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

项目摘要/摘要 我们建议评估一种新的αvβ6整合素分子靶向治疗方法用于检测和 转移性癌症的治疗。αvβ6整合素是一种细胞表面受体，在正常情况下很低或检测不到 成体上皮细胞，但广泛表达于多种癌组织。在统计上有显著的关联 αvβ6整合素的高表达、远处扩散和生存不良之间的关系。我们之前开发了 一种与整合素αvβ66具有纳摩尔亲和力和高选择性的整合素vα6结合肽(BP)。我们以前的临床 数据显示，使用[18F]-αvβ6-BPPET/CT成像，我们可以检测出原发肿瘤和 转移瘤。PET图像显示正常脑、肺、肝和骨骼的低背景摄取率。 这是转移性疾病的常见部位。此外，转移到这些器官的亚厘米是 用[18F]αvβ6-bpPET/CT检测。我们进一步将我们的αvβ6-BP发展成一种新的热敏对，[68Ga]Ga DOTA-5G和[177Lu]Lu DOTA-ABM-5G，其中[68Ga]Ga DOTA-5G正在被开发用于诊断和 [177 Lu]Lu DOTA-ABM-5G正在开发用于放射治疗。我们现在提议进行一项前瞻性临床试验，以 在转移性疾病患者中检测[68Ga]Ga DOTA-5G和[177Lu]Lu DOTA-ABM-5G。患者会 接受[68Ga]Ga DOTA-5G PET/CT扫描，以确认[177Lu]Lu DOTA-ABM-5G治疗的资格和 随访[68Ga]Ga DOTA-5GPET/CT扫描，评价治疗效果。我们假设a)[68Ga]Ga DOTA-5G将检测转移性癌症患者的病变b)治疗对[68Ga]Ga DOTA-5G/ [177Lu]Lu DOTA-ABM-5G将是安全和耐受性良好的；以及c)将通过 单剂[177Lu]Lu DOTA-ABM-5G。这项建议利用了萨克利夫博士免费提供的专业知识 开发和翻译治疗药物，福斯特博士治疗病人并翻译治疗图像 回应。在这项研究中，萨克利夫实验室为接受治疗的患者产生治疗药物的能力 加州大学戴维斯分校最大限度地利用现有资源和PI之间良好的成功协作， 提高这些治疗药物从研究到第二阶段试验的转换速度，最终， 转移性疾病患者的标准护理选择。鉴于αvβ6整合素受体在 α-v-β-6在肿瘤侵袭和转移过程中的作用 癌症，并可能对多种癌症产生广泛影响。[68Ga]GA DOTA-5G将更准确和 非侵入性检测疾病和所提出的治疗药物的有前景的药代动力学曲线 这种[177Lu]Lu DOTA-ABM-5G疗法的非靶向毒性是没有预期的。这是一个重大的进步。 目前已知会导致骨髓毒性、肝胆毒性和心脏毒性的治疗方法。 总的来说，这项提议将大大有助于改变对晚期疾病患者的癌症治疗。

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.