scholarly journals Novel Apoptosis-Inducing Agents for the Treatment of Cancer, a New Arsenal in the Toolbox

Cancers ◽  
2019 ◽  
Vol 11 (8) ◽  
pp. 1087 ◽  
Author(s):  
Lim ◽  
Greer ◽  
Lipkowitz ◽  
Takebe
Keyword(s):  
Predictive Biomarkers ◽  
Cancer Therapeutics ◽  
Hematologic Malignancies ◽  
Resistance Mechanisms ◽  
Protein Protein Interaction ◽  
Combination Strategies ◽  
Successful Induction ◽  
Apoptosis Pathways ◽  
Apoptosis Process ◽  
Apoptosis Inducing Agents

: Evasion from apoptosis is an important hallmark of cancer cells. Alterations of apoptosis pathways are especially critical as they confer resistance to conventional anti-cancer therapeutics, e.g., chemotherapy, radiotherapy, and targeted therapeutics. Thus, successful induction of apoptosis using novel therapeutics may be a key strategy for preventing recurrence and metastasis. Inhibitors of anti-apoptotic molecules and enhancers of pro-apoptotic molecules are being actively developed for hematologic malignancies and solid tumors in particular over the last decade. However, due to the complicated apoptosis process caused by a multifaceted connection with cross-talk pathways, protein–protein interaction, and diverse resistance mechanisms, drug development within the category has been extremely challenging. Careful design and development of clinical trials incorporating predictive biomarkers along with novel apoptosis-inducing agents based on rational combination strategies are needed to ensure the successful development of these molecules. Here, we review the landscape of currently available direct apoptosis-targeting agents in clinical development for cancer treatment and update the related biomarker advancement to detect and validate the efficacy of apoptosis-targeted therapies, along with strategies to combine them with other agents.

scholarly journals Combination strategies to overcome resistance to the BCL2 inhibitor venetoclax in hematologic malignancies

2020 ◽  
Vol 20 (1) ◽  
Author(s):  
XiaoYan Yue ◽  
Qingxiao Chen ◽  
JingSong He
Keyword(s):  
Intracellular Signaling ◽  
B Cell Lymphoma ◽  
Hematologic Malignancies ◽  
The United States ◽  
Resistance Mechanisms ◽  
Lymphocytic Leukemia ◽  
Bcl2 Family ◽  
Combination Strategies ◽  
United States Food ◽  
Major Factors

Abstract Venetoclax has been approved by the United States Food and Drug Administration since 2016 as a monotherapy for treating patients with relapsed/refractory chronic lymphocytic leukemia having 17p deletion. It has led to a breakthrough in the treatment of hematologic malignancies in recent years. However, unfortunately, resistance to venetoclax is inevitable. Multiple studies confirmed that the upregulation of the anti-apoptotic proteins of the B-cell lymphoma 2 (BCL2) family mediated by various mechanisms, such as tumor microenvironment, and the activation of intracellular signaling pathways were the major factors leading to resistance to venetoclax. Therefore, only targeting BCL2 often fails to achieve the expected therapeutic effect. Based on the mechanism of resistance in specific hematologic malignancies, the combination of specific drugs with venetoclax was a clinically optional treatment strategy for overcoming resistance to venetoclax. This study aimed to summarize the possible resistance mechanisms of various hematologic tumors to venetoclax and the corresponding clinical strategies to overcome resistance to venetoclax in hematologic malignancies.

scholarly journals Gut microbiome and CAR-T therapy

2019 ◽  
Vol 8 (1) ◽  
Author(s):  
Muhammad Bilal Abid ◽  
Nirav N. Shah ◽  
Theresa C. Maatman ◽  
Parameswaran N. Hari
Keyword(s):  
T Cells ◽  
Gut Microbiota ◽  
Gut Microbiome ◽  
Cancer Therapeutics ◽  
Hematologic Malignancies ◽  
Resistance Mechanisms ◽  
Significant Heterogeneity ◽  
Car T Cells ◽  
Car T ◽  
Made In

