Quantitative HER3 PET Imaging for Assessing Resistance and Guiding Therapy

用于评估耐药性和指导治疗的定量 HER3 PET 成像

基本信息

批准号：
10305640
负责人：
Umar Mahmood
金额：
$ 37.04万
依托单位：
MASSACHUSETTS GENERAL HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-12-01 至 2024-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10305640
关键词：
AKT inhibition Aftercare Anatomy Antibodies Biochemical Biological Markers Biopsy Breast Cancer Model Breast Cancer Patient Breast Cancer cell line Caring Cell Line Clinic Clinical DNA Sequence Alteration Development Disease Drug Kinetics ERBB2 gene Effectiveness Epidermal Growth Factor Epidermal Growth Factor Receptor Evolution Feedback Future Goals Grant Growth Histologic Homeostasis Human Image Implant Individual Mediating Methodology Methods Molecular Profiling Molecular Target Monitor Mus Neoplasm Metastasis PIK3CG gene Pathway interactions Patient risk Patient-derived xenograft models of breast cancer Patients Pattern Peptides Positron-Emission Tomography Procedures Process Proto-Oncogene Proteins c-akt Protocols documentation Receptor Activation Receptor Protein-Tyrosine Kinases Receptor Up-Regulation Regimen Resistance Resistance development Risk Role Signal Pathway Signal Transduction Site Surface Testing Therapeutic Time Tissue Banks Tissue Sample Tissues Translations Treatment Failure Treatment Protocols Up-Regulation Xenograft Model Xenograft procedure aggressive breast cancer alternative treatment anatomic imaging cancer subtypes chemotherapy clinical application clinical heterogeneity clinical practice clinical translation cost disease heterogeneity dosimetry early phase clinical trial efficacy testing established cell line hormone therapy human imaging image guided imaging agent imaging approach improved inhibitor insight lapatinib malignant breast neoplasm monomer mouse model neoplastic cell novel patient derived xenograft model preclinical study predicting response quantitative imaging rapid detection receptor expression receptor upregulation resistance mechanism response side effect standard of care targeted treatment therapy resistant traditional therapy treatment response treatment strategy triple-negative invasive breast carcinoma tumor tumor heterogeneity uptake

项目摘要

Abstract Aggressive forms of breast cancer, often resistant to standard chemotherapy, are increasingly treated with targeted signaling pathway inhibitors. HER2 inhibitors are standard of care for treatment of HER2+ breast cancer, and inhibitors of PI3K as well as AKT both demonstrate promise for the treatment of triple negative breast cancer. While these therapies have shown improvements over traditional therapies, there are several mechanisms that can limit response, with accumulating evidence suggesting that a dominant mechanism limiting efficacy is the release of an intrinsic negative feedback loop that causes upregulation of the receptor tyrosine kinase human epidermal growth factor 3 (HER3). Excess HER3 forms heterodimers with HER2 monomers (in HER2+ breast cancer) or EGFR monomers (in triple negative breast cancer) and allows for continued growth pathway signaling. This dynamic upregulation of HER3 occurs within days of therapy initiation, and is not the result of acquired genetic mutations, but rather an intrinsic cellular response to attempt to maintain homeostasis. Furthermore, this pathway is variably active across patients, without any current method of predicting its activity prior to therapy initiation. Understanding if and when this resistance mechanism is active in a given patient started on targeted inhibitors remains clinically impractical, as it requires invasive tissue biopsy both before therapy initiation as well as during treatment. Such paired biopsies have associated patient-risk, and moreover a single-site biopsy does not reflect intrinsic tumoral heterogeneity. To rapidly and noninvasively identify breast cancer patients that will develop resistance to targeted inhibitors through increased HER3 expression and rationally guide subsequent therapeutic choices (such as HER3 inhibitors) to overcome this resistance, we propose to develop and utilize a clinically-translatable HER3 PET imaging paradigm. To this end we have developed a first-in-class HER3 targeted peptide for PET imaging. In the envisioned imaging paradigm patients would be imaged with HER3 PET prior to and again shortly after starting therapy, to assess for change in tumoral HER3 expression. We will investigate this approach in both established cell lines of HER2+ and triple-negative breast cancers. We will determine threshold levels of HER3 expression change, as assessed by HER3 PET SUV, that are predictive of a tumor overcoming targeted inhibition through increase in HER3 expression. We will demonstrate the ability of such imaging to predict resistance and subsequently guide adaptive therapy by testing in patient-derived xenografts, which more closely resemble the heterogeneity of clinical practice. This approach represents an evolution in the use of imaging to guide therapy on a personalized basis, providing immediate insight to mechanisms of therapy resistance and guiding alternative treatment strategies in a non-invasive manner, a major advancement over both standard anatomical imaging or invasive biopsy.

