Project 3: Credentialing CDK 4/6 inhibitors used with radiation as an effective treatment strategy in locally advanced ER+ and TNBC

项目总结/摘要 放射（RT）治疗仍然是治疗女性乳腺癌（BC）的主要手段，但局部区域放射治疗（RT）的效果不佳。 疾病复发仍然是影响生存的重要临床问题，局部复发 在具有>3个淋巴结（LN）ER+ BC或TNBC的女性中，10年时的比率约为20-25%。超过28万名女性 在美国，每年有37%的人被诊断患有乳腺癌，其中37%的人在诊断时患有N+乳腺癌， 包括美国每年> 100，000名患有>3 LN或每年患有TNBC的女性。25%的风险 在这一数量的潜在可治愈的女性中，复发代表着比许多其他女性更大的死亡风险。 并强调了这些研究的潜在影响。评价临床药物的功能， 放射增敏剂是一个活跃但研究不足的领域。细胞周期蛋白依赖性激酶4和6抑制剂（CDK 4/6 i）用作一线治疗，治疗转移性雌激素受体阳性（ER+）乳腺癌女性 癌症和正在进行的研究继续完善其在前期，非转移性设置的妇女， 高危ER+乳腺癌。尽管有这些有希望的研究，但CDK 4/6抑制剂尚未在临床上使用。 与作为护理标准的一部分的患者接受的放射疗法组合，并且目前 对于患有三阴性乳腺癌（TNBC）的女性来说， 美国女人 我们以前发现，CDK 4/6抑制导致多个Rb-完整ER+乳腺癌细胞的放射增敏。 癌细胞系以及TNBC模型。这种放射增敏作用与palbociclib相似， ribociclib和abemaciclib，三种临床批准的CDK 4/6抑制剂。我们的数据显示 CDK 4/6抑制和DNA损伤反应之间的关联。事实上，我们已经证明， 短期CDK 4/6抑制导致DNA修复蛋白如CHK 1和RAD 51的表达降低 其在同源重组中起作用并导致ER+乳腺癌模型中的放射增敏。这 然而，从未在TNBC中得到证实。虽然我们已经证明了所有三个CDK 4/6 抑制剂导致ER+的放射增敏，这种放射增敏的机制仍然不清楚， 这种方法在患有TNBC的妇女中的效用。我们假设患有局部晚期多发性硬化症的女性 淋巴结阳性Rb完整乳腺癌（包括大多数ER+和高达70%的TNBC）将受益于联合治疗 用CDK 4/6抑制剂和放射治疗。此外，我们假设CDK 4/6的组合， RT在BC局部复发高风险的女性中是安全、可耐受和有效的。 在这个提议中，我们将1）确定CDK 4/6介导的ER+放射增敏的机制， TNBC模型; 2）确定CDK 4/6转运蛋白介导的放射增敏在TNBC模型中的测序和功效。 ER+和TNBC的体内模型和3）确定这种组合方法在女性中的安全性和功效 局部晚期ER+和TNBC的患者进行I期临床试验。

PROJECT SUMMARY/ABSTRACT Radiation (RT) therapy remains a mainstay in the treatment of women with breast cancer (BC), but locoregional disease recurrence remains a significant clinical issue that compromises survival, with locoregional recurrence rates ~20-25% at 10 years in women with >3 lymph nodes (LNs) ER+ BC or TNBC. As over 280,000 women are diagnosed with breast cancer in the US each year and 37% have N+ breast cancer at diagnosis, this population includes >100,000 women in the US each year who have either >3 LN or have TNBC each year. A 25% risk of recurrence in this number of potentially curable women represents a greater mortality risk than many other cancers and underscores the potential impact of these studies. Evaluation of clinical agents that function as radiosensitizers is an area of active yet understudied interest. Cyclin-dependent kinase 4 and 6 inhibitors (CDK 4/6i) are used as frontline therapy to treat women with metastatic estrogen receptor positive (ER+) breast cancers and ongoing studies continue to refine their utility in the upfront, non-metastatic setting for women with high-risk ER+ breast cancers. Despite these promising studies, CDK4/6 inhibitors are not yet given in combination with the radiation therapy that patients receive as part of the standard of care, and there currently is no indication for women with triple-negative breast cancer (TNBC) which disproportionately affects African American women. We previously showed that CDK4/6 inhibition leads to the radiosensitization of multiple Rb-intact ER+ breast cancer cell lines as well as TNBC models. This radiosensitization occurs to a similar degree with palbociclib, ribociclib, and abemaciclib, the three clinically approved CDK4/6 inhibitors. Our data suggests a novel association between CDK 4/6 inhibition and the DNA damage response. Indeed, we have demonstrated that short term CDK4/6 inhibition leads to a decrease in expression of DNA repair proteins like CHK1 and RAD51 that play a role in homologous recombination and leads to radiosensitization in ER+ breast cancer models. This has not, however, ever been demonstrated in TNBC. Although we have demonstrated that all three CDK4/6 inhibitors lead to the radiosensitization of ER+, the mechanism of this radiosensitization remains unclear as does the utility of this approach in women with TNBC. We hypothesize that women with locally advanced multiple node positive Rb intact breast cancer (including most ER+ and up to 70% of TNBC) will benefit from combination treatment with CDK4/6 inhibitor with radiation. Furthermore, we hypothesize that the combination of CDK 4/6i with RT is safe, tolerable, and effective in women at high risk of local recurrence of BC. In this proposal, we will 1) determine the mechanism of CDK4/6 inhibitor-mediated radiosensitization in ER+ and TNBC models; 2) determine the sequencing and efficacy of CDK4/6 inhibitor-mediated radiosensitization in in vivo models of ER+ and TNBC and 3) determine the safety and efficacy of this combination approach in women with locally advanced ER+ and TNBC in a phase I clinical trial.