AbstractConsiderable progress has been made in cancer therapeutics recently with targeted strategies that are efficacious and less toxic. Immunotherapy and chimeric antigen receptor (CAR) T-cells are increasingly being evaluated in a variety of tumors in the relapsed/refractory as well as frontline disease settings, predominantly in hematologic malignancies (HM). Despite impressive outcomes in select patients, there remains significant heterogeneity in clinical response to CAR T-cells. The gut microbiome has emerged as one of the key host factors that could potentially be modulated to enhance responses to immunotherapy. Several recent human studies receiving immunotherapy showed a significantly superior response and survival in patients with the more diverse gut microbiome. Currently, it is unknown if gut microbiota modulates anti-tumor responses to CAR T-cells. Based on molecular and immunological understanding, we hypothesize that strategically manipulating gut microbiota may enhance responses to CAR T-cells. In this review, we further discuss resistance mechanisms to CAR T-cells in HM, potential approaches to overcome resistance by harnessing gut microbiota and other related novel strategies.

scholarly journals Cancer Vaccines for Genitourinary Tumors: Recent Progresses and Future Possibilities

Vaccines ◽  
2021 ◽  
Vol 9 (6) ◽  
pp. 623
Author(s):  
Brigida Anna Maiorano ◽  
Giovanni Schinzari ◽  
Davide Ciardiello ◽  
Maria Grazia Rodriquenz ◽  
Antonio Cisternino ◽  
...  
Keyword(s):  
Cancer Vaccines ◽  
Viral Vectors ◽  
Checkpoint Inhibitors ◽  
Treatment Options ◽  
Tumor Development ◽  
Resistance Mechanisms ◽  
High Morbidity ◽  
Therapeutic Vaccines ◽  
Combination Strategies ◽  
New Treatment

Background: In the last years, many new treatment options have widened the therapeutic scenario of genitourinary malignancies. Immunotherapy has shown efficacy, especially in the urothelial and renal cell carcinomas, with no particular relevance in prostate cancer. However, despite the use of immune checkpoint inhibitors, there is still high morbidity and mortality among these neoplasms. Cancer vaccines represent another way to activate the immune system. We sought to summarize the most recent advances in vaccine therapy for genitourinary malignancies with this review. Methods: We searched PubMed, Embase and Cochrane Database for clinical trials conducted in the last ten years, focusing on cancer vaccines in the prostate, urothelial and renal cancer. Results: Various therapeutic vaccines, including DNA-based, RNA-based, peptide-based, dendritic cells, viral vectors and modified tumor cells, have been demonstrated to induce specific immune responses in a variable percentage of patients. However, these responses rarely corresponded to significant survival improvements. Conclusions: Further preclinical and clinical studies will improve the knowledge about cancer vaccines in genitourinary malignancies to optimize dosage, select targets with a driver role for tumor development and growth, and finally overcome resistance mechanisms. Combination strategies represent possibly more effective and long-lasting treatments.

scholarly journals Embryo Buoyancy and Cell Death Gene Expression During Embryogenesis of Yellow-Tail Kingfish Seriola lalandi

2021 ◽  
Vol 9 ◽  
Author(s):  
Jaime Palomino ◽  
Camila Gómez ◽  
María Teresa Otarola ◽  
Phillip Dettleff ◽  
Daniel Patiño-García ◽  
...  
Keyword(s):  
Cell Death ◽  
Developmental Stages ◽  
Pelagic Fish ◽  
Terminal Deoxynucleotidyl Transferase ◽  
Fish Embryo ◽  
Developmental Potential ◽  
Protein Levels ◽  
Apoptosis Pathways ◽  
Apoptosis Process ◽  
Seriola Lalandi

In pelagic fish, embryo buoyancy is a noteworthy aspect of the reproductive strategy, and is associated with overall quality, survival, and further developmental success. In captivity, the loss of buoyancy of early embryos correlates with high mortality that might be related to massive cell death. Therefore, the aim of this study was to evaluate under captivity conditions the expression of genes related to the apoptosis process during the early embryonic development of the pelagic fish Seriola lalandi, and its relationship to the buoyancy of embryos. The relative expression of bcl2, bax-like, casp9, casp8, and casp3 was evaluated by RT-qPCR and FasL/Fas protein levels by western blot in five development stages of embryos sorted as floating or low-floating. All genes examined were expressed in both floating and low-floating embryos up to 24 h of development. Expression of the pro-apoptotic factors bax, casp9, casp8, and casp3 was higher in low-floating as compared with floating embryos in a developmental stage-specific manner. In contrast, there was no difference in expression of bcl2 between floating and low-floating embryos. Fas protein was detected as a single band in floating embryos without changes in expression throughout development; however, in low-floating embryos, three higher intensity reactive bands were detected in the 24-h embryos. Interestingly, FasL was only detected at 24-h in floating embryos, whereas in low-floating samples this ligand was present at all stages, with a sharp increase as development progressed. Cell death, as evaluated by the terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling assay, was highly increased in low-floating embryos as compared to floating embryos throughout all developmental stages, with the highest levels observed during the gastrula stage and at 24 h. The results of this study suggest that an increase in cell death, probably associated with the intrinsic and extrinsic apoptosis pathways, is present in low-floating embryos that might explain their lower developmental potential under captivity conditions.

