ijms-logo

Journal Browser

Journal Browser

Receptor-Targeted Cancer Therapy

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: closed (30 September 2018) | Viewed by 86251

Special Issue Editor

Department of Radiation Oncology, University of Alabama at Birmingham, Birmingham, AL 35294, USA
Interests: cancer immunotherapy; radioimmunotherapy; monoclonal antibody therapy; targeting cancer stem cells; TRAIL-DR5 therapy; Wnt/β-catenin inhibitors
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

There has been considerable recent research progress in receptor-targeted cancer therapy. This Special Issue is focused on summarizing the various approaches under investigation which include targeting of growth factor receptors, hormonal receptors, chemokine receptors, tumor necrosis factor family of receptors, cluster of differentiation antigens, chimeric antigen receptors, and checkpoint inhibitor antigens with monoclonal antibodies, antibody drug conjugates, peptides, viral vectors, nanoparticles, and immune cells.

This Special Issue will cover a series of papers that will provide a state-of-the-art summary of the advances ongoing in targeted cancer therapy. All manuscripts will undergo a rigorous review by experts in the field and the guest editor. Original papers and review articles are welcomed. All accepted papers will be immediately published and gathered together on the website.

Prof. Dr. Donald J. Buchsbaum
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • targeted cancer therapy

  • antibody drug conjugate therapy

  • molecular targets

  • molecularly targeted drugs

  • molecularly targeted therapies

  • monoclonal antibodies

  • receptor-targeting

Published Papers (10 papers)

Order results
Result details
Select all
Export citation of selected articles as:

Research

Jump to: Review

29 pages, 16105 KiB  
Article
Cytotoxicity of Selenium Immunoconjugates against Triple Negative Breast Cancer Cells
by Soni Khandelwal, Mallory Boylan, Julian E. Spallholz and Lauren Gollahon
Int. J. Mol. Sci. 2018, 19(11), 3352; https://doi.org/10.3390/ijms19113352 - 26 Oct 2018
Cited by 12 | Viewed by 5334
Abstract
Within the subtypes of breast cancer, those identified as triple negative for expression of estrogen receptor α (ESR1), progesterone receptor (PR) and human epidermal growth factor 2 (HER2), account for 10–20% of breast cancers, yet result in 30% of global breast cancer-associated deaths. [...] Read more.
Within the subtypes of breast cancer, those identified as triple negative for expression of estrogen receptor α (ESR1), progesterone receptor (PR) and human epidermal growth factor 2 (HER2), account for 10–20% of breast cancers, yet result in 30% of global breast cancer-associated deaths. Thus, it is critical to develop more targeted and efficacious therapies that also demonstrate less side effects. Selenium, an essential dietary supplement, is incorporated as selenocysteine (Sec) in vivo into human selenoproteins, some of which exist as anti-oxidant enzymes and are of importance to human health. Studies have also shown that selenium compounds hinder cancer cell growth and induce apoptosis in cancer cell culture models. The focus of this study was to investigate whether selenium-antibody conjugates could be effective against triple negative breast cancer cell lines using clinically relevant, antibody therapies targeted for high expressing breast cancers and whether selenium cytotoxicity was attenuated in normal breast epithelial cells. To that end, the humanized monoclonal IgG1 antibodies, Bevacizumab and Trastuzumab were conjugated with redox selenium to form Selenobevacizumab and Selenotrastuzumab and tested against the triple negative breast cancer (TNBC) cell lines MDA-MB-468 and MDA-MB-231 as well as a normal, immortalized, human mammary epithelial cell line, HME50-5E. VEGF and HER2 protein expression were assessed by Western. Although expression levels of HER2 were low or absent in all test cells, our results showed that Selenobevacizumab and Selenotrastuzumab produced superoxide (O2•−) anions in the presence of glutathione (GSH) and this was confirmed by a dihydroethidium (DHE) assay. Interestingly, superoxide was not elevated within HME50-5E cells assessed by DHE. The cytotoxicity of selenite and the selenium immunoconjugates towards triple negative cells compared to HME-50E cells was performed in a time and dose-dependent manner as measured by Trypan Blue exclusion, MTT assay and Annexin V assays. Selenobevacizumab and Selenotrastuzumab were shown to arrest the cancer cell growth but not the HME50-5E cells. These results suggest that selenium-induced toxicity may be effective in treating TNBC cells by exploiting different immunotherapeutic approaches potentially reducing the debilitating side effects associated with current TNBC anticancer drugs. Thus, clinically relevant, targeting antibody therapies may be repurposed for TNBC treatment by attachment of redox selenium. Full article
(This article belongs to the Special Issue Receptor-Targeted Cancer Therapy)
Show Figures

