scholarly journals Targeting MCL-1 in cancer: current status and perspectives

2021 ◽  
Vol 14 (1) ◽  
Author(s):  
Haolan Wang ◽  
Ming Guo ◽  
Hudie Wei ◽  
Yongheng Chen
Keyword(s):  
Clinical Trials ◽  
Cancer Therapy ◽  
Myeloid Leukemia ◽  
Poor Prognosis ◽  
Current Status ◽  
Significant Progress ◽  
Apoptotic Pathway ◽  
Antiapoptotic Protein ◽  
Tumor Types

AbstractMyeloid leukemia 1 (MCL-1) is an antiapoptotic protein of the BCL-2 family that prevents apoptosis by binding to the pro-apoptotic BCL-2 proteins. Overexpression of MCL-1 is frequently observed in many tumor types and is closely associated with tumorigenesis, poor prognosis and drug resistance. The central role of MCL-1 in regulating the mitochondrial apoptotic pathway makes it an attractive target for cancer therapy. Significant progress has been made with regard to MCL-1 inhibitors, some of which have entered clinical trials. Here, we discuss the mechanism by which MCL-1 regulates cancer cell apoptosis and review the progress related to MCL-1 small molecule inhibitors and their role in cancer therapy.

SET Protein in Cancer: A Potential Therapeutic Target

2021 ◽  
Vol 21 ◽  
Author(s):  
Xinjie Liang ◽  
Xuefei Bao ◽  
Guoliang Chen
Keyword(s):  
Drug Resistance ◽  
Clinical Trials ◽  
Cancer Therapy ◽  
Tumor Cells ◽  
Strong Correlation ◽  
Therapeutic Target ◽  
Poor Prognosis ◽  
Therapeutic Options ◽  
Potential Therapeutic Target ◽  
Bona Fide

: SET protein is a multi-functional oncoprotein that is ubiquitously expressed in most tumor cells. Dysregulation of SET has been associated with many types of cancer. Due to ever-accumulating evidence of its strong correlation with both poor prognosis and drug resistance, the targeting of SET is starting to be explored. SET is currently regarded as a potential target for cancer therapy, and several inhibitors are being developed for clinical trials. In this review, the physiological and pathological functions of SET, as well as its antagonists, will be discussed along with the prospects and challenges involved with translating SET inhibitors into bona fide therapeutic options.

Monoclonal antibodies in cancer therapy.

1983 ◽  
Vol 1 (9) ◽  
pp. 582-590 ◽  
Author(s):  
R K Oldham
Keyword(s):  
Monoclonal Antibody ◽  
Clinical Trials ◽  
Monoclonal Antibodies ◽  
Cancer Therapy ◽  
Experimental Approach ◽  
Preliminary Evidence ◽  
Current Status ◽  
Experimental Animals ◽  
Specific Targeting ◽  
Specific Tumor

The need for improved specificity in cancer therapy is apparent. With the advent of monoclonal antibodies, the possibility of specifically targeted therapy is being considered. Early trials of monoclonal antibody in experimental animals and humans have indicated its ability to traffic to specific tumor sites and to localize on or around the tumor cells displaying antigens to which the antibody is directed. This evidence of specific targeting, along with preliminary evidence of therapeutic efficacy for monoclonal antibodies and immunoconjugates with drugs, toxins, and isotopes is encouraging. The current status of clinical trials with monoclonal antibodies is reviewed and an example of the experimental approach for the development of immunoconjugates in animal models is presented.

scholarly journals RDNA-06. TARGETING IDH1/2-MUTANT GLIOMAS WITH UNIQUE COMBINATIONS OF DNA REPAIR INHIBITORS

2019 ◽  
Vol 21 (Supplement_6) ◽  
pp. vi208-vi208
Author(s):  
Amrita Sule ◽  
Ranjit Bindra
Keyword(s):  
Clinical Trials ◽  
Dna Repair ◽  
Myeloid Leukemia ◽  
Parp Inhibitors ◽  
Low Grade ◽  
High Fidelity ◽  
Isocitrate Dehydrogenase 1 ◽  
Dna Repair Inhibitors ◽  
Mutant Idh1 ◽  
Tumor Types

