Secondary Prevention through Surveillance and Intervention

通过监测和干预进行二级预防

• 批准号: 10051407
• 负责人: LEWIS A CHODOSH
• 金额: $ 63.43万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-12-13 至 2022-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10051407
• 关键词: Address; Adjuvant Therapy; Aftercare; Aspirate substance; Autophagocytosis; Biological; Biological Assay; Biological Markers; Biology; Bone Marrow; Breast Cancer Cell; Breast Cancer Patient; Breast Cancer Prevention; Breast Cancer Treatment; Breast Cancer survivor; Breast Cancer therapy; Cancer Etiology; Cell Survival; Cells; Cessation of life; Chloroquine; Clinic; Clinical; Clinical Treatment; Clinical Trials; Coupled; Data; Detection; Development; Disease; Distant; Dose; Early Diagnosis; FRAP1 gene; Flow Cytometry; Future; Genetically Engineered Mouse; Genomics; Human; Hydroxychloroquine; Immunohistochemistry; Intervention; Investigation; Laboratories; Lung Neoplasms; Malignant Neoplasms; Mammary gland; Measures; Metastatic breast cancer; Metastatic to; Methods; Modeling; Molecular; Monitor; Mus; Neoplasm Metastasis; Oncogenic; Operative Surgical Procedures; Outcome; Pathologic; Pathway interactions; Patients; Pharmacology; Phenotype; Positive Lymph Node; Primary Neoplasm; Radiation therapy; Randomized; Recurrence; Residual Cancers; Residual Neoplasm; Residual Tumors; Residual state; Risk; SDZ RAD; Safety; Secondary Prevention; Signal Transduction; Sirolimus; Site; Testing; Therapeutic; Translating; Tumor Biology; Woman; base; cancer cell; cancer recurrence; chemotherapy; clinical efficacy; co-clinical trial; detection sensitivity; improved; innovation; insight; malignant breast neoplasm; molecular phenotype; mortality; mouse model; neoplastic cell; next generation; novel; novel strategies; open label; pilot trial; pre-clinical; preclinical trial; prevent; prognostic tool; response; safety and feasibility; screening; surveillance study; targeted agent; therapeutic target; tool; triple-negative invasive breast carcinoma; tumor

Project Summary Despite early detection and adjuvant therapy, breast cancer remains the leading cause of cancer mortality in women, largely due to distant, incurable recurrences arising years, or even decades, after treatment of the primary tumor. These recurrent, metastatic tumors arise from the pool of residual local and disseminated tumor cells (DTCs) that survive primary treatment and remain in the host in a presumed dormant state. Indeed, the presence of bone marrow DTCs following treatment is independently associated with a substantially increased risk of recurrence. At present, however, the mechanisms enabling residual tumor cells to maintain dormancy and ultimately recur are poorly understood, and DTC-directed surveillance and treatment approaches are non-existent. Consequently, the ability to biologically characterize, accurately measure and therapeutically target dormant DTCs would be a transformational new approach to preventing recurrence. We hypothesize that disabling the survival mechanisms employed by dormant DTCs will reduce tumor recurrence and thereby improve survival. Using genetically engineered mouse models that faithfully recapitulate tumor dormancy and recurrence, we have discovered that autophagy and mTOR signaling are each critical to the survival of DTCs, and that agents inhibiting these pathways deplete the reservoir of dormant residual tumor cells, thereby preventing tumor recurrence. The objective of this proposal is to translate these biological insights and preclinical therapeutic data to generate the interventional approach, requisite laboratory assays, and demonstration of feasibility, safety and clinical efficacy of targeting DTCs that will be required for large-scale, definitive clinical trials and surveillance studies. The specific aims of this application are to: 1) Perform a proof-of-concept clinical trial of everolimus (EVE, targeting mTOR), and hydroxychloroquine (HCQ, targeting autophagy) in women with detectable DTCs after primary treatment; and 2) Employ preclinical mouse models to concurrently optimize therapeutic approaches and advance discoveries for the eradication of DTCs. The randomized, open-label pilot trial in Aim 1 will investigate the feasibility and safety of HCQ, EVE or the combination, and their effects on DTC burden. We will also refine and validate a novel flow cytometric assay to improve the sensitivity of detection, enumeration and molecular characterization of the DTC biomarker. In Aim 2, a co-clinical trial in mice will optimize the effects of HCQ, EVE, and their combination, investigate critical parameters of these effects necessary to inform clinical trials, and extend these models to more closely reflect clinical treatment. In addition, molecular phenotyping of residual tumor cells will uncover additional targets for future trials. Ultimately, the ability to identify, enumerate and therapeutically target DTCs has the potential to transform surveillance and treatment options for breast cancer survivors and prevent women from succumbing to this deadly disease.

