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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.

摘要侵袭性乳腺癌通常对标准化疗有抵抗力，靶向信号通路抑制剂。HER2抑制剂是治疗HER2+乳腺癌的标准治疗 PI3K和AKT的抑制剂都显示出治疗三阴性的希望。乳腺癌虽然这些疗法比传统疗法有所改进，但仍有一些缺点。可以限制反应的机制，越来越多的证据表明，限制功效的是导致受体上调的内在负反馈环的释放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 EGFR单体（在HER2+乳腺癌中）或EGFR单体（在三阴性乳腺癌中），并允许持续的生长信号通路。HER3的这种动态上调发生在治疗的几天内启动，并不是获得性基因突变的结果，而是一种内在的细胞反应，试图来维持体内平衡此外，该途径在患者中是双活性的，没有任何电流。在治疗开始之前预测其活性的方法。了解这种阻力是否以及何时在开始靶向抑制剂治疗的给定患者中，在治疗开始之前以及治疗期间进行侵入性组织活检。这种成对的活组织检查相关的患者风险，而且单部位活检并不能反映内在的肿瘤异质性。到快速和非侵入性地识别对靶向抑制剂产生耐药性的乳腺癌患者通过增加HER3表达并合理指导后续治疗选择（如HER3 为了克服这种耐药性，我们建议开发和利用临床上可翻译的HER3 PET 成像范例为此，我们开发了一种用于PET成像的一流HER3靶向肽。在所设想的成像范例患者将在之前和之后不久用HER3PET成像开始治疗，以评估肿瘤HER3表达的变化。我们将在以下两个方面研究这种方法建立HER2+和三阴性乳腺癌的细胞系。我们将确定通过HER3 PET SUV评估的HER3表达变化，可预测肿瘤克服靶向治疗。通过增加HER3表达抑制。我们将展示这种成像预测耐药性，并随后通过在患者来源的异种移植物中进行测试来指导适应性治疗，与临床实践的异质性非常相似。这种方法代表了使用成像以个性化的基础指导治疗，提供对治疗机制的即时洞察耐药性和指导替代治疗策略，以非侵入性的方式，一个重大的进步，标准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.

HER3 PET成像可以预测胃癌中对PAN受体酪氨酸激酶抑制疗法的反应。

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