Hyperthermia-mediated gene therapy approach for cancer

描述(申请人提供)：在癌症基因治疗成为临床现实之前，必须克服两个主要障碍：肿瘤特异性治疗基因激活和有效地将基因治疗载体输送到肿瘤组织中。基因疗法与传统癌症疗法的不同之处在于，它能够特异性地激活癌细胞中的治疗基因。在之前的资金周期中，我们在开发一种新的基因治疗方法方面取得了实质性进展，通过这种方法，热疗可以调节治疗基因。我们已经证明，在实验肿瘤模型中，治疗基因可以通过热疗以非常有效和有针对性的方式进行调节，具有令人印象深刻的抗肿瘤效果。然而，我们仍然面临着基因治疗载体传递效率低下的问题，这可能严重阻碍我们原本非常有希望的策略的应用。在这项应用中，我们希望在以前成功的基础上，继续改进我们的高温调节基因治疗方法。我们将同时处理基因治疗的监管问题和交付问题。我们会采取双管齐下的方法。一方面，我们将继续探索新的基因调控方法，以进一步改善/增强我们的热诱导治疗性基因激活策略。另一方面，我们将通过开发高温调节的复制能力腺病毒载体来解决基因传递问题，该载体可以在肿瘤块中选择性复制。特别是，我们将有两个具体目标。在具体目标1中，我们将开发一种新的基因调控策略，可能进一步增强热疗激活的治疗性基因的表达。为此，我们将尝试设计一种新型的基于Cre-lox的不可逆基因开关，该开关可以潜在地增强热激活基因治疗的调节和表达。在特定的目标2，我们将发展有条件的复制型腺病毒载体，在高温或低氧的控制下进行病毒复制。我们将设计重组腺病毒载体，使其能够在经高温处理的肿瘤细胞中选择性复制，或在低氧肿瘤细胞中选择性复制。众所周知的抗血管生成基因内皮抑素将被改造到载体中。然后将评估这些载体单独或与热疗和/或电离辐射联合使用的抗肿瘤效果。在新的资金周期结束时，我们希望在热疗介导的基因治疗方法的交付和监管方面取得重大进展，从而使其更接近临床人类癌症治疗。

DESCRIPTION (provided by applicant): There are two major hurdles that must be overcome before cancer gene therapy becomes a clinical reality: tumor-specific therapeutic gene activation and efficient delivery of gene therapy vectors into the tumor mass. The ability to specifically activate therapeutic genes in cancer cells is what differentiates gene therapy from conventional cancer therapies. In the previous funding cycle, we have made substantial progress in developing a novel gene therapy approach by which therapeutic genes can be regulated by hyperthermia. We have shown that therapeutic genes can be regulated by hyperthermia in a very efficient and targeted fashion in the tumor mass with impressive anti-tumor efficacy in experimental tumor models. However, we are still faced with the problem of inefficient delivery of the gene therapy vectors, which can serious hinder the application of our otherwise very promising strategy. In this application, we want to build upon our previous successes and continue to improve our hyperthermia-regulated gene therapy approach. We will deal with both the regulation issue and the delivery issue for gene therapy. A two-pronged approach will be employed. On the one hand, we will continue to explore new gene regulation approaches that may further improve/enhance our heat-induced therapeutic gene activation strategy. On the other hand, we will tackle the gene delivery issue by developing hyperthermia-regulated replication competent adenovirus vectors that can selectively replicate in the tumor mass. In particular, we will have two specific aims. In specific aim 1, we will develop a novel gene regulation strategy that may further enhance hyperthermia-activated therapeutic gene expression. For this specific aim, we will attempt to design a novel Cre-lox based irreversible genetic switch that can potentially enhance the regulation and expression of heat-activated gene therapy. In specific aim 2, we will develop conditionally replicative adenovirus vectors with virus replication under the control of hyperthermia or hypoxia. We will engineer recombinant adenovirus vectors that can selectively replicate in hyperthermia-treated tumor cells or those that can selectively replicate in hypoxic tumor cells. The well-known anti-angiogenic gene endostatin will be engineered into the vectors. The vectors will then be evaluated for their anti-tumor efficacy either alone or in combination with hyperthermia and/or ionizing radiation. At the end of the new funding cycle, we hope to make significant advancement in both the delivery and the regulation of the hyperthermia-mediated gene therapy approach, thereby making it even closer to clinical human cancer treatment.