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

精确肿瘤学要求在正确的时间将正确的药物送到正确的患者手中，但“时间”很少 在新药进入临床之前进行临床前研究。因此，被证明可以防止癌症进展的药物 在以下情况下，晚期/转移性实体肿瘤有时在预防复发方面无效 在佐剂或新佐剂环境中给药。辅助剂和辅助剂的长期临床益处 新辅助治疗在于对残留/播散/微转移、临床上处于休眠状态的肿瘤的抗癌作用 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基础 几乎是未知的，这为评估新药创造了一个空白。临床上潜伏的癌细胞存活下来 (NEO)辅助治疗最终会导致复发/晚期肿瘤，这些肿瘤往往会产生耐药性。 所有经过批准的治疗方法。因此，了解临床上处于休眠状态的癌细胞与已建立的肿瘤之间的关系 对新疗法的反应将指导在适当的疾病背景下的临床测试(S)，并揭示目标 综合治疗以提高疗效。更全面地描述有关药物的疗效 临床前模型将提高临床试验中的药物成功率，从而降低药物成本 发展。雌激素受体α(ER)阳性的乳腺癌是一种经过改进的药物治疗的疾病 这种发展最终可能会影响数十万患者的治疗选择。患有疾病的患者 早期ER+乳腺癌采用辅助抗雌激素治疗，中和ER和 抑制但不能消除启动肿瘤的细胞。我们和其他人已经牵涉到激活 磷脂酰肌醇3-激酶(PI3K)途径在抗雌激素抵抗中的作用，以及PI3K抑制剂(PI3Ki)的研究进展 联合应用抗雌激素药物的临床进展。根据我们的初步发现，我们假设 抗雌激素/PI3Ki联合疗法短期治疗可杀死临床上处于休眠状态的ER+乳腺 癌细胞和预防复发(目标2)，而已建立的肿瘤对抗药性产生耐药性 雌激素/PI3Ki通过抑制细胞凋亡治疗(目标1)部分由于微环境细胞因子 信令(目标3)。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联合治疗对已建立的ER+乳腺肿瘤有强烈的细胞毒作用，但不是持久的； 2)确定临床上处于休眠状态的ER+乳腺肿瘤细胞对短期抗雌激素/PI3Ki的反应 联合治疗；3)确定基质来源的分泌体中的细胞因子，这些细胞因子推动了对抗肿瘤药物的抵抗 雌激素和抗雌激素/PI3Ki治疗ER+乳腺癌。这些研究与NCI保持一致 克服耐药性的精准医学倡议，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提出的挑衅性问题：什么是癌症 可以开发模型或其他方法来研究临床上稳定的疾病和随后的转变 到进展性疾病吗？

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?'