Novel molecular multilevel targeted antitumor agents

Sonawane, Poonam; Choi, Young A.; Pandya, Hetal; Herpai, Denise; Fokt, Izabela; Priebe, Waldemar; Debinski, Waldemar

doi:10.4103/ctm.ctm_12_17

Cited by 11 publications

(8 citation statements)

References 49 publications

(46 reference statements)

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“…It appears that we still have room to improve the conjugation conditions, which may translate into even more active conjugates. We successfully conjugated the QUAD 3.0 to three variants of doxorubicin: WP936 [11,79,80], WP1737, and WP1244 [81] ( Figure 1c); these variants are designed to be thiol reactive. Berubicin is the first powerful anthracycline known to cross the BBB and sequester primarily in the tumor tissue [82,83].…”

Section: Quad 30 Was Successfully Conjugated To Dox Derivativesmentioning

confidence: 99%

“…Among the three variants, WP1244 was the most potent. It was cytotoxic to U87 and D54 glioma cells, Colo357-FG metastatic pancreatic adenocarcinoma cells, and H441 papillary adenocarcinoma cells, with IC 50 values of 0.2, 1.08, 3.1, and 0.91 nM respectively [11,[79][80][81][82][83][84]. Our results show that the QUAD 3.0-Dox conjugates were cytotoxic to established and patient-derived GBM cell lines in vitro, with IC 50 values in the low nM range.…”

Section: Introductionmentioning

confidence: 99%

“…IL-13RA2 is a GBM TAA that has been shown to be overexpressed in up to 75% of GBM patients [44]. Since its discovery, IL-13RA2 has been used as a target for GBM in more than 30 different experimental, preclinical, and clinical therapies, making it one of the most well-studied and promising targets for GBM [10,11,17,18,23,[43][44][45][46][47][48][49][50][51][52][53][54][55]. Studies have demonstrated that the overexpression of IL-13RA2 correlates with a higher GBM grade and poor patient survival [56].…”

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confidence: 99%

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Drug Conjugates for Targeting Eph Receptors in Glioblastoma

et al. 2020

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Glioblastoma (GBM) is a complex and heterogeneous tumor that warrants a comprehensive therapeutic approach for treatment. Tumor-associated antigens offer an opportunity to selectively target various components of the GBM microenvironment while sparing the normal cells within the central nervous system. In this study, we conjugated a multivalent vector protein, QUAD 3.0, that can target four receptors: EphA3, EphA2, EphB2, and also IL-13RA2, spanning virtually 100% of the GBM microenvironment, to doxorubicin derivatives. The conjugates effectively bound to all four receptors, although to varying degrees, and delivered cytotoxic loads to both established and patient-derived GBM cell lines, with IC 50 values in the low nM range. The conjugates were also non-toxic to animals. We anticipate that the QUAD 3.0 Dox conjugates will be further used in preclinical models and possibly clinics in the foreseeable future.Pharmaceuticals 2020, 13, 77 2 of 17 in tumor cells and its microenvironment but not in their normal counterparts. The targeting of such receptors has been achieved in different ways. These include the use of ligand- [11-13], antibody-[14,15], and liposome/nanoparticles-based therapeutic agents [16,17]. Additionally, immunotherapy has utilized antigen-pulsed dendritic cells [18], chimeric antigen receptor T-cells (CAR T-cells) [19][20][21][22], and vaccines [23-25] to selectively target TAA in tumors. While immunotherapy has yet to show clinical benefit in GBM, it is considered a fourth pillar of cancer treatment and holds much promise [26].The Eph receptors represent the largest family of receptor tyrosine kinases. It comprises nine EphA receptors that bind to five ephrinA ligands, and five EphB receptors that bind to three ephrinB ligands. Receptors EphB2 and EphA4 can bind to ephrin ligands of different classes [27]. Their implications have been discovered in various developmental [28,29], physiological [30][31][32], and pathological phenomena [33][34][35]. Moreover, increasing indications of their involvement in tumor invasion, initiation [36], tumor immunity [37], and tumor angiogenesis [12,35] have been observed. Specifically, EphA2 and EphA3 have been shown to be expressed individually in 60% of GBM patients, including in regions of tumor neovasculature, tumor-associated immune cells, and tumor-infiltrating cells [12,35,38]. The increased expression of EphA2 and EphA3 in GBM patients is associated with poor patient prognosis and survival [39,40]. Similarly, the expression of EphB2 has been coupled with increased migration and invasion of GBM cells [41,42].The Eph receptors have been targeted using antibodies, kinase inhibitors, radionucides, and peptides that mimic the receptor ligand and carry a cytotoxic load [10]. The Eph receptors internalize once bound to their ligands and resurface later [12,13]. This allows ligand-based or ligand-mimicking peptide-based therapeutics to be administered in multiple doses given the re-expression of the receptors over time. Recently, an ephrinA5-based cytotoxin that c...