scholarly journals Based on Integrated Bioinformatics Analysis Identification of Biomarkers in Hepatocellular Carcinoma Patients from Different Regions

2019 ◽  
Vol 2019 ◽  
pp. 1-17 ◽  
Author(s):  
Linxin Teng ◽  
Kaiyuan Wang ◽  
Yu Liu ◽  
Yanxia Ma ◽  
Weiping Chen ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Predictive Biomarkers ◽  
Principal Component ◽  
Roc Curves ◽  
Core Gene ◽  
Gene Expression Omnibus ◽  
The Cancer Genome Atlas ◽  
Protein Protein Interaction ◽  
The Core ◽  
Kaplan Meier

Accumulating statistics have shown that liver cancer causes the second highest mortality rate of cancer-related deaths worldwide, of which 80% is hepatocellular carcinoma (HCC). Given the underlying molecular mechanism of HCC pathology is not fully understood yet, identification of reliable predictive biomarkers is more applicable to improve patients’ outcomes. The results of principal component analysis (PCA) showed that the grouped data from 1557 samples in Gene Expression Omnibus (GEO) came from different populations, and the mean tumor purity of tumor tissues was 0.765 through the estimate package in R software. After integrating the differentially expressed genes (DEGs), we finally got 266 genes. Then, the protein-protein interaction (PPI) network was established based on these DEGs, which contained 240 nodes and 1747 edges. FOXM1 was the core gene in module 1 and highly associated with FOXM1 transcription factor network pathway, while FTCD was the core gene in module 2 and was enriched in the metabolism of amino acids and derivatives. The expression levels of hub genes were in line with The Cancer Genome Atlas (TCGA) database. Meanwhile, there were certain correlations among the top ten genes in the up- and downregulated DEGs. Finally, Kaplan–Meier curves and receiver operating characteristic (ROC) curves were plotted for the top five genes in PPI. Apart from CDKN3, the others were closely concerned with overall survival. In this study, we detected the potential biomarkers and their involved biological processes, which would provide a new train of thought for clinical diagnosis and treatment.

Molecular characterization of circulating tumor cells (CTC) and CTC subpopulations in progressive metastatic castration resistant prostate cancer (mCRPC).

2014 ◽  
Vol 32 (4_suppl) ◽  
pp. 132-132 ◽  
Author(s):  
Ryan Dittamore ◽  
Jessica Louw ◽  
Rachel Krupa ◽  
Aseem Anand ◽  
Daniel Costin Danila ◽  
...  
Keyword(s):  
Molecular Characterization ◽  
Predictive Biomarkers ◽  
Clinical History ◽  
Resistance Mechanisms ◽  
Test Methods ◽  
Castration Resistant Prostate Cancer ◽  
Detection Rates ◽  
Pten Loss ◽  
Radiographic Disease

132 Background: Numerous resistance mechanisms have been postulated in progressive mCRPC. Determining the presence of putative predictive biomarkers in patients requires a real-time tumor assessment because the biology changes under the influence of the specific therapy(ies) that a patient (Pt) has received. We examined CTC and CTC subpopulation incidence and molecular characterization of tumors from Pts with progressive mCRPC to assess if determinants of resistance can be assessed through a CTC test. Methods: 48 samples from 21 unique progressive mCRPC pts treated with androgen receptor targeted (AR tx) therapies, 9 (43%) on Abiraterone plus Prednisone (AA+P) and 12 (57%) on Enzalutamide (E). Samples were collected and shipped to Epic Sciences, where cells were stained and CTC identified by fluorescent scanners and algorithmic analysis. CTCs, defined as classic (CK+ CD45- w/intact DAPI nuclei and distinct), apopotic (CK+, CD45-, non-intact nuclei) and CK- (CK-, CD45-, intact and distinct) were identified. CTCs reported per mL of blood and were examined for AR, PTEN & ERG. CTC data were analyzed in context of PSA, Veridex CTC (reported per 7.5mL of blood), and clinical history. Results: With Epic, all 21 pts had detectable CTCs (mdn 23 cells/ml, range 2 to 249), whereas with Veridex, 14 (67%) pts had > 5 CTC/7.5 ml (mdn 5 cells/7.5 ml, range 0 to >200). 0/7 (0%) with high AR responded to AA+P or E, 8/14 (53%) with low AR had a PSA decline and stable radiographic disease (median follow-up 12 wks). Variations in AR protein expression and localization heterogeneity was seen in all pts to varying degrees. 6/21 (29%) Pts demonstrated CK- CTC/CTC ratio >50% (mdn 9 cells/ml, range 5-38). ERG rearrangement and PTEN loss were correlated. Conclusions: Epic CTC analysis provides higher detection rates, while enabling individual cell analyses for predictive biomarkers of sensitivity to AR directed therapies. Notable was the marked heterogeneity of detection of AR, ERG, and PTEN of individual CTCs. Studies are ongoing to further explore associations with outcomes. [Table: see text]

