Deciphering the Acidic Tumor Environment: A Phase I/IIa Study of Pre-Operative Multiparametric MRI and pHLIP® ICG Intra-Operative Fluorescence Imaging of Primary Breast Cancer

破译酸性肿瘤环境：原发性乳腺癌术前多参数 MRI 和 pHLIP® ICG 术中荧光成像的 I/IIa 期研究

• 批准号: 10586615
• 负责人: Monica Morrow
• 金额: $ 70.65万
• 依托单位: SLOAN-KETTERING INST CAN RESEARCH
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-03-01 至 2026-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10586615
• 关键词: Acidity; Adjuvant Therapy; Adverse event; Anxiety; Breast Cancer Patient; Breast-Conserving Surgery; Cancerous; Cd68; Cell surface; Cessation of life; Characteristics; Chemicals; Clinical; Clinical Research; Clinical Trials; Development; Diffusion Magnetic Resonance Imaging; Dose; Drug Kinetics; Dyes; Environment; Excision; FDA approved; Female; Goals; Growth; Histologic; Histopathology; Image; Image-Guided Surgery; Immunohistochemistry; Indocyanine Green; Injections; Intravenous; Lesion; MMP9 gene; Magnetic Resonance Imaging; Magnetic Resonance Spectroscopy; Malignant Neoplasms; Mastectomy; Metalloproteases; Monitor; Motion; Neoadjuvant Therapy; Nuclear Protein; Operative Surgical Procedures; Patient-Focused Outcomes; Patients; Peptides; Phase; Phenotype; Primary Neoplasm; Prognosis; Proliferating; Property; Protocols documentation; Reference Standards; Resistance; Safety; Specimen; Stains; Structure; Technology; Testing; Time; Tissues; Tumor Biology; Tumor Markers; Tumor Tissue; Tumor Volume; Tumor stage; Tumor-associated macrophages; Visualization; Woman; breast lumpectomy; carbonate dehydratase; first-in-human; fluorescence imaging; holistic approach; human study; imaging agent; improved; insight; lactate dehydrogenase A; malignant breast neoplasm; neoplastic cell; novel; phase I trial; prospective; real-time images; risk stratification; standard of care; targeted imaging; targeted treatment; tool; treatment planning; treatment strategy; tumor; tumor microenvironment

PROJECT SUMMARY/ABSTRACT Breast cancer (BC) is the most common cancer in women and the most common cause of female cancer deaths. While breast conserving surgery (lumpectomy) with neo/adjuvant therapy is the best desirable treatment option, about 25% of cases require secondary surgery when tumors are incompletely removed, with possible additional complications, patient anxiety, and conversion to mastectomy. Re-excision rates are especially high among patients with more aggressive tumors, which are characterized by acidic tumor microenvironment (TME). We propose to develop and implement a holistic approach for tumor acidity imaging with pre-operative multi- parametric MRI (mpMRI) and novel pHLIP® ICG near infrared fluorescent (NIRF) intra-operative imaging. pHLIP- ICG is an ICG, FDA-approved NIRF indocyanine green dye, conjugated to a pH-sensitive pH-Low Insertion Peptide (pHLIP) for targeting tumor cell surface acidity and for marking the invasive acidic tumor-stroma interface, thereby allowing pHLIP-ICG to target cancer lesions and to delineate positive tumor margins. Our clinical study consists of a prospective first-in-human phase I trial and a feasibility phase IIa trial. Aim 1 (phase I and IIa): To prospectively develop, implement, and optimize novel mpMRI sequences in consecutive BC patients undergoing lumpectomy for clinical non-contrast non-invasive assessment of the TME and tissue acidity including intravoxel incoherent motion diffusion-weighted imaging, diffusion tensor imaging, lactate MR spectroscopy, and chemical exchange saturation transfer imaging. Aim 2 (phase I): To evaluate the safety and tolerability of intravenous pHLIP-ICG administration in 4 dose levels in patients with primary BC undergoing lumpectomy, and to establish the “optimal” dose which will be used in the phase IIa trial. This optimal dose is defined as the lowest dose that is safe and that allows the best intra-operative visualization of BC with pHLIP- ICG NIRF imaging. Aim 3 (phase IIa): To establish the feasibility of pHLIP-ICG targeting and intra-operative imaging of primary BC and margin delineation at the selected optimal dose of pHLIP-ICG using histopathology as the reference standard. Aim 4 (phase IIa): To correlate TME acidity imaging (non-contrast non-invasive pre- operative mpMRI, and intra-operative and ex vivo pHLIP-ICG NIRF imaging) with standard histopathology and investigational immunohistochemistry for concordance and accuracy of BC visualization, margin status, and properties of the TME including different levels of acidity, lesion extent, and TME structure. The overarching long-term goal is to improve the standard of care: i) pre-operative non-invasive, non-contrast TME acidity imaging with mpMRI will allow the identification of more aggressive tumor phenotypes that require intensified treatment, improve planning of surgical and treatment strategies, and enable monitoring spatial-longitudinal of tumor biology with treatment; and ii) intra-operative pHLIP-ICG NIRF imaging will allow an improved up-front resection of primary breast cancer, which could allow a shift from more extensive surgeries to highly accurate tissue-sparing lumpectomies – therefore improving the quality of patients’ lives.

