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Pharmaceuticals
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Novel Therapeutic Targets in Cancer
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Novel Therapeutic Targets in Cancer

A special issue of Pharmaceuticals (ISSN 1424-8247). This special issue belongs to the section "Pharmacology".

Deadline for manuscript submissions: closed (31 December 2021) | Viewed by 48949

Special Issue Editor

Dr. Carlo Marchetti

E-Mail Website
Guest Editor
Anschutz Medical Campus, University of Colorado Denver, Denver, CO, USA
Interests: kinase; cytotoxicity; therapy resistance; small molecule; drug delivery; cytokines; chemokine; metastasis and mitochondria
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

I would like to inform you that the Pharmaceuticals Special Issue “Novel Therapeutic Targets in Cancer” is now accepting manuscripts for publication. In recent years, significant advances have been made in the management of cancer with the introduction of targeted therapies and immunotherapy. However, there continues to be an unmet clinical need for those patients who progress while on novel therapies. Thus, the identification of new mechanisms involved in tumor progression is critical to improve survival in this population. The scope of this Special Issue is to publish translational articles with the potential to provide a rationale for new strategies in cancer treatment. Appropriate subjects include novel molecular targets, intrinsic pathways involved in tumor immune escape mechanisms, drug development, physiological and pharmacological bases of drug action, and metabolism. Contributions to this issue include submission of original articles, review, short communications, and editorials.

Dr. Carlo Marchetti
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. Pharmaceuticals is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2900 CHF (Swiss Francs). 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

  • kinase
  • cytotoxicity
  • therapy resistance
  • small molecule
  • drug delivery
  • cytokines
  • chemokine
  • metastasis and mitochondria

Published Papers (14 papers)

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Research

Jump to: Review

13 pages, 1548 KiB  
Article
Activation of Host-NLRP3 Inflammasome in Myeloid Cells Dictates Response to Anti-PD-1 Therapy in Metastatic Breast Cancers
by Isak W. Tengesdal, Suzhao Li, Nicholas E. Powers, Makenna May, Charles P. Neff, Leo A. B. Joosten, Carlo Marchetti and Charles A. Dinarello
Pharmaceuticals 2022, 15(5), 574; https://0-doi-org.brum.beds.ac.uk/10.3390/ph15050574 - 04 May 2022
Cited by 11 | Viewed by 3160
Abstract
Tumor-associated inflammation leads to dysregulated cytokine production that promotes tumor immune evasion and anti-tumor immunity dysfunction. In advanced stage breast cancer, the proinflammatory cytokine IL-1β is overexpressed due to large proportions of activated myeloid cells in the tumor microenvironment (TME). Here, we demonstrate [...] Read more.
Tumor-associated inflammation leads to dysregulated cytokine production that promotes tumor immune evasion and anti-tumor immunity dysfunction. In advanced stage breast cancer, the proinflammatory cytokine IL-1β is overexpressed due to large proportions of activated myeloid cells in the tumor microenvironment (TME). Here, we demonstrate the role of the host nucleotide-binding domain, leucine-rich containing family, pyrin domain-containing 3 (NLRP3) inflammasome in metastatic breast cancer. In vitro, we show that stimulation of THP-1 cells with conditioned media collected from MDA-MB-468 cells induced NLRP3 activation and increased Pdcd1l1 expression. In vivo, mice deficient in NLRP3 orthotopically implanted with metastatic breast cancer cell line (E0771) showed significant reduction in tumor growth (p < 0.05) and increased survival (p < 0.01). Inhibition of NLRP3 with the small molecule OLT1177® reduced expression of