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Section: Quad 30 Was Successfully Conjugated To Dox Derivativesmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Drug Conjugates for Targeting Eph Receptors in Glioblastoma

et al. 2020

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“…These agents have been exploited as carriers of tumor suppressor genes, such as p53, or to deliver cytotoxic suicide genes. This has the potential to be a self-limiting mechanism because tumor cell death results in clearance of the vector [ 57 ]. An example of immune-modulating gene therapy that just entered first-in-human trials is an adenovirus encoding for human FlT3L to elicit an antitumor immunity [ 58 ].…”

Section: Microbial Strategies Attempted To Datementioning

confidence: 99%

White paper on microbial anti-cancer therapy and prevention

Forbes¹,

Coffin²,

Deng³

et al. 2018

j. immunotherapy cancer

121

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In this White Paper, we discuss the current state of microbial cancer therapy. This paper resulted from a meeting (‘Microbial Based Cancer Therapy’) at the US National Cancer Institute in the summer of 2017. Here, we define ‘Microbial Therapy’ to include both oncolytic viral therapy and bacterial anticancer therapy. Both of these fields exploit tumor-specific infectious microbes to treat cancer, have similar mechanisms of action, and are facing similar challenges to commercialization. We designed this paper to nucleate this growing field of microbial therapeutics and increase interactions between researchers in it and related fields. The authors of this paper include many primary researchers in this field. In this paper, we discuss the potential, status and opportunities for microbial therapy as well as strategies attempted to date and important questions that need to be addressed. The main areas that we think will have the greatest impact are immune stimulation, control of efficacy, control of delivery, and safety. There is much excitement about the potential of this field to treat currently intractable cancer. Much of the potential exists because these therapies utilize unique mechanisms of action, difficult to achieve with other biological or small molecule drugs. By better understanding and controlling these mechanisms, we will create new therapies that will become integral components of cancer care.

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“…The IL-13.E13K ligand has been incorporated in a single-chain protein with domain 2 (D2) of PE, and a nuclear localization signal (NLS) used to precisely deliver to nuclei the portion of the engineered protein produced by a proteolytic cleavage in an endocytic compartment [ 78 , 79 , 102 ]. A doxorubicin variant was also conjugated to the C-terminal end of the engineered protein and was toxic to glioma cells.…”

Section: Interleukin 13 Receptor Alpha 2 (Il-13ra2) In Glioma Treamentioning

confidence: 99%

Receptor-Targeted Glial Brain Tumor Therapies

Sharma

Debinski

2018

IJMS

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Among primary brain tumors, malignant gliomas are notably difficult to manage. The higher-grade tumors represent an unmet need in medicine. There have been extensive efforts to implement receptor-targeted therapeutic approaches directed against gliomas. These approaches include immunotherapies, such as vaccines, adoptive immunotherapy, and passive immunotherapy. Targeted cytotoxic radio energy and pro-drug activation have been designed specifically for brain tumors. The field of targeting through receptors progressed significantly with the discovery of an interleukin 13 receptor alpha 2 (IL-13RA2) as a tumor-associated receptor over-expressed in most patients with glioblastoma (GBM) but not in normal brain. IL-13RA2 has been exploited in novel experimental therapies with very encouraging clinical responses. Other receptors are specifically over-expressed in many patients with GBM, such as EphA2 and EphA3 receptors, among others. These findings are important in view of the heterogeneity of GBM tumors and multiple tumor compartments responsible for tumor progression and resistance to therapies. The combined targeting of multiple receptors in different tumor compartments should be a preferred way to design novel receptor-targeted therapeutic approaches in gliomas.

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Novel molecular multilevel targeted antitumor agents

Cited by 11 publications

References 49 publications

Drug Conjugates for Targeting Eph Receptors in Glioblastoma

Drug Conjugates for Targeting Eph Receptors in Glioblastoma

White paper on microbial anti-cancer therapy and prevention

Receptor-Targeted Glial Brain Tumor Therapies

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