Abstract 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.
The folate receptor (FR) is a potentially useful biological target for the management of many human cancers. This membrane protein binds extracellular folates with very high affinity and, through an ...endocytic process, physically delivers them inside the cell for biological consumption. There are now many examples of how this physiological system can be exploited for the targeted delivery of biologically active molecules to cancer. In fact, strong preclinical as well as emerging clinical evidence exists showing how FR-positive cancers can be (i) anatomically identified using folate conjugates of radiodiagnostic imaging agents and (ii) effectively treated with companion folate-targeted chemotherapies. While the biological results are compelling, it is of equal importance to understand the conjugation chemistries that were developed to produce these active molecules. Therefore, this review will focus on the methods utilized to construct folate-based small-molecule drug conjugates (SMDCs), with particular attention focused on modular design, hydrophilic spacers, and self-immolative linkers.
Although chimeric antigen receptor (CAR) T cell therapies have demonstrated considerable success in treating hematologic malignancies, they have simultaneously been plagued by a cytokine release ...syndrome (CRS) that can harm or even kill the cancer patient. We describe a CAR T cell strategy in which CAR T cell activation and cancer cell killing can be sensitively regulated by adjusting the dose of a low molecular weight adapter that must bridge between the CAR T cell and cancer cell to initiate tumor eradication. By controlling the concentration and dosing schedule of adapter administration, we document two methods that can rapidly terminate (<3 h) a pre-existing CRS-like toxicity and two unrelated methods that can pre-emptively prevent a CRS-like toxicity that would have otherwise occurred. Because all four methods concurrently enhance CAR T cell potency, we conclude that proper use of bispecific adapters could potentially avoid a life-threatening CRS while enhancing CAR T cell tumoricidal activity.
Despite advances in the development of molecularly targeted therapies, limited improvements in overall survival have been noted among many cancer patients with solid tumors, primarily due to ...development of drug resistance. Accordingly, there is an unmet need for new targeted therapies and treatment approaches for cancer, especially for overcoming resistance. Expression of the folate receptor is upregulated in many tumor types and thus represents an ideal target for cancer treatment. Several folate receptor targeted therapies are in development, including the small molecule drug conjugate vintafolide, the monoclonal antibody farletuzumab, and the antibody-drug conjugate IMGN853. The role of the folate receptor as a target in cancer progression and resistance as well as emerging preclinical and clinical data from studies on those folate receptor targeted agents that are in development with a focus on vintafolide are reviewed. The folate receptor has several unique properties, such as high expression in several tumor types, that make it a rational target for cancer treatment, and allow for selective delivery of folate receptor targeted agents. Early-stage clinical data in lung and ovarian cancer suggest that vintafolide has the potential for combination with other standard approved agents.
The folate receptor (FR) is a valuable therapeutic target that is highly expressed on a variety of cancers. The current development of folate-targeted cancer therapies has created the need for ...quantitating functional FRs in clinical specimens. In this article, we report on the creation of a highly sensitive radioactive binding method for quantitatively measuring FR expression in frozen tissue homogenates. Expression was positive in approximately 89% of human ovarian carcinomas but was negligible in both mucinous ovarian carcinomas and normal ovary. Expression was also significant in carcinomas of the kidney, endometrium, lung, breast, bladder, and pancreas. Normal tissues from humans and six different laboratory species were also analyzed; surprisingly, some interspecies variability in FR expression (especially in kidney, spleen, and lung tissue) was found. Interestingly, normal human lung tissue displayed high expression levels, whereas expression in normal lung of the other species was negligible. However, considering that folate–drug conjugates fail to accumulate in the lungs of patients, the consequence of this finding was not considered to be of clinical concern. Overall, this new methodology is reliable for determining functional FR expression levels in tissues, and it could possibly be a useful clinical test to determine patient candidacy for FR-targeted therapeutics.
Folate receptors and transporters and one-carbon metabolism continue to be important areas of study given their essential roles in an assortment of diseases and as targets for treatment of cancer and ...inflammation. Reflecting this, every 2 years, the Folate Receptor Society organizes an international meeting, alternating between North America and Europe, where basic and translational scientists, clinical oncologists and rheumatologists from both academia and industry convene in an informal setting. The 7th International Symposium on Folate Receptors and Transporters was held in Sant'Alessio Siculo (ME), Taormina, Italy from 1st to 5th of October 2018, organized by Dr. Mariangela Figini from Fondazione IRCCS Istituto Nazionale dei Tumori, Milan. Following the format of previous meetings, more than 50 scientists from 9 different countries attended the 2018 meeting to share ongoing developments, discuss current research challenges and identify new avenues in basic and translational research. An important feature of this meeting was the participation of young investigators and trainees in this area, two (A. Dekhne and N. Verweij) of whom were awarded fellowships to attend this meeting as a recognition of the high scientific quality of their work. This report provides a synopsis of the highlights presented in the following sessions: Barton Kamen Lecture; Targeting one-carbon metabolism in cytosol and mitochondria; Structure and biology of the one-carbon solute transporters; Physiology and pathophysiology of folate receptors and transporters; Folate receptors for targeting tumors and inflammatory diseases; Conventional and new anti-folate drugs for treating inflammatory diseases and cancer; Imaging; Ongoing clinical trials; and Chimeric Antigen Receptor cell therapies of cancer.
