Timing is everything: applications in precision oncology for ER+ breast cancer

时机就是一切：ER 乳腺癌精准肿瘤学中的应用

• 批准号: 10411360
• 负责人: Todd W Miller
• 金额: $ 7.45万
• 依托单位: DARTMOUTH COLLEGE
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-04 至 2022-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10411360
• 关键词: 1-Phosphatidylinositol 3-Kinase; Acute; Adjuvant; Adjuvant Therapy; Antiestrogen Therapy; Apoptosis; Apoptotic; Biology; Breast Cancer Cell; Cancer Model; Cell Line; Cells; Clinic; Clinical; Clinical Trials; Combined Modality Therapy; Communication; Cytokine Signaling; Data; Disease; Drug Costs; Drug Targeting; Drug resistance; Estrogen Antagonists; Estrogen Receptor alpha; Estrogen receptor positive; Estrogens; Failure; Growth; Malignant Neoplasms; Mammary Neoplasms; Methods; Morbidity - disease rate; Mus; Neoadjuvant Therapy; No Evidence of Disease; Operative Surgical Procedures; Paracrine Communication; Pathway interactions; Patient Rights; Patients; Pharmaceutical Preparations; Phosphotransferases; Pre-Clinical Model; Precision Medicine Initiative; Primary Neoplasm; Progressive Disease; Recommendation; Recurrence; Resected; Residual state; Resistance; Resistance development; Shapes; Signal Pathway; Signal Transduction; Solid Neoplasm; Stable Disease; Stromal Cells; Systemic Therapy; Testing; Therapeutic; Time; Tissues; Treatment Efficacy; Work; anti-cancer; base; cancer cell; clinical development; clinical implementation; clinically relevant; cytokine; cytotoxic; cytotoxicity; drug development; drug efficacy; expectation; extracellular; improved; inhibitor/antagonist; kinase inhibitor; malignant breast neoplasm; mortality; neoplastic cell; novel; novel therapeutics; patient derived xenograft model; pre-clinical; precision oncology; preclinical study; preservation; prevent; research clinical testing; response; stem; subcutaneous; success; targeted treatment; therapy resistant; tumor

Precision oncology requires delivering the right drug to the right patient at the right time, but “time” is rarely studied preclinically before a new drug enters the clinic. As a result, drugs shown to prevent progression of advanced/metastatic solid tumors are sometimes found to be ineffective at preventing recurrence when administered in the adjuvant or neoadjuvant settings. The long-term clinical benefit realized from adjuvant and neoadjuvant therapies lies in anti-cancer effects on residual/disseminated/micrometastatic, clinically dormant cancer cells that are undetectable by routine clinical methods; the biology underlying such anti-cancer effects is practically unknown, creating a gap for evaluating new drugs. Clinically dormant cancer cells that survive (neo)adjuvant therapy can ultimately give rise to recurrent/advanced tumors that frequently develop resistance to all approved therapies. Thus, understanding how clinically dormant cancer cells vs. established tumors respond to a novel therapy will guide clinical testing in the appropriate disease setting(s), and reveal targets for combination therapies to enhance efficacy. More thorough characterization of drug efficacy in relevant preclinical models will increase the drug success rate in clinical trials, thus decreasing the cost of drug development. Estrogen receptor α (ER)-positive breast cancer is a disease for which improved drug development could ultimately impact treatment options for hundreds of thousands of patients. Patients with early-stage ER+ breast cancer are treated with adjuvant anti-estrogen therapies that neutralize ER and suppress, but do not eliminate, tumor-initiating cells. We and others have implicated activation of the phosphatidylinositol 3-kinase (PI3K) pathway in anti-estrogen resistance, and PI3K inhibitors (PI3Ki) are in clinical development in combination with anti-estrogens. Based on our preliminary findings, we hypothesize that short-term treatment with anti-estrogen/PI3Ki combination therapy kills clinically dormant ER+ breast cancer cells and prevents recurrence (Aim 2), while established tumors develop resistance to anti- estrogen/PI3Ki therapy via suppression of apoptosis (Aim 1) due in part to microenvironmental cytokine signaling (Aim 3). We will test this hypothesis through the following Specific Aims: 1) To determine why anti- estrogen/PI3Ki combination therapy is acutely but not sustainably cytotoxic in established ER+ breast tumors; 2) To determine how clinically dormant ER+ breast tumor cells respond to short-term anti-estrogen/PI3Ki combination therapy; 3) To identify cytokines in stroma-derived secretomes that drive resistance to anti- estrogen and anti-estrogen/PI3Ki therapies in ER+ breast cancer. These studies are aligned with the NCI Precision Medicine Initiative of Overcoming Drug Resistance, the Cancer Moonshot Panel recommendation to develop ways to overcome cancer's resistance to therapy, and the NCI Provocative Question `What cancer models or other approaches can be developed to study clinically stable disease and the subsequent transition to progressive disease?'

精准肿瘤学需要在正确的时间向正确的患者提供正确的药物，但“时间”很少 在新药进入临床之前进行了临床前研究，结果表明药物可以预防疾病进展。 有时发现晚期/转移性实体瘤在预防复发方面无效 在辅助或新辅助环境中施用从辅助和新辅助中实现的长期临床益处。 新辅助治疗在于对残留/播散/微转移、临床休眠的肿瘤的抗癌作用 通过常规临床方法无法检测到的癌细胞；这种抗癌作用背后的生物学原理 实际上是未知的，这为评估存活的临床休眠癌细胞创造了一个空白。 （新）辅助治疗最终可能导致经常产生耐药性的复发/晚期肿瘤 因此，了解临床上休眠的癌细胞与已建立的肿瘤的情况如何。 对新疗法的反应将指导适当疾病环境中的临床测试，并揭示治疗目标 联合疗法以增强疗效。更全面地表征相关药物疗效。 临床前模型将提高药物临床试验的成功率，从而降低药物成本 雌激素受体α（ER）阳性乳腺癌是一种需要改进药物治疗的疾病。 开发最终可能会影响数十万患者的治疗选择。 早期 ER+ 乳腺癌采用辅助抗雌激素疗法治疗，以中和 ER 和 我们和其他人发现，它可以抑制但不消除肿瘤起始细胞。 磷脂酰肌醇 3 激酶 (PI3K) 通路在抗雌激素抵抗中的作用，而 PI3K 抑制剂 (PI3Ki) 则在 根据我们的初步研究结果，我们结合抗雌激素进行了临床开发。 抗雌激素/PI3Ki 联合疗法的短期治疗会杀死临床休眠的 ER+ 乳房 癌细胞并防止复发（目标 2），而已形成的肿瘤则对抗肿瘤药物产生抗药性 雌激素/PI3Ki 通过抑制细胞凋亡（目标 1）进行治疗，部分原因是微环境细胞因子 我们将通过以下具体目标来检验这一假设： 1) 确定为什么反- 雌激素/PI3Ki 联合疗法对已确定的 ER+ 乳腺肿瘤具有急性但不可持续的细胞毒性； 2) 确定临床休眠的 ER+ 乳腺肿瘤细胞如何响应短期抗雌激素/PI3Ki 联合治疗；3) 鉴定基质来源的分泌组中驱动抗-抗药性的细胞因子 ER+ 乳腺癌中的雌激素和抗雌激素/PI3Ki 疗法与 NCI 一致。 克服耐药性的精准医学计划，癌症登月小组建议 开发克服癌症对治疗的抵抗力的方法，以及 NCI 的挑衅性问题“什么是癌症” 可以开发模型或其他方法来研究临床稳定的疾病和随后的转变 进展性疾病？