阶段：羟氯喹增强帕博昔单抗和来曲唑治疗ER+/HER2−乳腺癌症的疗效的试验-动脉网

Phase：trial of hydroxychloroquine to enhance palbociclib and letrozole efficacy in ER+/HER2− breast cancer

Nature 等信源发布 2025-01-26 20:09

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Abstract

摘要

Endocrine therapy with CDK4/6 inhibitors is standard for estrogen receptor-positive, HER2−negative metastatic breast cancer (ER+/HER2− MBC), yet clinical resistance develops. Previously, we demonstrated that low doses of palbociclib activate autophagy, reversing initial G1 cell cycle arrest, while high concentrations induce off-target senescence.

使用CDK4/6抑制剂进行内分泌治疗是雌激素受体阳性，HER2阴性转移性乳腺癌（ER+/HER2-MBC）的标准治疗方法，但会产生临床耐药性。以前，我们证明了低剂量的palbociclib激活自噬，逆转初始G1细胞周期停滞，而高浓度诱导脱靶衰老。

The autophagy inhibitor hydroxychloroquine (HCQ) induced on-target senescence at lower palbociclib doses. We conducted a phase I trial (NCT03774472 registered in ClinicalTrials.gov on 8/20/2018) of HCQ (400, 600, 800 mg/day) with palbociclib (75 mg/day continuous) and letrozole, using a 3 + 3 design.

自噬抑制剂羟氯喹（HCQ）在较低的palbociclib剂量下诱导靶向衰老。我们使用palbociclib（连续75毫克/天）和来曲唑进行了HCQ（400600800毫克/天）的I期临床试验（NCT03774472于2018年8月20日在ClinicalTrials.gov注册），使用3+3设计。

Primary objectives included safety, tolerability, and determining the recommended phase 2 dose (RP2D) of HCQ. Secondary objectives included tumor response and biomarker analysis. Fourteen ER+/HER2− MBC patients were evaluable [400 mg (.

主要目标包括安全性，耐受性和确定HCQ的推荐2期剂量（RP2D）。次要目标包括肿瘤反应和生物标志物分析。14名ER+/HER2-MBC患者可评估[400 mg（。

= 4), 600 mg (

=4），600毫克(

= 4), 800 mg (

=4），800毫克(

= 6)]. Grade 3 adverse events (AEs) included hematological (3 at 800 mg), skin rash (2 at 600 mg), and anorexia (1 at 400 mg), with no serious AEs. The best responses were partial (2), stable (11), and progression (1). Tumor reductions ranged from 11% to 30%, with one 55% increase. The two partial responders sustained tumor size reductions of 30% to 55% over an extended treatment period, lasting nearly 300 days.

3级不良事件（AE）包括血液学（3例800 mg），皮疹（2例600 mg）和厌食症（1例400 mg），无严重AE。最佳反应是部分（2），稳定（11）和进展（1）。肿瘤减少率从11%到30%不等，增加了55%。两名部分缓解者在延长的治疗期内持续肿瘤大小减少30%至55%，持续近300天。

Biomarker analysis in responders demonstrated significant decreases in Ki67, Rb, and nuclear cyclin E levels and increases in autophagy markers p62 and LAMP1, suggesting a correlation between these biomarkers and treatment response. This phase I study demonstrated that HCQ is safe and well-tolerated and the RP2D was established at 800 mg/day with continuous low-dose palbociclib (75 mg/day) and letrozole (2.5 mg/day).

应答者的生物标志物分析显示Ki67，Rb和核细胞周期蛋白E水平显着降低，自噬标志物p62和LAMP1增加，表明这些生物标志物与治疗反应之间存在相关性。这项I期研究表明，HCQ是安全且耐受性良好的，RP2D建立在800毫克/天，连续低剂量palbociclib（75毫克/天）和来曲唑（2.5毫克/天）。

These findings suggest that adding HCQ could potentially enhance the efficacy of low-dose palbociclib and standard letrozole therapy, pending verification in larger randomized studies..

这些发现表明，添加HCQ可能会提高低剂量palbociclib和标准来曲唑治疗的疗效，有待更大规模的随机研究验证。。

Introduction

简介

Hormone receptor-positive (HR+) and human epidermal growth factor receptor 2 (HER2)-negative breast cancer represents the largest subtype of breast cancer, accounting for 75% of cases in the U.S., including the largest number of breast cancer deaths annually

激素受体阳性（HR+）和人表皮生长因子受体2（HER2）阴性乳腺癌是乳腺癌的最大亚型，占美国病例的75%，包括每年乳腺癌死亡人数最多

. It is estimated that 155,000 patients are living with metastatic breast cancer (MBC) in the US, and that 35,000 new cases of metastatic HR+/HER2− breast cancer are diagnosed either de novo (presenting with metastatic disease), or as a result of recurrence of previously treated disease, with 30,000 deaths expected each year.

据估计，美国有155000名患者患有转移性乳腺癌（MBC），并且有35000例新的转移性HR+/HER2-乳腺癌病例被从头诊断（出现转移性疾病），或者是由于先前治疗过的疾病复发，预计每年有30000人死亡。

. While survival rates for breast cancer have been improving due to earlier detection and newer treatments, the trends for MBC are lagging behind, with 5-year survival rates for HR+/HER2− breast cancer of 34%

尽管由于早期发现和更新的治疗方法，乳腺癌的生存率一直在提高，但MBC的趋势却滞后，HR+/HER2-乳腺癌的5年生存率为34%

The use of endocrine therapy (ET) as initial treatment for HR+/HER2− MBC has become more common, as studies show chemotherapy is not necessarily superior in terms of survival, especially compared with ET plus cyclin-dependent kinase 4 and 6 inhibitors (CDK4/6i)

使用内分泌治疗（ET）作为HR+/HER2-MBC的初始治疗已变得越来越普遍，因为研究表明，化疗在生存方面并不一定优于ET加细胞周期蛋白依赖性激酶4和6抑制剂（CDK4/6i）

. However, early progression within 8 weeks occurs in ~20% of patients with ET/CDK4/6i first-line therapy, and later-line treatments typically yield progressively shorter response times

然而，约20%的ET/CDK4/6i一线治疗患者在8周内出现早期进展，而后期治疗通常会产生逐渐缩短的反应时间

. There is a need to better understand mechanisms of intrinsic resistance and early adaptive responses to ET/CDK4/6i therapy to extend breast cancer control time in the first-line setting.

。需要更好地了解对ET/CDK4/6i治疗的内在抵抗机制和早期适应性反应，以延长一线乳腺癌控制时间。

The cell cycle apparatus has long been explored as a target in cancer treatment as its dysregulation is a hallmark of cancer, with multiple mutations ascribed to positive and negative regulatory components

长期以来，人们一直将细胞周期仪作为癌症治疗的靶标，因为其失调是癌症的标志，多种突变归因于正调控成分和负调控成分

. The development of specific small molecule inhibitors to CDK4/6, kinases that activate both G1/S transition and cross-talk with other oncogenic pathways, demonstrated the expected preclinical effects, particularly in HR+ breast cancer cell line models and exhibited acceptable toxicity in early-phase clinical trials.

CDK4/6的特异性小分子抑制剂的开发，激活G1/S转换和与其他致癌途径的串扰的激酶，证明了预期的临床前效应，特别是在HR+乳腺癌细胞系模型中，并且在早期阶段表现出可接受的毒性临床试验。

. In 2015, the approval of palbociclib augured a new era of targeted therapy when added to the AI letrozole, and a doubling of progression-free survival was observed

2015年，palbociclib的批准预示着在AI来曲唑中加入靶向治疗的新时代，并且观察到无进展生存期增加了一倍

. Subsequently, several phase III randomized trials showed a similar impact with palbociclib, and other CDK4/6i ribociclib and abemaciclib combined with AI in first-line as well as with fulvestrant in first or second-line therapy

随后，几项III期随机试验显示，palbociclib和其他CDK4/6i ribociclib和abemaciclib联合AI一线治疗以及氟维司群一线或二线治疗的效果相似

. Longer follow-up has now demonstrated improvement in overall survival (OS) with ribociclib and abemaciclib

更长时间的随访表明，使用ribociclib和abemaciclib可以改善总生存期（OS）

. The use of CDK4/6i is now a standard and preferred option in the first-line setting for patients with advanced HR+/HER2− breast cancer

。对于晚期HR+/HER2-乳腺癌患者，CDK4/6i的使用现在是一线治疗的标准和首选选择

However, treatment with CDK4/6is does introduce new toxicities that require additional monitoring and may infrequently cause significant morbidity. For example, in the first-line setting, 66% of patients on palbociclib experience grade 3 and 4 neutropenia, and adverse events (AEs) necessitated a palbociclib dose reduction in 36% and discontinuation in 7.4% of patients.

然而，用CDK4/6is治疗确实会引入新的毒性，需要额外的监测，并且可能很少引起严重的发病率。例如，在一线治疗中，66%的palbociclib患者出现3级和4级中性粒细胞减少症，不良事件（AE）需要palbociclib剂量减少36%，7.4%的患者停药。

. Additionally, palbociclib must be dosed with a 7-day break, which was shown to be associated with a proliferative burst in a neoadjuvant serial biopsy study

此外，palbociclib必须休息7天，这在新辅助系列活检研究中被证明与增殖性爆发有关

. Also, a precise biological mechanism of palbociclib’s action is still unknown, and there are no known independent biomarkers to predict response and/or resistance to palbociclib. Many patients do not respond to therapy, and most importantly, virtually all eventually develop resistance. Biomarkers that may reduce response to ET and CDK4/6i including estrogen receptor-alpha (.

此外，palbociclib作用的确切生物学机制仍然未知，并且没有已知的独立生物标志物来预测对palbociclib的反应和/或抗性。许多患者对治疗没有反应，最重要的是，几乎所有患者最终都会产生耐药性。可能降低对ET和CDK4/6i反应的生物标志物，包括雌激素受体α（。

ESR1

) and phosphatidylinositol-4,5-Bisphosphate 3-Kinase Catalytic Subunit Alpha (

)和磷脂酰肌醇-4,5-二磷酸3-激酶催化亚基α(

PIK3CA)

PIK3CA）

mutations, loss of the retinoblastoma protein function, high proliferative antigen Ki67 expression,

突变，视网膜母细胞瘤蛋白功能丧失，高增殖抗原Ki67表达，

cyclin D1

细胞周期蛋白D1

gene amplification or loss of the cyclin-dependent kinase inhibitor

细胞周期蛋白依赖性激酶抑制剂的基因扩增或丢失

have not correlated with the relative benefits of palbociclib-associated response or time to progression

与palbociclib相关反应或进展时间的相对益处无关

Previously, we reported that breast cancer cells activate autophagy in response to low doses of palbociclib and that the combination with autophagy inhibitors (i.e., hydroxychloroquine) induces irreversible growth inhibition and senescence in vitro, and diminish growth of cell line and patient-derived xenograft tumors in vivo.

此前，我们报道乳腺癌细胞响应低剂量的palbociclib激活自噬，并且与自噬抑制剂（即羟氯喹）的组合在体外诱导不可逆的生长抑制和衰老，并减少体内细胞系和患者来源的异种移植肿瘤的生长。

. The low concentrations of palbociclib are on-target and specific inhibitors of CDK4 and CDK6, as shown with small interfering RNA (siRNA) knockdown of CDK4 and CDK6. High concentrations of palbociclib induce senescence, but these are not related to CDK4/6 inhibition and are off-target effects of the drug.

低浓度的palbociclib是CDK4和CDK6的靶向和特异性抑制剂，如CDK4和CDK6的小干扰RNA（siRNA）敲低所示。。

These results show that autophagy inhibition significantly improves the efficacy of low-dose (on-target) palbociclib in vivo and facilitates irreversible tumor growth inhibition- suggesting that palbociclib activates the autophagy pathway to protect HR+ breast cancer cells from palbociclib-induced senescence, and inhibition of autophagy sensitizes cells to lower doses of palbociclib in vitro and in vivo.