Pdcd1l1 (p < 0.001), Casp1 (p < 0.01) and Il1b (p < 0.01) in primary tumors. Furthermore, tumor-bearing mice receiving OLT1177® showed reduced infiltration of myeloid-derived suppressor cells (MDSCs) (p < 0.001) and increased CD8+ T cells (p < 0.05) and NK cells (p < 0.05) in the TME. NLRP3 inhibition in addition to anti-PD-1 treatment significantly reduced tumor growth from the monotherapies (p < 0.05). These data define NLRP3 activation as a key driver of immune suppression in metastatic breast cancers. Furthermore, this study suggests NLRP3 as a valid target to increase efficacy of immunotherapy with checkpoint inhibitor in metastatic breast cancers. Full article
(This article belongs to the Special Issue Novel Therapeutic Targets in Cancer)
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16 pages, 3733 KiB  
Article
A Humanized Monoclonal Antibody Targeting Extracellular Nicotinamide Phosphoribosyltransferase Prevents Aggressive Prostate Cancer Progression
by Belinda L. Sun, Lin Tang, Xiaoguang Sun, Alexander N. Garcia, Sara M. Camp, Edwin Posadas, Anne E. Cress and Joe G. N. Garcia
Pharmaceuticals 2021, 14(12), 1322; https://0-doi-org.brum.beds.ac.uk/10.3390/ph14121322 - 17 Dec 2021
Cited by 12 | Viewed by 2886
Abstract
Prostate cancer (PCa) is the major cause of cancer-related death in males; however, effective treatments to prevent aggressive progression remain an unmet need. We have previously demonstrated that secreted extracellular nicotinamide phosphoribosyltransferase (eNAMPT) is a multifunctional innate immunity regulator that promotes PCa invasion. [...] Read more.
Prostate cancer (PCa) is the major cause of cancer-related death in males; however, effective treatments to prevent aggressive progression remain an unmet need. We have previously demonstrated that secreted extracellular nicotinamide phosphoribosyltransferase (eNAMPT) is a multifunctional innate immunity regulator that promotes PCa invasion. In the current study, we further investigate the therapeutic effects of an eNAMPT-neutralizing humanized monoclonal antibody (ALT-100 mAb) in preclinical PCa orthotopic xenograft models. We utilized human aggressive PCa cells (DU145 or PC3) for prostate implantation in SCID mice receiving weekly intraperitoneal injections of either ALT-100 mAb or IgG/PBS (control) for 12 weeks. Prostatic tumors and solid organs were examined for tumor growth, invasion, and metastasis and for biochemical and immunohistochemistry evidence of NFκB activation. ALT-100 mAb treatment significantly improved overall survival of SCID mice implanted with human PCa orthotopic prostate xenografts while inducing tumor necrosis, decreasing PCa proliferation and reducing local invasion and distal metastases. The ALT-100 mAb inhibits NFκB phosphorylation and signaling in PCa cells both in vitro and in vivo. This study demonstrates that eNAMPT neutralization effectively prevents human PCa aggressive progression in preclinical models, indicating its high potential to directly address the unmet need for an effective targeted therapy for patients with aggressive PCa. Full article
(This article belongs to the Special Issue Novel Therapeutic Targets in Cancer)
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14 pages, 2990 KiB  
Article
A Novel Regimen for Treating Melanoma: MCL1 Inhibitors and Azacitidine
by Chiara R. Dart, Nabanita Mukherjee, Carol M. Amato, Anabel Goulding, Morgan MacBeth, Robert Van Gulick, Kasey L. Couts, James R. Lambert, David A. Norris, William A. Robinson and Yiqun G. Shellman
Pharmaceuticals 2021, 14(8), 749; https://0-doi-org.brum.beds.ac.uk/10.3390/ph14080749 - 30 Jul 2021
Cited by 2 | Viewed by 2224
Abstract
Although treatment options for melanoma patients have expanded in recent years with the approval of immunotherapy and targeted therapy, there is still an unmet need for new treatment options for patients that are ineligible for, or resistant to these therapies. BH3 mimetics, drugs [...] Read more.