项目摘要 尽管早期发现和辅助治疗，乳腺癌仍然是癌症的主要原因 女性的死亡率，主要是由于遥远的，无法治愈的复发，几年，甚至几十年后， 治疗原发性肿瘤。这些复发性转移性肿瘤是由残留的局部和局部淋巴结转移引起的。 在初次治疗后存活并以假定的休眠状态留在宿主中的播散性肿瘤细胞（DTC） 状态事实上，治疗后骨髓DTC的存在与治疗后的免疫反应独立相关。 大大增加了复发的风险。然而，目前， 维持休眠并最终复发的机制知之甚少， 方法是不存在的。因此，生物学表征、准确测量和 治疗靶向休眠DTC将是预防复发的一种变革性新方法。 我们假设，禁用休眠DTC所采用的生存机制将减少肿瘤的发生。 从而提高生存率。使用基因工程小鼠模型， 概括肿瘤的休眠和复发，我们发现自噬和mTOR信号传导是 每一种对DTC的生存至关重要，抑制这些途径的药物消耗了休眠的 残留肿瘤细胞，从而防止肿瘤复发。本提案的目的是将这些 生物学见解和临床前治疗数据，以生成介入方法，必要的实验室 试验，并证明靶向DTC的可行性、安全性和临床有效性， 大规模、明确的临床试验和监测研究。 本申请的具体目的是：1）进行依维莫司（EVE， 靶向mTOR）和羟氯喹（HCQ，靶向自噬）在治疗后可检测到DTC的女性中的作用。 采用临床前小鼠模型同时优化治疗方法 并推动发现DTC的根除。Aim 1中的随机、开放标签初步试验将 探讨HCQ、EVE或两者联合应用的可行性、安全性及对DTC负担的影响。我们 还将完善和验证一种新的流式细胞术检测，以提高检测，计数， 和DTC生物标志物的分子表征。在目标2中，小鼠联合临床试验将优化 HCQ，EVE及其组合的影响，调查这些影响的关键参数，以告知 临床试验，并扩展这些模型，以更密切地反映临床治疗。此外，分子 残留肿瘤细胞的表型分析将为未来的试验发现更多的目标。最终， 识别、计数和治疗靶向DTC有可能改变监测和治疗 为乳腺癌幸存者提供选择，并防止妇女死于这种致命的疾病。

项目成果

Can a Late Interception by Circulating Tumor DNA Deliver a Win in Estrogen Receptor-Positive Early Breast Cancer?

通过循环肿瘤 DNA 进行晚期拦截能否在雌激素受体阳性早期乳腺癌中取得胜利？

• DOI: 10.1200/jco.22.01026
• 发表时间: 2022
• 期刊: Journal of clinical oncology : official journal of the American Society of Clinical Oncology
• 作者: Cescon,DavidW;Kalinsky,Kevin;DeMichele,AngelaM
• 通讯作者: DeMichele,AngelaM

PAQR8 promotes breast cancer recurrence and confers resistance to multiple therapies.

• DOI: 10.1186/s13058-022-01559-3
• 发表时间: 2023-01-03
• 期刊: Breast cancer research : BCR

Therapeutic Targeting of Minimal Residual Disease to Prevent Late Recurrence in Hormone-Receptor Positive Breast Cancer: Challenges and New Approaches.

• DOI: 10.3389/fonc.2021.667397
• 发表时间: 2021
• 期刊: Frontiers in oncology
• 影响因子: 4.7
• 作者: Cescon DW;Kalinsky K;Parsons HA;Smith KL;Spears PA;Thomas A;Zhao F;DeMichele A
• 通讯作者: DeMichele A

Cellular dormancy in minimal residual disease following targeted therapy.

靶向治疗后，最小残留疾病的细胞休眠。

• DOI: 10.1186/s13058-021-01416-9
• 发表时间: 2021-06-04
• 期刊: Breast cancer research : BCR
• 作者: Ruth JR;Pant DK;Pan TC;Seidel HE;Baksh SC;Keister BA;Singh R;Sterner CJ;Bakewell SJ;Moody SE;Belka GK;Chodosh LA
• 通讯作者: Chodosh LA

Escape from breast tumor dormancy: The convergence of obesity and menopause.

• DOI: 10.1073/pnas.2204758119
• 发表时间: 2022-10-11
• 期刊: Proceedings of the National Academy of Sciences of the United States of America
• 影响因子: 11.1