A novel molecularly targeted theranostic approach via the alphavbeta6 integrin for the detection and treatment of metastatic cancers

一种通过 alphavbeta6 整合素检测和治疗转移性癌症的新型分子靶向治疗诊断方法

• 批准号: 10636199
• 负责人: Cameron Carl Foster
• 金额: $ 66.47万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-21 至 2028-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10636199
• 关键词: Adult; Affinity; Aftercare; Anterior; Binding; Biodistribution; Biological Assay; Blood; Blood specimen; Bone Marrow; Brain; Carcinoma; Cardiotoxicity; Cell Surface Receptors; Cells; Clinical; Clinical Data; Clinical Research; Clinical Trials; Collaborations; Cyclic GMP; Detection; Development; Diagnostic; Discipline of Nuclear Medicine; Disease; Disseminated Malignant Neoplasm; Distant; Dose; Drug Kinetics; Early Diagnosis; Early treatment; Eligibility Determination; Epithelium; Evaluation; Excretory function; Fostering; Goals; Hematology; Hepatobiliary; Hour; Image; Image Analysis; In Vitro; Infusion procedures; Injections; Integrins; Invaded; Kidney; Laboratories; Lesion; Link; Liver; Lung; Malignant Neoplasms; Metastatic Carcinoma; Molecular Target; Neoplasm Metastasis; Non-Invasive Detection; Oncology; Organ; Outcome; PET/CT scan; Patient-Focused Outcomes; Patients; Peptides; Positron-Emission Tomography; Prevalence; Primary Neoplasm; Process; Property; Prospective Studies; Radiation Oncology; Radiation therapy; Radiochemistry; Radiopharmaceuticals; Research; Resources; Role; Safety; Schedule; Site; Skeleton; Specificity; Speed; Survival Rate; Testing; Therapeutic; Time; Toxic effect; Translating; Translational Research; Translations; Treatment Efficacy; Tumor stage; X-Ray Computed Tomography; absorption; advanced disease; bone; cancer imaging; cancer therapy; cancer type; clinical care; clinical translation; dosimetry; efficacy evaluation; follow-up; improved; in vivo; interest; intravenous injection; mouse model; nanomolar; novel; participant enrollment; phase II trial; preclinical study; primary outcome; prospective; receptor; single photon emission computed tomography; standard of care; theranostics; treatment response; uptake

PROJECT SUMMARY/ABSTRACT We propose to evaluate a novel αvβ6 integrin molecularly targeted theranostic approach for the detection and treatment of metastatic cancers. The αvβ6 integrin is a cell surface receptor that is low or undetectable in normal adult epithelium but is widely expressed on numerous carcinomas. There is a statistically significant association between the high expression of the αvβ6 integrin, distant spread, and poor survival. We previously developed an αvβ6 -Binding Peptide (BP) with nanomolar affinity and high selectivity for the integrin αvβ66. Our prior clinical data demonstrates that using [18F]-αvβ6 -BP PET/CT imaging we can detect both primary tumors and metastases. PET images showed low background uptake in normal brain, lungs, liver, and osseous skeleton which are common sites of metastatic disease. Furthermore, sub-centimeter metastases to these organs were detected using [18F]αvβ6 -BP PET/CT. We further developed our αvβ6-BP into a novel theranostic pair, [68Ga]Ga DOTA-5G and [177Lu]Lu DOTA-ABM-5G in which [68Ga]Ga DOTA-5G is being developed as a diagnostic and [177Lu]Lu DOTA-ABM-5G is being developed as a radiotherapy. We now propose a prospective clinical trial to test the [68Ga]Ga DOTA-5G and [177Lu]Lu DOTA-ABM-5G in patients with metastatic disease. Patients will undergo [68Ga]Ga DOTA-5G PET/CT scans to confirm eligibility for the [177Lu]Lu DOTA-ABM-5G therapy and follow up [68Ga]Ga DOTA-5G PET/CT scans to evaluate treatment response. We hypothesize that a) [68Ga]Ga DOTA-5G will detect lesions in patients with metastatic cancers b) the theranostic pair [68Ga]Ga DOTA-5G/ [177Lu]Lu DOTA-ABM-5G will be safe and well tolerated; and c) a therapeutic response will be achieved with a single dose of [177Lu]Lu DOTA-ABM-5G. This proposal leverages the complimentary expertise of Dr. Sutcliffe to develop and translate the theranostic agents, and Dr. Foster to treat patients and interpret images for treatment response. The ability of the Sutcliffe lab to generate the theranostic agents in this study for patients treated at UC Davis maximizes existing resources and a well-established successful collaboration between the PIs, increasing the speed of translation of these theranostic agents from research to Phase II trials and ultimately, a standard of care option for patients with metastatic disease. Given the role of the αvβ6 integrin receptor in the processes of invasion and metastasis, αvβ6 is a very attractive target for the detection and treatment of metastatic cancers and could have broad impact across multiple cancers. [68Ga]Ga DOTA-5G will more accurately and non-invasively detect disease and the promising pharmacokinetic profile of the theranostics proposed suggests that off-target toxicity of this [177Lu]Lu DOTA-ABM-5G therapy is not expected. This poses a major improvement over current treatments that are known to cause bone marrow toxicity, hepatobiliary toxicity, and cardiotoxicity. Collectively, this proposal will significantly help transform cancer treatment for patients with advanced disease.

