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.

项目概要/摘要 放射 (RT) 治疗仍然是治疗女性乳腺癌 (BC) 的主要方法，但局部区域 疾病复发仍然是一个影响生存的重要临床问题，局部区域复发 对于有 >3 个淋巴结 (LN) ER+ BC 或 TNBC 的女性，10 岁时发生率约为 20-25%。由于超过 280,000 名女性 美国每年诊断出乳腺癌，其中 37% 的人在诊断时患有 N+ 乳腺癌，该人群 包括每年超过 100,000 名美国女性，她们每​​年有超过 3 个 LN 或患有 TNBC。 25% 的风险 与许多其他可能治愈的女性相比，复发的死亡风险更大 癌症并强调了这些研究的潜在影响。评估临床药物的作用 放射增敏剂是一个活跃但尚未得到充分研究的领域。细胞周期蛋白依赖性激酶 4 和 6 抑制剂 (CDK 4/6i) 用作治疗转移性雌激素受体阳性 (ER+) 乳房女性的一线疗法 癌症和正在进行的研究继续完善其在患有癌症的女性的前期、非转移环境中的效用 高风险 ER+ 乳腺癌。尽管有这些有希望的研究，但 CDK4/6 抑制剂尚未用于治疗 与患者接受的放射治疗相结合作为标准护理的一部分，目前 没有迹象表明患有三阴性乳腺癌（TNBC）的女性，这种癌症对非洲人的影响尤为严重 美国妇女。 我们之前表明 CDK4/6 抑制导致多个 Rb 完整 ER+ 乳腺的放射增敏 癌细胞系以及 TNBC 模型。这种放射增敏作用与 palbociclib 发生的程度相似， ribociclib 和 abemaciclib，三种临床批准的 CDK4/6 抑制剂。我们的数据表明一部小说 CDK 4/6 抑制与 DNA 损伤反应之间的关联。事实上，我们已经证明了 短期 CDK4/6 抑制会导致 CHK1 和 RAD51 等 DNA 修复蛋白表达减少 在同源重组中发挥作用，并导致 ER+ 乳腺癌模型中的放射增敏。这 然而，这一点尚未在 TNBC 中展示过。虽然我们已经证明了所有三个 CDK4/6 抑制剂导致 ER+ 的放射增敏，但这种放射增敏的机制仍不清楚。 这种方法在患有 TNBC 的女性中的实用性。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）将从联合治疗中受益 CDK4/6 抑制剂联合放射治疗。此外，我们假设 CDK 4/6i 的组合 对于 BC 局部复发高风险的女性来说，放疗是安全、可耐受且有效的。 在本提案中，我们将 1) 确定 ER+ 和 ER+ 中 CDK4/6 抑制剂介导的放射增敏机制 TNBC 模特； 2) 确定 CDK4/6 抑制剂介导的放射增敏的测序和功效 ER+ 和 TNBC 的体内模型以及 3) 确定了这种组合方法对女性的安全性和有效性 与当地先进的 ER+ 和 TNBC 进行 I 期临床试验。