Profile of vintafolide (EC145) and its use in the treatment of platinum-resistant ovarian cancer

Luyckx, Mathieu; Votino, Raffaella; Squifflet, Jean-Luc; Baurain, Jean‐François

doi:10.2147/ijwh.s39696

Cited by 18 publications

(10 citation statements)

References 46 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…FR-a expression is reported in a majority ovarian cancers. 27,28 However, FR-a expression and its prognostic association with progression free survival (PFS) or overall survival (OS) is complex. 29 FR-a expression has been generally associated with tumor progression and prognosis although this generalization does not hold true for all cases as for patients with high grade serous carcinoma, where overall survival benefit was identified during the first two years of follow up.…”

Section: Discussionmentioning

confidence: 99%

In Vitro and In Vivo evaluation of a novel folate-targeted theranostic nanoemulsion of docetaxel for imaging and improved anticancer activity against ovarian cancers

Patel

Piroyan

Ganta

et al. 2018

Cancer Biology & Therapy

View full text Add to dashboard Cite

Ovarian cancer ranks fifth in cancer related deaths for women in USA. The high mortality rate associated with ovarian cancer is due to diagnosis at later stages of disease and the high recurrence rate of 60-80%. Recurrent ovarian cancers are more likely to present as multidrug resistance (MDR) leading to unfavorable response from 2 and 3 line chemotherapy. Nanoemulsions (NEs) are emerging as an attractive drug delivery system to overcome MDR challenges. NEs can also minimize exposure of therapeutic cargo to normal tissues potentially reducing side effects. In >80% of ovarian cancers, Folate Receptor-α (FR-α) is expressed at 10- to 100-fold higher levels than on non-pathological tissues. Therefore, folate (FA) is being evaluated as an active targeting moiety for FR-α ovarian cancer. To improve therapeutic outcome with reduced toxicity, we developed NMI-500, a FA targeted gadolinium (Gd) annotated NE loaded with docetaxel (DTX). NMI-500 has been developed as theranostic agents as Gd will enable physician to acquire real time pharmacodynamics data on NE + DTX accumulation in target lesions. In present study, characterization for key translational metrics of NMI-500 showed size distribution in range of 120 to 150 nm and zeta potential around -45 mV. Active targeting of FA was evaluated against FR-α KB cells and results demonstrated significant improvement in cell association which was surface ligand density dependent. We found that NMI-500 was able to inhibit tumor growth in a spontaneous transgenic ovarian cancer model with improved safety profile and this growth inhibition could be longitudinally followed by MRI. These results indicate NMI-500 warrants advancement to clinical trials.

show abstract

Section: Discussionmentioning

confidence: 99%

In Vitro and In Vivo evaluation of a novel folate-targeted theranostic nanoemulsion of docetaxel for imaging and improved anticancer activity against ovarian cancers

Patel

Piroyan

Ganta

et al. 2018

Cancer Biology & Therapy

View full text Add to dashboard Cite

show abstract

“…Preclinical and clinical anti-tumor activities of FRα-targeted therapies have thus far mostly been examined in the context of lung and ovarian carcinomas. These include monoclonal antibodies farletuzumab (15) and MOv18-IgG1 (16), antibody-drug conjugate (ADC) Mirvetuximab Soravtansine (17), and small molecule drug vintafolide (18). Encouraging results have recently been reported for the thymidylate synthase inhibitor ONX-0801 in ovarian carcinoma (19).…”

Section: Introductionmentioning

confidence: 99%

Anti-Folate Receptor Alpha–Directed Antibody Therapies Restrict the Growth of Triple-negative Breast Cancer