项目总结/摘要 我们建议评估一种新的αvβ6整合素分子靶向治疗诊断方法， 转移性癌症的治疗。αvβ6整联蛋白是一种细胞表面受体，在正常人中很低或检测不到。 但在许多癌细胞中广泛表达。有统计学意义的关联 αvβ6整合素高表达、远处转移和生存率低之间的关系。我们之前开发了 一种αvβ6结合肽（BP），对整联蛋白αvβ66具有纳摩尔亲和力和高选择性。我们以前的临床 数据表明，使用[18 F]-αvβ6 -BP PET/CT成像，我们可以检测原发性肿瘤， 转移PET图像显示正常脑、肺、肝和骨骼的背景摄取较低 这是转移性疾病的常见部位。此外，这些器官的亚厘米转移是 使用[18 F]αvβ6 -BP PET/CT检测。我们进一步发展了我们的αvβ6-BP到一个新的治疗诊断对，[68 Ga]Ga D 0 TA-5G和[177 Lu]Lu D 0 TA-ABM-5G，其中[68 Ga]Ga D 0 TA-5G正在被开发作为诊断剂， [177 Lu]Lu DOTA-ABM-5G正在开发作为放射治疗。我们现在提出一项前瞻性临床试验， 在转移性疾病患者中测试[68 Ga]Ga DOTA-5G和[177 Lu]Lu DOTA-ABM-5G。患者将 接受[68 Ga]Ga DOTA-5G PET/CT扫描，以确认[177 Lu]Lu DOTA-ABM-5G治疗的合格性， 随访[68 Ga]Ga DOTA-5G PET/CT扫描以评价治疗反应。我们假设a）[68 Ga]Ga DOTA-5G将检测患有转移性癌症的患者中的病变B）治疗诊断对[68 Ga]Ga DOTA-5G/ [177 Lu]Lu DOTA-ABM-5G将是安全的并且耐受良好;以及c）将在[177 Lu] DOTA-ABM-5G的存在下实现治疗反应。 单剂量[177 Lu]Lu DOTA-ABM-5G。该提案利用Sutcliffe博士的专业知识， 开发和翻译治疗诊断剂，福斯特博士治疗患者并解释治疗图像 反应Sutcliffe实验室在本研究中为接受以下治疗的患者生产治疗诊断剂的能力 加州大学戴维斯分校最大限度地利用现有资源和PI之间建立良好的成功合作， 加快这些治疗诊断剂从研究到II期试验的转化速度， 转移性疾病患者的标准治疗选择。考虑到αvβ6整合素受体在细胞凋亡中的作用， αvβ6是一个非常有吸引力的检测和治疗转移性肿瘤的靶点， 癌症，并可能对多种癌症产生广泛影响。[68 Ga]Ga DOTA-5G将更准确， 非侵入性检测疾病和治疗诊断学的有前途的药代动力学特征表明， 这种[177 Lu]Lu DOTA-ABM-5G疗法的脱靶毒性是预期不到的。这是一个重大的进步 目前已知会引起骨髓毒性、肝胆毒性和心脏毒性的治疗。 总的来说，这一提议将大大有助于改变晚期癌症患者的治疗方式。