Evaluation of HSET as a Novel Theranostic Target for Breast Cancer Therapy

描述（由申请人提供）：化疗的“圣杯”是确定可以选择性地识别和破坏癌细胞，同时保留正常细胞的药物。癌症和正常细胞之间的一个被广泛接受的生物学区别是称为中心体的细胞器的数量。正常细胞严格地拥有两个中心体，而癌细胞有太多的中心体。中心体精心安排了一个优雅的双极细胞分裂装置的组装，称为有丝分裂纺锤体，用于在两个子细胞之间忠实地分离遗传物质。虽然额外的中心体为癌细胞提供了生长优势，但这些过多的细胞器可能导致多极纺锤体的形成，这对细胞存活不利。为了对抗这种潜在的灾难，癌细胞已经进化出“复杂而聪明”的机制来聚集多余的中心体，并组装一个有利于细胞分裂的假双极有丝分裂纺锤体，从而使癌细胞存活，茁壮成长并“快乐”。“我们合理地解释说，耗尽乳腺癌细胞的中心体聚集武器库将导致细胞具有高度异常的多极纺锤体，这将成为一个“不归点”，并导致混乱的有丝分裂，使细胞死亡。我们的实验室已经确定，最近发现的中心体聚集蛋白，HSET，是选择性上调人类乳腺癌组织相比，正常乳腺上皮细胞。有趣的是，HSET表达的增强与肿瘤分级和疾病进展的增加直接相关。大多数目前可用的抗癌药物靶向正常细胞中具有重要功能的细胞组分。HSET在正常细胞中是非必需的，但对于癌细胞存活是必需的。正常细胞与癌细胞对HSET的生存能力的差异依赖性使得HSET成为非常宝贵的癌细胞选择性化疗靶点。我们假设HSET是一种新的癌基因，可以作为乳腺癌预后的临床生物标志物和癌细胞选择性治疗靶点，用于设计和临床前开发无毒乳腺癌治疗的小分子HSET抑制剂。因此，我们的目标是a）确定HSET在乳腺癌发展和进展中的致癌作用，B）评估HSET是否可以作为乳腺癌检测和预后的临床生物标志物，和c）临床前开发一类新的HSET抑制剂，其稳健地使中心体去簇化。我们的提案具有很强的临床和翻译相关性。我们预计，该项目的成功完成将有助于 a）产生用于乳腺癌检测和预后的新的临床生物标志物，其可以潜在地影响用于定制治疗的患者分层，B）帮助开发新的生物标志物， 这类HSET抑制剂可以选择性地靶向乳腺癌细胞，同时保留正常细胞，从而改善乳腺癌患者的生活质量，以及c）增强乳腺癌生物学的知识基础，以发现基于中心体的新靶点，中心体是细胞分裂的关键协调者。

DESCRIPTION (provided by applicant): The "Holy Grail" of chemotherapy is to identify drugs that can selectively recognize and destroy cancer cells while sparing normal cells. One widely-accepted biological distinction between cancer and normal cells is the number of cellular organelles called centrosomes. While normal cells stringently possess two centrosomes, cancer cells have far too many centrosomes. Centrosomes exquisitely orchestrate the assembly of an elegant bipolar cell division apparatus, called the mitotic spindle, for faithful segregation of genetic material between two daughter cells. Although extra centrosomes offer a growth advantage to cancer cells, these overabundant organelles might lead to multipolar spindle formation that is detrimental to cell survival. To combat this potential catastrophe, cancer cells have evolved "sophisticated and clever" mechanisms to cluster excess centrosomes and assemble a pseudo-bipolar mitotic spindle that is conducive to cell division, thereby allowing cancer cells to survive, thrive and "be merry." We rationalize that depleting breast cancer cells of their centrosome-clustering arsenal will result in cells with highly aberrant multipolar spindle, which will serve as a "point of no return" and result in a chaotic mitosis that consigns cells to their demise. Our laboratory has identified that a recently discovered centrosome clustering protein, HSET, is selectively upregulated in human breast cancer tissues compared to normal breast epithelia. Interestingly, the enhanced expression of HSET directly correlates with increasing tumor grade and disease progression. Most currently-available anticancer drugs target cellular components with vital functions in normal cells. HSET is non-essential in normal cells but is required for cancer cell survival. The differential dependence of normal versus cancer cells on HSET for viability makes HSET an invaluable cancer-cell selective chemotherapeutic target. We hypothesize that HSET is a novel oncogene that can serve as a clinical biomarker for breast cancer prognosis and a cancer-cell selective therapeutic target for the design and preclinical development of small-molecule HSET inhibitors for non-toxic breast cancer therapy. Thus our objectives are a) to establish the oncogenic role of HSET in breast cancer development and progression, b) evaluate whether HSET can serve as a clinical biomarker for breast cancer detection and prognosis, and c) preclinically develop a novel class of HSET inhibitors that robustly decluster centrosomes. Our proposal has strong clinical and translational relevance. We anticipate that the successful completion of this project will serve to a) yield a new clinical biomarker for breast cancer detection and prognosis, which can potentially impact patient stratification for customized therapy, b) aid the development of a novel class of HSET inhibitors that can selectively target breast cancer cells while sparing normal cells, thus improving breast cancer patients' quality of life, and c) enhance the knowledge base of breast cancer biology to uncover novel targets based upon the centrosome, a key orchestrator of cell division.