A novel approach to target Rb mutant cancers

描述(由申请人提供)：癌症治疗的成功通常取决于其针对癌细胞的特定独特需求的能力，这些需求与体内正常细胞的需求不同。目前处于不同发展阶段的靶向癌症治疗主要集中在抑制去调控的致癌途径。对酪氨酸激酶抑制剂，如Gefitinib和Gleevec(分别是EGFR和Abl酪氨酸激酶的抑制剂)的临床研究揭示了这些靶向抗癌药物的两个一般特性：1)它们通常只对一小部分癌症有效，这些癌症的基因改变使这些癌症对靶向去调控的致癌信号“上瘾”；2)对这些抑制剂产生抗药性的癌症最终会发展起来。这些观察表明，需要有大量针对不同癌细胞特征的抗癌药物。在这种情况下，可以使用不同的靶向抗癌药物组合来专门针对不同的癌症亚类，并防止耐药癌症的发展。除了去调控的致癌基因激活外，癌细胞还经常有肿瘤抑制基因的失活。然而，很少有人致力于开发针对癌症中这种肿瘤抑制功能丧失的治疗方法。靶向功能缺失的肿瘤抑制因子的主要困难是缺乏直接的方法来恢复所有癌细胞中丧失的肿瘤抑制因子功能，或者用灭活的肿瘤抑制因子特异性地杀死癌细胞。在不同类型的癌症中，Rb肿瘤抑制基因通常由于Rb基因本身的突变、Rb表达的缺失或其功能失活而失活。Rb通路在果蝇中高度保守。我们在果蝇中进行了一项遗传筛选，以确定能够调节Rb突变细胞凋亡的基因。我们的基因筛查导致了一种基因的鉴定，该基因是在发育中的苍蝇组织和癌细胞中阻止Rb突变细胞凋亡所必需的。这些观察表明，我们的通用筛选导致了一个基因的鉴定，该基因可能被用来作为靶点，用灭活的Rb肿瘤抑制因子特异性地杀死癌细胞。在这笔拨款中，我们将进一步研究这一想法，以确定涉及的机制，并调查潜在的靶向癌细胞亚群。此外，我们将开发检测方法来筛选小分子抑制物，这些小分子抑制物可以用来通过失活的Rb途径特异性地杀死癌细胞。

DESCRIPTION (provided by applicant): The success of a cancer therapy generally depends on its ability to target certain unique requirements of the cancer cells that are distinct from those of the normal cells in the body. Current targeted cancer therapies at different stages of development mostly focus on inhibiting the deregulated oncogenic pathways. clinical studies of tyrosine kinase inhibitors such as Gefitinib and Gleevec (inhibitors of EGFR and Abl tyrosine kinases, respectively) revealed two general properties of these targeted cancer drugs: 1) they are generally only effective to a small subset of cancers with genetic alterations that make these cancers "addicted" to the deregulated oncogenic signaling being targeted; 2) cancers that are resistant to these inhibitors will eventually develop. These observations suggested the need to have large number of cancer drugs that target different features of cancer cells. In this case, different combinations of targeted cancer drugs can be used to specifically target different subsets of cancers and to prevent the development of resistant cancers. In addition to deregulated oncogenic activation, cancer cells also often have inactivation of tumor suppressor genes. However, very little effort has been devoted to develop therapeutic approaches that target such loss of tumor suppressor function in cancers. The main difficulty with targeting the loss of function tumor suppressors is the lack of straightforward approaches to either restore the lost tumor suppressor function in all the cancer cells or to specifically kill cancer cells with inactivated tumor suppressors. The Rb tumor suppressor is often inactivated in different types of cancers by mutation of the Rb gene itself, by loss of Rb expression, or by its functional inactivation. The Rb pathway is highly conserved in Drosophila. We have carried out a genetic screen in Drosophila to identify genes that can modulate the apoptosis of Rb mutant cells. Our genetic screen has led to the identification of a gene that is required specifically for preventing the apoptosis of Rb mutant cells both in developing fly tissues and in cancer cells. These observations suggest that our generic screen have led to the identification of a gene that can potentially be used as a target to specifically kill cancer cells with inactivated Rb tumor suppressor. In this grant, we will further investigate this idea to determine the mechanisms involved and to investigate the subset of cancer cells that can potentially be targeted. Furthermore we will develop assays to screen for small molecule inhibitors that can be used to specifically kill cancer cells with inactivated Rb pathway.