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.