Although treatment options for melanoma patients have expanded in recent years with the approval of immunotherapy and targeted therapy, there is still an unmet need for new treatment options for patients that are ineligible for, or resistant to these therapies. BH3 mimetics, drugs that mimic the activity of pro-apoptotic BCL2 family proteins, have recently achieved remarkable success in the clinical setting. The combination of BH3 mimetic ABT-199 (venetoclax) plus azacitidine has shown substantial benefit in treating acute myelogenous leukemia. We evaluated the efficacy of various combinations of BH3 mimetic + azacitidine in fourteen human melanoma cell lines from cutaneous, mucosal, acral and uveal subtypes. Using a combination of cell viability assay, BCL2 family knockdown cell lines, live cell imaging, and sphere formation assay, we found that combining inhibition of MCL1, an anti-apoptotic BCL2 protein, with azacitidine had substantial pro-apoptotic effects in multiple melanoma cell lines. Specifically, this combination reduced cell viability, proliferation, sphere formation, and induced apoptosis. In addition, this combination is highly effective at reducing cell viability in rare mucosal and uveal subtypes. Overall, our data suggest this combination as a promising therapeutic option for some patients with melanoma and should be further explored in clinical trials. Full article
(This article belongs to the Special Issue Novel Therapeutic Targets in Cancer)
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14 pages, 5011 KiB  
Article
Protective Effects of Irbesartan, an Angiotensin Receptor Blocker with PPARγ Agonistic Activity, against Estradiol Benzoate-Induced Endometrial Hyperplasia and Atypia in Female Rats via Modulation of TNFα/Survivin Pathway
by Mohamed A. Morsy, Wedad M. Abdelraheem, Maram El-Hussieny and Marwa M. M. Refaie
Pharmaceuticals 2021, 14(7), 649; https://0-doi-org.brum.beds.ac.uk/10.3390/ph14070649 - 06 Jul 2021
Cited by 4 | Viewed by 2246
Abstract
Endometrial hyperplasia (EH) is a common gynecological problem and may progress to carcinoma. Early detection and management of EH are mandatory for the prevention of endometrial cancer. Activation of the renin–angiotensin system and angiotensin II signaling are involved in the progression of precancerous [...] Read more.
Endometrial hyperplasia (EH) is a common gynecological problem and may progress to carcinoma. Early detection and management of EH are mandatory for the prevention of endometrial cancer. Activation of the renin–angiotensin system and angiotensin II signaling are involved in the progression of precancerous and cancerous lesions. However, no studies have evaluated the role of this system in estradiol benzoate (EB)-induced EH and atypia. Irbesartan (IRB), an angiotensin II receptor blocker with peroxisome proliferator-activated receptor gamma (PPARγ) agonistic activity was administered (30 mg/kg/d) in EB-treated (60 µg/100 g bodyweight, intramuscularly, three times per week) or untreated rats for 4 weeks. Uterine weight changes, malondialdehyde, superoxide dismutase (SOD), tumor necrosis factor-alpha (TNFα), survivin, cleaved caspase 3, interleukin-10 (IL10), and PPARγ were measured in addition to undergoing histopathological examination. Results showed that EB-induced EH and atypia significantly increased the uterine body weight, malondialdehyde, TNFα, and survivin, accompanied with significantly decreased SOD, cleaved caspase 3, IL10, and PPARγ, with typical histopathological changes of EH and atypia. Coadministration of IRB significantly prevented EB-induced biochemical and histopathological changes. The protective effects of IRB may be attributed to its anti-inflammatory and antioxidant properties, reduction of survivin, and increased levels of cleaved caspase 3. Full article
(This article belongs to the Special Issue Novel Therapeutic Targets in Cancer)
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12 pages, 2923 KiB  
Article
Discovery and Characterization of a Novel MASTL Inhibitor MKI-2 Targeting MASTL-PP2A in Breast Cancer Cells and Oocytes
by Minsung Kang, Chijung Kim, Jiyeon Leem, Ye-hyun Kim, Young-ju Kwon, Yi Na Yoon, Chong Hak Chae, Jiyeon Ahn, Kwan-Young Jung, Jeong Su Oh and Jae-Sung Kim
Pharmaceuticals 2021, 14(7), 647; https://doi.org/10.3390/ph14070647 - 05 Jul 2021
Cited by 5 | Viewed by 3768
Abstract
Although microtubule-associated serine/threonine kinase-like (MASTL) is a promising target for selective anticancer treatment, MASTL inhibitors with nano range potency and antitumor efficacy have not been reported. Here, we report a novel potent and selective MASTL inhibitor MASTL kinase inhibitor-2 (MKI-2) identified in silico [...] Read more.