这些结果表明，自噬抑制显着提高了低剂量（靶向）palbociclib在体内的功效，并促进了不可逆的肿瘤生长抑制-表明palbociclib激活自噬途径以保护HR+乳腺癌细胞免受palbociclib诱导的衰老，并且抑制自噬使细胞在体外和体内对较低剂量的palbociclib敏感。

Autophagy is a cellular process known for its dual role in tumor suppression

自噬是一种细胞过程，以其在肿瘤抑制中的双重作用而闻名

and promotion

和推广

, as well as in contributing to drug resistance by clearing damaged cellular components and promoting survival

，以及通过清除受损的细胞成分和促进生存来促进耐药性

. Various inhibitors of autophagy have been investigated to enhance cancer therapy. These include: Bafilomycin A1, which inhibits the vacuolar-type H + -ATPase, disrupting lysosomal acidification and autophagic flux

已经研究了各种自噬抑制剂以增强癌症治疗。这些包括：巴弗洛霉素A1，它抑制液泡型H+-ATPase，破坏溶酶体酸化和自噬通量

; 3-Methyladenine (3-MA), an inhibitor of class III PI3K necessary for early autophagy stages

；3-甲基腺嘌呤（3-MA），一种早期自噬阶段所必需的III类PI3K抑制剂

; Wortmannin- another PI3K inhibitor that hinders autophagosome formation

；渥曼青霉素-另一种阻碍自噬体形成的PI3K抑制剂

and Spautin-1, inhibiting deubiquitinating enzymes USP10 and USP13, which target the class III PI3K complex

和Spautin-1，抑制靶向III类PI3K复合物的去泛素化酶USP10和USP13

. Chloroquine (CQ) and hydroxychloroquine (HCQ) are the most extensively studied autophagy inhibitors. These lysosomotropic agents block autophagy by preventing lysosomal acidification, thereby impeding autophagic vesicle degradation

氯喹（CQ）和羟氯喹（HCQ）是研究最广泛的自噬抑制剂。这些溶酶体抑制剂通过阻止溶酶体酸化来阻断自噬，从而阻止自噬囊泡降解

. HCQ is favored clinically for several reasons: (i) its long-standing safety record in treating malaria and autoimmune diseases like lupus and rheumatoid arthritis

HCQ在临床上受到青睐的原因有几个：（i）其在治疗疟疾和自身免疫性疾病（如狼疮和类风湿性关节炎）方面的长期安全记录

: (ii) high clinical tolerability with fewer severe side effects compared to other inhibitors

：（ii）与其他抑制剂相比，临床耐受性高，严重副作用少

; (iii) oral administration, enabling convenient long-term use and combination with other cancer therapies

；（iii）口服给药，便于长期使用并与其他癌症疗法结合使用

and (iv) efficacy in blocking autophagic flux at the lysosomal level

（iv）在溶酶体水平阻断自噬通量的功效

Based on these findings, we aimed to evaluate the safety and tolerability (phase I) of adding HCQ to continuous low-dose (on-target) palbociclib and letrozole in metastatic HR+, HER2− breast cancer through a dose-escalation phase 1 study to determine the recommended phase 2 dose (RP2D), the dose-limiting toxicities (DLT) and efficacy of this combination..

基于这些发现，我们旨在通过剂量递增1期研究评估在转移性HR+，HER2-乳腺癌中连续低剂量（靶向）palbociclib和来曲唑中添加HCQ的安全性和耐受性（I期），以确定推荐的2期剂量（RP2D），剂量限制性毒性（DLT）和这种组合的疗效。。

Methods

方法

Patient selection

患者选择

Eligible patients were age ≥18 years with a histologically confirmed diagnosis of HR+/HER2− MBC by ASCO/CAP criteria

符合条件的患者年龄≥18岁，经ASCO/CAP标准组织学确诊为HR+/HER2-MBC

and were candidates for treatment with CDK4/6 inhibitor (CDK4/6i) and ET with an aromatase inhibitor (AI) as standard of care. Patients had to have adequate renal (serum creatinine concentration <1.5 × ULN), hepatic (bilirubin level <1.5 × ULN. Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) < 3 × ULN or alkaline phosphatase ≤2.5 ULN), and hematologic (ANC ≥ 1500 cells/μl; platelet count ≥100,000/μl) function; with an Eastern Cooperative Oncology Group (ECOG) performance status score of 0 or 1.

并且是用CDK4/6抑制剂（CDK4/6i）和ET与芳香化酶抑制剂（AI）作为标准治疗的候选者。患者必须有足够的肾脏（血清肌酐浓度<1.5××ULN），肝脏（胆红素水平<1.5××ULN）。天冬氨酸氨基转移酶（AST）或丙氨酸氨基转移酶（ALT）<3×ULN或碱性磷酸酶≤2.5 ULN）和血液学（ANC≥1500个细胞/μl；血小板计数≥100000/μl）功能；东部肿瘤协作组（ECOG）的表现状态得分为0或1。

Female patients had to be postmenopausal-defined as age ≥ 55 years and 1 year or more of amenorrhea; age <55 years and 1 year or more of amenorrhea with luteinizing hormone (LH) and/or follicle-stimulating hormone (FSH) levels in the postmenopausal range; age <55 with prior hysterectomy but intact ovaries with LH and/or FSH levels in the postmenopausal range; chemotherapy or medically induced ovarian suppression with 1 year or more of amenorrhea and with LH and/or FSH levels in the postmenopausal range; status after bilateral oophorectomy (≥28 days prior to first study treatment).

女性患者必须是绝经后定义为年龄≥55岁，闭经1年或更长时间；年龄<55岁，闭经1年或以上，黄体生成素（LH）和/或促卵泡激素（FSH）水平在绝经后范围内；年龄<55岁，既往有子宫切除术，但卵巢完整，LH和/或FSH水平在绝经后范围内；化疗或药物诱导的卵巢抑制，闭经1年或更长时间，LH和/或FSH水平在绝经后范围内；双侧卵巢切除术后的状态（首次研究治疗前≥28天）。

Premenopausal patients were allowed on a later protocol amendment if receiving a gonadotropin-releasing hormone agonist..

如果接受促性腺激素释放激素激动剂，绝经前患者可以接受后来的方案修正案。。

The exclusion criteria were defined as follows: patients with prior exposure to CDK4/6 inhibitor therapy; a history of retinal disease or active visual disturbances (a normal baseline retinal examination, as specified by the study, was required); acute illnesses, including infections requiring medical therapy, known bleeding disorders, or the need for anticoagulation; and recent treatment with any of the following within 4 weeks prior to initiating study treatment: oral estrogens, including hormone replacement therapy; investigational agents (within 4 weeks or 5 half-lives of the agent, whichever was longer); or medications requiring concurrent use of strong CYP3A inhibitors or inducers.

排除标准定义如下：先前接触CDK4/6抑制剂治疗的患者；有视网膜疾病或活动性视力障碍的病史（需要进行研究规定的正常基线视网膜检查）；急性疾病，包括需要药物治疗的感染，已知的出血性疾病或需要抗凝治疗；在开始研究治疗之前的4周内，最近接受了以下任何一种治疗：口服雌激素，包括激素替代疗法；研究药物（在药物的4周或5个半衰期内，以较长者为准）；或需要同时使用强CYP3A抑制剂或诱导剂的药物。

Additional exclusion criteria included psychological, familial, sociological, or geographical factors that could impede compliance with the study protocol; a life expectancy of less than 6 months; and pregnancy, lactation, or plans to become pregnant..

其他排除标准包括可能阻碍遵守研究方案的心理，家庭，社会学或地理因素；预期寿命不到6个月；怀孕、哺乳或计划怀孕。。

Treatment plan

治疗计划

This is a single-center, open-label, non-randomized, standard 3 + 3 dose-escalation design

这是一个单中心，开放标签，非随机，标准的3++3剂量递增设计

phase I study (NCT03774472 registered in ClinicalTrials.gov on 8/20/2018) with the primary objective to evaluate the safety and tolerability of combining HCQ with continuous low-dose palbociclib (75 mg/day) and letrozole in patients with HR+/HER2− MBC and to establish the RP2D of HCQ (see Results section for the study design).

I期研究（NCT03774472于2018年8月20日在ClinicalTrials.gov注册），主要目的是评估HCQ与连续低剂量palbociclib（75mg/天）和来曲唑联合治疗HR+/HER2-MBC患者的安全性和耐受性，并建立HCQ的RP2D（见研究设计的结果部分）。

The decision to use continuous low-dose palbociclib (75 mg/day) in this trial was based on emerging evidence from neoadjuvant studies showing spikes in cell proliferation during the 7 days off therapy in the standard 125 mg/day dosing schedule (administered 21 days on, 7 days off). These proliferation spikes, reflected by increases in both the proliferative index and serum thymidine kinase levels, suggest that the off-treatment interval may allow tumor regrowth, potentially reducing therapeutic efficacy.

在该试验中使用连续低剂量palbociclib（75毫克/天）的决定是基于新辅助研究的新证据，显示在标准125毫克/天给药方案（21天给药，7天休息）治疗7天期间细胞增殖出现峰值。这些增殖峰值反映在增殖指数和血清胸苷激酶水平的增加上，表明非治疗间隔可能允许肿瘤再生，可能降低治疗效果。

. To address this concern, we hypothesized that continuous dosing of palbociclib, when combined with HCQ and letrozole, could sustain therapeutic pressure and prevent these regrowth periods. At the time of this trial, preliminary data from other ongoing studies at Pfizer testing continuous palbociclib dosing at 75 mg/day supported the feasibility and tolerability of this regimen, providing a basis for its inclusion in our study design.

为了解决这个问题，我们假设连续服用palbociclib，当与HCQ和来曲唑联合使用时，可以维持治疗压力并防止这些再生期。毫克/天支持该方案的可行性和耐受性，为其纳入我们的研究设计提供了基础。

This dosing strategy enabled the evaluation of continuous cell cycle inhibition as a means to optimize the therapeutic potential of the drug combination while maintaining safety and tolerability..

这种给药策略能够评估连续的细胞周期抑制，作为优化药物组合治疗潜力的手段，同时保持安全性和耐受性。。

The secondary objective was to determine the response rate and clinical benefit rate at 8 weeks of the assigned HCQ dose plus continuous low-dose palbociclib and letrozole. For the Phase I portion of this study, tumor biopsies were optional, as the primary objective was to assess safety and establish the RP2D of HCQ.

次要目标是确定指定HCQ剂量加连续低剂量palbociclib和来曲唑在8周时的缓解率和临床获益率。对于本研究的I期部分，肿瘤活检是可选的，因为主要目标是评估安全性并建立HCQ的RP2D。

Tissue acquisition and analysis, including the use of archival specimens, were exploratory aims of this phase. As a result, not all patients provided tissue samples, and pre- and on-treatment biopsies were not universally collected. Only one patient had paired pre- and on-treatment biopsies available which were analyzed.

组织采集和分析，包括档案标本的使用，是这一阶段的探索性目标。因此，并非所有患者都提供了组织样本，治疗前和治疗中的活检也没有普遍收集。只有一名患者进行了配对的治疗前和治疗中活检，并进行了分析。

The results presented here include IHC analysis for Ki67, Rb, and nuclear cyclin E for the pre-treatment samples from patients 2, 3, 4, 6, 8, 9, 10, 12, 13, and 15. We also are providing pre and on-treatment IHC results for Ki67, Rb, cyclin E, and 2 autophagy markers, p62, and LAMP1, for patient 3..

这里给出的结果包括对来自患者2、3、4、6、8、9、10、12、13和15的治疗前样品的Ki67，Rb和核细胞周期蛋白E的IHC分析。。。

The study was approved by MD Anderson Cancer Center’s (Houston, TX) Institutional Review Board and was conducted in accordance with the declaration of Helsinki and Good Clinical Practice principles

这项研究得到了MD安德森癌症中心（德克萨斯州休斯顿）机构审查委员会的批准，并根据赫尔辛基宣言和良好临床实践原则进行

. All patients provided written informed consent before starting any study-related procedures. The IRB protocol (MDACC 2017-0071) is included in the Supplementary material.

。所有患者在开始任何与研究相关的程序之前都提供了书面知情同意书。IRB协议（MDACC 2017-0071）包含在补充材料中。

The study design schema is shown in the results section. A cycle was defined as 28 days, with DLT assessed over the first 28-day cycle. DLT is defined as grade 3 or 4 attributed to the study drug and excepting uncomplicated neutropenia ≤7 days (for a more detailed definition, refer to the protocol in the supplementary material).

研究设计方案显示在结果部分。一个周期定义为28天，DLT在第一个28天周期内进行评估。DLT被定义为归因于研究药物的3级或4级，除了≤7天的无并发症中性粒细胞减少症（有关更详细的定义，请参阅补充材料中的方案）。

The dose escalation followed a standard 3 + 3 design.

剂量递增遵循标准的3 + 3设计。

to evaluate escalating doses of HCQ in combination with palbociclib (75 mg/kg taken orally once daily) and letrozole (2.5 mg/day taken orally once daily). At each dose level, three patients were initially enrolled and monitored for DLTs over one treatment cycle (28 days). If no DLTs were observed, the dose was escalated to the next cohort.

评估递增剂量的HCQ联合palbociclib（75 mg/kg，每日口服一次）和来曲唑（2.5 mg/天，每日口服一次）。在每个剂量水平下，最初招募三名患者，并在一个治疗周期（28天）内监测DLT。如果未观察到DLT，则将剂量升级至下一队列。

If one patient experienced a DLT, the cohort was expanded to include an additional three patients. Escalation ceased if two or more patients in a cohort experienced DLTs, with the prior dose defined as the maximum tolerated dose. To define an RP2D, at least six evaluable patients were required at a given dose level..

如果一名患者经历了DLT，则该队列将扩大到包括另外三名患者。。为了定义RP2D，在给定剂量水平下至少需要六名可评估的患者。。

For this trial, 14 patients were enrolled to determine the RP2D. Two patients (Study IDs 1 and 8) were excluded from the DLT assessment due to protocol-specified reasons: non-compliance during treatment (Study ID 1) and early disease progression before completing the DLT period (Study ID 8). These patients were replaced, ensuring 12 evaluable patients were included in the analysis.

。由于方案规定的原因，两名患者（研究ID 1和8）被排除在DLT评估之外：治疗期间不合规（研究ID 1）和完成DLT期之前的早期疾病进展（研究ID 8）。这些患者被替换，确保分析中包括12名可评估的患者。

The RP2D was determined based on the safety and tolerability data from 3 patients treated at 400 mg HCQ, 3 at 600 mg HCQ, and 6 at 800 mg HCQ daily. Full details of patient outcomes and DLT assessments are provided in Table .

