scholarly journals Current Status and Future Prospects of Clinically Exploiting Cancer-specific Metabolism—Why Is Tumor Metabolism Not More Extensively Translated into Clinical Targets and Biomarkers?

2019 ◽  
Vol 20 (6) ◽  
pp. 1385 ◽  
Author(s):  
Magesh Muthu ◽  
Anders Nordström
Keyword(s):  
Tumor Cells ◽  
Drug Target ◽  
Tumor Metabolism ◽  
Current Status ◽  
Proliferating Cells ◽  
Specialized Metabolism ◽  
Biochemical Mechanisms ◽  
Endogenous Metabolites ◽  
Cancer Clinic ◽  
Present Ability

Tumor cells exhibit a specialized metabolism supporting their superior ability for rapid proliferation, migration, and apoptotic evasion. It is reasonable to assume that the specific metabolic needs of the tumor cells can offer an array of therapeutic windows as pharmacological disturbance may derail the biochemical mechanisms necessary for maintaining the tumor characteristics, while being less important for normally proliferating cells. In addition, the specialized metabolism may leave a unique metabolic signature which could be used clinically for diagnostic or prognostic purposes. Quantitative global metabolic profiling (metabolomics) has evolved over the last two decades. However, despite the technology’s present ability to measure 1000s of endogenous metabolites in various clinical or biological specimens, there are essentially no examples of metabolomics investigations being translated into actual utility in the cancer clinic. This review investigates the current efforts of using metabolomics as a tool for translation of tumor metabolism into the clinic and further seeks to outline paths for increasing the momentum of using tumor metabolism as a biomarker and drug target opportunity.

Current Status in the Design and Development of Agonists and Antagonists of Adenosine A3 Receptor as Potential Therapeutic Agents

2019 ◽  
Vol 25 (25) ◽  
pp. 2772-2787 ◽  
Author(s):  
Raghu P. Mailavaram ◽  
Omar H.A. Al-Attraqchi ◽  
Supratik Kar ◽  
Shinjita Ghosh
Keyword(s):  
Drug Target ◽  
Therapeutic Agents ◽  
G Protein Coupled Receptors ◽  
Current Status ◽  
Renal Diseases ◽  
Adenosine A3 Receptor ◽  
Drug Candidates ◽  
Novel Drugs ◽  
The Family ◽  
G Protein Coupled

Adenosine receptors (ARs) belongs to the family of G-protein coupled receptors (GPCR) that are responsible for the modulation of a wide variety of physiological functions. The ARs are also implicated in many diseases such as cancer, arthritis, cardiovascular and renal diseases. The adenosine A3 receptor (A3AR) has emerged as a potential drug target for the progress of new and effective therapeutic agents for the treatment of various pathological conditions. This receptor’s involvement in many diseases and its validity as a target has been established by many studies. Both agonists and antagonists of A3AR have been extensively investigated in the last decade with the goal of developing novel drugs for treating diseases related to immune disorders, inflammation, cancer, and others. In this review, we shall focus on the medicinal chemistry of A3AR ligands, exploring the diverse chemical classes that have been projected as future leading drug candidates. Also, the recent advances in the therapeuetic applications of A3AR ligands are highlighted.

scholarly journals Damage-Associated Molecular Patterns Modulation by microRNA: Relevance on Immunogenic Cell Death and Cancer Treatment Outcome

Cancers ◽  
2021 ◽  
Vol 13 (11) ◽  
pp. 2566
Author(s):  
María Julia Lamberti ◽  
Annunziata Nigro ◽  
Vincenzo Casolaro ◽  
Natalia Belén Rumie Vittar ◽  
Jessica Dal Col
Keyword(s):  
Cell Death ◽  
Tumor Cells ◽  
Cell Activation ◽  
Adaptive Immune Response ◽  
Current Status ◽  
Immunogenic Cell Death ◽  
Basal Expression ◽  
Antigen Presenting ◽  
Molecular Patterns ◽  
Damage Associated Molecular Patterns