Graphical abstract

7 pages, 1350 KiB  
Communication
Identification of an Actionable Mutation of KIT in a Case of Extraskeletal Myxoid Chondrosarcoma
by Milena Urbini, Valentina Indio, Annalisa Astolfi, Giuseppe Tarantino, Salvatore Lorenzo Renne, Silvana Pilotti, Angelo Paolo Dei Tos, Roberta Maestro, Paola Collini, Margherita Nannini, Maristella Saponara, Ludovica Murrone, Gian Paolo Dagrada, Chiara Colombo, Alessandro Gronchi, Andrea Pession, Paolo Giovanni Casali, Silvia Stacchiotti and Maria Abbondanza Pantaleo
Int. J. Mol. Sci. 2018, 19(7), 1855; https://doi.org/10.3390/ijms19071855 - 23 Jun 2018
Cited by 4 | Viewed by 4427
Abstract
Extraskeletal myxoid chondrosarcoma (EMC) is an extremely rare soft tissue sarcoma, marked by a translocation involving the NR4A3 gene. EMC is usually indolent and moderately sensitive to anthracycline-based chemotherapy. Recently, we reported on the therapeutic activity of sunitinib in a series of EMC [...] Read more.
Extraskeletal myxoid chondrosarcoma (EMC) is an extremely rare soft tissue sarcoma, marked by a translocation involving the NR4A3 gene. EMC is usually indolent and moderately sensitive to anthracycline-based chemotherapy. Recently, we reported on the therapeutic activity of sunitinib in a series of EMC cases, however the molecular target of sunitinib in EMC is unknown. Moreover, there is still the need to identify alternative therapeutic strategies. To better characterize this disease, we performed whole transcriptome sequencing in five EMC cases. Peculiarly, in one sample, an in-frame deletion (c.1735_1737delGAT p.D579del) was identified in exon 11 of KIT. The deletion was somatic and heterozygous and was validated both at DNA and mRNA level. This sample showed a marked high expression of KIT at the mRNA level and a mild phosphorylation of the receptor. Sanger sequencing of KIT in additional 15 Formalin Fixed Paraffin Embedded (FFPE) EMC did not show any other mutated cases. In conclusion, exon 11 KIT mutation was detected only in one out of 20 EMC cases analyzed, indicating that KIT alteration is not a recurrent event in these tumors and cannot explain the EMC sensitivity to sunitinib, although it is an actionable mutation in the individual case in which it has been identified. Full article
(This article belongs to the Special Issue Receptor-Targeted Cancer Therapy)
Show Figures

Graphical abstract

17 pages, 4794 KiB  
Article
Preferential Inhibition of Wnt/β-Catenin Signaling by Novel Benzimidazole Compounds in Triple-Negative Breast Cancer
by Abhishek Gangrade, Vibha Pathak, Corinne E. Augelli-Szafran, Han-Xun Wei, Patsy Oliver, Mark Suto and Donald J. Buchsbaum
Int. J. Mol. Sci. 2018, 19(5), 1524; https://doi.org/10.3390/ijms19051524 - 20 May 2018
Cited by 33 | Viewed by 6873
Abstract
Wnt/β-catenin signaling is upregulated in triple-negative breast cancer (TNBC) compared to other breast cancer subtypes and normal tissues. Current Wnt/β-catenin inhibitors, such as niclosamide, target the pathway nonspecifically and exhibit poor pharmacokinetics/pharmacodynamics in vivo. Niclosamide targets other pathways, including mTOR, STAT3 and Notch. [...] Read more.
Wnt/β-catenin signaling is upregulated in triple-negative breast cancer (TNBC) compared to other breast cancer subtypes and normal tissues. Current Wnt/β-catenin inhibitors, such as niclosamide, target the pathway nonspecifically and exhibit poor pharmacokinetics/pharmacodynamics in vivo. Niclosamide targets other pathways, including mTOR, STAT3 and Notch. Novel benzimidazoles have been developed to inhibit Wnt/β-catenin signaling with greater specificity. The compounds SRI33576 and SRI35889 were discovered to produce more cytotoxicity in TNBC cell lines than in noncancerous cells. The agents also downregulated Wnt/β-catenin signaling mediators LRP6, cyclin D1, survivin and nuclear active β-catenin. In addition, SRI33576 did not affect mTOR, STAT3 and Notch signaling in TNBC and noncancerous cells. SRI35889 inhibited mTOR signaling less in noncancerous than in cancerous cells, while not affecting STAT3 and Notch pathways. Compounds SRI32529, SRI35357 and SRI35361 were not selectively cytotoxic against TNBC cell lines compared to MCF10A cells. While SRI32529 inhibited Wnt/β-catenin signaling, the compound also mitigated mTOR, STAT3 and Notch signaling. SRI33576 and SRI35889 were identified as cytotoxic and selective inhibitors of Wnt/β-catenin signaling with therapeutic potential to treat TNBC in vivo. Full article
(This article belongs to the Special Issue Receptor-Targeted Cancer Therapy)
Show Figures

