Conventional cancer treatment modalities have several limitations including lack of sufficient efficacy, serious untoward toxicity, as well as innate and acquired drug resistance. In contrast, targeted imaging agents can identify patients with receptors overexpressed on the surface of cancer cells, thus allowing appropriate selection of patients for personalized treatment with a desirable targeted therapeutic. The folate receptor (FR) has been identified as a new molecularly targeted entity, which is highly overexpressed on the surface of a spectrum of solid tumor cells, including ovarian, kidney, lung, brain, endometrial, colorectal, pancreatic, gastric, prostate, testicular, bladder, head and neck, breast, and non-small cell lung cancer. Folic acid conjugation is a novel approach for targeting FR-expressing tissues for personalized treatment. With the development of FRα-targeted therapies comes a concomitant prerequisite for reliable methods for the quantification of FRα tissue expression. Therefore, attaching a radioactive probe to folic acid to target diseased tissue has become a novel and powerful imaging technique. Currently available diagnostic tools frequently require invasive surgical biopsy. In contrast, the noninvasive single-photon emission computed tomography-based companion imaging agent, (99m)Tc-etarfolatide ((99m)Tc-EC20), is in development for use as a companion diagnostic with the FRα-targeted folate conjugate, vintafolide (EC145), to identify patients whose tumors express FRα. Vintafolide is a folic acid conjugate of Vinca alkaloid (desacetylvinblastine hydrazide) that targets FRα-expressing tumors, thereby disrupting microtubule polymerization. (99m)Tc-etarfolatide is taken up by FR-positive tumors and allows for noninvasive, whole-body monitoring of FRα expression status throughout treatment. The combination of vintafolide plus etarfolatide has been evaluated in three Phase 2 studies for the treatment of various solid tumors, including ovarian, endometrial, peritoneal, and platinum-resistant ovarian cancer, as well as lung cancer. Patients with FR-positive tumors, as identified by etarfolatide uptake, have had better clinical outcomes than patients with FR-negative tumors, indicating the potential of etarfolatide as a companion biomarker for predicting vintafolide response. Targeted therapies combined with a reliable companion diagnostic test represent a novel approach toward efficient personalized medicine for malignant and nonmalignant disorders. Furthermore, the recent availability of the crystal structures of FRα and FRβ in complex with folates and antifolates forms a realistic basis for the rational design and implementation of novel FR-targeted drugs for the treatment of cancer and inflammatory disorders.

中文翻译：

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叶酸受体是个性化癌症治疗的合理治疗靶标。

常规的癌症治疗方式具有几个局限性，包括缺乏足够的疗效，严重的不良毒性以及先天和后天的耐药性。与此相反，靶向成像剂可确定患者中过表达的癌细胞的表面上的受体，从而允许患者适当地选择用于与期望的靶向性治疗的个性化治疗。叶酸受体（FR）已被确定为一种新型的分子靶向实体，在一系列实体肿瘤细胞（包括卵巢，肾脏，肺，脑，子宫内膜，结直肠，胰腺，胃，前列腺，睾丸癌，膀胱癌，头颈癌，乳腺癌和非小细胞肺癌。叶酸结合是一种针对表达FR的组织进行个性化治疗的新方法。随着针对FRα的疗法的发展，随之而来的是定量FRα组织表达的可靠方法的先决条件。因此，将放射性探针与叶酸结合以靶向患病组织已成为一种新颖而强大的成像技术。当前可用的诊断工具经常需要侵入性手术活检。相比之下，基于无创单光子发射计算机断层摄影的伴随成像剂（99m）Tc-etarfolatide（（99m）Tc-EC20）正在开发中，可与FRα靶向的叶酸结合物，长春花环素一起用作伴随诊断（EC145），以鉴定其肿瘤表达FRα的患者。Vintafolide是长春花生物碱（去乙酰长春碱酰肼）的叶酸结合物，可靶向表达FRα的肿瘤，从而破坏微管聚合。（99m）Tc-etarfolatide被FR阳性肿瘤吸收，并允许在整个治疗过程中对FRα表达状态进行无创，全身监测。在三个2期研究中已评估了长春花环素加依他福拉肽的组合用于治疗各种实体瘤，包括卵巢癌，子宫内膜癌，腹膜癌和铂耐药性卵巢癌以及肺癌。如依法洛太肽摄取所鉴定，患有FR阳性肿瘤的患者比具有FR阴性肿瘤的患者具有更好的临床结局，表明依他福拉肽作为预测长春新碱反应的伴侣生物标志物的潜力。靶向疗法与可靠的伴随诊断测试相结合，是针对恶性和非恶性疾病的高效个性化药物的新方法。此外，