RP2D是根据3名接受400 mg HCQ治疗的患者，3名接受600 mg HCQ治疗的患者和6名每天接受800 mg HCQ治疗的患者的安全性和耐受性数据确定的。表中提供了患者结局和DLT评估的全部细节。

The primary objective of this trial phase was to assess safety and establish the RP2D of HCQ in combination with palbociclib and letrozole. Since the focus was on toxicity management rather than treatment response, measurable disease was not required for enrollment. Continued treatment beyond 8 weeks was reserved for patients demonstrating clear benefits, particularly those with partial responses (PR) as defined by RECIST criteria (≥30% reduction in the sum of the longest diameters of target lesions).

该试验阶段的主要目的是评估安全性，并建立HCQ与palbociclib和来曲唑联合使用的RP2D。由于重点是毒性管理而不是治疗反应，因此登记不需要可测量的疾病。对于表现出明显益处的患者，特别是RECIST标准定义的部分缓解（PR）患者（目标病变最长直径总和减少≥30%），保留8周以上的持续治疗。

Patients with stable disease (SD), defined as <30% decrease or less than a 20% increase in tumor size from baseline, were not treated beyond the DLT assessment phase. This approach prioritized safety while limiting exposure to potentially toxic therapy in patients without significant responses, aligning with the trial’s objective of defining a safe dosing strategy (IRB protocol included in the Supplementary Material)..

疾病稳定（SD）的患者（定义为肿瘤大小比基线减少30%或增加不到20%）未在DLT评估阶段之后接受治疗。这种方法优先考虑安全性，同时限制无明显反应的患者接触潜在毒性治疗，符合试验确定安全给药策略的目标（补充材料中包括IRB方案）。。

Efficacy and safety assessments

疗效和安全性评估

For the first 2 cycles (8 weeks), all patients were monitored with weekly office visits for physical exams and blood tests including complete blood count and leukocyte differential, electrolytes, blood urea nitrogen, creatinine, glucose, albumin, AST, and alanine aminotransferase, total bilirubin, alkaline phosphatase at baseline; thereafter patients were seen every 4 weeks.

在前2个周期（8周）中，每周对所有患者进行体检和血液检查，包括全血细胞计数和白细胞差异，电解质，血尿素氮，肌酐，葡萄糖，白蛋白，AST和丙氨酸氨基转移酶，总胆红素，基线碱性磷酸酶；此后，每4周观察一次患者。

At baseline, urine or serum pregnancy test and urinalysis with microscopic exam were also performed. Additionally, a baseline HCQ screening ophthalmological exam per the latest guidelines of the American Academy of Ophthalmology (AAO) was performed on all patients, with repeat assessment required for new or worsening eye symptoms..

在基线时，还进行了尿液或血清妊娠试验以及显微镜检查的尿液分析。此外，根据美国眼科学会（AAO）的最新指南，对所有患者进行了基线HCQ筛查眼科检查，新的或恶化的眼部症状需要重复评估。。

AEs were evaluated systematically to ensure comprehensive safety assessment and accurate attribution to the study drugs. A detailed breakdown of drug-associated AEs is provided in Table

对AE进行了系统评估，以确保全面的安全性评估和对研究药物的准确归因。表中提供了与药物相关的AE的详细分类

S1级

, where each AE is classified based on its potential relationship to the study drugs. Attribution of AEs was determined by the Principal Investigator (PI) or a designated co-investigator using a conservative approach, recognizing the potential for overlapping toxicities due to combination therapy. Consequently, some AEs were attributed to multiple drugs when definitive causation could not be established..

，其中每个AE根据其与研究药物的潜在关系进行分类。AE的归因由主要研究者（PI）或指定的共同研究者使用保守方法确定，认识到由于联合治疗可能导致重叠毒性。因此，当无法确定确切的因果关系时，一些AE被归因于多种药物。。

All AEs were assessed using the CTCAE Version 4.03 criteria, which included classification by type of adverse effect, severity grading (from mild, Grade 1, to severe, Grade 4), and attribution to one or more study drugs as suspected or unrelated. The duration of each AE was documented, noting the start and end dates or if the AE was ongoing at the time of the final examination.

所有不良事件均使用CTCAE 4.03版标准进行评估，其中包括按不良反应类型分类，严重程度分级（从轻度1级到严重4级），以及归因于一种或多种可疑或不相关的研究药物。记录每个AE的持续时间，注意开始和结束日期，或者AE在最终检查时是否正在进行。

Actions taken in response to AEs, such as dose adjustment, temporary interruption, permanent discontinuation, or administration of concomitant medications, were also recorded. For serious adverse events (SAEs), criteria for severity and impact were evaluated to determine if they met SAE designation.

还记录了针对AE采取的行动，例如剂量调整，暂时中断，永久停药或同时服用药物。对于严重不良事件（SAE），评估严重程度和影响标准，以确定它们是否符合SAE指定。

This structured approach ensured thorough monitoring and documentation of AEs, facilitating a detailed understanding of the safety profile of the study drugs, both individually and in combination..

这种结构化的方法确保了对不良事件的彻底监测和记录，有助于详细了解研究药物的安全性，无论是单独使用还是联合使用。。

DLTs were defined as any death not clearly due to the underlying disease or extraneous causes; any grade 3 or higher non-hematologic toxicity; liver function abnormalities meeting Hy’s law

DLT被定义为由于潜在疾病或外来原因而不明确的任何死亡；任何3级或更高级别的非血液学毒性；

; neutropenic fever; grade 4 neutropenia or thrombocytopenia >7 days; grade 3 or higher thrombocytopenia with bleeding; grade 3 or higher nausea/vomiting or diarrhea ≥72 hours with adequate antiemetic and other supportive care; grade 3 or higher fatigue ≥1 week; grade 3 or higher electrolyte abnormality lasting >72 hours or of any duration with clinical symptoms..

；中性粒细胞减少症；4级中性粒细胞减少症或血小板减少症>7天；3级或更高血小板减少症伴出血；3级或更高级别的恶心/呕吐或腹泻≥72小时，并有足够的止吐和其他支持治疗；3级或以上疲劳≥1周；3级或更高级别的电解质异常持续>72小时或任何持续时间的临床症状。。

Tumor response and progression were evaluated using Response Evaluation Criteria in Solid Tumors (RECIST) (version 1.1)

使用实体瘤反应评估标准（RECIST）（版本1.1）评估肿瘤反应和进展

once every 8 weeks or as clinically indicated. At week 8, if tumor response was observed, patients were allowed to continue treatment until progression or significant toxicities up to a maximum of 1 year. This timeframe was due to concerns about HCQ toxicities that could be treatment cumulative and would be tested in a follow-up controlled longer-term trial.

每8周一次或根据临床指示。在第8周，如果观察到肿瘤反应，则允许患者继续治疗直至进展或显着毒性，最长可达1年。这个时间范围是由于担心HCQ毒性可能是治疗累积的，并将在后续控制的长期试验中进行测试。

Patients who showed progression or stability of disease at week 8 came off the study and continued standard treatment (standard dose palbociclib and letrozole) or alternate therapy at the discretion of the treating physician..

在第8周表现出疾病进展或稳定的患者退出研究，并继续标准治疗（标准剂量palbociclib和来曲唑）或由主治医师自行决定的替代治疗。。

Correlative biomarker assays

相关生物标志物测定

Sections of formalin-fixed, paraffin-embedded blocks (5 microns) of patient primary or metastatic tumor tissue were de-paraffinized (30 minutes at 72 °C) and rehydrated with antigen retrieval at 100 °C for 30 minutes with citrate buffer, pH 6.0. Endogenous peroxidase was blocked with 3% peroxide for 5 minutes.

将患者原发性或转移性肿瘤组织的福尔马林固定，石蜡包埋的块（5微米）切片脱石蜡（72℃30分钟），并用柠檬酸盐缓冲液（pH 6.0）在100℃下用抗原修复再水化30分钟。内源性过氧化物酶用3%过氧化物封闭5分钟。

Slides from each patient were stained for antibodies against cyclin E (C-19, sc-198; Santa Cruz Biotechnology), Ki67 (#ab16667, 1:500 dilution; Abcam), and Rb (clone G3-245, BD Pharmagen.

对每位患者的载玻片进行抗细胞周期蛋白E（C-19，sc-198；Santa Cruz Biotechnology），Ki67（#ab16667，1:500稀释；Abcam）和Rb（克隆G3-245，BD Pharmagen）的抗体染色。

TM公司

, RRID:AB_385259) as described

，RRID:AB_385259），如所述

. For patient 3, where pre and on-treatment slides were available, in addition to the three aforementioned antibodies, the slides were stained with two autophagy markers LAMP1 [Santa Cruz #sc-20011 RRID:AB_626853 (1:400)] and for p62 [Cell Signaling Technology #88588S, RRID:AB_2800125 (1:800)]. Post-primary antibody detection was conducted using a commercial polymer system (Bond Polymer Refine Detection, Leica), and stain development was achieved by incubating cells with DAB and DAB Enhancer (Leica).

对于患者3，除了上述三种抗体外，还有治疗前和治疗中的载玻片，载玻片用两种自噬标记LAMP1[Santa Cruz#sc-20011 RRID:AB#626853（1:400）]和p62[Cell Signaling Technology#88588S，RRID:AB#U 2800125（1:800）]染色。使用商业聚合物系统（Bond polymer Refine detection，Leica）进行一抗后检测，并通过将细胞与DAB和DAB增强子（Leica）孵育来实现染色发展。

A positive batch of control slides was added for every immunohistochemistry run and on-control to each slide. Stained slides were scanned using the Aperio CS2 slide scanner (20X magnification) and subsequently analyzed for staining intensity using the positive pixel count tool in the Leica ImageScope software program (version 12.3), which measures both the area and intensity of positive staining per square millimeter of tissue.

对于每次免疫组织化学运行和每个载玻片的对照，都添加了一批阳性对照载玻片。使用Aperio CS2载玻片扫描仪（放大20倍）扫描染色的载玻片，随后使用Leica ImageScope软件程序（版本12.3）中的阳性像素计数工具分析染色强度，该工具测量每平方毫米组织阳性染色的面积和强度。

Percent staining positivity was defined as the number of positive cells per square millimeter of tissue analyzed for each sample..

染色阳性百分比定义为每个样品分析的每平方毫米组织中阳性细胞的数量。。

Statistical analysis

统计分析

Descriptive summary statistics were used to characterize demographics, safety, and antitumor activity. AEs were identified for each drug and at each dose level for HCQ and reported by type and grade. Categorical data were summarized using frequencies, percentages, and 95% exact confidence intervals (CIs).

描述性总结统计用于表征人口统计学，安全性和抗肿瘤活性。针对每种药物和HCQ的每种剂量水平鉴定AE，并按类型和等级报告。使用频率，百分比和95%精确置信区间（CI）总结分类数据。

Differences in categorical variables were assessed by Fisher’s exact tests. Continuous data were summarized by medians with 95% CIs and ranges..

通过Fisher精确检验评估分类变量的差异。连续数据由95%可信区间和范围的中位数汇总。。

Results

结果

Patient characteristics

患者特征

Between September 2018 and December 2020, 23 patients signed informed consent for study enrollment at the MD Anderson Cancer Center as depicted in the study design schema (Fig.

在2018年9月至2020年12月期间，23名患者在MD安德森癌症中心签署了知情同意书，如研究设计方案所示（图）。

1A级

); of these 6 patients did not meet secondary requirements and were considered “screen failures”, and 3 registered patients withdrew consent prior to receiving any treatment on the study (Fig.

)；这6名患者不符合次要要求，被认为是“筛查失败”，3名注册患者在接受研究治疗之前撤回了同意（图）。

1B级

). Two patients with measurable disease and documented response continued the study beyond 8 weeks (50 and 52 weeks) per protocol (Fig.

)。两名患有可测量疾病和记录反应的患者按照方案继续研究超过8周（50周和52周）（图）。

1B级

). The baseline clinical characteristics of these 14 patients are shown in Table

)。这14例患者的基线临床特征如表所示

. All were female and non-Hispanic, and their median age was 41 years (range 39–69), with the majority being Caucasian (79%).

。均为女性和非西班牙裔，中位年龄为41岁（39-69岁），其中大多数为白种人（79%）。

Fig. 1: Study Design and Participant Flow in a Phase I Trial of Hydroxychloroquine, Palbociclib, and Letrozole in HR+/HER2- Metastatic Breast Cancer.

图1：羟氯喹，Palbociclib和来曲唑在HR+/HER2转移性乳腺癌中的I期试验的研究设计和参与者流程。

Study schema for dose escalation and dose expansion of hydroxychloroquine (HCQ) (400 mg, 600 mg, and 800 mg/day) in combination with fixed-dose continuous palbociclib (75 mg/day) and letrozole (2.5 mg/day).

羟氯喹（HCQ）（400 mg，600毫克和800毫克/天）与固定剂量连续palbociclib（75毫克/天）和来曲唑（2.5毫克/天）联合使用。

B类

Flow chart (CONSORT diagram) of study participants (enrollment and disposition).

研究参与者的流程图（CONSORT图）（登记和处置）。

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Table 1 Patient characteristics

表1患者特征

Full size table

全尺寸表

None of the 14 patients on the trial received CDK4/6 inhibitor (CDK4/6i) therapy prior to enrollment, as this was explicitly excluded per the study protocol. Twelve patients (Study IDs 1, 2, 3, 5, 8, 9, 10, 11, 12, 13, 14, and 15) were diagnosed with metastatic disease at the time of accrual (between September 2018 and December 2020) and entered the trial immediately following their diagnosis, without exposure to any prior CDK4/6i therapy.