抽象的侵略性形式的乳腺癌通常对标准化学疗法有抵抗力，越来越多地接受靶向信号通路抑制剂。 HER2抑制剂是治疗HER2+乳房的护理标准癌症和PI3K的抑制剂以及AKT都表现出对三重阴性治疗的希望乳腺癌。尽管这些疗法对传统疗法有所改善，但有几种可以限制反应的机制，积累的证据表明一种主要的机制限制功效是释放固有的负反馈回路，导致受体上调酪氨酸激酶人表皮生长因子3（HER3）。过量的HER3与HER2形成异二聚体单体（在HER2+乳腺癌中）或EGFR单体（在三重阴性乳腺癌中），允许持续的生长途径信号传导。这种动态上调HER3发生在治疗的几天之内起始，不是获得遗传突变的结果，而是尝试的固有细胞反应维持体内平衡。此外，该途径在患者中具有可变的活性，没有任何电流在治疗开始之前预测其活性的方法。了解是否以及何时抵抗机制在给定患者开始使用靶向抑制剂的特定患者中保持临床不切实际，因为它需要侵入性组织活检在治疗开始前和治疗过程中。这样的配对活检有相关的患者风险，此外，单位活检不反映固有的肿瘤异质性。到快速和非侵袭性地识别乳腺癌患者，这些患者将对靶向抑制剂产生抗性通过增加Her3表达和合理指导随后的治疗选择（例如Her3 抑制剂）为了克服这种抵抗力，我们建议开发和利用临床上可转移的Her3 PET 成像范式。为此，我们开发了一种一流的HER3靶向肽进行宠物成像。在设想的成像范式患者将在不久之前和之后与Her3 Pet成像开始治疗，以评估肿瘤HER3表达的变化。我们将在两者中调查这种方法建立的HER2+和三阴性乳腺癌的细胞系。我们将确定阈值水平 HER3表达变化，如Her3 Pet SUV所评估的，这些肿瘤是克服了靶向的肿瘤通过增加HER3表达来抑制。我们将展示这种成像预测的能力耐药性和随后通过在患者衍生的异种移植物中进行测试来指导自适应疗法，这更多非常类似于临床实践的异质性。这种方法代表了使用的发展成像以在个性化的基础上指导治疗，从而立即了解治疗机制抵抗和指导替代治疗策略以非侵入性的方式，主要进步标准的解剖成像或侵入性活检。

项目成果

期刊论文数量（4）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

HER3 PET Imaging Predicts Response to Pan Receptor Tyrosine Kinase Inhibition Therapy in Gastric Cancer.

DOI：
10.1007/s11307-022-01763-9
发表时间：
2023-04
期刊：
Molecular imaging and biology
影响因子：
3.1
作者：
通讯作者：

HER3 Differentiates Basal From Claudin Type Triple Negative Breast Cancer and Contributes to Drug and Microenvironmental Induced Resistance.

DOI：
10.3389/fonc.2020.554704
发表时间：
2020
期刊：
Frontiers in oncology
影响因子：
4.7
作者：
Sinevici N;Ataeinia B;Zehnder V;Lin K;Grove L;Heidari P;Mahmood U
通讯作者：
Mahmood U

Phage Display Selection, In Vitro Characterization, and Correlative PET Imaging of a Novel HER3 Peptide.

DOI：
10.1007/s11307-017-1106-6
发表时间：
2018-04
期刊：
Molecular imaging and biology
影响因子：
3.1
作者：
Larimer BM;Phelan N;Wehrenberg-Klee E;Mahmood U
通讯作者：
Mahmood U

HER3 PET Imaging Identifies Dynamic Changes in HER3 in Response to HER2 Inhibition with Lapatinib.

DOI：
10.1007/s11307-021-01619-8
发表时间：
2021-12
期刊：
Molecular imaging and biology
影响因子：
3.1
作者：
Wehrenberg-Klee E;Sinevici N;Nesti S;Kalomeris T;Austin E;Larimer B;Mahmood U
通讯作者：
Mahmood U