Abstract Mutations in the Isocitrate Dehydrogenase-1 and -2 (IDH1/2) genes occur in the vast majority of low-grade and secondary high-grade gliomas. These neomorphic mutations occur early on in gliomagenesis leading to the production of 2-Hydroxyglutarate (2HG). 2HG has been implicated in tumorigenesis via inhibiting α-ketoglutarate (αKG)-dependent dioxygenases. Our group recently demonstrated that the production of 2HG suppresses the high-fidelity homologous recombination (HR) DNA repair pathway, resulting in a state of “BRCAness”. We initially found that mutant IDH1/2-induced BRCAness confers exquisite sensitivity to poly(ADP-ribose) polymerase (PARP) inhibitors, a finding which now has been replicated by multiple independent laboratories. Although IDH1/2 mutations were first identified in gliomas and acute myeloid leukemia (AML) cells, multiple other tumor types have subsequently been shown to harbor these mutations. Current clinical trials are testing the efficacy of PARP inhibitors as a monotherapy, as well as in combination with other DNA repair inhibitors. Here, we demonstrate that novel combinations of DNA repair inhibitors can be utilized to synergistically target IDH1/2-mutant glioma cells. In particular, we demonstrate potent synergy with ATRi and PARPis, a finding which was validated in multiple structurally unique drugs within these classes. As this combination is active in BRCA1/2-mutant cancers, in particular after the emergence of PARPi resistance, these data suggest are consistent with an underlying HR defect in IDH1/2-mutant gliomas. These preclinical investigations will provide a blueprint for future clinical trials combining PARP and ATR inhibitors in the treatment of glioblastoma.

Impact of metformin on outcomes in patients (pts) with metastatic renal cell carcinoma (mRCC): Results from a pooled clinical trials database.

2016 ◽  
Vol 34 (2_suppl) ◽  
pp. 531-531
Author(s):  
Lana Hamieh ◽  
Rana R. McKay ◽  
Suzanne S Mickey ◽  
Xun Lin ◽  
Ronit Simantov ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Cox Regression ◽  
Mapk Pathway ◽  
Risk Groups ◽  
Diabetic Patients ◽  
First Line Therapy ◽  
Kaplan Meier ◽  
Tumor Types ◽  
Phase Ii And Iii

531 Background: Metformin has been shown to confer anti-neoplastic properties in several tumor types. Its effect on outcomes in mRCC patients has not been completely characterized. In this study, we evaluated the role of metformin on survival outcomes in pts with mRCC. Methods: We conducted a retrospective study of pts with mRCC treated on several phase II and III clinical trials from 2003-2013. We analyzed overall survival (OS) in the metformin users versus non-users using the Cox regression model and the Kaplan-Meier method. Results: We identified 4,736 pts with mRCC including 486 diabetic pts of whom 218 (4.6%) were metformin users. The majority were <65 years of age (69%), male (71%), with clear-cell histology (89%) and prior nephrectomy (70%). With regard to IMDC risk groups, 14%, 42%, and 24% had favorable, intermediate, and poor-risk disease, respectively. Pts received treatment with sunitinib (n=1,059), sorafenib (n=772), axitinib (n=896), temsirolimus (TEM) (n=457), TEM + interferon (IFN)-α (n=208), bevacizumab (BEV) + TEM (n=393), BEV + IFN-α (n=391), or IFN-α (n=560); overall 3,044 (64%) received first-line therapy. In the total cohort, metformin use did not impact OS when compared to users of other anti-diabetic agents (p=0.17) or non-diabetics (p=0.69). In diabetic pts, metformin use did not confer a survival advantage when stratified by type of therapy and IMDC risk group. However, in the cohort of diabetic pts receiving sunitinib (n=128), metformin use was associated with an improvement in OS when compared to users of non-metformin anti-diabetic agents (29.3 versus 20.9 months, respectively, p=0.0008, HR 0.051, 95% CI 0.009, 0.292). Conclusions: This is the largest study to date investigating the role of metformin on outcomes in mRCC pts. In this analysis, we demonstrate that concomitant use of metformin may improve survival in diabetic pts with mRCC treated with sunitinib. Based on preclinical data, we hypothesize that the mechanism underlying this survival benefit may be related to synergistic inhibition of the MAPK pathway. However, the study is limited by the small number of diabetic patients. Larger prospective studies are warranted to validate these results.