试验中的14名患者在入组前均未接受CDK4/6抑制剂（CDK4/6i）治疗，因为根据研究方案明确排除了这一点。12名患者（研究ID 1,2,3,5,8,9,10,11,12,13,14和15）在应计时（2018年9月至2020年12月）被诊断出患有转移性疾病，并在诊断后立即进入试验，没有接触任何先前的CDK4/6i治疗。

Two patients who had been diagnosed with metastatic disease prior to the accrual period had received multiple lines of therapy for metastatic disease, but none of these treatments included CDK4/6i. For patient Study ID 4, prior treatments included Taxol (chemotherapy) in 2013, fulvestrant, and the combination of everolimus and exemestane (endocrine therapies) in 2014, followed by Xeloda (chemotherapy) until 2018.

在应计期之前被诊断出患有转移性疾病的两名患者接受了多种转移性疾病治疗，但这些治疗均未包括CDK4/6i。对于患者研究ID 4，之前的治疗包括2013年的紫杉醇（化疗），2014年的氟维司群以及依维莫司和依西美坦（内分泌治疗）的联合治疗，然后是希罗达（化疗），直到2018年。

This patient subsequently enrolled in a Phase 1 trial involving a STING agonist and PDR001 in 2018, progressed on that therapy, and was then enrolled in our clinical trial without prior CDK4/6i exposure. Similarly, patient Study ID 7 received fulvestrant and the combination of everolimus and exemestane (endocrine therapies) until 2016, followed by Xeloda (chemotherapy) until 2019, after which she enrolled in our trial.

该患者随后于2018年参加了一项涉及STING激动剂和PDR001的1期临床试验，该治疗取得了进展，然后在没有事先接触CDK4/6i的情况下参加了我们的临床试验。同样，患者研究ID 7在2016年之前接受氟维司群以及依维莫司和依西美坦的联合治疗（内分泌治疗），然后在2019年之前接受希罗达（化疗），之后她参加了我们的试验。

Like the other patients, this individual had no prior exposure to CDK4/6is before participating in the study. This ensures that all enrolled patients met the exclusion criterion regarding prior CDK4/6i treatment. In summary, out of 14 patients identified, 12 patients received study treatment as 1st line and 2 patients as 4th line and 7th line..

。这确保了所有登记的患者都符合先前CDK4/6i治疗的排除标准。总之，在确定的14名患者中，12名患者接受了一线研究治疗，2名患者接受了四线和七线研究治疗。。

Most patients underwent additional therapy after coming off the study, which included CDK4/6i + ET, chemotherapy/targeted therapies, or enrollment in other clinical trials. Table

大多数患者在退出研究后接受了额外的治疗，包括CDK4/6i+ET，化疗/靶向治疗或参加其他临床试验。表

summarizes the sequence and frequency of subsequent therapies received by 14 patients after discontinuation of the trial.

总结了停止试验后14名患者接受后续治疗的顺序和频率。

Table 2 Subsequent therapy following the Phase I trial

表2 I期试验后的后续治疗

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全尺寸表

Safety and dose escalation

安全性和剂量递增

All 14 patients who had received at least one dose of HCQ in any of the three cohorts, were evaluable for safety and efficacy (4 at 400 mg, 4 at 600 mg, and 6 at 800 mg). Of the 14 patients enrolled in the study, two were not evaluable for DLT (Fig.

在三个队列中的任何一个队列中接受过至少一剂HCQ的所有14名患者都可以评估其安全性和有效性（400 mg时为4名，600 mg时为4名，800 mg时为6名）。在参加研究的14名患者中，有2名无法评估DLT（图）。

1B级

). One patient in the first cohort discontinued the study at week 3 due to non-compliance, and one patient in the second cohort experienced early disease progression at week 4, just prior to completing the DLT period. As per protocol, these two patients were replaced, resulting in 12 patients being evaluated for DLT analysis across the three dose levels.

)。第一组中的一名患者由于不依从而在第3周停止了研究，第二组中的一名患者在完成DLT期之前的第4周经历了早期疾病进展。根据方案，这两名患者被替换，导致12名患者在三个剂量水平上接受DLT分析评估。

There were no treatment-related deaths in the study. Treatment-related AEs according to grade and drug attribution (palbociclib, letrozole, or HCQ) are shown in Fig. .

该研究中没有与治疗相关的死亡。根据等级和药物归因（palbociclib，来曲唑或HCQ）的治疗相关AE如图所示。

and Supplementary Table

和补充表

. Figure

.图

depicts dose-specific AEs associated with HCQ. The majority of patients (79%) treated with any of the three doses of HCQ (400, 600, or 800 mg/day) experienced only grade 1 or 2 AEs. AEs of grade 3 associated with HCQ were hematological in 3 of the patients at the 800 mg dose level, skin rash in 2 of the patients at the 600 mg dose level, and anorexia in 1 of the patients at the 400 mg dose level and (Supplementary Table .

描述了与HCQ相关的剂量特异性AE。用三种剂量的HCQ（400600或800mg/天）中的任何一种治疗的大多数患者（79%）仅经历1级或2级AE。与HCQ相关的3级AE在800mg剂量水平的3名患者中为血液学，在600mg剂量水平的2名患者中为皮疹，在400mg剂量水平的1名患者中为厌食症（补充表）。

and Fig.

和图。

). HCQ treatment was not associated with any grade 4 AEs at any dose level in any of the patients. One patient discontinued early at 4 weeks shortly after the DLT period with a grade 3 rash that was attributed to HCQ (but worsened by sun exposure). Ocular toxicities were seen in 4 patients (29%) and were all grade 1.

)。在任何患者中，HCQ治疗与任何剂量水平的任何4级AE均无关。一名患者在DLT期后不久的第4周早期停药，出现3级皮疹，归因于HCQ（但因阳光照射而恶化）。4例患者（29%）出现眼部毒性，均为1级。

The only grade 3 AEs associated with letrozole were skin rash in 1 patient and anorexia in 1 patient. Letrozole treatment was not associated with any grade 4 AEs (Fig. .

与来曲唑相关的唯一3级AE是1例患者的皮疹和1例患者的厌食症。来曲唑治疗与任何4级AE无关（图）。

and Supplementary Tables

和补充表格

and

和

). The AEs of grade ≥3 associated with palboclicib were hematologic in ten patients (71%), skin rash in two patients (14%), and anorexia in one patient (7%), with no serious AEs reported.

)。与palbocicib相关的≥3级AE为10例患者（71%）的血液学，2例患者（14%）的皮疹和1例患者（7%）的厌食症，未报告严重AE。

Fig. 2: Summary of Treatment-Emergent Adverse Events by Severity for Each of the Three Study Drugs.

图2：三种研究药物中每一种的严重程度的治疗紧急不良事件总结。

Toxicity assessment board for frequencies and grades of unique treatment-emergent adverse events for HCQ (top panels), letrozole (middle panels and palbociclib (bottom panels); Grades 1 and 2 adverse events per each drug are depicted to the right, and grades 3 and 4 adverse events per each drug are depicted to the left..

HCQ（上图），来曲唑（中图和palbociclib（下图））独特治疗紧急不良事件的频率和等级的毒性评估委员会；每种药物的1级和2级不良事件描绘在右侧，每种药物的3级和4级不良事件描绘在左侧。。

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Fig. 3: Adverse Event Profile of Hydroxychloroquine Across Escalating Dose Levels. Unique adverse events for frequencies and grades for each of the 3 doses of HCQ (400, 600, and 800 mg/day), with grades 1 and 2 events on the left and grade 3 on the right.

图3：羟氯喹在递增剂量水平下的不良事件概况。3剂HCQ（400600和800mg/天）的频率和等级的独特不良事件，左侧为1级和2级事件，右侧为3级。

No grade 4 adverse events for any dose of HCQ were observed in any of the patients.

在任何患者中均未观察到任何剂量的HCQ的4级不良事件。

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No DLTs were seen in the 1st cohort (400 mg/day) and hence the 2nd cohort (600 mg/day) and 3rd cohort (and final target dose) of 800 mg of HCQ per day in combination with continuous dosing palbociclib at 75 mg/day and letrozole at 2.5 mg/day were successively activated. No DLTs were observed in the overall study; hence, 800 mg was declared as the RP2D for HCQ..

在第一组（400毫克/天）中没有观察到DLT，因此第二组（600毫克/天）和第三组（和最终目标剂量）每天800毫克HCQ联合连续给药palbociclib 75毫克/天和来曲唑2.5毫克/天被相继激活。在整个研究中没有观察到DLT；因此，800毫克被宣布为HCQ的RP2D。。

There were no dose modifications or reductions of HCQ. Nine patients (64%) had at least one dose delay of palbociclib because of grade 3 neutropenia (Supplementary Table

没有剂量改变或HCQ减少。9名患者（64%）因3级中性粒细胞减少症至少延迟了一次palbociclib剂量（补充表）

). No clear association was observed between HCQ dose level and the percent of total days of palbociclib dosing (ranging from 0 to 37.5%) that was delayed due to neutropenia (absolute neutrophil count <1000).

)。HCQ剂量水平与由于中性粒细胞减少（绝对中性粒细胞计数<1000）而延迟的palbociclib给药总天数百分比（范围从0到37.5%）之间没有明显的相关性。

Efficacy and biomarker assessments

功效和生物标志物评估

The median follow-up time for all patients was 47.1 months. All patients underwent restaging CT scans at 8 weeks to assess initial response according to RECIST 1.1. Patients with measurable disease and responses were eligible to continue treatment, undergoing scans every 8-12 weeks for up to 1 year, provided there was no progression or as decided by the patient and/or by the investigator-defined response.

所有患者的中位随访时间为47.1个月。根据RECIST 1.1，所有患者均在8周时进行了CT扫描，以评估初始反应。具有可测量疾病和反应的患者有资格继续治疗，每8-12周进行一次扫描，持续长达1年，前提是没有进展或由患者和/或研究者确定的反应决定。

One patient had a progression of disease at 4 weeks, detected clinically as progression in an ipsilateral axillary node at 3 weeks, and was taken off the study. Of the 14 patients, PR was observed in two patients (14.3%), SD at 8 weeks was observed in 11 (78.6%), and clinical progression in one patient (7.1%).

一名患者在4周时出现疾病进展，在3周时临床检测为同侧腋窝淋巴结进展，并被取消研究。在14例患者中，2例（14.3%）观察到PR，11例（78.6%）观察到8周时的SD，1例（7.1%）观察到临床进展。

For measurable disease, tumor decreases by RECIST criteria of 11%, 12%, 21%, 26%, 30%, and 55%, and an increase in 1 patient by 55% progressive disease (PD) was observed (Fig. .

对于可测量的疾病，RECIST标准的肿瘤减少了11%，12%，21%，26%，30%和55%，并且观察到1名患者的进展性疾病（PD）增加了55%（图）。

4A级

). The percentage change in tumor size from baseline over time is depicted in a spider plot (Fig.

)。随着时间的推移，肿瘤大小相对于基线的百分比变化描绘在蜘蛛图中（图）。

4B级

) for individual patients treated with HCQ, palbociclib, and letrozole, categorized according to RECIST criteria: PR, SD, or PD. One patient (Patient 5) exhibited PD with a rapid tumor size increase exceeding 50% within the first 50 days. Seven patients (Patients 3, 8, 9, 14, 2, 13, and 15) demonstrated SD, with tumor size changes fluctuating slightly but remaining within a stable range (<30% decrease or less than 20% increase).

)对于接受HCQ，palbociclib和来曲唑治疗的个体患者，根据RECIST标准进行分类：PR，SD或PD。一名患者（患者5）在前50天内表现出PD，肿瘤大小迅速增加超过50%。7名患者（患者3、8、9、14、2、13和15）表现出SD，肿瘤大小变化略有波动，但保持在稳定范围内（减少30%或增加不到20%）。

Two patients (Patients 6 and 4) achieved PRs, with tumor size reductions exceeding 30%. Notably, Patient 6 maintained a 55% reduction, the maximum observed, over ~300 days, suggesting a durable response. Two patients (Patients 10 and 12) lacked sufficient imaging data to quantify their response..

两名患者（患者6和4）达到PRs，肿瘤大小减少超过30%。值得注意的是，患者6在约300天内保持了55%的减少，这是观察到的最大值，表明反应持久。两名患者（患者10和12）缺乏足够的成像数据来量化他们的反应。。

Fig. 4: Tumor Response by RECIST Criteria and Biomarker Analysis of Ki67, Rb, Cyclin E, p62, and LAMP1 in Patients Treated with HCQ + Palbociclib + Letrozole.

图4:RECIST标准的肿瘤反应和HCQ+Palbociclib+来曲唑治疗患者Ki67，Rb，细胞周期蛋白E，p62和LAMP1的生物标志物分析。

Waterfall plot depicting the best percentage change in the sums of the diameters of target lesions per RECIST 1.1 in patients with measurable disease.