Although microtubule-associated serine/threonine kinase-like (MASTL) is a promising target for selective anticancer treatment, MASTL inhibitors with nano range potency and antitumor efficacy have not been reported. Here, we report a novel potent and selective MASTL inhibitor MASTL kinase inhibitor-2 (MKI-2) identified in silico through a drug discovery program. Our data showed that MKI-2 inhibited recombinant MASTL activity and cellular MASTL activity with IC50 values of 37.44 nM and 142.7 nM, respectively, in breast cancer cells. In addition, MKI-2 inhibited MASTL kinase rather than other AGC kinases, such as ROCK1, AKT1, PKACα, and p70S6K. Furthermore, MKI-2 exerted various antitumor activities by inducing mitotic catastrophe resulting from the modulation of the MASTL-PP2A axis in breast cancer cells. The MKI-2 treatment showed phenocopies with MASTL-null oocyte in mouse oocytes, which were used as a model to validate MKI-2 activity. Therefore, our study provided a new potent and selective MASTL inhibitor MKI-2 targeting the oncogenic MAST-PP2A axis in breast cancer cells. Full article
(This article belongs to the Special Issue Novel Therapeutic Targets in Cancer)
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15 pages, 2786 KiB  
Article
NLRP1 Functions Downstream of the MAPK/ERK Signaling via ATF4 and Contributes to Acquired Targeted Therapy Resistance in Human Metastatic Melanoma
by Zili Zhai, Prasanna K. Vaddi, Jenny Mae Samson, Tomoya Takegami and Mayumi Fujita
Pharmaceuticals 2021, 14(1), 23; https://0-doi-org.brum.beds.ac.uk/10.3390/ph14010023 - 30 Dec 2020
Cited by 5 | Viewed by 2731
Abstract
The BRAF V600E mutation leads to constitutive activation of the mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) pathway and its downstream effector responses. Uncovering the hidden downstream effectors can aid in understanding melanoma biology and improve targeted therapy efficacy. The inflammasome sensor, NACHT, [...] Read more.
The BRAF V600E mutation leads to constitutive activation of the mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) pathway and its downstream effector responses. Uncovering the hidden downstream effectors can aid in understanding melanoma biology and improve targeted therapy efficacy. The inflammasome sensor, NACHT, LRR, and PYD domains-containing protein 1 (NLRP1), is responsible for IL-1β maturation and itself is a melanoma tumor promoter. Here, we report that NLRP1 is a downstream effector of MAPK/ERK signaling through the activating transcription factor 4 (ATF4), creating regulation in metastatic melanoma cells. We confirmed that the NLRP1 gene is a target of ATF4. Interestingly, ATF4/NLRP1 regulation by the MAPK/ERK pathway uses distinct mechanisms in melanoma cells before and after the acquired resistance to targeted therapy. In parental cells, ATF4/NLRP1 is regulated by the MAPK/ERK pathway through the ribosomal S6 kinase 2 (RSK2). However, vemurafenib (VEM) and trametinib (TRA)-resistant cells lose the signaling via RSK2 and activate the cAMP/protein kinase A (PKA) pathway to redirect ATF4/NLRP1. Therefore, NLRP1 expression and IL-1β secretion were downregulated in response to VEM and TRA in parental cells but enhanced in drug-resistant cells. Lastly, silencing NLRP1 in drug-resistant cells reduced their cell growth and inhibited colony formation. In summary, we demonstrated that NLRP1 functions downstream of the MAPK/ERK signaling via ATF4 and is a player of targeted therapy resistance in melanoma. Targeting NLRP1 may improve the therapeutic efficacy of targeted therapy in melanoma. Full article
(This article belongs to the Special Issue Novel Therapeutic Targets in Cancer)
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18 pages, 5130 KiB  
Article
Novel mTORC1 Inhibitors Kill Glioblastoma Stem Cells
by Jose A. Sandoval, Alexey Tomilov, Sandipan Datta, Sonia Allen, Robert O’Donnell, Thomas Sears, Kevin Woolard, Dmytro Kovalskyy, James M. Angelastro and Gino Cortopassi
Pharmaceuticals 2020, 13(12), 419; https://0-doi-org.brum.beds.ac.uk/10.3390/ph13120419 - 24 Nov 2020
Cited by 6 | Viewed by 2666
Abstract
Glioblastoma (GBM) is an aggressive tumor of the brain, with an average post-diagnosis survival of 15 months. GBM stem cells (GBMSC) resist the standard-of-care therapy, temozolomide, and are considered a major contributor to tumor resistance. Mammalian target of rapamycin Complex 1 (mTORC1) regulates [...] Read more.
