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Promising Molecular Targeted Strategies Disrupting Tumour-Microenvironment Communication in Solid Tumours

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 (31 December 2020) | Viewed by 25276

Special Issue Editor

Department of Biomedical Sciences, Co-Leader of the DOGBONE Research Platform, Ontario Veterinary College, University of Guelph, 50 Stone Road East, Guelph, ON N1G 2W1, Canada
Interests: comparative oncology; metastasis; osteosarcoma; breast cancer; molecular-targeted therapy of solid tumors

Special Issue Information

Dear Colleagues,

The last 30 years of cancer research has greatly improved our understanding of the interplay between the cancer cell and its microenvironment, and have led to the design of therapies targeting key intrinsic and extrinsic drivers of tumor progression in cells. Some of these therapies have been approved and are currently improving the life of cancer patients. Such is the case for drugs targeting the epidermal growth factor receptor family, or those targeting the PD-1/PD-L1 immune checkpoint. In this Special Issue, we aim to present an overview of the ongoing research into promising and approved molecular targeting strategies for the treatment of solid tumors. These include strategies initially designed to target specific molecules or malignancy-associated events, but also those involving the repurposing of conventional anticancer agents or drugs intended to treat other diseases. We welcome contributions that advance our fundamental knowledge on these strategies, with particular emphasis on their feasible clinical use and capacity to improve cancer treatment outcomes.

Prof. Alicia Mercedes Viloria-Petit
Guest Editor

Manuscript Submission Information

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Keywords

  • molecular targeted therapy
  • solid tumors
  • personalized cancer medicine
  • tumor microenvironment
  • small-molecule inhibitors
  • antibodies
  • nanotechnology
  • cancer immunotherapy
  • cell signaling inhibitors
  • drug repurposing

Published Papers (6 papers)