瀑布图描绘了可测量疾病患者每个RECIST 1.1的目标病变直径总和的最佳百分比变化。

B类

Tumor Response Over Time by RECIST Criteria in Patients on Treatment. percentage change from baseline in tumor size over time (days on treatment) for individual patients treated with a combination of HCQ, palbociclib, and letrozole. Each patient’s response is color-coded to indicate their response category according to RECIST criteria: progressive disease (PD), stable disease (SD), or partial response (PR).

RECIST标准对治疗患者的肿瘤反应随时间的推移。。根据RECIST标准，每位患者的反应都进行了颜色编码，以指示其反应类别：进行性疾病（PD），稳定疾病（SD）或部分反应（PR）。

Patients 10 and 12 are labeled as “No QIAC,” indicating they were on treatment but lacked quantifiable imaging data to determine their exact response. .

。

C级

Immunohistochemistry (IHC) staining on biopsy from patient 5 (Pt. 5) with PD after treatment (post-Rx) indicates increased proliferation (Ki67), lack of RB expression in tumor (arrow indicates positive RB expression in stromal cells), and cyclin E levels. IHC for Ki67, RB, and cyclin E was performed on biopsies obtained from Pt.

治疗后（Rx后）PD患者5（Pt。5）活检的免疫组织化学（IHC）染色显示增殖增加（Ki67），肿瘤中缺乏RB表达（箭头表示基质细胞中RB阳性表达）和细胞周期蛋白E水平。对从Pt获得的活组织检查进行Ki67，RB和细胞周期蛋白E的IHC。

4 with PR and Pt 13 SD prior to treatment (baseline). .

4治疗前PR和Pt 13 SD（基线）。

Pt. 3 had two biopsies: baseline and on treatment (On-Rx), and each was stained with Ki67, Rb, and cyclin E as well as two autophagy markers, p62 and LAMP1.

。

Quantification of Ki67 in C at baseline for Pt 13, Pt 3, and Pt 4.

Pt 13，Pt 3和Pt 4基线时C中Ki67的定量。

F级

Quantification of Ki67, p62, and LAMP1 in matched biopsies from Pt.3. There is a 10% reduction in Ki67 and a 25% and 35%% increase in p62 and LAMP1, respectively, while on treatment from baseline. PD progressive disease, SD stable disease, PR partial response.

来自Pt.3的匹配活组织检查中Ki67，p62和LAMP1的定量。从基线开始治疗时，Ki67降低了10%，p62和LAMP1分别增加了25%和35%。PD进行性疾病，SD稳定疾病，PR部分缓解。

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IHC analysis of Rb, cyclin E, and Ki67 was performed on available tumor biopsies (Fig.

对可用的肿瘤活检组织进行了Rb、细胞周期蛋白E和Ki67的IHC分析（图）。

4C级

and Supplementary Fig.

和补充图。

). The results revealed that Rb was expressed in tumors from patients with SD and PR but was absent in the tumor cells of the one patient who experienced PD (patient 5, Fig.

)。结果显示，Rb在SD和PR患者的肿瘤中表达，但在一名经历PD的患者的肿瘤细胞中不存在（患者5，图）。

4C级

). Notably, in patient 5, Rb expression was restricted to the stromal compartment, as indicated by the arrow in Fig.

)。值得注意的是，在患者5中，Rb表达仅限于基质区室，如图1中的箭头所示。

4C级

. Nuclear cyclin E expression was detected in all patient tumors, indicating no evidence of cytoplasmic cyclin E-mediated intrinsic resistance to CDK4/6i. Ki67 expression in pre-treatment biopsies ranged from 13 to 37% in patients 13, 3, and 4. Importantly, Ki67 levels in patient 3 decreased to below 2.7% during treatment, consistent with the therapeutic activity of the regimen (Fig.

在所有患者肿瘤中均检测到核细胞周期蛋白E表达，表明没有证据表明细胞质细胞周期蛋白E介导的对CDK4/6i的内在抗性。在患者13、3和4中，治疗前活检中Ki67的表达范围为13%至37%。重要的是，患者3的Ki67水平在治疗期间降至2.7%以下，与该方案的治疗活性一致（图）。

4D–F

). Additionally, the autophagy markers p62 and LAMP1

)。此外，自噬标记p62和LAMP1

were evaluated in pre-treatment and on-treatment samples for patient 3. The analysis showed increased expression of both markers in the on-treatment sample compared to the pre-treatment sample (Fig.

在治疗前和治疗样本中对患者3进行了评估。分析显示，与预处理样品相比，处理样品中两种标记物的表达均增加（图）。

D、，

F级

), suggesting that the addition of HCQ to the treatment regimen effectively inhibited the autophagy pathway in this patient.

)，表明在治疗方案中添加HCQ可有效抑制该患者的自噬途径。

Discussion

讨论

To our knowledge, this is the first prospective clinical trial reporting results on CDK4/6 inhibitor (CDK4/6i) and ET concurrently with an autophagy inhibitor, HCQ. The combination of low-dose palbociclib, letrozole, and HCQ, in which palbociclib was administered continuously at 75 mg/day, letrozole at 2.5 mg/day (FDA-approved dose) and HCQ at 3 dose levels (400 mg/day, 600 mg/day and 800 mg/day) demonstrated an acceptable safety profile and clinical feasibility in hormone receptor-positive and HER2− MBC.

据我们所知，这是第一个关于CDK4/6抑制剂（CDK4/6i）和ET与自噬抑制剂HCQ同时报告结果的前瞻性临床试验。低剂量palbociclib，来曲唑和HCQ的组合，其中palbociclib以75 mg/天连续给药，来曲唑以2.5 mg/天（FDA批准的剂量）和HCQ以3个剂量水平（400 mg/天，600毫克/天和800毫克/天）在激素受体阳性和HER2-MBC中表现出可接受的安全性和临床可行性。

Safe escalation to 800 mg HCQ was accomplished with no DLTs. The RPD2 of HCQ was 800 mg with continuous palbociclib at 75 mg/d and letrozole 2.5 mg/d. There appears to be an accentuation of fatigue, gastrointestinal symptoms, dysgeusia, and rash with the addition of HCQ. Prominent neutropenia was seen, necessitating delays in palbociclib with this regimen compared to standard palbociclib at 125, 100, or 75 mg for 21 days on and 7 days off.

在没有DLT的情况下，安全升级至800 mg HCQ。HCQ的RPD2为800 mg，连续palbociclib为75 mg/d，来曲唑为2.5 mg/d。添加HCQ似乎会加重疲劳，胃肠道症状，味觉障碍和皮疹。观察到明显的中性粒细胞减少症，与标准的palbociclib相比，该方案需要延迟palbociclib的125100或75mg，持续21天和7天。

It is not clear if this is due to continuous dosing palbociclib or the addition of HCQ. There was a trend toward more neutropenia at the highest HCQ level, or days of palbociclib held due to neutropenia (palbociclib held for absolute neutrophil count <1000). Additionally, the overall rate of 14.2% of days of delay of palbociclib may overestimate hematologic toxicity since most patients waited 7 or more days prior to rechecking blood counts..

目前尚不清楚这是由于连续给药palbociclib还是添加HCQ。在最高HCQ水平下，或由于中性粒细胞减少而导致的palbociclib天数（palbociclib的绝对中性粒细胞计数小于1000）有中性粒细胞减少的趋势。此外，palbociclib延迟天数的14.2%的总发生率可能高估了血液学毒性，因为大多数患者在重新检查血液计数之前等待了7天或更长时间。。

Our preclinical study

我们的临床前研究

supported the continuous dosing of palbociclib used in this study, and a neoadjuvant trial testing palbociclib with anastrozole did, in fact, show that more patients exhibited a proliferative burst as assessed by the proliferative antigen Ki67 when stopping palbociclib with a longer break before surgery than a short or no break.

支持本研究中使用的palbociclib的连续给药，事实上，用阿那曲唑测试palbociclib的新辅助试验确实表明，当停止palbociclib时，更多患者表现出增殖性爆发，如增殖抗原Ki67所评估的那样，手术前休息时间比短或不休息时间长。

. Efforts are ongoing to explore lower continuous dosing, with a schedule of 5 days on and two days off weekly at a palbociclib dose of 125 mg/d preliminarily showing this dose was feasible, with 36% of patients experiencing grade 3 neutropenia, less than the hypothesized rate

.正在努力探索较低的连续给药，时间表为每周5天，休息两天，palbociclib剂量为125 mg/d初步表明该剂量是可行的，36%的患者出现3级中性粒细胞减少症，低于假设的发生率

. Thus, the concept of autophagy inhibition with a lower dose of continuous palbociclib is expected to be feasible. As described earlier, these findings have implications for augmenting the effects of other approved CDK4/6is, mTOR, PI3K, and AKT inhibitors used with ET.

因此，预计用较低剂量的连续palbociclib抑制自噬的概念是可行的。如前所述，这些发现对于增强与ET一起使用的其他批准的CDK4/6is，mTOR，PI3K和AKT抑制剂的作用具有重要意义。

Responses reported after the initial 8-week period may not be representative of the long-term activity that would be assessed in a phase II trial, but our design to limit longer-term treatment was necessary until we better understand the toxicity profile such that patients could receive standard care for their disease.

最初8周后报告的反应可能不能代表II期试验中评估的长期活动，但我们限制长期治疗的设计是必要的，直到我们更好地了解毒性特征，以便患者可以接受标准的疾病护理。

Nevertheless, the combination exhibited encouraging activity, eliciting two durable PRs and 11 patients with SD that requires confirmation with a Phase II trial. The overall response rate was 2 of 7 (29%) in those with measurable disease and 8-week disease control was seen in 11 of 12 evaluable patients (92%)..

然而，这种组合表现出令人鼓舞的活性，引发了两个持久的PRs和11名SD患者，需要通过II期试验进行确认。在可测量疾病的患者中，总有效率为7分之2（29%），在12名可评估患者中有11名（92%）观察到8周的疾病控制。。

Responses were independent of prior exposure to ET, which suggests that triple combination can overcome mechanisms of resistance; however, the small numbers of patients treated in our study preclude any definite conclusion. In addition, two patients who had measurable and responsive disease remained on therapy for at least 50 weeks..

反应与先前暴露于ET无关，这表明三联疗法可以克服抵抗机制；。此外，两名患有可测量和反应性疾病的患者仍在接受治疗至少50周。。

Our preclinical findings demonstrate that combining autophagy inhibitors, such as HCQ, with CDK4/6is induces irreversible growth arrest and establishes a stable state of cellular senescence in cancer cells

我们的临床前研究结果表明，将自噬抑制剂（例如HCQ）与CDK4/6is结合使用可诱导不可逆的生长停滞，并在癌细胞中建立稳定的细胞衰老状态

. This combination is particularly relevant in the adjuvant setting, where the primary goal is to achieve durable tumor suppression and prevent late recurrences

这种组合在辅助治疗中尤其重要，其主要目标是实现持久的肿瘤抑制并防止晚期复发

. While senescence is a critical tumor-suppressive mechanism, its associated secretory phenotype (SASP) can drive drug resistance and promote a pro-tumorigenic microenvironment over time

虽然衰老是一种关键的肿瘤抑制机制，但其相关的分泌表型（SASP）可以随着时间的推移驱动耐药性并促进促肿瘤发生的微环境

. Autophagy inhibition addresses this challenge by destabilizing the survival pathways of senescent cells, creating a “senescence lock” that prevents these cells from re-entering the cell cycle or escaping dormancy

自噬抑制通过破坏衰老细胞的存活途径来解决这一挑战，产生“衰老锁”，阻止这些细胞重新进入细胞周期或逃避休眠

. Additionally, autophagy inhibitors function as senolytics, selectively eliminating senescent cells and mitigating SASP-driven effects that could facilitate tumor recurrence

. By clearing these cells and preventing their escape from dormancy, this approach enhances the antitumor durability of CDK4/6is, reduces the residual disease burden, and fosters a tumor microenvironment less conducive to recurrence, thereby improving long-term outcomes in patients.

通过清除这些细胞并防止其从休眠中逃脱，这种方法增强了CDK4/6is的抗肿瘤耐久性，减少了残留的疾病负担，并促进了不太利于复发的肿瘤微环境，从而改善了患者的长期预后。

Although the study regimen is feasible, extended HCQ dosing may increase toxicities and potentially disrupt optimal long-term palbociclib administration. The combination demonstrated encouraging activity, such as PRs, prolonged SD (in patients without measurable disease), and promising overall survival benefits.

虽然研究方案是可行的，但延长HCQ剂量可能会增加毒性，并可能破坏最佳的长期palbociclib给药。该组合显示出令人鼓舞的活动，例如PRs，延长的SD（在没有可测量疾病的患者中），以及有希望的总体生存益处。

However, newer autophagy inhibitors with fewer off-target toxicities may offer more favorable responses and improved tolerability. One such inhibitor is Lys05 is a potent next-generation autophagy inhibitor that outperforms HCQ.