Glioblastoma (GBM) is an aggressive tumor of the brain, with an average post-diagnosis survival of 15 months. GBM stem cells (GBMSC) resist the standard-of-care therapy, temozolomide, and are considered a major contributor to tumor resistance. Mammalian target of rapamycin Complex 1 (mTORC1) regulates cell proliferation and has been shown by others to have reduced activity in GBMSC. We recently identified a novel chemical series of human-safe piperazine-based brain-penetrant mTORC1-specific inhibitors. We assayed the piperazine-mTOR binding strength by two biophysical measurements, biolayer interferometry and field-effect biosensing, and these confirmed each other and demonstrated a structure–activity relationship. As mTORC1 is altered in human GBMSC, and as mTORC1 inhibitors have been tested in previous GBM clinical trials, we tested the killing potency of the tightest-binding piperazines and observed that these were potent GBMSC killers. GBMSCs are resistant to the standard-of-care temozolomide therapy, but temozolomide supplemented with tight-binding piperazine meclizine and flunarizine greatly enhanced GBMSC death over temozolomide alone. Lastly, we investigated IDH1-mutated GBMSC mutations that are known to affect mitochondrial and mTORC1 metabolism, and the tight-binding meclizine provoked ‘synthetic lethality’ in IDH1-mutant GBMSCs. In other words, IDH1-mutated GBMSC showed greater sensitivity to the coadministration of temozolomide and meclizine. These data tend to support a novel clinical strategy for GBM, i.e., the co-administration of meclizine or flunarizine as adjuvant therapy in the treatment of GBM and IDH1-mutant GBM. Full article
(This article belongs to the Special Issue Novel Therapeutic Targets in Cancer)
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14 pages, 2624 KiB  
Article
Development of a High-throughput Agar Colony Formation Assay to Identify Drug Candidates against Medulloblastoma
by Mohammed Sedeeq, Ahmed Maklad, Nuri Gueven and Iman Azimi
Pharmaceuticals 2020, 13(11), 368; https://0-doi-org.brum.beds.ac.uk/10.3390/ph13110368 - 05 Nov 2020
Cited by 5 | Viewed by 2989
Abstract
Medulloblastoma (MB) is the most common malignant childhood brain cancer. High-risk MB tumours have a high incidence of metastasis and result in poor patient survival. Drug screens, commonly used to identify potential novel therapeutic agents against MB, focus on 2D cell proliferation and [...] Read more.
