Targeting BUB 1 for radio- and immuno-sensitization of Triple Negative Breast Cancer (TNBC)

项目摘要 背景：乳腺癌是美国44至55岁女性的头号杀手。 据估计，2020年将有超过276，480名女性新诊断患有乳腺癌， 预计今年将有42，170名女性死于乳腺癌（BC）。虽然ER+肿瘤可以有效地 尽管已经治疗过，但对于ER-和特别是三阴性乳腺癌（TNBC）没有有效的疗法。 TNBC占所有BC的30%，更具侵略性，对治疗反应较低，因此死亡率最高 rates.目前，还没有批准用于TNBC的分子疗法可以与放射性或免疫治疗相结合。 免疫疗法 目的：放射抵抗的机制知之甚少，免疫治疗在很大程度上 令人失望，但改善任何一个都可以显着影响TNBC妇女的结果。因此，在本发明中， 识别可有效靶向的辐射抗性和免疫调节的驱动因素代表了一个关键的 未满足的临床需求。该提案的目的是将BUB 1确立为一种可行的分子靶点， 放射增敏和免疫引发以及用于预测TNBC中的治疗结果。 假设：为了鉴定用于TNBC的辐射和免疫致敏的可操作的分子靶标， 我们已经确定BUB 1表达与侵袭性疾病和临床不良预后密切相关， 结果。我们假设BUB 1介导辐射抗性，并且BUB 1抑制将使抗性敏感化。 电离辐射。此外，我们假设BUB 1在肿瘤中调节TGFβ信号传导， 微环境导致髓源性抑制细胞（MDSC）群体增加， 交叉致敏和免疫疗法抗性。我们认为BUB 1的基因组缺失或抑制将 减少TGFβ和MDSC，并将确定分化回抗原呈递细胞（APC）， 恢复先天免疫，使肿瘤对免疫检查点阻断敏感。 影响：拟议的研究将验证BUB 1作为TNBC治疗的分子靶点。本研究将提供 靶向BUB 1与放射或免疫治疗联合的基本原理，并将提供结论性的临床前 为未来临床翻译提供数据。我们确定我们的目标是BUB 1结合无线电- 免疫疗法从根本上比目前的疗法更好，因为它利用了 BUB 1在细胞周期、DNA损伤反应和TGFβ信号转导中的作用。我们认为，成功的 完成拟议的研究将导致新的治疗模式，超越微小的改善， 将对乳腺癌治疗产生重大影响，尤其是对TNBC。

PROJECT SUMMARY-ABSTRACT Background: Breast cancer is the number one killer of women between the ages of 44 and 55 in this country. It is estimated that more than 276,480 women will be newly diagnosed with breast cancer in 2020 and about 42,170 women are expected to die of breast cancer (BC) this year. Although ER+ tumors can be effectively treated, there are no effective therapies available for ER- and specially triple negative breast cancers (TNBC). TNBC accounts for 30% of all BC, is more aggressive and less responsive to treatment thus has highest mortality rates. Currently, there are no molecular therapies approved for TNBC which could be combined with radio- or immunotherapies. Objective: Mechanisms of radioresistance are poorly understood, and immunotherapy has been largely disappointing, but improvement of either could significantly impact outcomes for women with TNBC. Thus, identifying drivers of radioresistance and immune regulation that can be effectively targeted represents a critical unmet clinical need. The objective of this proposal is to establish BUB1 as a viable molecular target for radiosensitization and immune priming as well as for predicting therapeutic outcome in TNBC. Hypothesis: In an effort to identify actionable molecular targets for radiation- and immune- sensitization of TNBC, we have identified BUB1 expression as a strong prognostic correlate of aggressive disease and poor clinical outcome. We hypothesize that BUB1 mediates radioresistance and that BUB1 inhibition will sensitize resistant TNBC to ionizing radiation. Furthermore, we hypothesize that BUB1 regulates TGFβ signaling in tumor microenvironment leading to an increase in myeloid derived suppressor cells (MDSCs) population, decrease in cross-priming and immunotherapy resistance. We propose that genomic depletion or inhibition of BUB1 will reduce TGFβ and MDSCs, and will ascertain differentiation back to antigen presenting cells (APC) which will restore innate immunity and make tumors sensitive to immune checkpoint blockade. Impact: The proposed studies will validate BUB1 as a molecular target for TNBC therapy. This study will provide rationale for targeting BUB1 in combination with radio- or immune-therapy and will provide conclusive pre-clinical data for future clinical translation. We are certain that our approach of targeting BUB1 in combination with radio- and immunotherapy is fundamentally better than the current therapies as it exploits the multiple functions of BUB1 including cell-cycle, DNA- damage response and TGFβ signaling. We envision that the successful completion of the proposed study will lead to new treatment paradigms that go beyond minor improvements and will have major impact on breast cancer treatment, especially on TNBC.