scholarly journals Current status and novel directions in triple negative breast cancer patients. Risk factors. Role of the platinum-based chemotherapy

2016 ◽  
Vol 11 (2) ◽  
pp. 122-126
Author(s):  
Olivia IONESCU ◽  
◽  
Irina BALESCU ◽  
Nicolae BACALBASA ◽  
◽  
...  
Keyword(s):  
Breast Cancer ◽  
Risk Factors ◽  
Clinical Trials ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Controlled Vocabulary ◽  
Current Status ◽  
Platinum Based Chemotherapy ◽  
Therapeutic Possibilities

Rationale. Breast cancer (BC) has been recognized to be the most common type of cancer in women all over the world. One of the most aggressive subtype of BC is the triple negative breast cancer (TNBC) which is defined by the absence of estrogen receptor (ER) and progesterone receptor (PR) as well as the lack of overexpression of the human epidermal growth factor 2 (HER 2). Aim. As the estrogen and progesterone receptors as well as the expression of HER2 are lacking, a targeted therapy with anti-hormone agents and anti-HER2 cannot be utilized, the therapeutic possibilities for TNBC women are limited. The aim of this review is to present the current scientific data as well as the latest research in TNBC with focus on the risk factors as well as the current role of platinum-based chemotherapeutic agents and their future implications in TNBC treatment. Method. Information about the risk factors associated to TNBC as well as the chemotherapeutic regimens was searched through Pubmed and Medline using controlled vocabulary (e.g. breast cancer) and key words (e.g. neoadjuvant, triple negative, platinum). Systematic reviews, randomized and controlled clinical trials were analyzed. No restrictions regarding date or language were used. Conclusions. TNBC is a complex and heterogeneous disease, divided into many subtypes and with an aggressive evolution. Premenopausal women and African American women are far more likely to develop TNBC. More research is required in order to confirm the association between obesity, BMI, parity, use of oral contraceptives, alcohol and cigarette smoking and TNBC. Randomized clinical trials presented at the San Antonio Symposium suggest that platinum chemotherapy play an important role in the treatment of TNBC, especially early stage TNBC. Tumor-based measures of genomic instability will help to clarify the optimal use and activity of platinum in TNBC. However, it is clear than more epidemiological studies as well as the discovery of novel therapeutic possibilities are mandatory in order to unravel the complexity of this BC subtype, hence offering a chance to women diagnosed with TNBC.

scholarly journals Platelet Function and Therapeutic Applications in Dogs: Current Status and Future Prospects

Animals ◽  
2020 ◽  
Vol 10 (2) ◽  
pp. 201
Author(s):  
Laura Cortese ◽  
Pete W. Christopherson ◽  
Alessandra Pelagalli
Keyword(s):  
Platelet Function ◽  
Platelet Rich Plasma ◽  
Functional Characterization ◽  
Current Status ◽  
Significant Progress ◽  
Therapeutic Benefits ◽  
Platelet Structure ◽  
Made In

Significant progress has been made in the functional characterization of canine platelets in the last two decades. The role of canine platelets in hemostasis includes their adhesion to the subendothelium, activation, and aggregation, leading to primary clot formation at the site of injury. Studies on canine platelet function and advancements in laboratory testing have improved the diagnosis and understanding of platelet-related disorders as well as the knowledge of the mechanisms behind these diseases. This review focuses on the most recent discoveries in canine platelet structure, function, and disorders; and discusses the efficacy of various tests in the diagnosis of platelet-related disorders. With the relatively recent discovery of angiogenetic and reparative effects of growth factors found in platelets, this review also summarizes the use of canine platelet-rich plasma (PRP) alone or in association with stem cells in regenerative therapy. The characterization of proteomic and lipidomic profiles and development of platelet gene therapy in veterinary species are areas of future study with potential for major therapeutic benefits.