Medulloblastoma (MB) is the most common malignant childhood brain cancer. High-risk MB tumours have a high incidence of metastasis and result in poor patient survival. Drug screens, commonly used to identify potential novel therapeutic agents against MB, focus on 2D cell proliferation and viability assays given that these assays are easily adaptable to high-throughput regimes. However, 2D models fail to address invasive characteristics that are crucial to MB metastasis and are thus not representative of tumour growth in vivo. In this study, we developed a 3D 384-well agar colony formation assay using MB cells of molecular subgroup 3 that is associated with the highest level of metastasis. Two fluorescence substrates, resazurin and glycyl-phenylalanyl-aminofluorocoumarin (GF-AFC) that measure cell viability via distinct mechanisms were used to assess the growth of MB cells in the agar matrix. The assay was optimised for seeding density, growth period, substrate incubation time and homogeneity of the fluorescent signals within individual wells. Our data demonstrate the feasibility to multiplex the two fluorescent substrates without detectable signal interference. This assay was validated by assessing the concentration-dependent effect of two commonly used chemotherapeutic agents clinically used for MB treatment, vincristine and lomustine. Subsequently, a panel of plasma membrane calcium channel modulators was screened for their effect on the 3D growth of D341 MB cells, which identified modulators of T-type voltage gated and ORAI calcium channels as selective growth modulators. Overall, this 3D assay provides a reproducible, time and cost-effective assay for high-throughput screening to identify potential drugs against MB. Full article
(This article belongs to the Special Issue Novel Therapeutic Targets in Cancer)
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12 pages, 1992 KiB  
Article
Anticancer Activity of Amb4269951, a Choline Transporter-Like Protein 1 Inhibitor, in Human Glioma Cells
by Saiichiro Watanabe, Nozomi Nishijima, Kaho Hirai, Kaoru Shibata, Akane Hase, Tsuyoshi Yamanaka and Masato Inazu
Pharmaceuticals 2020, 13(5), 104; https://0-doi-org.brum.beds.ac.uk/10.3390/ph13050104 - 25 May 2020
Cited by 12 | Viewed by 3492
Abstract
Choline transporter-like protein 1 (CTL1) is highly expressed in glioma cells, and inhibition of CTL1 function induces apoptotic cell death. Therefore, CTL1 is a potential target molecule for glioma therapy. Here, we investigated the therapeutic mechanism underlying the antitumor effects of Amb4269951, a [...] Read more.
Choline transporter-like protein 1 (CTL1) is highly expressed in glioma cells, and inhibition of CTL1 function induces apoptotic cell death. Therefore, CTL1 is a potential target molecule for glioma therapy. Here, we investigated the therapeutic mechanism underlying the antitumor effects of Amb4269951, a recently discovered novel CTL1 inhibitor, in the human glioma cell line U251MG, and evaluated its in vivo effects in a mouse xenograft model. Amb4269951 inhibited choline uptake and cell viability and increased caspase-3/7 activity. CTL1-mediated choline uptake is associated with cell viability, and the functional inhibition of CTL1 by Amb4269951 may promote apoptotic cell death via ceramide-induced suppression of the expression of survivin, an apoptotic inhibitory factor. Finally, Amb4269951 demonstrated an antitumor effect in a mice xenograft model by significantly inhibiting tumor growth without any weight loss. Amb4269951 is the lead compound in the treatment of glioma and exhibits a novel therapeutic mechanism. These results may lead to the development of novel anticancer drugs targeting the choline transporter CTL1, which has a different mechanism of action than conventional anticancer drugs against gliomas. Full article
(This article belongs to the Special Issue Novel Therapeutic Targets in Cancer)
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Review

Jump to: Research

15 pages, 1763 KiB  
Review
Implications of Antigen Selection on T Cell-Based Immunotherapy
by Faye A. Camp and Jill E. Slansky
Pharmaceuticals 2021, 14(10), 993; https://0-doi-org.brum.beds.ac.uk/10.3390/ph14100993 - 29 Sep 2021
Cited by 6 | Viewed by 2413
Abstract
Many immunotherapies rely on CD8+ effector T cells to recognize and kill cognate tumor cells. These T cell-based immunotherapies include adoptive cell therapy, such as CAR T cells or transgenic TCR T cells, and anti-cancer vaccines which expand endogenous T cell populations. Tumor [...] Read more.