然而，具有较少脱靶毒性的新型自噬抑制剂可能提供更有利的反应和改善的耐受性。一种这样的抑制剂是Lys05，它是一种有效的下一代自噬抑制剂，优于HCQ。

. It effectively accumulates in lysosomes and inhibits autophagy, making it ideal for combination cancer therapies. Lys05 enhances the impact of radiation on NSCLC cells

它有效地积累在溶酶体中并抑制自噬，使其成为联合癌症治疗的理想选择。Lys05增强辐射对NSCLC细胞的影响

and boosts the cytotoxicity of BRAF inhibitors in melanoma, particularly in resistant cells

. It also enhances palbociclib’s effect in breast cancer models at lower doses than HCQ

。它还以比HCQ更低的剂量增强了palbociclib在乳腺癌模型中的作用

, potentially reducing toxicity in clinical trials. Additionally, ULK1/2 inhibitors, such as SBI-0206965

，可能会降低临床试验中的毒性。此外，ULK1/2抑制剂，例如SBI-0206965

and DCC-3116

和DCC-3116

, have shown effectiveness in blocking autophagy initiation, offering targeted approaches for cancer treatment. Combining ULK1/2 inhibitors with existing therapies can improve outcomes by selectively inhibiting autophagy pathways. Currently, DCC-3116 is undergoing Phase 1/2 clinical trials (NCT04892017, NCT05957367) to evaluate its safety, tolerability, and preliminary efficacy as both a monotherapy and in combination with other cancer therapies, such as MEK and KRAS G12C inhibitors, in patients with advanced or metastatic solid tumors..

，已显示出阻止自噬启动的有效性，为癌症治疗提供了有针对性的方法。将ULK1/2抑制剂与现有疗法相结合可以通过选择性抑制自噬途径来改善结果。目前，DCC-3116正在进行1/2期临床试验（NCT04892017，NCT05957367），以评估其作为单一疗法以及与其他癌症疗法（如MEK和KRAS G12C抑制剂）联合使用对晚期或转移性实体瘤患者的安全性，耐受性和初步疗效。。

Our study also had some limitations. We enrolled relatively few patients with diverse tumor characteristics. Dose escalation also limited the optimal interpretation of activity. Our study did not include analyses of additional factors, which could have impacted outcomes, such as autophagy biomarkers pre and post-treatment samples or pharmacokinetics assessments.

我们的研究也有一些局限性。我们招募了相对较少的具有不同肿瘤特征的患者。剂量递增也限制了对活动的最佳解释。我们的研究不包括可能影响结果的其他因素的分析，例如自噬生物标志物治疗前和治疗后样品或药代动力学评估。

Despite these limitations, our study demonstrated that the combination of palbociclib, letrozole, and HCQ has a favorable safety profile. Recognizing the limitations of the exploratory tissue analysis in this Phase I study, we have designed a future randomized Phase II “window” trial in the early-stage setting to address these gaps.

尽管存在这些局限性，但我们的研究表明，palbociclib，来曲唑和HCQ的组合具有良好的安全性。认识到第一阶段研究中探索性组织分析的局限性，我们在早期阶段设计了一项未来的随机II期“窗口”试验，以解决这些差距。

This trial will evaluate the feasibility and efficacy of autophagy inhibition with HCQ in combination with low-dose continuous CDK4/6i to reverse resistance or enhance therapeutic activity. Conducted in the neoadjuvant setting, this study will include mandatory pre- and post-treatment biopsies, allowing for a brief (2-week) exposure period to thoroughly investigate biomarkers and pharmacodynamic changes.

该试验将评估HCQ联合低剂量连续CDK4/6i抑制自噬的可行性和有效性，以逆转耐药性或增强治疗活性。在新辅助治疗环境中进行，这项研究将包括强制性的治疗前和治疗后活检，允许短暂（2周）的暴露期，以彻底研究生物标志物和药效学变化。

Particular focus will be given to biomarkers strongly associated with autophagy modulation, providing critical insights into their potential role in predicting clinical outcomes and guiding therapeutic strategies. Additional studies using more targeted autophagy inhibitors in development may provide a better benefit/toxicity ratio needed for longer-term testing if this concept is proven in the phase II setting..

将特别关注与自噬调节密切相关的生物标志物，为其在预测临床结果和指导治疗策略中的潜在作用提供重要见解。如果在II期环境中证明了这一概念，那么在开发中使用更有针对性的自噬抑制剂的其他研究可能会为长期测试提供更好的益处/毒性比。。

Data availability

数据可用性

The data that support the findings of this study are available from the corresponding author, upon reasonable request.

根据合理的要求，通讯作者可以提供支持本研究结果的数据。

References

参考文献

Noone, A. M. et al. Cancer incidence and survival trends by subtype using data from the surveillance epidemiology and end results program, 1992-2013.

Noone，A.M.等人，使用1992-2013年监测流行病学和最终结果计划的数据，按亚型划分的癌症发病率和生存趋势。

Cancer Epidemiol. Biomark. Prev.

癌症流行病学。。

, 632–641 (2017).

Article

文章

Google Scholar

谷歌学者

Howlader, N. et al. US incidence of breast cancer subtypes defined by joint hormone receptor and HER2 status.

Howlader，N。等人。美国由关节激素受体和HER2状态定义的乳腺癌亚型的发病率。

J. Natl. Cancer Inst.

J、纳特尔。癌症研究所。

106

, dju055 (2014)

动物055（2014）

Mariotto, A. B., Etzioni, R., Hurlbert, M., Penberthy, L. & Mayer, M. Estimation of the number of women living with metastatic breast cancer in the United States.

Mariotto，A.B.，Etzioni，R.，Hurlbert，M.，Penberthy，L。＆Mayer，M。估计美国患有转移性乳腺癌的女性人数。

Cancer Epidemiol. Biomark. Prev.

癌症流行病学。。

, 809–815 (2017).

Article

文章

Google Scholar

谷歌学者

Deluche, E. et al. Contemporary outcomes of metastatic breast cancer among 22,000 women from the multicentre ESME cohort 2008–2016.

Deluche，E.等人，《2008-2016年多中心ESME队列中22000名女性转移性乳腺癌的当代结果》。

Eur. J. cancer

Eur. J. 癌症

129

, 60–70 (2020).

Article

文章

CAS

中科院

PubMed

Google Scholar

谷歌学者

Rugo, H. et al. Palbociclib plus letrozole as first-line therapy in estrogen receptor-positive/human epidermal growth factor receptor 2-negative advanced breast cancer with extended follow-up.

Rugo，H.等人，Palbociclib联合来曲唑作为雌激素受体阳性/人表皮生长因子受体2阴性晚期乳腺癌的一线治疗，并延长随访时间。

Breast Cancer Res. Treat.

。

174

, 719–729 (2019).

Article

文章

CAS

中科院

PubMed

PubMed Central

PubMed 中央

Google Scholar

谷歌学者

Hortobagyi, G. N. et al. Updated results from MONALEESA-2, a phase III trial of first-line ribociclib plus letrozole versus placebo plus letrozole in hormone receptor-positive, HER2−negative advanced breast cancer.

Hortobagyi，G.N.等人更新了Monalesa-2的结果，Monalesa-2是一线ribociclib加来曲唑与安慰剂加来曲唑治疗激素受体阳性，HER2阴性晚期乳腺癌的III期临床试验。

Ann. Oncol.

安科。

, 1541–1547 (2018).

Article

文章

CAS

中科院

PubMed

Google Scholar

谷歌学者

Goetz, M. P. et al. MONARCH 3: abemaciclib as initial therapy for advanced breast cancer.

Goetz，M.P.等。MONARCH 3：abemaciclib作为晚期乳腺癌的初始治疗。

J. Clin. Oncol.

J、克林。肿瘤。

, 3638–3646 (2017).

Article

文章

CAS

中科院

PubMed

Google Scholar

谷歌学者

Martin, M. et al. Palbociclib in combination with endocrine therapy versus capecitabine in hormonal receptor-positive, human epidermal growth factor 2-negative, aromatase inhibitor-resistant metastatic breast cancer: a phase III randomised controlled trial—PEARL.

Martin，M。等人。Palbociclib联合内分泌治疗与卡培他滨治疗激素受体阳性，人表皮生长因子2阴性，芳香化酶抑制剂耐药的转移性乳腺癌：一项III期随机对照试验PEARL。

Ann. Oncol.

安科。

, 488–499 (2021).

Article

文章

CAS

中科院

PubMed

Google Scholar

谷歌学者

Cardoso, F. et al. 4th ESO–ESMO international consensus guidelines for advanced breast cancer (ABC 4).

Cardoso，F.等人，《第四期ESO–ESMO国际晚期乳腺癌共识指南》（ABC 4）。

Ann. Oncol.

安科。

, 1634–1657 (2018).

Article

文章

CAS

中科院

PubMed

Google Scholar

谷歌学者

Cardoso, F. et al. 5th ESO-ESMO international consensus guidelines for advanced breast cancer (ABC 5).

Cardoso，F。等人，《第五期ESO-ESMO国际晚期乳腺癌共识指南》（ABC 5）。

Ann. Oncol.

安科。

, 1623–1649 (2020).

Article

文章

CAS

中科院

PubMed

Google Scholar

谷歌学者

Cristofanilli, M. et al. Fulvestrant plus palbociclib versus fulvestrant plus placebo for treatment of hormone-receptor-positive, HER2−negative metastatic breast cancer that progressed on previous endocrine therapy (PALOMA-3): final analysis of the multicentre, double-blind, phase 3 randomised controlled trial.

Cristofanilli，M。等人。氟维司群加palbociclib与氟维司群加安慰剂治疗激素受体阳性，HER2阴性的转移性乳腺癌，这些转移性乳腺癌在先前的内分泌治疗（PALOMA-3）中进展：多中心，双盲，3期随机对照试验的最终分析。

Lancet Oncol.

柳叶刀Oncol。

, 425–439 (2016).

Article

文章

CAS

中科院

PubMed

Google Scholar

谷歌学者

Tripathy, D. et al. Ribociclib plus endocrine therapy for premenopausal women with hormone-receptor-positive, advanced breast cancer (MONALEESA-7): a randomised phase 3 trial.

Tripathy，D。等人。Ribociclib联合内分泌治疗绝经前激素受体阳性晚期乳腺癌（Monalesa-7）：一项随机3期临床试验。

Lancet Oncol.

柳叶刀Oncol。

, 904–915 (2018).

Article

文章

CAS

中科院

PubMed

Google Scholar

谷歌学者

Suski, J. M., Braun, M., Strmiska, V. & Sicinski, P. Targeting cell-cycle machinery in cancer.

Suski，J.M.，Braun，M.，Strmiska，V。＆Sicinski，P。靶向癌症中的细胞周期机制。

Cancer Cell

癌细胞

, 759–778 (2021).

Article

文章

CAS

中科院

PubMed

PubMed Central

PubMed 中央

Google Scholar

谷歌学者

O’Leary, B., Finn, R. S. & Turner, N. C. Treating cancer with selective CDK4/6 inhibitors.

O'Leary，B.，Finn，R.S。＆Turner，N.C。用选择性CDK4/6抑制剂治疗癌症。

Nat. Rev. Clin. Oncol.

国家修订临床。Oncol公司。

, 417–430 (2016).

Article

文章

PubMed

Google Scholar

谷歌学者

Finn, R. S. et al. The cyclin-dependent kinase 4/6 inhibitor palbociclib in combination with letrozole versus letrozole alone as first-line treatment of oestrogen receptor-positive, HER2−negative, advanced breast cancer (PALOMA-1/TRIO-18): a randomised phase 2 study.

Finn，R.S.等人。细胞周期蛋白依赖性激酶4/6抑制剂palbociclib联合来曲唑与单独来曲唑作为雌激素受体阳性，HER2阴性，晚期乳腺癌（PALOMA-1/TRIO-18）的一线治疗：一项随机2期研究。

Lancet Oncol.

柳叶刀Oncol。

, 25–35 (2015).

Article

文章

CAS

中科院

PubMed

Google Scholar

谷歌学者

Finn, R. S. et al. Palbociclib and letrozole in advanced breast cancer.

Finn，R.S.等人，Palbociclib和来曲唑治疗晚期乳腺癌。

N. Engl. J. Med.

恩格尔。J·梅德

375

, 1925–1936 (2016).

Article

文章

CAS

中科院

PubMed

Google Scholar

谷歌学者

Hortobagyi, G. N. et al. Ribociclib as first-line therapy for hr-positive, advanced breast cancer.

Hortobagyi，G.N.等人，Ribociclib作为hr阳性晚期乳腺癌的一线治疗。

N. Engl. J. Med.

N.Engl。医学杂志。

375

, 1738–1748 (2016).

Article

文章

CAS

中科院

PubMed

Google Scholar

谷歌学者

Slamon, D. J. et al. Phase III randomized study of ribociclib and fulvestrant in hormone receptor-positive, human epidermal growth factor receptor 2-negative advanced breast cancer: MONALEESA-3.

Slamon，D.J.等人。ribociclib和氟维司群在激素受体阳性，人表皮生长因子受体2阴性晚期乳腺癌中的III期随机研究：Monalesa-3。

J. Clin. Oncol.

J、克林。肿瘤。

, 2465–2472 (2018).

Article

文章

CAS

中科院

PubMed

Google Scholar

谷歌学者

Turner, N. C. et al. Palbociclib in hormone-receptor-positive advanced breast cancer.

Turner，N.C.等人，Palbociclib治疗激素受体阳性晚期乳腺癌。

N. Engl. J. Med.

恩格尔。J·梅德

373

, 209–219 (2015).

Article

文章

CAS

中科院

PubMed

Google Scholar

谷歌学者

Sledge, G. W. Jr. et al. MONARCH 2: abemaciclib in combination with fulvestrant in women with hr+/her2− advanced breast cancer who had progressed while receiving endocrine therapy.