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Review

32 pages, 783 KiB  
Review
Targeting Intercellular Communication in the Bone Microenvironment to Prevent Disseminated Tumor Cell Escape from Dormancy and Bone Metastatic Tumor Growth
by Lauren M. Kreps and Christina L. Addison
Int. J. Mol. Sci. 2021, 22(6), 2911; https://doi.org/10.3390/ijms22062911 - 13 Mar 2021
Cited by 4 | Viewed by 3618
Abstract
Metastasis to the bone is a common feature of many cancers including those of the breast, prostate, lung, thyroid and kidney. Once tumors metastasize to the bone, they are essentially incurable. Bone metastasis is a complex process involving not only intravasation of tumor [...] Read more.
Metastasis to the bone is a common feature of many cancers including those of the breast, prostate, lung, thyroid and kidney. Once tumors metastasize to the bone, they are essentially incurable. Bone metastasis is a complex process involving not only intravasation of tumor cells from the primary tumor into circulation, but extravasation from circulation into the bone where they meet an environment that is generally suppressive of their growth. The bone microenvironment can inhibit the growth of disseminated tumor cells (DTC) by inducing dormancy of the DTC directly and later on following formation of a micrometastatic tumour mass by inhibiting metastatic processes including angiogenesis, bone remodeling and immunosuppressive cell functions. In this review we will highlight some of the mechanisms mediating DTC dormancy and the complex relationships which occur between tumor cells and bone resident cells in the bone metastatic microenvironment. These inter-cellular interactions may be important targets to consider for development of novel effective therapies for the prevention or treatment of bone metastases. Full article
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23 pages, 792 KiB  
Review
Clinical Potential of Kinase Inhibitors in Combination with Immune Checkpoint Inhibitors for the Treatment of Solid Tumors
by Ryuhjin Ahn and Josie Ursini-Siegel
Int. J. Mol. Sci. 2021, 22(5), 2608; https://doi.org/10.3390/ijms22052608 - 05 Mar 2021
Cited by 11 | Viewed by 2930
Abstract
Oncogenic kinases contribute to immunosuppression and modulate the tumor microenvironment in solid tumors. Increasing evidence supports the fundamental role of oncogenic kinase signaling networks in coordinating immunosuppressive tumor microenvironments. This has led to numerous studies examining the efficacy of kinase inhibitors in inducing [...] Read more.
Oncogenic kinases contribute to immunosuppression and modulate the tumor microenvironment in solid tumors. Increasing evidence supports the fundamental role of oncogenic kinase signaling networks in coordinating immunosuppressive tumor microenvironments. This has led to numerous studies examining the efficacy of kinase inhibitors in inducing anti-tumor immune responses by increasing tumor immunogenicity. Kinase inhibitors are the second most common FDA-approved group of drugs that are deployed for cancer treatment. With few exceptions, they inevitably lead to intrinsic and/or acquired resistance, particularly in patients with metastatic disease when used as a monotherapy. On the other hand, cancer immunotherapies, including immune checkpoint inhibitors, have revolutionized cancer treatment for malignancies such as melanoma and lung cancer. However, key hurdles remain to successfully incorporate such therapies in the treatment of other solid cancers. Here, we review the recent literature on oncogenic kinases that regulate tumor immunogenicity, immune suppression, and anti-tumor immunity. Furthermore, we discuss current efforts in clinical trials that combine kinase inhibitors and immune checkpoint inhibitors to treat breast cancer and other solid tumors. Full article
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35 pages, 4236 KiB  
Review
Receptor Tyrosine Kinase Signaling and Targeting in Glioblastoma Multiforme
by Manali Tilak, Jennifer Holborn, Laura A. New, Jasmin Lalonde and Nina Jones
Int. J. Mol. Sci. 2021, 22(4), 1831; https://doi.org/10.3390/ijms22041831 - 12 Feb 2021
Cited by 35 | Viewed by 6133
Abstract
Glioblastoma multiforme (GBM) is amongst the deadliest of human cancers, with a median survival rate of just over one year following diagnosis. Characterized by rapid proliferation and diffuse infiltration into the brain, GBM is notoriously difficult to treat, with tumor cells showing limited [...] Read more.
Glioblastoma multiforme (GBM) is amongst the deadliest of human cancers, with a median survival rate of just over one year following diagnosis. Characterized by rapid proliferation and diffuse infiltration into the brain, GBM is notoriously difficult to treat, with tumor cells showing limited response to existing therapies and eventually developing resistance to these interventions. As such, there is intense interest in better understanding the molecular alterations in GBM to guide the development of more efficient targeted therapies. GBM tumors can be classified into several molecular subtypes which have distinct genetic signatures, and they show aberrant activation of numerous signal transduction pathways, particularly those connected to receptor tyrosine kinases (RTKs) which control glioma cell growth, survival, migration, invasion, and angiogenesis. There are also non-canonical modes of RTK signaling found in GBM, which involve G-protein-coupled receptors and calcium channels. This review uses The Cancer Genome Atlas (TCGA) GBM dataset in combination with a data-mining approach to summarize disease characteristics, with a focus on select molecular pathways that drive GBM pathogenesis. We also present a unique genomic survey of RTKs that are frequently altered in GBM subtypes, as well as catalog the GBM disease association scores for all RTKs. Lastly, we discuss current RTK targeted therapies and highlight emerging directions in GBM research. Full article