Many immunotherapies rely on CD8+ effector T cells to recognize and kill cognate tumor cells. These T cell-based immunotherapies include adoptive cell therapy, such as CAR T cells or transgenic TCR T cells, and anti-cancer vaccines which expand endogenous T cell populations. Tumor mutation burden and the choice of antigen are among the most important aspects of T cell-based immunotherapies. Here, we highlight various classes of cancer antigens, including self, neojunction-derived, human endogenous retrovirus (HERV)-derived, and somatic nucleotide variant (SNV)-derived antigens, and consider their utility in T cell-based immunotherapies. We further discuss the respective anti-tumor/anti-self-properties that influence both the degree of immunotolerance and potential off-target effects associated with each antigen class. Full article
(This article belongs to the Special Issue Novel Therapeutic Targets in Cancer)
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18 pages, 1451 KiB  
Review
Dickkopf Proteins and Their Role in Cancer: A Family of Wnt Antagonists with a Dual Role
by Irina Giralt, Gabriel Gallo-Oller, Natalia Navarro, Patricia Zarzosa, Guillem Pons, Ainara Magdaleno, Miguel F. Segura, José Sánchez de Toledo, Lucas Moreno, Soledad Gallego and Josep Roma
Pharmaceuticals 2021, 14(8), 810; https://0-doi-org.brum.beds.ac.uk/10.3390/ph14080810 - 18 Aug 2021
Cited by 12 | Viewed by 3648
Abstract
The Wnt signaling pathway regulates crucial aspects such as cell fate determination, cell polarity and organogenesis during embryonic development. Wnt pathway deregulation is a hallmark of several cancers such as lung, gastric and liver cancer, and has been reported to be altered in [...] Read more.
The Wnt signaling pathway regulates crucial aspects such as cell fate determination, cell polarity and organogenesis during embryonic development. Wnt pathway deregulation is a hallmark of several cancers such as lung, gastric and liver cancer, and has been reported to be altered in others. Despite the general agreement reached by the scientific community on the oncogenic potential of the central components of the pathway, the role of the antagonist proteins remains less clear. Deregulation of the pathway may be caused by overexpression or downregulation of a wide range of antagonist proteins. Although there is growing information related to function and regulation of Dickkopf (DKK) proteins, their pharmacological potential as cancer therapeutics still has not been fully developed. This review provides an update on the role of DKK proteins in cancer and possible potential as therapeutic targets for the treatment of cancer; available compounds in pre-clinical or clinical trials are also reviewed. Full article
(This article belongs to the Special Issue Novel Therapeutic Targets in Cancer)
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24 pages, 1610 KiB  
Review
Kynurenines as a Novel Target for the Treatment of Malignancies
by Adrian Mor, Anna Tankiewicz-Kwedlo and Dariusz Pawlak
Pharmaceuticals 2021, 14(7), 606; https://0-doi-org.brum.beds.ac.uk/10.3390/ph14070606 - 23 Jun 2021
Cited by 17 | Viewed by 3594
Abstract
Malignancies are unquestionably a significant public health problem. Their effective treatment is still a big challenge for modern medicine. Tumors have developed a wide range of mechanisms to evade an immune and therapeutic response. As a result, there is an unmet clinical need [...] Read more.
