融合活性纳入溶瘤性单纯疱疹病毒（HSV）可以显著增强该病毒对乳腺癌的肿瘤杀伤作用。此外，双重融合性溶瘤HSV （Synco-2D）破坏肿瘤可引起有效的抗肿瘤免疫反应。目前的建议建立在这些先前的进展和研究策略，可以最大限度地提高Synco-2D的抗肿瘤作用，从而增加其临床成功的可能性。我们提出的研究的目的1将检验Synco-2D的抗肿瘤活性是否可以通过合理设计的组合策略进一步增强，包括将血栓形成诱导因子并入病毒和改变肿瘤微环境以促进病毒复制。目的2将探索可以改善由synco - 2d介导的肿瘤溶解引起的抗肿瘤免疫反应功能的策略。特别是，我们将研究是否表观遗传上调共刺激分子可以显著提高诱导抗肿瘤免疫的功能。我们还将确定酸性肿瘤微环境是否会影响免疫效应细胞的抗肿瘤活性，并探索可以逆转这种不利影响的策略。目标3将寻求开发策略，使Synco-2D能够破坏肿瘤干细胞以获得持久的治疗效果。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应用。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很差。本提案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患有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.