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

基本信息

批准号：
9761285
负责人：
Todd W Miller
金额：
$ 35.95万
依托单位：
DARTMOUTH COLLEGE
依托单位国家：
美国
项目类别：
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/9761285
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 Tumor Initiators Work Xenograft Model Xenograft procedure 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 pre-clinical precision oncology preclinical study preservation prevent research clinical testing response stem subcutaneous success targeted treatment therapy resistant tumor

项目摘要

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?'

精度肿瘤学需要在正确的时间向正确的患者提供正确的药物，但是“时间”很少在新药进入诊所之前，已经非常明智地进行了研究。结果，显示的药物可以防止有时发现晚期/转移性实体瘤在预防复发方面无效在调整或新辅助设置中管理。从适应和新辅助疗法在于抗癌对残留/分布/微转移的临床休眠的影响通过常规临床方法无法检测到的癌细胞；这种抗癌作用的生物学实际上是未知的，为评估新药的差距造成了差距。生存的临床休眠癌细胞（NEO）辅助治疗最终会引起经常产生抗性的复发/晚期肿瘤所有批准的疗法。这是了解临床上休眠的癌细胞与已建立肿瘤的方式对新疗法的反应将指导适当疾病环境中的临床测试，并揭示了针对的目标结合疗法以提高效率。相关药物效率的更彻底表征临床前模型将在临床试验中提高药物成功率，从而降低药物的成本发展。雌激素受体α（ER）阳性乳腺癌是一种改善药物的疾病开发最终可能会影响成千上万的患者的治疗选择。患者早期ER+乳腺癌通过调整抗雌激素疗法治疗，中和ER和抑制但不会消除肿瘤发射细胞。我们和其他人已经实施了激活抗雌激素耐药性中的磷脂酰肌醇3-激酶（PI3K）途径，PI3K抑制剂（PI3KI）在临床发育与抗雌激素结合。根据我们的初步发现，我们假设抗雌激素/PI3KI联合疗法的短期治疗杀死了临床上的ER+乳房癌细胞并防止复发（AIM 2），而已建立的肿瘤发育抗性抗性通过抑制细胞凋亡（AIM 1），雌激素/PI3KI治疗部分归因于微环境细胞因子信号传导（AIM 3）。我们将通过以下特定目的检验该假设：1）确定为什么抗雌激素/PI3KI组合疗法在已建立的ER+乳腺肿瘤中敏锐但不能可持续的细胞毒性。 2）确定临床上休眠的ER+乳腺肿瘤细胞对短期抗雌激素/PI3KI的反应联合疗法； 3）鉴定基质衍生的秘密组中细胞因子，以抗抗 ER+乳腺癌中的雌激素和抗雌激素/PI3KI疗法。这些研究与NCI一致克服耐药性的精密医学计划，癌症月光面板建议开发克服癌症对治疗的抵抗的方法，以及NCI挑衅性问题`什么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过渡进行性疾病？