Malignancies are unquestionably a significant public health problem. Their effective treatment is still a big challenge for modern medicine. Tumors have developed a wide range of mechanisms to evade an immune and therapeutic response. As a result, there is an unmet clinical need for research on solutions aimed at overcoming this problem. An accumulation of tryptophan metabolites belonging to the kynurenine pathway can enhance neoplastic progression because it causes the suppression of immune system response against cancer cells. They are also involved in the development of the mechanisms responsible for the resistance to antitumor therapy. Kynurenine belongs to the most potent immunosuppressive metabolites of this pathway and has a significant impact on the development of malignancies. This fact prompted researchers to assess whether targeting the enzymes responsible for its synthesis could be an effective therapeutic strategy for various cancers. To date, numerous studies, both preclinical and clinical, have been conducted on this topic, especially regarding the inhibition of indoleamine 2,3-dioxygenase activity and their results can be considered noteworthy. This review gathers and systematizes the knowledge about the role of the kynurenine pathway in neoplastic progression and the findings regarding the usefulness of modulating its activity in anticancer therapy. Full article
(This article belongs to the Special Issue Novel Therapeutic Targets in Cancer)
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16 pages, 826 KiB  
Review
Targeting the Copper Transport System to Improve Treatment Efficacies of Platinum-Containing Drugs in Cancer Chemotherapy
by Macus Tien Kuo, Yu-Fang Huang, Cheng-Yang Chou and Helen H. W. Chen
Pharmaceuticals 2021, 14(6), 549; https://0-doi-org.brum.beds.ac.uk/10.3390/ph14060549 - 08 Jun 2021
Cited by 17 | Viewed by 3749
Abstract
The platinum (Pt)-containing antitumor drugs including cisplatin (cis-diamminedichloroplatinum II, cDDP), carboplatin, and oxaliplatin, have been the mainstay of cancer chemotherapy. These drugs are effective in treating many human malignancies. The major cell-killing target of Pt drugs is DNA. Recent findings underscored the important [...] Read more.
The platinum (Pt)-containing antitumor drugs including cisplatin (cis-diamminedichloroplatinum II, cDDP), carboplatin, and oxaliplatin, have been the mainstay of cancer chemotherapy. These drugs are effective in treating many human malignancies. The major cell-killing target of Pt drugs is DNA. Recent findings underscored the important roles of Pt drug transport system in cancer therapy. While many mechanisms have been proposed for Pt-drug transport, the high-affinity copper transporter (hCtr1), Cu chaperone (Atox1), and Cu exporters (ATP7A and ATP7B) are also involved in cDDP transport, highlighting Cu homeostasis regulation in Pt-based cancer therapy. It was demonstrated that by reducing cellular Cu bioavailable levels by Cu chelators, hCtr1 is transcriptionally upregulated by transcription factor Sp1, which binds the promoters of Sp1 and hCtr1. In contrast, elevated Cu poisons Sp1, resulting in suppression of hCtr1 and Sp1, constituting the Cu-Sp1-hCtr1 mutually regulatory loop. Clinical investigations using copper chelator (trientine) in carboplatin treatment have been conducted for overcoming Pt drug resistance due in part to defective transport. While results are encouraging, future development may include targeting multiple steps in Cu transport system for improving the efficacies of Pt-based cancer chemotherapy. The focus of this review is to delineate the mechanistic interrelationships between Cu homeostasis regulation and antitumor efficacy of Pt drugs. Full article
(This article belongs to the Special Issue Novel Therapeutic Targets in Cancer)
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17 pages, 1056 KiB  
Review
Targeting Loss of Heterozygosity: A Novel Paradigm for Cancer Therapy
by Xiaonan Zhang and Tobias Sjöblom
Pharmaceuticals 2021, 14(1), 57; https://0-doi-org.brum.beds.ac.uk/10.3390/ph14010057 - 13 Jan 2021
Cited by 20 | Viewed by 7580
Abstract
Loss of heterozygosity (LOH) is a common genetic event in the development of cancer. In certain tumor types, LOH can affect more than 20% of the genome, entailing loss of allelic variation in thousands of genes. This reduction of heterozygosity creates genetic differences [...] Read more.
Loss of heterozygosity (LOH) is a common genetic event in the development of cancer. In certain tumor types, LOH can affect more than 20% of the genome, entailing loss of allelic variation in thousands of genes. This reduction of heterozygosity creates genetic differences between tumor and normal cells, providing opportunities for development of novel cancer therapies. Here, we review and summarize (1) mutations associated with LOH on chromosomes which have been shown to be promising biomarkers of cancer risk or the prediction of clinical outcomes in certain types of tumors; (2) loci undergoing LOH that can be targeted for development of novel anticancer drugs as well as (3) LOH in tumors provides up-and-coming possibilities to understand the underlying mechanisms of cancer evolution and to discover novel cancer vulnerabilities which are worth a further investigation in the near future. Full article
(This article belongs to the Special Issue Novel Therapeutic Targets in Cancer)
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