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26 pages, 4741 KiB  
Review
Targeting the Ubiquitin Signaling Cascade in Tumor Microenvironment for Cancer Therapy
by Qi Liu, Bayonle Aminu, Olivia Roscow and Wei Zhang
Int. J. Mol. Sci. 2021, 22(2), 791; https://doi.org/10.3390/ijms22020791 - 14 Jan 2021
Cited by 23 | Viewed by 4292
Abstract
Tumor microenvironments are composed of a myriad of elements, both cellular (immune cells, cancer-associated fibroblasts, mesenchymal stem cells, etc.) and non-cellular (extracellular matrix, cytokines, growth factors, etc.), which collectively provide a permissive environment enabling tumor progression. In this review, we focused on the [...] Read more.
Tumor microenvironments are composed of a myriad of elements, both cellular (immune cells, cancer-associated fibroblasts, mesenchymal stem cells, etc.) and non-cellular (extracellular matrix, cytokines, growth factors, etc.), which collectively provide a permissive environment enabling tumor progression. In this review, we focused on the regulation of tumor microenvironment through ubiquitination. Ubiquitination is a reversible protein post-translational modification that regulates various key biological processes, whereby ubiquitin is attached to substrates through a catalytic cascade coordinated by multiple enzymes, including E1 ubiquitin-activating enzymes, E2 ubiquitin-conjugating enzymes and E3 ubiquitin ligases. In contrast, ubiquitin can be removed by deubiquitinases in the process of deubiquitination. Here, we discuss the roles of E3 ligases and deubiquitinases as modulators of both cellular and non-cellular components in tumor microenvironment, providing potential therapeutic targets for cancer therapy. Finally, we introduced several emerging technologies that can be utilized to develop effective therapeutic agents for targeting tumor microenvironment. Full article
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30 pages, 820 KiB  
Review
Targeting Mechanotransduction in Osteosarcoma: A Comparative Oncology Perspective
by Anita K. Luu and Alicia M. Viloria-Petit
Int. J. Mol. Sci. 2020, 21(20), 7595; https://doi.org/10.3390/ijms21207595 - 14 Oct 2020
Cited by 6 | Viewed by 3391
Abstract
Mechanotransduction is the process in which cells can convert extracellular mechanical stimuli into biochemical changes within a cell. While this a normal process for physiological development and function in many organ systems, tumour cells can exploit this process to promote tumour progression. Here [...] Read more.
Mechanotransduction is the process in which cells can convert extracellular mechanical stimuli into biochemical changes within a cell. While this a normal process for physiological development and function in many organ systems, tumour cells can exploit this process to promote tumour progression. Here we summarise the current state of knowledge of mechanotransduction in osteosarcoma (OSA), the most common primary bone tumour, referencing both human and canine models and other similar mesenchymal malignancies (e.g., Ewing sarcoma). Specifically, we discuss the mechanical properties of OSA cells, the pathways that these cells utilise to respond to external mechanical cues, and mechanotransduction-targeting strategies tested in OSA so far. We point out gaps in the literature and propose avenues to address them. Understanding how the physical microenvironment influences cell signalling and behaviour will lead to the improved design of strategies to target the mechanical vulnerabilities of OSA cells. Full article
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26 pages, 987 KiB  
Review
Modulating the Crosstalk between the Tumor and Its Microenvironment Using RNA Interference: A Treatment Strategy for Hepatocellular Carcinoma
by Mariam Mroweh, Thomas Decaens, Patrice N Marche, Zuzana Macek Jilkova and Flora Clément
Int. J. Mol. Sci. 2020, 21(15), 5250; https://doi.org/10.3390/ijms21155250 - 24 Jul 2020
Cited by 12 | Viewed by 4296
Abstract
Hepatocellular carcinoma (HCC) is the most common primary liver malignancy with one of the highest mortality rates among solid cancers. It develops almost exclusively in the background of chronic liver inflammation, which can be caused by viral hepatitis, chronic alcohol consumption or an [...] Read more.
Hepatocellular carcinoma (HCC) is the most common primary liver malignancy with one of the highest mortality rates among solid cancers. It develops almost exclusively in the background of chronic liver inflammation, which can be caused by viral hepatitis, chronic alcohol consumption or an unhealthy diet. Chronic inflammation deregulates the innate and adaptive immune responses that contribute to the proliferation, survival and migration of tumor cells. The continuous communication between the tumor and its microenvironment components serves as the overriding force of the tumor against the body’s defenses. The importance of this crosstalk between the tumor microenvironment and immune cells in the process of hepatocarcinogenesis has been shown, and therapeutic strategies modulating this communication have improved the outcomes of patients with liver cancer. To target this communication, an RNA interference (RNAi)-based approach can be used, an innovative and promising strategy that can disrupt the crosstalk at the transcriptomic level. Moreover, RNAi offers the advantage of specificity in comparison to the treatments currently used for HCC in clinics. In this review, we will provide the recent data pertaining to the modulation of a tumor and its microenvironment by using RNAi and its potential for therapeutic intervention in HCC. Full article
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