Discovery of BRG1 Inhibitors for Breast Cancer Therapy

描述(申请人提供)：乳腺癌仍然是仅次于皮肤癌的美国女性最常见的癌症。美国癌症协会预测，2013年美国将有超过22.5万例新诊断乳腺癌病例和约4万例死亡病例，仅次于肺癌死亡的女性。乳腺癌的辅助和新辅助化疗是许多乳腺癌患者治疗方案中不可或缺的一部分，目前临床上使用的药物和药物组合很多。其中许多药物针对的是癌细胞快速分裂的增殖机制，而其他药物则干扰激素信号或其他信号转导途径。表观遗传调节蛋白的小分子抑制剂作为治疗人类疾病的药物已被验证可用于其他癌症的治疗，并仍是一个迅速扩大的研究领域。在这里，我们建议识别小分子抑制物，以对抗先前未定位的表观遗传调控因子，该调控因子参与控制基因组DNA转录的可及性。BRG1是一种ATPase，是人类SWI/SNF染色质重塑酶复合体的催化亚单位，是染色质结构和整个基因组可及性的重要调节因子。尽管它最初被标记为肿瘤 抑制蛋白在乳腺癌中，我们有强有力的证据表明，BRG1在大多数人类乳腺肿瘤中过度表达，无论分期或激素状态如何。我们发现，通过实验降低培养的乳腺癌细胞中BRG1水平会降低它们在组织培养中的增殖速度，并极大地减少，在某些情况下，当癌细胞原位种植到小鼠乳房脂肪垫中时，肿瘤的形成。细胞增殖减少和肿瘤起始的机制是BRG1表达脂质，特别是脂肪酸合成所必需的酶的普遍要求。重要的是，BRG1水平降低的细胞对乳腺癌治疗中使用的标准化疗药物和脂质合成抑制剂的敏感性增加。我们提供BRG1染色质重塑酶作为乳腺癌治疗的重要新靶点。我们将开发和优化高通量、高含量的显微分析方法，以发现小分子BRG1抑制剂。这些药物将成为表观遗传乳腺癌化疗的新候选药物。

DESCRIPTION (provided by applicant): Breast cancer remains second only to skin cancer as the most common cancer among women in the United States. The American Cancer Society predicts over 225,000 new diagnoses and about 40,000 deaths in the US from breast cancer in 2013, second in women only to lung cancer deaths. Adjuvant and neoadjuvant chemotherapies for breast cancer are an integral part of the treatment regimen for many breast cancer patients, with many drugs and combinations of drugs in current clinical use. Many of these drugs target proliferative mechanisms in rapidly dividing cancer cells, while others interfere with hormone signaling or other signal transduction pathways. Small molecule inhibitors of epigenetic regulatory proteins as therapeutics for human disease have been validated for treatment of other cancers and remain a rapidly expanding area of research. Here we propose to identify small molecule inhibitors against a previously untargeted epigenetic regulator that is involved in controlling genomic DNA accessibility for transcription. BRG1 is an ATPase that is a catalytic subunit of the human SWI/SNF chromatin remodeling enzyme complex, an important regulator of chromatin structure and accessibility across the genome. Despite its initial labeling as a tumor suppressor protein in breast cancer, we have strong evidence that BRG1 is over-expressed in most human breast tumors, regardless of stage or hormone status. We find that experimentally reducing BRG1 levels in cultured breast cancer cells reduces their rate of proliferation in tissue culture and greatly reduces, and in some cases prevents, tumor formation when cancer cells are orthotopically implanted in mouse mammary fat pads. The mechanism for the decrease in cell proliferation and tumor initiation is a general requirement for BRG1 in the expression of enzymes necessary for lipid, and specifically, fatty acid, synthesis. Importantly, cells with decreased BRG1 levels show increased susceptibility to both standard chemotherapeutic agents used in breast cancer treatment and to inhibitors of lipid synthesis. We offer the BRG1 chromatin remodeling enzyme as an important new target for breast cancer therapy. We will develop and optimize high-throughput, high-content microscopy assays for the discovery of small molecule BRG1 inhibitors. These will be novel candidate drugs for epigenetic breast cancer chemotherapy.