Immunogenic cell death (ICD) in cancer is a functionally unique regulated form of stress-mediated cell death that activates both the innate and adaptive immune response against tumor cells. ICD makes dying cancer cells immunogenic by improving both antigenicity and adjuvanticity. The latter relies on the spatiotemporally coordinated release or exposure of danger signals (DAMPs) that drive robust antigen-presenting cell activation. The expression of DAMPs is often constitutive in tumor cells, but it is the initiating stressor, called ICD-inducer, which finally triggers the intracellular response that determines the kinetics and intensity of their release. However, the contribution of cell-autonomous features, such as the epigenetic background, to the development of ICD has not been addressed in sufficient depth. In this context, it has been revealed that several microRNAs (miRNAs), besides acting as tumor promoters or suppressors, can control the ICD-associated exposure of some DAMPs and their basal expression in cancer. Here, we provide a general overview of the dysregulation of cancer-associated miRNAs whose targets are DAMPs, through which new molecular mediators that underlie the immunogenicity of ICD were identified. The current status of miRNA-targeted therapeutics combined with ICD inducers is discussed. A solid comprehension of these processes will provide a framework to evaluate miRNA targets for cancer immunotherapy.

scholarly journals CBIO-11. NOVEL THERAPY TO TARGET PR-RECURRENT GLIOMA

2020 ◽  
Vol 22 (Supplement_2) ◽  
pp. ii17-ii18
Author(s):  
Masum Rahman ◽  
Ian E Olson ◽  
Rehan Saber ◽  
Jibo Zhang ◽  
Lucas P Carlstrom ◽  
...  
Keyword(s):  
Tumor Cells ◽  
Tumor Recurrence ◽  
Primary Brain Tumor ◽  
Differential Sensitivity ◽  
Proliferating Cells ◽  
Novel Therapy ◽  
Conventional Radiation ◽  
Long Time ◽  
Radiation Induced

Abstract BACKGROUND Glioblastoma is a fatal infiltrative primary brain tumor, and standard care includes maximal safe surgical resection followed by radiation and Temozolomide (TMZ). Therapy-resistant residual cells persist in a latent state a long time before inevitable recurrence. Conventional radiation and Temozolomide (TMZ) treatment cause oxidative stress and DNA damage resulting senescent-like state of cell-cycle arrest. However, increasing evidence demonstrates escaping senescence leads to tumor recurrence. Thus, the ablation of senescent tumor cells after chemoradiation may be an avenue to limit tumor recurrence. METHODS 100uM TMZ for 7days or 10-20Gy radiation (cesium gamma radiator) was used for senescence induction in human glioblastoma in vitro and confirmed by SA-Beta gal staining and PCR. Replication arrest assessed by automated quantification of cellular confluence (Thermo Scientific Series 8000 WJ Incubator). We evaluated the IC50 for several senolytics targeting multiple SCAPs, including Dasatinib, Quercetin, AMG-232, Fisetin, Onalespib, Navitoclax, and A1331852, and in senescent vs. proliferating cells. RESULTS Among the senolytic tested, the Bcl-XL inhibitors A1331852 and Navitoclax both shown senolytic effect by selectively killing radiated, senescent tumor cells at lower concentrations as compared to 0Gy treated non-senescent cells. Across 12 GBM cell lines, IC50 for senescent cells was 6–500 times lower than non-senescent GBM(p< 0.005). Such differential sensitivity to Bcl-XL inhibition after radiation has also observed by BCL-XL knockdown in radiated glioma. CONCLUSION These findings suggest the potential to harness radiation-induced biology to ablate surviving quiescent cells and demonstrate Bcl-XL dependency as a potential vulnerability of surviving tumor cells after exposure to chemoradiation.

scholarly journals Why TKI Therapy Targeting Minority Population of Tumor Cells Could Achieve Complete Control of Entire Tumor: The Self-Driven and Non-Autonomous Replication in Cancer and Their Connection through Inflammation

2020 ◽  
Vol 5 (3) ◽  
Keyword(s):  
Tumor Cells ◽  
Kinase Inhibitors ◽  
Extended Period ◽  
Target Population ◽  
Minority Population ◽  
Complete Control ◽  
Therapy Efficacy ◽  
The Common ◽  
Two Populations ◽  
Cancer Clinic

Despite wide application of targeted therapy with small molecule tyrosine kinase inhibitors (TKI) in cancer clinic, some questions for the mechanisms of these inhibitors remain unresolved. For example, how can a tumor be completely controlled for extended period (more than a year) by the drug when the target population in the tumor is not even in majority? Here we report our observations in one such case of lung cancer and provide explanation for this long-awaited clinical puzzle. Our analyses indicate that in many of the similar cases, the cancer is composed of two populations of tumor cells, one capable of autonomous (or self-driven) replication through the known mutation, and the replication of the other is inflammationdependent. The connection is through inflammation induced by the tumor cells capable of self-driven replication. The control of this population by TKI terminates induction of inflammation thus results in control of the non-autonomous population. The identification of these two replicating tumor cells and their relationship holds many answers to current clinical confusions in many cancer cases where accelerated tumor progression, high inflammation and loss of therapy efficacy are often the common feature. By understanding these processes, we can begin to manage cancer in a more proactive manner to avoid the once recognized unavoidable fate of cancer

scholarly journals Circulating Tumor Cells in Early and Advanced Breast Cancer; Biology and Prognostic Value

