Quantitative HER3 PET Imaging for Assessing Resistance and Guiding Therapy

摘要 侵袭性乳腺癌，通常对标准化疗耐药，越来越多地被用来治疗 靶向信号通路抑制剂。HER2抑制剂是治疗HER2阳性乳房的标准护理 癌症，以及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善，但也有几种 可以限制反应的机制，越来越多的证据表明，占主导地位的机制 限制疗效是释放导致受体上调的内在负反馈环路 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(在三阴性乳腺癌中)并允许 持续生长途径信号。这种HER3的动态上调发生在治疗的几天内 启动，而且不是后天基因突变的结果，而是对尝试的内在细胞反应 以维持动态平衡。此外，这一通路在患者中是可变的活跃的，没有任何电流 在治疗开始前预测其活性的方法。理解这种抵抗是否以及何时发生 在特定的患者中机制是活跃的，开始使用靶向抑制剂在临床上仍然是不切实际的，因为它需要 治疗开始前和治疗期间的侵入性组织活检。这种配对的活组织检查 相关的患者风险，而且单部位活检并不能反映肿瘤的内在异质性。至 快速、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的表达，合理地指导后续的治疗选择(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成像的一流的HER3靶向多肽。在……里面 设想的成像范例患者将在之前和之后不久用HER3PET进行成像 开始治疗，评估肿瘤HER3表达的变化。我们将在这两个方面研究这种方法 建立了HER2+和三阴性乳腺癌细胞系。我们将确定门槛水平 HER3 PET SUV评估的HER3表达变化可预测肿瘤克服靶向 通过增加HER3的表达来抑制。我们将展示这种成像预测的能力 耐药性，并随后通过测试患者来源的异种移植物来指导适应性治疗，这比 与临床实践的异质性非常相似。这种方法代表了使用 影像指导个性化治疗，提供对治疗机制的即时洞察 以非侵入性方式抵抗和指导替代治疗策略，这是相对于 无论是标准解剖成像还是侵入性活检。

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.