Figure 1

16 pages, 1359 KiB  
Article
212Pb-Labeled Antibody 225.28 Targeted to Chondroitin Sulfate Proteoglycan 4 for Triple-Negative Breast Cancer Therapy in Mouse Models
by Benjamin B. Kasten, Patsy G. Oliver, Harrison Kim, Jinda Fan, Soldano Ferrone, Kurt R. Zinn and Donald J. Buchsbaum
Int. J. Mol. Sci. 2018, 19(4), 925; https://doi.org/10.3390/ijms19040925 - 21 Mar 2018
Cited by 30 | Viewed by 4697
Abstract
Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer with a poor prognosis. There is a clinical need for effective, targeted therapy strategies that destroy both differentiated TNBC cells and TNBC cancer initiating cells (CICs), as the latter are implicated in [...] Read more.
Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer with a poor prognosis. There is a clinical need for effective, targeted therapy strategies that destroy both differentiated TNBC cells and TNBC cancer initiating cells (CICs), as the latter are implicated in the metastasis and recurrence of TNBC. Chondroitin sulfate proteoglycan 4 (CSPG4) is overexpressed on differentiated tumor cells and CICs obtained from TNBC patient specimens, suggesting that CSPG4 may be a clinically relevant target for the imaging and therapy of TNBC. The purpose of this study was to determine whether α-particle radioimmunotherapy (RIT) targeting TNBC cells using the CSPG4-specific monoclonal antibody (mAb) 225.28 as a carrier was effective at eliminating TNBC tumors in preclinical models. To this end, mAb 225.28 labeled with 212Pb (212Pb-225.28) as a source of α-particles for RIT was used for in vitro Scatchard assays and clonogenic survival assays with human TNBC cells (SUM159 and 2LMP) grown as adherent cells or non-adherent CIC-enriched mammospheres. Immune-deficient mice bearing orthotopic SUM159 or 2LMP xenografts were injected i.v. with the targeted (225.28) or irrelevant isotype-matched control (F3-C25) mAbs, labeled with 99mTc, 125I, or 212Pb for in vivo imaging, biodistribution, or tumor growth inhibition studies. 212Pb-225.28 bound to adherent SUM159 and 2LMP cells and to CICs from SUM159 and 2LMP mammospheres with a mean affinity of 0.5 nM. Nearly ten times more binding sites per cell were present on SUM159 cells and CICs compared with 2LMP cells. 212Pb-225.28 was six to seven times more effective than 212Pb-F3-C25 at inhibiting SUM159 cell and CIC clonogenic survival (p < 0.05). Radiolabeled mAb 225.28 showed significantly higher uptake than radiolabeled mAb F3-C25 in SUM159 and 2LMP xenografts (p < 0.05), and the uptake of 212Pb-225.28 in TNBC xenografts was correlated with target epitope expression. 212Pb-225.28 caused dose-dependent growth inhibition of SUM159 xenografts; 0.30 MBq 212Pb-225.28 was significantly more effective than 0.33 MBq 212Pb-F3-C25 at inhibiting tumor growth (p < 0.01). These results suggest that CSPG4-specific 212Pb-225.28 is a useful reagent for RIT of CSPG4-expressing tumors, including metastatic TNBC. Full article
(This article belongs to the Special Issue Receptor-Targeted Cancer Therapy)
Show Figures