项目摘要/摘要 乳腺癌（BC）是女性最常见的癌症，也是女性癌症死亡的最常见原因。 虽然采用新/辅助治疗的乳房保存手术（肿块切除术）是最好的期望治疗选择，但 大约25％的病例需要肿瘤不完全切除时需要进行继发手术，并可能额外 并发症，患者焦虑和转化为乳房切除术。重新调查率在 具有更侵略性肿瘤的患者，其特征是酸性肿瘤微环境（TME）。我们 提议开发和实施一种整体方法，用于肿瘤酸度成像 参数MRI（MPMRI）和新型Phlip®ICG附近红外荧光（NIRF）术中成像。 ph ICG是ICG，由FDA批准的NIRF吲哚烷绿色染料，共轭到pH敏感的pH-low插入 用于靶向肿瘤细胞表面酸度的肽（phlip）和标志着浸润性酸性肿瘤细胞瘤 界面，从而允许Phlip-ICG靶向癌症病变并描绘阳性肿瘤边缘。我们的 临床研究包括一项前瞻性第一阶段I期试验和一项可行性IIA试验。目标1（阶段） I和IIA）：前瞻性地开发，实施和优化连续BC中的新型MPMRI序列 进行肿块切除术进行临床非对比度非侵入性评估的患者对TME和组织酸度 包括内腔内不相干运动扩散加权成像，扩散张量成像，使MR变形 光谱和化学交换满意度转移成像。目标2（I阶段）：评估安全性和 原发性BC患者4剂量水平静脉注射phlip-ICG的耐受性 乳房切除术，并建立将在IIA期试验中使用的“最佳”剂量。这种最佳剂量是 定义为安全的最低剂量，可以使用phlip-允许BC的最佳术中可视化 ICG NIRF成像。 AIM 3（IIA期）：建立Phlip-ICG靶向和术中的可行性 使用组织病理学选定的PHLIP-ICG最佳剂量在选定的最佳剂量下对原发性BC的成像和边缘描述的成像 作为参考标准。 AIM 4（IIA期）：将TME酸度成像相关联（非对比度非侵入性前 - 具有标准的组织病理学和 卑诗省可视化，保证金状态的一致性和准确性研究性免疫组织化学 TME的性质，包括不同水平的酸度，病变范围和TME结构。总体 长期目标是提高护理标准：i）术前非侵入性，非对比度TME酸度 用mpMRI成像将允许鉴定需要强烈的侵略性肿瘤表型 治疗，改善外科手术和治疗策略的规划，并为监测 治疗肿瘤生物学； ii）术中phlip-icg NIRF成像将允许改进 切除原发性乳腺癌，这可以从更广泛的手术转变为高度准确 肿块的肿块切除术 - 因此改善了患者生活的质量。