scholarly journals BET Proteins as Attractive Targets for Cancer Therapeutics

2021 ◽  
Vol 22 (20) ◽  
pp. 11102
Author(s):  
Joanna Sarnik ◽  
Tomasz Popławski ◽  
Paulina Tokarz
Keyword(s):  
Homologous Recombination ◽  
Transcriptional Control ◽  
Synthetic Lethality ◽  
Clinical Success ◽  
Predictive Biomarkers ◽  
Cancer Therapeutics ◽  
Parp Inhibitors ◽  
Novel Approach ◽  
Bet Inhibitors ◽  
Recombination Pathway

Transcriptional dysregulation is a hallmark of cancer and can be an essential driver of cancer initiation and progression. Loss of transcriptional control can cause cancer cells to become dependent on certain regulators of gene expression. Bromodomain and extraterminal domain (BET) proteins are epigenetic readers that regulate the expression of multiple genes involved in carcinogenesis. BET inhibitors (BETis) disrupt BET protein binding to acetylated lysine residues of chromatin and suppress the transcription of various genes, including oncogenic transcription factors. Phase I and II clinical trials demonstrated BETis’ potential as anticancer drugs against solid tumours and haematological malignancies; however, their clinical success was limited as monotherapies. Emerging treatment-associated toxicities, drug resistance and a lack of predictive biomarkers limited BETis’ clinical progress. The preclinical evaluation demonstrated that BETis synergised with different classes of compounds, including DNA repair inhibitors, thus supporting further clinical development of BETis. The combination of BET and PARP inhibitors triggered synthetic lethality in cells with proficient homologous recombination. Mechanistic studies revealed that BETis targeted multiple essential homologous recombination pathway proteins, including RAD51, BRCA1 and CtIP. The exact mechanism of BETis’ anticancer action remains poorly understood; nevertheless, these agents provide a novel approach to epigenome and transcriptome anticancer therapy.

scholarly journals Tailoring precision immunotherapy: coming to a clinic soon?

ESMO Open ◽  
2020 ◽  
Vol 5 (Suppl 1) ◽  
pp. e000631 ◽  
Author(s):  
Shuting Han ◽  
Wai Ho Shuen ◽  
Who-Whong Wang ◽  
Esdy Nazim ◽  
Han Chong Toh
Keyword(s):  
Predictive Biomarkers ◽  
Tumour Microenvironment ◽  
Resistance Mechanisms ◽  
Significant Survival ◽  
Rational Combination ◽  
Cancer Immunotherapies ◽  
Long Term Survivors ◽  
Improve Patient ◽  
Cancer Clinic

Cell-based and antibody-based cancer immunotherapies have been widely tested across increasing numbers of cancers with an unprecedented number of successful practice-changing immunotherapy clinical trials, achieving significant survival outcomes and, characteristically, some very long-term survivors. Still, a sizeable proportion of patients, especially with solid tumours, do not benefit from immunotherapy. Here, we summarise key literature on immunotherapy biomarkers and resistance mechanisms and discuss potential strategies to overcome such resistance to improve patient outcomes. The ever-expanding understanding of the tumour-immune interaction and the tumour microenvironment allows a real opportunity to identify predictive biomarkers and tailor immune-based therapies, including designing rational combination drugs to enhance clinical outcomes, and to identify patients most likely to benefit from immunotherapy. Where there has never been a precision chemotherapy clinic in the last 70 years since its inception, even with no shortage of trying, the hope and evolution of a functional precision immunotherapy cancer clinic is a much more likely reality.

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