Figure 1

Review

Jump to: Research

17 pages, 371 KiB  
Review
HER2 Directed Antibody-Drug-Conjugates beyond T-DM1 in Breast Cancer
by Gabriel Rinnerthaler, Simon Peter Gampenrieder and Richard Greil
Int. J. Mol. Sci. 2019, 20(5), 1115; https://doi.org/10.3390/ijms20051115 - 05 Mar 2019
Cited by 143 | Viewed by 18394
Abstract
Since the discovery of the human epidermal growth factor receptor 2 (HER2) as an oncogenic driver in a subset of breast cancers and the development of HER2 directed therapies, the prognosis of HER2 amplified breast cancers has improved meaningfully. Next to monoclonal anti-HER2 [...] Read more.
Since the discovery of the human epidermal growth factor receptor 2 (HER2) as an oncogenic driver in a subset of breast cancers and the development of HER2 directed therapies, the prognosis of HER2 amplified breast cancers has improved meaningfully. Next to monoclonal anti-HER2 antibodies and tyrosine kinase inhibitors, the antibody-drug conjugate T-DM1 is a pillar of targeted treatment of advanced HER2-positive breast cancers. Currently, several HER2 directed antibody-drug conjugates are under clinical investigation for HER2 amplified but also HER2 expressing but not amplified breast tumors. In this article, we review the current preclinical and clinical evidence of the investigational drugs A166, ALT-P7, ARX788, DHES0815A, DS-8201a, RC48, SYD985, MEDI4276 and XMT-1522. Full article
(This article belongs to the Special Issue Receptor-Targeted Cancer Therapy)
Show Figures

Figure 1

11 pages, 667 KiB  
Review
Targeting Multiple Receptors to Increase Checkpoint Blockade Efficacy
by David J. Zahavi and Louis M. Weiner
Int. J. Mol. Sci. 2019, 20(1), 158; https://doi.org/10.3390/ijms20010158 - 04 Jan 2019
Cited by 22 | Viewed by 4933
Abstract
Immune checkpoint blockade therapy is a powerful treatment strategy for many cancer types. Many patients will have limited responses to monotherapy targeted to a single immune checkpoint. Both inhibitory and stimulatory immune checkpoints continue to be discovered. Additionally, many receptors previously identified to [...] Read more.
Immune checkpoint blockade therapy is a powerful treatment strategy for many cancer types. Many patients will have limited responses to monotherapy targeted to a single immune checkpoint. Both inhibitory and stimulatory immune checkpoints continue to be discovered. Additionally, many receptors previously identified to play a role in tumor formation and progression are being found to have immunomodulatory components. The success of immunotherapy depends on maximizing pro-anti-tumor immunity while minimizing immunosuppressive signaling. Combining immune checkpoint targeted approaches with each other or with other receptor targets is a promising schema for future therapeutic regimen designs. Full article
(This article belongs to the Special Issue Receptor-Targeted Cancer Therapy)
Show Figures

Graphical abstract

19 pages, 3175 KiB  
Review
Perturbing the Dynamics and Organization of Cell Membrane Components: A New Paradigm for Cancer-Targeted Therapies
by Nuno Bernardes and Arsenio M. Fialho
Int. J. Mol. Sci. 2018, 19(12), 3871; https://doi.org/10.3390/ijms19123871 - 04 Dec 2018
Cited by 73 | Viewed by 9442
Abstract
Cancer is a multi-process disease where different mechanisms exist in parallel to ensure cell survival and constant adaptation to the extracellular environment. To adapt rapidly, cancer cells re-arrange their plasma membranes to sustain proliferation, avoid apoptosis and resist anticancer drugs. In this review, [...] Read more.
Cancer is a multi-process disease where different mechanisms exist in parallel to ensure cell survival and constant adaptation to the extracellular environment. To adapt rapidly, cancer cells re-arrange their plasma membranes to sustain proliferation, avoid apoptosis and resist anticancer drugs. In this review, we discuss novel approaches based on the modifications and manipulations that new classes of molecules can exert in the plasma membrane lateral organization and order of cancer cells, affecting growth factor signaling, invasiveness, and drug resistance. Furthermore, we present azurin, an anticancer protein from bacterial origin, as a new approach in the development of therapeutic strategies that target the cell membrane to improve the existing standard therapies. Full article
(This article belongs to the Special Issue Receptor-Targeted Cancer Therapy)
Show Figures

