HIJACKING CANCER DRIVERS TO ACTIVATE PROAPOPTOTIC GENES IN DLBCL

项目摘要 过去二十年的癌症研究已经确定了大多数人类的一个或多个驱动因素 恶性肿瘤。此外，已经确定了多种细胞死亡基因和途径。 正常保护生物体免受基因组发育突变或缺陷的影响 维修。这些观察表明，人们可能能够重新连接转录 导致癌细胞用自己的驱动器自杀的电路。我们创造了一个新的班级 利用化学诱导邻近性(CIP)重新连接癌细胞的分子 癌症驱动因素激活促细胞凋亡途径。我们称这些分子为转录分子 接近的化学诱导物或TCIP，因为它们诱导接近或招致癌症 原脱落体基因启动子的推动者。为了发展这些双面的、“双功能”的 分子方面，我们将重点研究弥漫性大细胞B细胞淋巴瘤(DLBCL)，使用 细胞死亡抑制因子BCL6作为锚定转录因子作用于细胞死亡抑制因子启动子 促凋亡基因。对于激活剂，我们使用几种异常表达的转录中的任何一种 或表观遗传激活剂，以同时解除抑制和激活促凋亡基因。我们有 人工合成的双功能小分子招募转录激活子在 DLBCL与BCL6正常结合和抑制的促凋亡基因启动子结合。在我们的 初步研究表明，这些分子能够迅速而有力地杀死DLBCL，优于 同类中最好的抑制剂，也是对过度表达靶点的细胞的特异性 双功能分子。使用类似于遗传显性功能获得突变的策略， TCIP可以使癌症与多个驱动因素接触，从而超越传统的抑制剂 和降级者。因为双功能分子依赖于两个单独过度表达的蛋白质， TCIP利用转录特异性的自然、基本基础提供 精确、可预测和选择性地杀死癌细胞。为了进一步发展这一方法，我们 将首先优化这些分子的稳定性、溶解性和杀灭DLBCL的特异性。 其次，我们将定义它们产生强大和快速杀戮的机制。最后， 我们将在已建立的PDX模型中对它们进行测试。我们的研究将涉及一个多学科的 借鉴化学、临床淋巴瘤治疗、癌症生物学和 基因组生物学。如果成功，我们将为新的治疗理念奠定基础。 淋巴瘤，更广泛地说，癌症化疗，比许多现有的更具特异性 接近了。TCIP使用一种新的主导性函数增益策略解决了 癌症的治疗问题，如DLBCL，具有多个同时存在的驱动因素。

Project Summary The past two decades of cancer research have identified one or more drivers for most human malignancies. In addition, multiple cell death genes and pathways have been identified that normally protect the organism against developmental mutations or defects in genomic maintenance. These observations suggest that one might be able to rewire the transcriptional circuitry to cause the cancer cell to kill itself with its own driver. We have invented a new class of molecules that use Chemically Induced Proximity (CIP) to rewire the cancer cell such that the cancer driver activates proapoptotic pathways. We call these molecules Transcriptional Chemical Inducers of Proximity or TCIPs because they induce proximity or recruit a cancer driver to the promoters of proapopotic genes. For development of these two-sided, “bifunctional” molecules, we will focus on Diffuse Large Cell B Cell Lymphoma (DLBCL), using the master inhibitor of cell death, BCL6, as an anchoring transcription factor on the promoters of proapoptotic genes. For an activator we use any of several aberrantly-expressed transcription or epigenetic activators, to simultaneously derepress and activate proapoptotic genes. We have synthesized bifunctional small molecules that recruit transcriptional activators over-expressed in DLBCL to the promoters of proapoptotic genes normally bound and repressed by BCL6. In our preliminary studies, these molecules lead to rapid and robust killing of DLBCL that is superior to the best-in-class inhibitors and also specific for cells that over-express the targets of the bifunctional molecule. Using a strategy similar to genetic dominant gain-of-function mutations, TCIP can engage cancers with multiple drivers, thereby going beyond conventional inhibitors and degraders. Because bifunctional molecules rely on two separately overexpressed proteins, TCIP takes advantage of the natural, fundamental basis of transcriptional specificity to provide precise, predictable and selective killing of cancer cells. To further develop this approach, we will first optimize these molecules for stability, solubility and specificity of killing of DLBCL. Secondly, we will define the mechanism by which they produce robust and rapid killing. Finally, we will test them in established PDX models. Our studies will involve a multidisciplinary approach drawing on expertise in chemistry, clinical lymphoma treatment, cancer biology and genomic biology. If successful, we will lay the foundation for a new concept in the treatment of lymphoma, and more broadly, cancer chemotherapy, that is more specific than many existing approaches. The use of a novel dominant gain-of-function strategy by TCIPs addresses the issue of treatment of cancers, such as DLBCL, that have multiple, concurrent drivers.