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:
  • 金额:
    $ 35.95万
  • 依托单位:
  • 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

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?'
精准肿瘤学需要在正确的时间将正确的药物输送给正确的患者,但“时间”很少 在新药进入临床前进行临床前研究。因此,药物显示,以防止进展, 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。从辅助治疗中实现的长期临床获益, 新辅助疗法的抗癌作用在于对残留/扩散/微转移,临床休眠 常规临床方法检测不到的癌细胞;这种抗癌作用的生物学基础 实际上是未知的,这为评估新药创造了一个空白。临床上处于休眠状态的癌细胞 (新)辅助治疗最终可能导致复发/晚期肿瘤, 所有批准的治疗方法。因此,了解临床休眠癌细胞与已建立的肿瘤 对新疗法的反应将指导适当疾病环境中的临床试验,并揭示 联合治疗以提高疗效。更全面地描述相关领域的药物疗效 临床前模型将提高药物在临床试验中的成功率,从而降低药物成本。 发展雌激素受体α(ER)阳性乳腺癌是一种疾病, 发展可能最终影响数十万患者的治疗选择。患者 早期ER+乳腺癌用辅助抗雌激素疗法治疗, 抑制但不消除肿瘤起始细胞。我们和其他人已经暗示激活了 磷脂酰肌醇3-激酶(PI 3 K)通路在抗雌激素抵抗中的作用,PI 3 K抑制剂(PI 3 Ki)在 与抗雌激素联合的临床开发。基于我们的初步发现,我们假设 短期抗雌激素/PI 3 Ki联合治疗杀死临床休眠ER+乳腺癌 癌细胞并防止复发(目标2),而已建立的肿瘤对抗-产生耐药性 雌激素/PI 3 Ki疗法通过抑制部分由微环境细胞因子引起的细胞凋亡(Aim 1) 信号(目标3)。我们将通过以下具体目的来检验这一假设:1)确定为什么反- 雌激素/PI 3 Ki联合治疗在已建立的ER+乳腺肿瘤中具有急性细胞毒性,但不具有可持续的细胞毒性; 2)确定临床休眠的ER+乳腺肿瘤细胞对短期抗雌激素/PI 3 Ki的反应 联合治疗; 3)鉴定基质来源的分泌组中驱动抗- 雌激素和抗雌激素/PI 3 Ki治疗ER+乳腺癌。这些研究与NCI一致 克服耐药性的精准医学倡议,癌症登月小组的建议, 开发克服癌症对治疗的抵抗力的方法,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转变 进展性疾病吗'

项目成果

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Todd W Miller其他文献

Todd W Miller的其他文献

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{{ truncateString('Todd W Miller', 18)}}的其他基金

A precision medicine basis for estrogen therapy for advanced breast cancer
晚期乳腺癌雌激素治疗的精准医学基础
  • 批准号:
    10930779
  • 财政年份:
    2023
  • 资助金额:
    $ 35.95万
  • 项目类别:
Uncovering the basis and implications of lineage plasticity in breast cancer
揭示乳腺癌谱系可塑性的基础和影响
  • 批准号:
    10544736
  • 财政年份:
    2022
  • 资助金额:
    $ 35.95万
  • 项目类别:
Therapeutically leveraging metabolic vulnerabilities in breast cancer
利用乳腺癌代谢脆弱性进行治疗
  • 批准号:
    10818782
  • 财政年份:
    2022
  • 资助金额:
    $ 35.95万
  • 项目类别:
Therapeutically leveraging metabolic vulnerabilities in breast cancer
利用乳腺癌代谢脆弱性进行治疗
  • 批准号:
    10659058
  • 财政年份:
    2022
  • 资助金额:
    $ 35.95万
  • 项目类别:
Uncovering the basis and implications of lineage plasticity in breast cancer
揭示乳腺癌谱系可塑性的基础和影响
  • 批准号:
    10907306
  • 财政年份:
    2022
  • 资助金额:
    $ 35.95万
  • 项目类别:
Uncovering the basis and implications of lineage plasticity in breast cancer
揭示乳腺癌谱系可塑性的基础和影响
  • 批准号:
    10357013
  • 财政年份:
    2022
  • 资助金额:
    $ 35.95万
  • 项目类别:
Therapeutically leveraging metabolic vulnerabilities in breast cancer
利用乳腺癌代谢脆弱性进行治疗
  • 批准号:
    10908068
  • 财政年份:
    2022
  • 资助金额:
    $ 35.95万
  • 项目类别:
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:
    10228617
  • 财政年份:
    2017
  • 资助金额:
    $ 35.95万
  • 项目类别:
A precision medicine basis for estrogen therapy for advanced breast cancer
晚期乳腺癌雌激素治疗的精准医学基础
  • 批准号:
    9311512
  • 财政年份:
    2017
  • 资助金额:
    $ 35.95万
  • 项目类别:
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:
    9383150
  • 财政年份:
    2017
  • 资助金额:
    $ 35.95万
  • 项目类别:

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血液转录组学作为 CT 佐剂排除急性中风出血
  • 批准号:
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  • 财政年份:
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