2020 ◽  
Vol 21 (5) ◽  
pp. 1671 ◽  
Author(s):  
Anna Fabisiewicz ◽  
Malgorzata Szostakowska-Rodzos ◽  
Anna J. Zaczek ◽  
Ewa A. Grzybowska
Keyword(s):  
Breast Cancer ◽  
Tumor Cells ◽  
Circulating Tumor Cells ◽  
Cancer Biology ◽  
Cancer Metastasis ◽  
Metastatic Breast ◽  
Breast Cancer Metastasis ◽  
Current Status ◽  
Molecular Profile ◽  
Breast Cancer Patients

Breast cancer metastasis is the leading cause of cancer deaths in women and is difficult to combat due to the long periods in which disseminated cells retain a potential to be re-activated and start the relapse. Assessing the number and molecular profile of circulating tumor cells (CTCs) in breast cancer patients, especially in early breast cancer, should help in identifying the possibility of relapse in time for therapeutic intervention to prevent or delay recurrence. While metastatic breast cancer is considered incurable, molecular analysis of CTCs still have a potential to define particular susceptibilities of the cells representing the current tumor burden, which may differ considerably from the cells of the primary tumor, and offer more tailored therapy to the patients. In this review we inspect the routes to metastasis and how they can be linked to specific features of CTCs, how CTC analysis may be used in therapy, and what is the current status of the research and efforts to include CTC analysis in clinical practice.

scholarly journals The effects of proliferation status and cell cycle phase on the responses of single cells to chemotherapy

2020 ◽  
Vol 31 (8) ◽  
pp. 845-857 ◽  
Author(s):  
Adrián E. Granada ◽  
Alba Jiménez ◽  
Jacob Stewart-Ornstein ◽  
Nils Blüthgen ◽  
Simone Reber ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Information Theory ◽  
Tumor Cells ◽  
Single Cells ◽  
Residual Tumor ◽  
Cell Cycle Phase ◽  
Cycle Phase ◽  
Proliferating Cells ◽  
Probability Of Death

DNA-damaging chemotherapy often leaves residual tumor cells. Combining single-cell long-term live imaging with information theory, we found an unexpected effect: highly proliferative cells were more likely to arrest than to die, whereas more slowly proliferating cells showed a higher probability of death.

MCM2 Is an Independent Predictor of Survival in Patients With Non–Small-Cell Lung Cancer

2001 ◽  
Vol 19 (22) ◽  
pp. 4259-4266 ◽  
Author(s):  
Nithya Ramnath ◽  
Francisco J. Hernandez ◽  
Dong-Feng Tan ◽  
Joel A. Huberman ◽  
Nachimuthu Natarajan ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Tumor Cells ◽  
Cell Lung Cancer ◽  
Small Cell ◽  
Response To Therapy ◽  
Positive Staining ◽  
Small Cell Lung ◽  
Proliferating Cells ◽  
Ki 67

PURPOSE: Minichromosome maintenance protein 2 (MCM2) is a component of the prereplicative complex. It is essential for eukaryotic DNA replication and is only expressed in proliferating cells. The prognostic utility of MCM2 compared with Ki-67, another marker of proliferating cells, on survival of patients with non–small-cell lung cancer (NSCLC) was studied. PATIENTS AND METHODS: We examined the immunohistochemical expression of MCM2 and Ki-67 in primary pathologic tumor specimens from 221 NSCLC patients. For each marker, the fraction of tumor cells with positive staining was assessed as a percentage and categorized into four groups: 0% to 24%, 25% to 49%, 50% to 74%, and ≥ 75%. MCM2 and Ki-67 immunoreactivities were compared with each other, and associations with pathologic and clinical parameters predictive of survival were analyzed with the χ2 test. Cox regression models were used to assess associations between MCM2 and Ki-67 and survival while controlling for confounders. RESULTS: Independent variables significantly associated with survival were tumor stage, performance status, and staining category. Patients with less than 25% MCM2 immunoreactivity had a longer median survival time than patients with ≥ 25% MCM2 immunoreactivity (46 v 31 months; P = .039) and a lower relative risk (RR) of death (RR, 0.55, 95% confidence interval, 0.34 to 0.88). There was no significant association between survival and Ki-67 expression. CONCLUSION: Immunostaining of tumor cells for MCM2 is an independent prognostic parameter of survival for patients with NSCLC. Interpretable results can be obtained on more than 96% of paraffin-embedded specimens, and approximately 35% will be in the favorable subgroup, with less than 25% positively stained tumor cells. Whether MCM2 is predictive of response to therapy needs to be studied.

