HIJACKING CANCER DRIVERS TO ACTIVATE PROAPOPTOTIC GENES IN DLBCL

劫持癌症驱动者激活 DLBCL 中的促凋亡基因

• 批准号: 10564195
• 负责人: Gerald R. Crabtree
• 金额: $ 43.91万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-12-22 至 2027-11-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10564195
• 关键词: Address; Altruism; Apoptosis; Apoptotic; B-Cell Lymphoma 6 Protein; B-Cell Lymphomas; B-Lymphocytes; BCL6 gene; Binding; Biology; Cancer Biology; Cancer Center; Cancer Etiology; Cell Death; Cell Death Induction; Cell Line; Cells; Characteristics; Chemicals; Chemistry; Chemotherapy-Oncologic Procedure; Clinical; Collaborations; Complex; Consult; DNA biosynthesis; Dana-Farber Cancer Institute; Data; Defect; Development; Diffuse; Dominant Genetic Conditions; Epigenetic Process; Estrogen Receptors; Foundations; Genes; Genetic Transcription; Genomics; Hematopoietic Neoplasms; Histone Deacetylation; Human; Lead; Lymphoma; Lymphoma cell; Maintenance; Malignant Neoplasms; Mediating; Modeling; Mutation; Neoplasm Metastasis; Normal Cell; Organism; Pathway interactions; Polycomb; Proliferating; Proteins; Publishing; Reporting; Repression; Research Personnel; Role; Side; Solubility; Specificity; TP53 gene; Testing; Therapeutic; Toxic effect; Transcription Coactivator; anticancer research; blood treatment; cancer cell; cancer genomics; cancer therapy; cell suicide; clinical development; derepression; effectiveness evaluation; gain of function; gain of function mutation; inhibitor; interdisciplinary approach; invention; novel; off-target site; overexpression; patient derived xenograft model; personalized medicine; promoter; recruit; small molecule; therapeutic development; transcription factor

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.

项目摘要 过去20年的癌症研究已经确定了一个或多个驱动因素，大多数人的癌症。 恶性肿瘤。此外，已经鉴定了多种细胞死亡基因和途径， 通常保护生物体免受发育突变或基因组缺陷的影响， 上维护这些观察结果表明，人们可能能够重新连接转录 使癌细胞用自己的驱动程序杀死自己的电路。我们发明了一种新的阶级 使用化学诱导邻近（CIP）重新连接癌细胞的分子， cancer driver激活proapoptotic凋亡pathways途径.我们称之为转录分子 化学邻近诱导剂或TCIP，因为它们诱导邻近或招募癌症 proapopotic基因启动子的驱动程序。为了发展这些双面的、“双功能的” 分子，我们将集中在弥漫性大细胞B细胞淋巴瘤（DLBCL），使用主 细胞死亡的抑制剂BCL 6，作为锚定转录因子在 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，以同时去抑制和激活促凋亡基因。我们有 合成的双功能小分子，其募集在细胞中过表达的转录激活因子， DLBCL与通常被BCL 6结合和抑制的促凋亡基因的启动子结合。在我们 初步研究表明，这些分子导致DLBCL的快速和稳健的杀伤，其上级于 最好的同类抑制剂，也是特异性的细胞，过表达的目标， 双功能分子使用类似于遗传显性功能获得性突变的策略， TCIP可以通过多种驱动因素参与癌症，从而超越传统的抑制剂 和退化者。因为双功能分子依赖于两种分别过表达的蛋白质， TCIP利用转录特异性的天然基础， 精确、可预测和选择性地杀死癌细胞。为了进一步发展这种方法，我们 将首先优化这些分子的稳定性、溶解性和杀死DLBCL的特异性。 其次，我们将定义它们产生强大和快速杀伤的机制。最后， 我们将在已建立的PDX模型中对其进行测试。我们的研究将涉及多学科 利用化学、临床淋巴瘤治疗、癌症生物学和 基因组生物学如果成功的话，我们将为一个新的治疗概念奠定基础。 淋巴瘤，更广泛地说，癌症化疗，这是更具体的比许多现有的 接近。TCIP使用一种新的显性功能获得策略， 具有多个并发驱动因素癌症（例如DLBCL）的治疗问题。