Cheung

Opzoomer

Ilieva

et al. 2018

Clinical Cancer Research

View full text Add to dashboard Cite

Highly aggressive triple-negative breast cancers (TNBCs) lack validated therapeutic targets and have high risk of metastatic disease. Folate receptor alpha (FRα) is a central mediator of cell growth regulation that could serve as an important target for cancer therapy. We evaluated FRα expression in breast cancers by genomic ( = 3,414) and IHC ( = 323) analyses and its association with clinical parameters and outcomes. We measured the functional contributions of FRα in TNBC biology by RNA interference and the antitumor functions of an antibody recognizing FRα (MOv18-IgG1), , and in human TNBC xenograft models. FRα is overexpressed in significant proportions of aggressive basal like/TNBC tumors, and in postneoadjuvant chemotherapy-residual disease associated with a high risk of relapse. Expression is associated with worse overall survival. TNBCs show dysregulated expression of thymidylate synthase, folate hydrolase 1, and methylenetetrahydrofolate reductase, involved in folate metabolism. RNA interference to deplete FRα decreased Src and ERK signaling and resulted in reduction of cell growth. An anti-FRα antibody (MOv18-IgG1) conjugated with a Src inhibitor significantly restricted TNBC xenograft growth. Moreover, MOv18-IgG1 triggered immune-dependent cancer cell death by human volunteer and breast cancer patient immune cells, and significantly restricted orthotopic and patient-derived xenograft growth. FRα is overexpressed in high-grade TNBC and postchemotherapy residual tumors. It participates in cancer cell signaling and presents a promising target for therapeutic strategies such as ADCs, or passive immunotherapy priming Fc-mediated antitumor immune cell responses. .

show abstract

“…Once folate-vinblastine binds to the folate receptor, it is subsequently internalized through endocytosis process and releases the drug to kill cancer cells ( Vergote and Leamon, 2015 ). Vintafolide has been tried in several aggressive cancers but failed to meet with primary endpoint of progression-free survival ( Luyckx et al, 2014 ). The poor metabolic stability may contribute to the low efficacy in clinical trials, and since there is no disclosed data concerning safety problems, cautions should be held for such types of conjugated drugs.…”

Section: Ligand-targeted Therapeutic Agentsmentioning

confidence: 99%

Current Strategies and Applications for Precision Drug Design

Wang

Zhang

et al. 2018

Front. Pharmacol.

View full text Add to dashboard Cite

Since Human Genome Project (HGP) revealed the heterogeneity of individuals, precision medicine that proposes the customized healthcare has become an intractable and hot research. Meanwhile, as the Precision Medicine Initiative launched, precision drug design which aims at maximizing therapeutic effects while minimizing undesired side effects for an individual patient has entered a new stage. One of the key strategies of precision drug design is target based drug design. Once a key pathogenic target is identified, rational drug design which constitutes the major part of precision drug design can be performed. Examples of rational drug design on novel druggable targets and protein–protein interaction surfaces are summarized in this review. Besides, various kinds of computational modeling and simulation approaches increasingly benefit for the drug discovery progress. Molecular dynamic simulation, drug target prediction and in silico clinical trials are discussed. Moreover, due to the powerful ability in handling high-dimensional data and complex system, deep learning has efficiently promoted the applications of artificial intelligence in drug discovery and design. In this review, deep learning methods that tailor to precision drug design are carefully discussed. When a drug molecule is discovered, the development of specific targeted drug delivery system becomes another key aspect of precision drug design. Therefore, state-of-the-art techniques of drug delivery system including antibody-drug conjugates (ADCs), and ligand-targeted conjugates are also included in this review.

show abstract

Profile of vintafolide (EC145) and its use in the treatment of platinum-resistant ovarian cancer

Cited by 18 publications

References 46 publications

In Vitro and In Vivo evaluation of a novel folate-targeted theranostic nanoemulsion of docetaxel for imaging and improved anticancer activity against ovarian cancers

In Vitro and In Vivo evaluation of a novel folate-targeted theranostic nanoemulsion of docetaxel for imaging and improved anticancer activity against ovarian cancers

Anti-Folate Receptor Alpha–Directed Antibody Therapies Restrict the Growth of Triple-negative Breast Cancer

Current Strategies and Applications for Precision Drug Design

Contact Info

Product

Resources

About