Graft-versus-leukemia reactions in allogeneic chimeras

Blood ◽  
2004 ◽  
Vol 103 (3) ◽  
pp. 767-776 ◽  
Author(s):  
Hans-Jochem Kolb ◽  
Christoph Schmid ◽  
A. John Barrett ◽  
Dolores J. Schendel
Keyword(s):  
T Cells ◽  
Stem Cell ◽  
Tumor Cells ◽  
Immune Therapy ◽  
Suicide Gene ◽  
Myelogenous Leukemia ◽  
Current Status ◽  
Cell Transplant ◽  
Normal Tissues ◽  
Graft Versus Leukemia

AbstractThere is a strong graft-versus-leukemia (GVL) effect of allogeneic stem cell transplantation (SCT) due to elimination of tumor cells by alloimmune effector lymphocytes. When leukemia relapses after allogeneic SCT, donor lymphocyte transfusions (DLTs) can induce sustained remissions in some patients. This review summarizes the current status on clinical use of DLT, the basis of GVL reactions, problems associated with this therapy, and new strategies to improve DLT. Several multicenter surveys demonstrated that the GVL effect of DLT is most effective in chronic myelogenous leukemia (CML), whereas it is less pronounced in acute leukemia and myeloma. Cytokine stimulation to induce differentiation of myeloid progenitor cells or to up-regulate costimulatory molecules on tumor cells may improve the efficacy of DLT. Infections and graft-versus-host disease (GVHD) are major complications of DLT. Control of GVHD may be improved using suicide gene–modified T cells for DLT, allowing T-cell elimination if severe GVHD develops. Hopefully, in the future, GVL effect can be separated from GVHD through adoptive transfer of selected T cells that recognize leukemia-specific antigens or minor histocompatibility antigens, which are expressed predominantly on hematopoietic cells, thereby precluding attack of normal tissues. In patients with leukemia and lymphomas with fast progression, tumor growth may outpace development of effector T cells. Here it may be preferable to select stem cell transplant donors with HLA-mismatches that allow alloreactive natural killer cells, which appear early after transplantation, to retain their cytolytic function. New approaches for adoptive immune therapy of leukemia, which promise a better prognosis for these patients, are being developed.

scholarly journals Nanoparticles in Cancer Imaging and Therapy

2012 ◽  
Vol 2012 ◽  
pp. 1-7 ◽  
Author(s):  
Leon Smith ◽  
Zdenka Kuncic ◽  
Kostya (Ken) Ostrikov ◽  
Shailesh Kumar
Keyword(s):  
Titanium Dioxide ◽  
Radiation Therapy ◽  
Tumor Cells ◽  
Titanium Dioxide Nanoparticles ◽  
Current Status ◽  
Considerable Research ◽  
Image Contrast Enhancement ◽  
Reduced Toxicity ◽  
Targeted Radiation Therapy ◽  
Selective Accumulation

Nanoparticle contrast agents offer the potential to significantly improve existing methods of cancer diagnosis and treatment. Advantages include biocompatibility, selective accumulation in tumor cells, and reduced toxicity. Considerable research is underway into the use of nanoparticles as enhancement agents for radiation therapy and photodynamic therapy, where they may be used to deliver treatment agents, produce localized enhancements in radiation dose and selectively target tumor cells for localized damage. This paper reviews the current status of nanoparticles for cancer treatment and presents preliminary results of a pilot study investigating titanium dioxide nanoparticles for dual-mode enhancement of computed tomography (CT) imaging and kilovoltage radiation therapy. Although titanium dioxide produced noticeable image contrast enhancement in the CT scans, more sensitive detectors are needed to determine whether the nanoparticles can also produce localized dose enhancement for targeted radiation therapy.

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