Sledge，G.W.Jr.等人，MONARCH 2：abemaciclib联合氟维司群治疗hr+/her2-晚期乳腺癌患者，这些患者在接受内分泌治疗的同时进展。

J. Clin. Oncol.

J、克林。肿瘤。

, 2875–2884 (2017).

Article

文章

CAS

中科院

PubMed

Google Scholar

谷歌学者

Im, S. A. et al. Overall survival with ribociclib plus endocrine therapy in breast cancer.

。

N. Engl. J. Med.

N.Engl。医学杂志。

381

, 307–316 (2019).

Article

文章

CAS

中科院

PubMed

Google Scholar

谷歌学者

Sledge, G. W. Jr. et al. The effect of abemaciclib plus fulvestrant on overall survival in hormone receptor-positive, ERBB2-negative breast cancer that progressed on endocrine therapy-MONARCH 2: a randomized clinical trial.

Sledge，G.W.Jr.等人。abemaciclib联合氟维司群对内分泌治疗进展的激素受体阳性，ERBB2阴性乳腺癌总体生存率的影响MONARCH 2：一项随机临床试验。

JAMA Oncol

JAMA 叔叔

https://doi.org/10.1001/jamaoncol.2019.4782

(2019)

Slamon, D. J. et al. Overall survival with ribociclib plus fulvestrant in advanced breast cancer.

Slamon，D.J.等人，《核糖环素联合氟维司群治疗晚期乳腺癌的总生存率》。

N. Engl. J. Med.

恩格尔。J·梅德

382

, 514–524 (2020).

Article

文章

CAS

中科院

PubMed

Google Scholar

谷歌学者

Lu, Y. S. et al. Updated overall survival of ribociclib plus endocrine therapy versus endocrine therapy alone in pre- and perimenopausal patients with HR+/HER2− advanced breast cancer in MONALEESA-7: a phase III randomized clinical trial.

Lu，Y.S.等人更新了monalesa-7绝经前和围绝经期HR+/HER2-晚期乳腺癌患者中ribociclib联合内分泌治疗与单独内分泌治疗的总生存期：一项III期随机临床试验。

Clin. Cancer Res

临床。癌症研究

, 851–859 (2022).

Article

文章

CAS

中科院

PubMed

Google Scholar

谷歌学者

Rugo, H. S. et al. Endocrine therapy for hormone receptor-positive metastatic breast cancer: American Society of Clinical Oncology Guideline.

Rugo，H.S.等。激素受体阳性转移性乳腺癌的内分泌治疗：美国临床肿瘤学会指南。

J. Clin. Oncol.

J、克林。肿瘤。

, 3069–3103 (2016).

Article

文章

CAS

中科院

PubMed

Google Scholar

谷歌学者

Johnston, S. et al. Randomized phase II study evaluating palbociclib in addition to letrozole as neoadjuvant therapy in estrogen receptor-positive early breast cancer: PALLET trial.

Johnston，S.等人的随机II期研究评估了palbociclib以及来曲唑作为雌激素受体阳性早期乳腺癌的新辅助治疗：PALLET试验。

J. Clin. Oncol.

J、克林。肿瘤。

, 178–189 (2019).

Article

文章

CAS

中科院

PubMed

Google Scholar

谷歌学者

DeMichele, A. et al. CDK 4/6 inhibitor palbociclib (PD0332991) in Rb+ advanced breast cancer: phase II activity, safety, and predictive biomarker assessment.

DeMichele，A。等人，《Rb+晚期乳腺癌中的CDK 4/6抑制剂palbociclib（PD0332991）：II期活性，安全性和预测性生物标志物评估》。

Clin. Cancer Res.

临床。癌症研究。

, 995–1001 (2015).

Article

文章

CAS

中科院

PubMed

Google Scholar

谷歌学者

Turner, N. C. et al. Efficacy of palbociclib plus fulvestrant (P+F) in patients (pts) with metastatic breast cancer (MBC) and ESR1 mutations (mus) in circulating tumor DNA (ctDNA).

Turner，N.C.等人。palbociclib联合氟维司群（P+F）治疗转移性乳腺癌（MBC）和循环肿瘤DNA（ctDNA）中ESR1突变（MU）患者的疗效。

J. Clin. Oncol.

J、克林。肿瘤。

, 512–512 (2016).

Article

文章

Google Scholar

谷歌学者

Vijayaraghavan, S. et al. CDK4/6 and autophagy inhibitors synergistically induce senescence in Rb positive cytoplasmic cyclin E negative cancers.

Vijayaraghavan，S。等人，CDK4/6和自噬抑制剂协同诱导Rb阳性细胞质细胞周期蛋白E阴性癌症的衰老。

Nat. Commun.

Nat.普通。

, 15916 (2017).

Article

文章

CAS

中科院

PubMed

PubMed Central

PubMed 中央

Google Scholar

谷歌学者

Levine, B. & Kroemer, G. Autophagy in the pathogenesis of disease.

Levine，B。＆Kroemer，G。疾病发病机制中的自噬。

Cell

细胞

132

, 27–42 (2008).

Article

文章

CAS

中科院

PubMed

PubMed Central

PubMed 中央

Google Scholar

谷歌学者

White, E. Deconvoluting the context-dependent role for autophagy in cancer.

White，E。解卷积癌症中自噬的上下文依赖性作用。

Nat. Rev. Cancer

Nat.Rev.癌症

, 401–410 (2012).

Article

文章

CAS

中科院

PubMed

PubMed Central

公共医学中心

Google Scholar

谷歌学者

Galluzzi, L. et al. Autophagy in malignant transformation and cancer progression.

Galluzzi，L。等人。恶性转化和癌症进展中的自噬。

EMBO J.

恩博·J。

, 856–880 (2015).

Article

文章

CAS

中科院

PubMed

PubMed Central

公共医学中心

Google Scholar

谷歌学者

Mauthe, M. et al. Chloroquine inhibits autophagic flux by decreasing autophagosome-lysosome fusion.

Mauthe，M。等人。氯喹通过减少自噬体-溶酶体融合来抑制自噬通量。

Autophagy

自噬

, 1435–1455 (2018).

Article

文章

CAS

中科院

PubMed

PubMed Central

PubMed 中央

Google Scholar

谷歌学者

Wu, Y. T. et al. Dual role of 3-methyladenine in modulation of autophagy via different temporal patterns of inhibition on class I and III phosphoinositide 3-kinase.

Wu，Y.T.等人。3-甲基腺嘌呤通过不同的时间模式抑制I类和III类磷酸肌醇3-激酶在调节自噬中的双重作用。

J. Biol. Chem.

J. 比尔化学。

285

, 10850–10861 (2010).

Article

文章

CAS

中科院

PubMed

PubMed Central

PubMed 中央

Google Scholar

谷歌学者

Blommaart, E. F., Krause, U., Schellens, J. P., Vreeling-Sindelarova, H. & Meijer, A. J. The phosphatidylinositol 3-kinase inhibitors wortmannin and LY294002 inhibit autophagy in isolated rat hepatocytes.

Blommaart，E.F.，Krause，U.，Schellens，J.P.，Vreeling Sindelarova，H。＆Meijer，A.J。磷脂酰肌醇3-激酶抑制剂渥曼青霉素和LY294002抑制分离的大鼠肝细胞中的自噬。

Eur. J. Biochem.

J. Biochem先生

243

, 240–246 (1997).

Article

文章

CAS

中科院

PubMed

Google Scholar

谷歌学者

Liu, J. et al. Beclin1 controls the levels of p53 by regulating the deubiquitination activity of USP10 and USP13.

Liu，J。等人，Beclin1通过调节USP10和USP13的去泛素化活性来控制p53的水平。

Cell

细胞

147

, 223–234 (2011).

Article

文章

CAS

中科院

PubMed

PubMed Central

PubMed 中央

Google Scholar

谷歌学者

Rebecca, V. W. et al. A unified approach to targeting the lysosome’s degradative and growth signaling roles.

Rebecca，V.W.等人。针对溶酶体降解和生长信号传导作用的统一方法。

Cancer Discov.

癌症发现。

, 1266–1283 (2017).

Article

文章

CAS

中科院

PubMed

PubMed Central

PubMed 中央

Google Scholar

谷歌学者

Schrezenmeier, E. & Dorner, T. Mechanisms of action of hydroxychloroquine and chloroquine: implications for rheumatology.

Schrezenmeier，E。＆Dorner，T。羟氯喹和氯喹的作用机制：对风湿病的影响。

Nat. Rev. Rheumatol.

风湿病杂志。

, 155–166 (2020).

Article

文章

CAS

中科院

PubMed

Google Scholar

谷歌学者

Bansal, P. et al. Hydroxychloroquine: a comprehensive review and its controversial role in coronavirus disease 2019.

Bansal，P。等人，《羟氯喹：综合综述及其在2019年冠状病毒病中的争议作用》。

Ann. Med.

。

, 117–134 (2021).

Article

文章

CAS

中科院

PubMed

Google Scholar

谷歌学者

Mahalingam, D. et al. Combined autophagy and HDAC inhibition: a phase I safety, tolerability, pharmacokinetic, and pharmacodynamic analysis of hydroxychloroquine in combination with the HDAC inhibitor vorinostat in patients with advanced solid tumors.

Mahalingam，D.等人，《自噬和HDAC联合抑制：羟氯喹联合HDAC抑制剂伏立诺他治疗晚期实体瘤的I期安全性、耐受性、药代动力学和药效学分析》。

Autophagy

自噬

, 1403–1414 (2014).

Article

文章

CAS

中科院

PubMed

PubMed Central

PubMed 中央

Google Scholar

谷歌学者

McChesney, E. W. Animal toxicity and pharmacokinetics of hydroxychloroquine sulfate.

McChesney，E.W。硫酸羟氯喹的动物毒性和药代动力学。

Am. J. Med.

美国医学杂志。

, 11–18 (1983).

Article

文章

CAS

中科院

PubMed

Google Scholar

谷歌学者

Vogl, D. T. et al. Combined autophagy and proteasome inhibition: a phase 1 trial of hydroxychloroquine and bortezomib in patients with relapsed/refractory myeloma.

Vogl，D.T.等。自噬和蛋白酶体联合抑制：羟氯喹和硼替佐米治疗复发/难治性骨髓瘤患者的1期临床试验。

Autophagy

自噬

, 1380–1390 (2014).

Article

文章

CAS

中科院

PubMed

PubMed Central

公共医学中心

Google Scholar

谷歌学者

Rangwala, R. et al. Phase I trial of hydroxychloroquine with dose-intense temozolomide in patients with advanced solid tumors and melanoma.

Rangwala，R。等人。羟氯喹与剂量较大的替莫唑胺治疗晚期实体瘤和黑色素瘤患者的I期临床试验。

Autophagy

自噬

, 1369–1379 (2014).

Article

文章

CAS

中科院

PubMed

PubMed Central

PubMed 中央

Google Scholar

谷歌学者

Rangwala, R. et al. Combined MTOR and autophagy inhibition: phase I trial of hydroxychloroquine and temsirolimus in patients with advanced solid tumors and melanoma.

Rangwala，R。等。MTOR和自噬联合抑制：羟氯喹和替西罗莫司治疗晚期实体瘤和黑色素瘤患者的I期临床试验。

Autophagy

自噬

, 1391–1402 (2014).

Article

文章

CAS

中科院

PubMed

PubMed Central

公共医学中心

Google Scholar

谷歌学者

Onorati, A. V., Dyczynski, M., Ojha, R. & Amaravadi, R. K. Targeting autophagy in cancer.

Onorati，A.V.，Dyczynski，M.，Ojha，R。＆Amaravadi，R.K。靶向癌症中的自噬。

Cancer

癌症

124

, 3307–3318 (2018).

Article

文章

PubMed

Google Scholar

谷歌学者

Hammond, M. E. et al. American Society of Clinical Oncology/College Of American Pathologists guideline recommendations for immunohistochemical testing of estrogen and progesterone receptors in breast cancer.

Hammond，M.E.等人，《美国临床肿瘤学会/美国病理学家学会乳腺癌雌激素和孕激素受体免疫组织化学检测指南建议》。

J. Clin. Oncol.

J、克林。肿瘤。

, 2784–2795 (2010).

Article

文章

PubMed

PubMed Central

PubMed 中央

Google Scholar

谷歌学者

Wolff, A. C. et al. Recommendations for human epidermal growth factor receptor 2 testing in breast cancer: American Society of Clinical Oncology/College of American Pathologists clinical practice guideline update.

Wolff，A.C.等人，《乳腺癌中人类表皮生长因子受体2检测的建议：美国临床肿瘤学会/美国病理学家学院临床实践指南更新》。

J. Clin. Oncol.

J、克林。肿瘤。

, 3997–4013 (2013).

Article

文章

PubMed

Google Scholar

谷歌学者

Le Tourneau, C., Lee, J. J. & Siu, L. L. Dose escalation methods in phase I cancer clinical trials.

。

J. Natl. Cancer Inst.

J、纳特尔。癌症研究所。

101

, 708–720 (2009).

Article

文章

PubMed

PubMed Central

PubMed 中央

Google Scholar

谷歌学者

Ma, C. X. et al. NeoPalAna: neoadjuvant palbociclib, a cyclin-dependent kinase 4/6 inhibitor, and anastrozole for clinical stage 2 or 3 estrogen receptor-positive breast cancer.