Small Molecules Targeting Mutant P53: A Promising Approach for Cancer Treatment

2020 ◽  
Vol 26 (41) ◽  
pp. 7323-7336 ◽  
Author(s):  
Elizabeth A. Lopes ◽  
Sara Gomes ◽  
Lucília Saraiva ◽  
Maria M.M. Santos
Keyword(s):  
Clinical Trials ◽  
Small Molecules ◽  
Poor Prognosis ◽  
Therapeutic Strategy ◽  
Colorectal Cancers ◽  
Mutant P53 ◽  
P53 Mutations ◽  
Wild Type ◽  
Tumor Types ◽  
Mutant Forms

: More than half of all human tumors express mutant forms of p53, with the ovary, lung, pancreas, and colorectal cancers among the tumor types that display the highest prevalence of p53 mutations. In addition, the expression of mutant forms of p53 in tumors is associated with poor prognosis due to increased chemoresistance and invasiveness. Therefore, the pharmacological restoration of wild-type-like activity to mutant p53 arises as a promising therapeutic strategy against cancer. This review is focused on the most relevant mutant p53 small molecule reactivators described to date. Despite some of them have entered into clinical trials, none has reached the clinic, which emphasizes that new pharmacological alternatives, particularly with higher selectivity and lower adverse toxic side effects, are still required.

High expression of CD52 predicts poor prognosis of cytogenetic normal acute myeloid leukemia

2020 ◽  
Author(s):  
Ping Cai ◽  
Wenzhi Cai ◽  
Xiaoyu Xu ◽  
xiaofei Yang ◽  
yemin Wang ◽  
...  
Keyword(s):  
Gene Expression ◽  
Myeloid Leukemia ◽  
Poor Prognosis ◽  
Leukemia Cell ◽  
Dna Demethylation ◽  
Rank Test ◽  
Log Rank Test ◽  
High Level ◽  
Acute Myeloid

Abstract Background: The prognosis of cytogenetic normal acute myeloid leukemia (CN-AML) varies. Finding new biomarkers affecting the prognosis of these patients may bring a new strategy for precise classification and treatment. CD52 play a significant role in chronic lymphocytic leukemia (CLL). However, the potential role of CD52 in CN-AML remains largely elusive. Methods: We analyzed the prognostic role of different expression levels of CD52 in 58 CN-AML from The Cancer Genome Atlas (TCGA) dataset and validate these results with 345 CN-AML patients from Gene Expression Omnibus (GEO) dataset. Results: CN-AML patients with high CD52 mRNA expression have a poorer prognosis compared to low CD52 expression ( event-free survival [EFS], P =0.056; overall survival [OS], P=0.043; log-rank test) and the results was verified by GSE12417 (OS, P=0.0197; log-rank test) and GSE71014 (OS, P=0.0197; log-rank test). Hematopoietic stem cell transplantation (HSCT) may improve prognosis of patients with CD52 high . Multivariate cox regression analysis show that the expression level of CD52 (HR=1.503; 95%CI:1.158-1.949 ; P=0.002) was a prognostic factor independent of age (HR=3.045; 95%CI:1.524-6.086; P=0.002) and FLT3 mutation status (HR=2.219; 95%CI:1.123-4.382; P=0.022). CD52 gene expression show a predictive effect on EFS (1-year survival- area under the curve [AUC]:0.685, 2-year survival-AUC:0.752) and OS (1-year survival-AUC: 0.717, 2-year survival-AUC:0.770). Besides, we also found that there is a significant negative correlation between CD52 mRNA expression and DNA methylation . CD52 DNA demethylation may responsible for the high level of CD52 mRNA. Functional enrichment analysis of differentially expressed genes in CD52 high and CD52 low suggests that leukemia cell adhesion-related pathways may be associated with poor prognosis in CD52 high patients . Conclusions: CD52 gene mRNA overexpression is an independent adverse prognostic factor for CN-AML, which could be reversed by HSCT. CD52 DNA demethylation may responsible for the high level of CD52 mRNA. The poor prognosis of patients with CD52 high may involves in leukemia cell adhesion-related pathways. Whether CD52 monoclonal antibodies play a role in high risk patients need further research.

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