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

项目 3：认证 CDK 4/6 抑制剂与放射结合使用作为局部晚期 ER 和 TNBC 的有效治疗策略

• 批准号: 10554474
• 负责人: Corey W. Speers
• 金额: $ 27.84万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-14 至 2028-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10554474
• 关键词: Address; Adjuvant; Affect; African American; Aftercare; Animals; Apoptosis; Area; Biological Assay; Biological Models; Biopsy; Breast Cancer Model; Breast Cancer cell line; Breast Epithelial Cells; CDK4 gene; CHEK1 gene; Cell Line; Clinical; Clinical Research; Clinical Trials; Combined Modality Therapy; Credentialing; Critical Pathways; DNA Damage; DNA Repair; DNA Repair Gene; Data; Dependence; Diagnosis; Disease; Dose; Estrogen receptor positive; Future; Growth; High Risk Woman; Histopathologic Grade; Immunohistochemistry; In Vitro; Ionizing radiation; Kinetics; Lasers; Lead; Locally Advanced Malignant Neoplasm; Lymph Node Involvement; Malignant Neoplasms; Mammospheres; Measures; Mediating; Microscopic; Modeling; Molecular Target; Mus; Neoadjuvant Therapy; Nonhomologous DNA End Joining; Nonmetastatic; Patient Selection; Patients; Pharmacodynamics; Phase; Phase I Clinical Trials; Population; Positive Lymph Node; Quality of life; Radiation; Radiation Tolerance; Radiation therapy; Radiation-Sensitizing Agents; Radiosensitization; Recommendation; Recurrence; Recurrent disease; Reporter; Reporting; Residual state; Retinoblastoma; Risk; Safety; Symptoms; Techniques; Testing; Therapeutic; Treatment Protocols; Treatment outcome; Western Blotting; Woman; Xenograft Model; Xenograft procedure; advanced breast cancer; cancer radiation therapy; clinically relevant; ds-DNA; effective therapy; efficacy evaluation; efficacy trial; first-in-human; high risk; homologous recombination; implantation; improved; in vivo; in vivo Model; inhibitor; interest; irradiation; liquid biopsy; lymph nodes; malignant breast neoplasm; mammary; mortality risk; mutant; novel; patient derived xenograft model; phase I trial; protein expression; radiation resistance; recombinational repair; research clinical testing; response; standard of care; treatment strategy; triple-negative invasive breast carcinoma; tumor; tumor xenograft

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.

项目摘要/摘要 放射线（RT）疗法仍然是乳腺癌女性（BC）治疗的主要中流 疾病复发仍然是损害生存的重大临床问题，局部复发 > 3个淋巴结（LNS）ER+ BC或TNBC的女性10年的比率约为20-25％。因为超过280,000名妇女 每年在美国被诊断为乳腺癌，诊断时有37％的乳腺癌患有N+乳腺癌 每年在美国包括> 3 ln或每年具有TNBC的> 100,000名妇女。 25％的风险 与许多其他人相比，这种潜在可治愈的妇女的复发代表着更大的死亡风险 癌症并强调了这些研究的潜在影响。评估起作用的临床药物 放射增敏剂是一个积极但已研究的领域。细胞周期蛋白依赖性激酶4和6抑制剂（CDK 4/6i）用作前线治疗，以治疗雌激素受体阳性（ER+）乳房的女性 癌症和正在进行的研究继续在前期的非转移环境中改善其实用性 高风险的ER+乳腺癌。尽管有这些有希望的研究，但CDK4/6抑制剂尚未给出 与患者作为护理标准的一部分接受的放射疗法的结合，目前 没有迹象表明三阴性乳腺癌（TNBC）的女性不成比例地影响非洲 美国妇女。 我们先前表明CDK4/6抑制会导致多个RB-Intact ER+乳房的放射敏化 癌细胞系以及TNBC模型。这种放射敏化与palbociclib的程度相似 Ribociclib和Abemaciclib，三种临床认可的CDK4/6抑制剂。我们的数据表明了一本小说 CDK 4/6抑制与DNA损伤反应之间的关联。确实，我们已经证明了 短期CDK4/6抑制导致DNA修复蛋白（如CHK1和RAD51）的表达降低 这在同源重组中起作用，并导致ER+乳腺癌模型中的放射敏化。这 但是，在TNBC中从未得到过证明。尽管我们已经证明了这三个CDK4/6 抑制剂导致ER+的放射敏化，这种放射敏化的机理尚不清楚 TNBC女性中这种方法的实用性。我们假设拥有本地高级多重的女性 节点阳性RB完整乳腺癌（包括大多数ER+和最多70％的TNBC）将受益于组合 用辐射用CDK4/6抑制剂处理。此外，我们假设CDK 4/6i的组合 使用RT是安全，可忍受的，并且在卑诗省局部复发的高风险的女性中是有效的。 在此提案中，我们将1）确定CDK4/6抑制剂介导的ER+和 TNBC模型； 2）确定CDK4/6抑制剂介导的放射性化的测序和功效 ER+和TNBC的体内模型以及3）确定女性组合方法的安全性和功效 在I期临床试验中，局部高级ER+和TNBC。