Figure 1

35 pages, 723 KiB  
Review
Receptor Tyrosine Kinase-Targeted Cancer Therapy
by Toshimitsu Yamaoka, Sojiro Kusumoto, Koichi Ando, Motoi Ohba and Tohru Ohmori
Int. J. Mol. Sci. 2018, 19(11), 3491; https://doi.org/10.3390/ijms19113491 - 06 Nov 2018
Cited by 185 | Viewed by 12737
Abstract
In the past two decades, several molecular targeted inhibitors have been developed and evaluated clinically to improve the survival of patients with cancer. Molecular targeted inhibitors inhibit the activities of pathogenic tyrosine kinases. Particularly, aberrant receptor tyrosine kinase (RTK) activation is a potential [...] Read more.
In the past two decades, several molecular targeted inhibitors have been developed and evaluated clinically to improve the survival of patients with cancer. Molecular targeted inhibitors inhibit the activities of pathogenic tyrosine kinases. Particularly, aberrant receptor tyrosine kinase (RTK) activation is a potential therapeutic target. An increased understanding of genetics, cellular biology and structural biology has led to the development of numerous important therapeutics. Pathogenic RTK mutations, deletions, translocations and amplification/over-expressions have been identified and are currently being examined for their roles in cancers. Therapies targeting RTKs are categorized as small-molecule inhibitors and monoclonal antibodies. Studies are underway to explore abnormalities in 20 types of RTK subfamilies in patients with cancer or other diseases. In this review, we describe representative RTKs important for developing cancer therapeutics and predicting or evaluated resistance mechanisms. Full article
(This article belongs to the Special Issue Receptor-Targeted Cancer Therapy)
Show Figures

Graphical abstract

38 pages, 1612 KiB  
Review
Receptor-Targeted Glial Brain Tumor Therapies
by Puja Sharma and Waldemar Debinski
Int. J. Mol. Sci. 2018, 19(11), 3326; https://doi.org/10.3390/ijms19113326 - 25 Oct 2018
Cited by 33 | Viewed by 6528
Abstract
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 [...] Read more.
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. Full article
(This article belongs to the Special Issue Receptor-Targeted Cancer Therapy)
Show Figures

Graphical abstract

26 pages, 2108 KiB  
Review
Targeting Oncogenic Signaling in Mutant FLT3 Acute Myeloid Leukemia: The Path to Least Resistance
by Dilana Staudt, Heather C. Murray, Tabitha McLachlan, Frank Alvaro, Anoop K. Enjeti, Nicole M. Verrills and Matthew D. Dun
Int. J. Mol. Sci. 2018, 19(10), 3198; https://doi.org/10.3390/ijms19103198 - 16 Oct 2018
Cited by 47 | Viewed by 12170
Abstract
The identification of recurrent driver mutations in genes encoding tyrosine kinases has resulted in the development of molecularly-targeted treatment strategies designed to improve outcomes for patients diagnosed with acute myeloid leukemia (AML). The receptor tyrosine kinase FLT3 is the most commonly mutated gene [...] Read more.
The identification of recurrent driver mutations in genes encoding tyrosine kinases has resulted in the development of molecularly-targeted treatment strategies designed to improve outcomes for patients diagnosed with acute myeloid leukemia (AML). The receptor tyrosine kinase FLT3 is the most commonly mutated gene in AML, with internal tandem duplications within the juxtamembrane domain (FLT3-ITD) or missense mutations in the tyrosine kinase domain (FLT3-TKD) present in 30–35% of AML patients at diagnosis. An established driver mutation and marker of poor prognosis, the FLT3 tyrosine kinase has emerged as an attractive therapeutic target, and thus, encouraged the development of FLT3 tyrosine kinase inhibitors (TKIs). However, the therapeutic benefit of FLT3 inhibition, particularly as a monotherapy, frequently results in the development of treatment resistance and disease relapse. Commonly, FLT3 inhibitor resistance occurs by the emergence of secondary lesions in the FLT3 gene, particularly in the second tyrosine kinase domain (TKD) at residue Asp835 (D835) to form a ‘dual mutation’ (ITD-D835). Individual FLT3-ITD and FLT3-TKD mutations influence independent signaling cascades; however, little is known about which divergent signaling pathways are controlled by each of the FLT3 specific mutations, particularly in the context of patients harboring dual ITD-D835 mutations. This review provides a comprehensive analysis of the known discrete and cooperative signaling pathways deregulated by each of the FLT3 specific mutations, as well as the therapeutic approaches that hold the most promise of more durable and personalized therapeutic approaches to improve treatments of FLT3 mutant AML. Full article
(This article belongs to the Special Issue Receptor-Targeted Cancer Therapy)
Show Figures

Graphical abstract

Back to TopTop