Therapeutic miRNAs in combination with conventional chemotherapy

描述(申请人提供)：位于德克萨斯州的miRNA治疗公司正在开发使用肿瘤抑制因子miRNAs的非小细胞肺癌(NSCLC)疗法。这种方法，“miRNA替代疗法”，是基于这样一个概念，即重新引入在癌细胞中耗尽的miRNAs会重新激活驱动治疗反应的细胞通路。MiRNA正在开发5个miRNA候选药物，并有大量数据表明，治疗性输送miRNAs可有效抑制肿瘤生长，并在临床前动物试验中耐受性良好。与初步数据一致，我们假设miRNAs将使癌细胞对传统疗法敏感，这将在正常组织中产生更有效的癌症治疗方法，毒性最小。在这项建议中，我们试图系统地评估目前临床上最常用的miRNA模拟物和传统疗法的组合效果。这些研究将以化疗药物顺铂、卡铂、吉西他滨和紫杉醇为特色，以及米尔纳在一个为期8年的研究计划中使用癌症细胞和动物模型确定的5种最有效的肿瘤抑制药的模拟物，现在是其治疗开发管道的一部分。这项提议的一个关键优势是获得对传统疗法的敏感性和耐药性得到很好证明的肺癌细胞系。在目标1中，将使用对个别化疗敏感或耐药的癌细胞来评估miRNA/化疗组合，以确定哪些细胞比单独化疗更有效。在目标2中，将在癌症动物模型中评估1-2种最有效的miRNA/化疗组合。这项建议的目标是确定一种具有更高疗效的miRNA/Chemo组合，用于进一步的临床开发。 公共卫生相关性：联合疗法被广泛认为是治疗癌症的最有效方法。利用肺癌模型，这项建议试图评估传统化疗与治疗性miRNAs的结合，miRNAs是一类有前途的抗癌药物。其目标是确定一种比单独化疗更有效的miRNA/化疗组合。

DESCRIPTION (provided by applicant): Mirna Therapeutics, a Texas-based company, is developing non-small cell lung cancer (NSCLC) therapies using tumor suppressor miRNAs. This approach, "miRNA replacement therapy", is based on the concept that re-introduction of miRNAs depleted in cancer cells reactivates cellular pathways that drive a therapeutic response. Mirna is developing 5 miRNA candidates and has extensive data showing that therapeutic delivery of miRNAs mimics robustly inhibits tumor growth and is well tolerated in pre-clinical animal studies. In agreement with preliminary data, we hypothesize that miRNAs will sensitize cancer cells to conventional therapies which will generate more efficacious cancer treatments with minimal toxicity in normal tissues. In this proposal, we seek to systematically evaluate the combinatorial effects of miRNA mimics and conventional therapies that are most commonly used in the clinic today. The studies will feature the chemotherapeutic agents cisplatin, carboplatin, gemcitabine and paclitaxel, as well as 5 mimics of the most efficacious tumor suppressors that Mirna has identified over the course of an 8-year research program using cell and animal models of cancer and are now part of its pipeline for therapeutic development. A key strength of this proposal is access to lung cancer cell lines for which sensitivity and resistance to conventional therapies are well documented. In Aim 1, miRNA/chemo combinations will be evaluated using cancer cells that are either sensitive or resistant to the individual chemotherapy to identify those that are more effective than chemo alone. In Aim 2, the 1-2 most effective miRNA/chemo combos will be evaluated in the animal models of cancer. The goal of this proposal is to identify a miRNA/chemo combination with improved efficacy for further clinical development. PUBLIC HEALTH RELEVANCE: Combinatorial therapy is broadly viewed as the most effective way to treat cancer. Using models of lung cancer, this proposal seeks to evaluate the combination of conventional chemotherapies with therapeutic miRNAs, a promising class of anti-cancer agents. The goal is to identify a miRNA/chemo combination that is more effective than chemotherapy alone.