Ma，C.X.等人NeoPalAna：新辅助palbociclib，一种细胞周期蛋白依赖性激酶4/6抑制剂，和阿那曲唑治疗临床2或3期雌激素受体阳性乳腺癌。

Clin. Cancer Res.

临床。癌症研究。

, 4055–4065 (2017).

Malorni, L. et al. Serum thymidine kinase activity in patients with HR-positive/HER2−negative advanced breast cancer treated with ribociclib plus letrozole: results from the prospective BioItaLEE trial.

Malorni，L。等人。用ribociclib加来曲唑治疗的HR阳性/HER2阴性晚期乳腺癌患者的血清胸苷激酶活性：来自前瞻性BioItaLEE试验的结果。

Eur. J. Cancer

Eur. J. 癌症

186

, 1–11 (2023).

Article

文章

CAS

中科院

PubMed

Google Scholar

谷歌学者

Cheng, Y. C. et al. Mathematical modeling identifies optimum palbociclib-fulvestrant dose administration schedules for the treatment of patients with estrogen receptor-positive breast cancer.

Cheng，Y.C.等人的数学模型确定了用于治疗雌激素受体阳性乳腺癌患者的最佳palbociclib-fulvestrant剂量给药方案。

Cancer Res. Commun.

癌症是常见的。

, 2331–2344 (2023).

Article

文章

CAS

中科院

PubMed

PubMed Central

公共医学中心

Google Scholar

谷歌学者

Association, W. M. World medical association declaration of Helsinki: ethical principles for medical research involving human subjects.

协会，W.M。世界医学协会赫尔辛基宣言：涉及人类受试者的医学研究的伦理原则。

JAMA

310

, 2191–2194 (2013).

Article

文章

Google Scholar

谷歌学者

Regev, A. & Bjornsson, E. S. Drug-induced liver injury: morbidity, mortality, and Hy’s law.

Regev，A。＆Bjornsson，E.S。药物引起的肝损伤：发病率，死亡率和Hy定律。

Gastroenterology

胃肠病学

147

, 20–24 (2014).

Article

文章

PubMed

Google Scholar

谷歌学者

Eisenhauer, E. A. et al. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1).

Eisenhauer，E.A.等人，《实体瘤新的反应评估标准：修订的RECIST指南（1.1版）》。

Eur. J. Cancer

Eur. J. 癌症

, 228–247 (2009).

Article

文章

CAS

中科院

PubMed

Google Scholar

谷歌学者

Nguyen, T. D. T. et al. Sequential targeting of retinoblastoma and DNA synthesis pathways is a therapeutic strategy for sarcomas that can be monitored in real time.

Nguyen，T.D.T.等人。视网膜母细胞瘤和DNA合成途径的顺序靶向是一种可以实时监测的肉瘤治疗策略。

Cancer Res.

癌症研究。

, 939–955 (2023).

Article

文章

CAS

中科院

PubMed

Google Scholar

谷歌学者

Navarro-Yepes, J. et al. Abemaciclib is effective in palbociclib-resistant hormone receptor-positive metastatic breast cancers.

Navarro-Yepes，J。等人Abemaciclib对palbociclib耐药的激素受体阳性转移性乳腺癌有效。

Cancer Res.

癌症研究。

, 3264–3283 (2023).

Article

文章

CAS

中科院

PubMed

PubMed Central

PubMed 中央

Google Scholar

谷歌学者

Mondal, K. et al. Hydroxychloroquine causes early inner retinal toxicity and affects autophagosome-lysosomal pathway and sphingolipid metabolism in the retina.

羟氯喹引起早期视网膜内毒性，并影响视网膜中的自噬体-溶酶体途径和鞘脂代谢。

Mol. Neurobiol.

他没有

, 3873–3887 (2022).

Article

文章

CAS

中科院

PubMed

PubMed Central

PubMed 中央

Google Scholar

谷歌学者

Krishnamurthy, J. et al. In:

Krishnamurthy，J.等人，在：

Cancer Research

癌症研究

. (Amer Assoc Cancer Research 615 Chestnut St, 17th Floor, Philadelphia, Pa …).

（美国癌症研究协会癌症研究615 Chestnut St，17楼，费城，宾夕法尼亚州…）。

Campisi, J. & d’Adda di Fagagna, F. Cellular senescence: when bad things happen to good cells.

Campisi，J。＆d'Adda di Fagagna，F。细胞衰老：当好细胞发生坏事时。

Nat. Rev. Mol. Cell Biol.

Nat。Rev。Mol。Cell Biol。

, 729–740 (2007).

Article

文章

CAS

中科院

PubMed

Google Scholar

谷歌学者

Young, A. R. et al. Autophagy mediates the mitotic senescence transition.

Young，A.R。等人。自噬介导有丝分裂衰老转变。

Genes Dev.

基因开发。

, 798–803 (2009).

Article

文章

CAS

中科院

PubMed

PubMed Central

公共医学中心

Google Scholar

谷歌学者

Amaravadi, R. K., Kimmelman, A. C. & Debnath, J. Targeting autophagy in cancer: recent advances and future directions.

Amaravadi，R.K.，Kimmelman，A.C。＆Debnath，J。靶向癌症中的自噬：最新进展和未来方向。

Cancer Discov.

癌症发现。

, 1167–1181 (2019).

Article

文章

CAS

中科院

PubMed

PubMed Central

PubMed 中央

Google Scholar

谷歌学者

Wang, L., Lankhorst, L. & Bernards, R. Exploiting senescence for the treatment of cancer.

Wang，L.，Lankhorst，L。和Bernards，R。利用衰老治疗癌症。

Nat. Rev. Cancer

Nat.Rev.癌症

, 340–355 (2022).

Article

文章

CAS

中科院

PubMed

Google Scholar

谷歌学者

Dorr, J. R. et al. Synthetic lethal metabolic targeting of cellular senescence in cancer therapy.

Dorr，J.R.等人。癌症治疗中细胞衰老的合成致死代谢靶向。

Nature

自然

501

, 421–425 (2013).

Article

文章

PubMed

Google Scholar

谷歌学者

Tchkonia, T., Zhu, Y., van Deursen, J., Campisi, J. & Kirkland, J. L. Cellular senescence and the senescent secretory phenotype: therapeutic opportunities.

Tchkonia，T.，Zhu，Y.，van Deursen，J.，Campisi，J。＆Kirkland，J.L。细胞衰老和衰老分泌表型：治疗机会。

J. Clin. Invest.

J、临床。投资。

123

, 966–972 (2013).

Article

文章

CAS

中科院

PubMed

PubMed Central

公共医学中心

Google Scholar

谷歌学者

Amaravadi, R. K. & Winkler, J. D. Lys05: a new lysosomal autophagy inhibitor.

Amaravadi，R.K。＆Winkler，J.D。Lys05：一种新的溶酶体自噬抑制剂。

Autophagy

自噬

, 1383–1384 (2012).

Article

文章

CAS

中科院

PubMed

PubMed Central

PubMed 中央

Google Scholar

谷歌学者

McAfee, Q. et al. Autophagy inhibitor Lys05 has single-agent antitumor activity and reproduces the phenotype of a genetic autophagy deficiency.

McAfee，Q。等人。自噬抑制剂Lys05具有单药抗肿瘤活性，并再现了遗传性自噬缺陷的表型。

Proc. Natl. Acad. Sci. USA

普罗克。晚上阿卡德滑雪。美国

109

, 8253–8258 (2012).

Article

文章

CAS

中科院

PubMed

PubMed Central

PubMed 中央

Google Scholar

谷歌学者

Cechakova, L. et al. A potent autophagy inhibitor (Lys05) enhances the impact of ionizing radiation on human lung cancer cells H1299.

Cechakova，L。等人。一种有效的自噬抑制剂（Lys05）增强电离辐射对人肺癌细胞H1299的影响。

Int. J. Mol. Sci.

Int.J.Mol.Sci。

, 5881 (2019)

Ma, X. H. et al. Targeting ER stress-induced autophagy overcomes BRAF inhibitor resistance in melanoma.

Ma，X.H.等人针对内质网应激诱导的自噬克服了黑色素瘤中BRAF抑制剂的耐药性。

J. Clin. Invest.

J、临床。投资。

124

, 1406–1417 (2014).

Article

文章

CAS

中科院

PubMed

PubMed Central

PubMed 中央

Google Scholar

谷歌学者

Ahwazi, D. et al. Investigation of the specificity and mechanism of action of the ULK1/AMPK inhibitor SBI-0206965.

Ahwazi，D。等人。ULK1/AMPK抑制剂SBI-0206965的特异性和作用机制的研究。

Biochem. J.

生物化学。J。

478

, 2977–2997 (2021).

Article

文章

CAS

中科院

PubMed

Google Scholar

谷歌学者

Ghazi, P. C. et al. Inhibition of ULK1/2 and KRAS (G12C) controls tumor growth in preclinical models of lung cancer.

Ghazi，P.C。等人。抑制ULK1/2和KRAS（G12C）控制肺癌临床前模型中的肿瘤生长。

bioRxiv

生物Rxiv

https://doi.org/10.1101/2024.02.06.579200

(2024)

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Acknowledgements

致谢

This study was funded by a research grant from the Cancer Prevention Research Institute of Texas (CPRIT) grant ID RP170079 to K.K. and D.T. and the (CPRIT- Multi-Investigator Research Awards (MIRA) grant ID RP180712 to K.K., K.K.H., and D.T. The study was also supported by an MD Anderson Cancer Center Support grant (NIH/ NCI P30 CA016672).

这项研究由德克萨斯州癌症预防研究所（CPRIT）授予K.K.和D.T.的研究资助，以及（CPRIT-多研究者研究奖（MIRA）授予K.K.，K.K.H.和D.T.的研究资助ID RP180712。该研究还得到了MD安德森癌症中心支持资助（NIH/NCI P30 CA016672）。

Palbociclib was provided through an investigator-initiated grant from Pfizer, Inc..

Palbociclib是通过辉瑞公司的研究者发起的资助提供的。。

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Department of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

美国德克萨斯州休斯顿德克萨斯大学安德森癌症中心乳腺肿瘤学系

Akshara Singareeka Raghavendra, Danielle Kwiatkowski, Senthil Damodaran, David Ramirez & Debu Tripathy

Akshara Singareeka Raghavendra，Danielle Kwiatkowski，Senthil Damodaran，David Ramirez和Debu Tripathy

Department of Experimental Radiation, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

德克萨斯大学MD安德森癌症中心实验辐射系，美国德克萨斯州休斯顿

Nicole M. Kettner, Yan Wang & Khandan Keyomarsi

Department of Head and Neck Surgery, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

Dan S. Gombos

丹·S·戈博斯

Department of Breast Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

美国德克萨斯州休斯顿德克萨斯大学安德森癌症中心乳腺外科肿瘤学系

Kelly K. Hunt

凯利·K·亨特

Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

美国德克萨斯州休斯顿德克萨斯大学安德森癌症中心生物统计学系

Yu Shen

余深（音）

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Contributions

捐款

A.S.R.: data curation, formal analysis, writing-original draft, writing-review, and editing. N.K.: investigation, data analysis, writing review, and editing. D.K.: resources, supervision, investigation, writing review, and editing. S.D.: writing-review and editing, provision and care of patients. D.R.: writing-review and editing, identification and care of patients.

A、 S.R.：数据管理，形式分析，撰写原稿，撰写评论和编辑。N、 K.：调查，数据分析，写作评论和编辑。D、 K.：资源，监督，调查，写作评论和编辑。S、 D：写作评论和编辑，提供和护理患者。D、 R.：撰写评论和编辑，识别和护理患者。

D.S.G.: investigation, writing review and editing, provision of patients. K.H.: investigation, project administration, funding acquisition, writing review, and editing. Y.S.: formal design and analysis, writing review, and editing. K.K.: conceptualization, investigation, project administration, methodology, funding acquisition, writing review and editing, provision of patients.

D、例如：调查，写作评论和编辑，提供患者。K、。Y、正式设计和分析，写作评论和编辑。K、 K.：概念化，调查，项目管理，方法论，资金获取，写作审查和编辑，提供患者。

D.T.: conceptualization, resources, data curation, formal analysis, supervision, funding acquisition, investigation, methodology, writing-original draft, project administration, writing-review and editing, oversight of and participation in the identification, care, and safety evaluation of patients..

D、。。

Corresponding authors

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Khandan Keyomarsi

Khandan 基奥马西

或

Debu Tripathy

Tripathy粉尘

Ethics declarations

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Competing interests

相互竞争的利益

D.T.: Quantum Leap Healthcare. K.K.H.: Armada Health, AstraZeneca, Cairn Surgical, Eli Lilly & Co, Lumicell. K.K.: Apeiron, BluePrint, REPARE, Schrodinger and Novartis. The authors declare no competing interests.

D、 T.：Quantum Leap Healthcare。K、 K.H.：阿玛达健康，阿斯利康，凯恩外科，礼来公司，卢米克尔。K、 K.：Apeiron、BluePrint、REPARE、Schrodinger和Novartis。作者声明没有利益冲突。

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Supplementary information

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Supplementary Figure 1, Supplementary Table 1 and Supplementary Table 2

补充图1，补充表1和补充表2

IRB protocol for the Palbociclib + HCQ clinical trial

Palbociclib+HCQ临床试验的IRB方案

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Raghavendra, A.S., Kettner, N.M., Kwiatkowski, D.

Raghavendra，A.S.，Kettner，N.M.，Kwiatkowski，D。