Vintafolide (EC145) is a folic acid-desacetylvinblastine conjugate that binds to the folate receptor (FR), which is expressed on the majority of epithelial ovarian cancers. This randomized phase II ...trial evaluated vintafolide combined with pegylated liposomal doxorubicin (PLD) compared with PLD alone. The utility of an FR-targeted imaging agent, (99m)Tc-etarfolatide (EC20), in selecting patients likely to benefit from vintafolide was also examined.
Women with recurrent platinum-resistant ovarian cancer who had undergone ≤ two prior cytotoxic regimens were randomly assigned at a 2:1 ratio to PLD (50 mg/m(2) intravenously IV once every 28 days) with or without vintafolide (2.5 mg IV three times per week during weeks 1 and 3). Etarfolatide scanning was optional. The primary objective was to compare progression-free survival (PFS) between the groups.
The intent-to-treat population comprised 149 patients. Median PFS was 5.0 and 2.7 months for the vintafolide plus PLD and PLD-alone arms, respectively (hazard ratio HR, 0.63; 95% CI, 0.41 to 0.96; P = .031). The greatest benefit was observed in patients with 100% of lesions positive for FR, with median PFS of 5.5 compared with 1.5 months for PLD alone (HR, 0.38; 95% CI, 0.17 to 0.85; P = .013). The group of patients with FR-positive disease (10% to 90%) experienced some PFS improvement (HR, 0.873), whereas patients with disease that did not express FR experienced no PFS benefit (HR, 1.806).
Vintafolide plus PLD is the first combination to demonstrate an improvement over standard therapy in a randomized trial of patients with platinum-resistant ovarian cancer. Etarfolatide can identify patients likely to benefit from vintafolide.
Folate-targeted chemotherapy Leamon, Christopher P; Reddy, Joseph A
Advanced drug delivery reviews,
04/2004, Letnik:
56, Številka:
8
Journal Article
Recenzirano
The folate receptor (FR) is a confirmed tumor-associated antigen that binds folate and folate–drug conjugates with very high affinity and shuttles these bound molecules inside cells via an endocytic ...mechanism. Using folate (or an analog thereof) as the ligand, a wide variety of drug payloads can be delivered to FR-positive cells, ranging from small radioactive imaging agents up to large DNA-containing formulations. For therapeutic purposes, attachment of small molecular weight, highly potent agents to folate is a novel approach. As such, this review will outline the manner in which folate–drug conjugates are screened preclinically, it will summarize published activity data of various conjugates, and it will also highlight some newly emerging animal data from novel compounds that are currently under preclinical investigation.
Activation of the mammalian target of rapamycin (mTOR) signaling pathway is aberrant in autosomal-dominant polycystic kidney disease (ADPKD). The mTOR inhibitors, such as rapamycin, ameliorate PKD in ...rodent models, but clinical trials have not shown benefit, possibly as a result of low tissue concentrations of rapamycin at clinically tolerable doses. To overcome this limitation, we synthesized a folate-conjugated form of rapamycin (FC-rapa) that is taken up by folate receptor-mediated endocytosis and cleaved intracellularly to reconstitute the active drug. We found that renal cyst-lining cells highly express the folate receptor in ADPKD and mouse models. In vitro, FC-rapa inhibited mTOR activity in a dose- and folate receptor-dependent manner. Treatment of a PKD mouse model with FC-rapa inhibited mTOR in the target tissue, strongly attenuated proliferation and growth of renal cysts and preserved renal function. Furthermore, FC-rapa inhibited mTOR activity in the kidney but not in other organs. In summary, these results suggest that targeting the kidney using FC-rapa may overcome the significant side effects and lack of renal efficacy observed in clinical trials with mTOR inhibitors in ADPKD.
The covalent attachment of the vitamin folic acid to almost any molecule yields a conjugate that can be endocytosed into folate receptor-bearing cells. Because folate receptors are significantly ...overexpressed in the majority of human cancers, this methodology is currently being investigated for the selective delivery of imaging and therapeutic agents to tumor tissue. Phase I and II clinical studies for the first folate-containing imaging agent were initiated in 1999, and clinical trials of folate-targeted therapeutic agents should soon follow. This review will summarize folate-mediated drug delivery and highlight those techniques undergoing active preclinical or clinical investigation.
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