scholarly journals Potential Biomarkers for Treatment Response to the BCL-2 Inhibitor Venetoclax: State of the Art and Future Directions

Cancers ◽  
2021 ◽  
Vol 13 (12) ◽  
pp. 2974
Author(s):  
Haneen T. Salah ◽  
Courtney D. DiNardo ◽  
Marina Konopleva ◽  
Joseph D. Khoury

Intrinsic apoptotic pathway dysregulation plays an essential role in all cancers, particularly hematologic malignancies. This role has led to the development of multiple therapeutic agents targeting this pathway. Venetoclax is a selective BCL-2 inhibitor that has been approved for the treatment of chronic lymphoid leukemia and acute myeloid leukemia. Given the reported resistance to venetoclax, understanding the mechanisms of resistance and the potential biomarkers of response is crucial to ensure optimal drug usage and improved patient outcomes. Mechanisms of resistance to venetoclax include alterations involving the BH3-binding groove, BCL2 gene mutations affecting venetoclax binding, and activation of alternative anti-apoptotic pathways. Moreover, various potential genetic biomarkers of venetoclax resistance have been proposed, including chromosome 17p deletion, trisomy 12, and TP53 loss or mutation. This manuscript provides an overview of biomarkers that could predict treatment response to venetoclax.

Tumor Biology ◽  
2017 ◽  
Vol 39 (3) ◽  
pp. 101042831769501 ◽  
Author(s):  
Isha Rani ◽  
Bhoomika Sharma ◽  
Sandeep Kumar ◽  
Satinder Kaur ◽  
Navneet Agnihotri

5-Fluorouracil has been considered as a cornerstone therapy for colorectal cancer; however, it suffers from low therapeutic response rate and severe side effects. Therefore, there is an urgent need to increase the clinical efficacy of 5-fluorouracil. Recently, fish oil rich in n-3 polyunsaturated fatty acids has been reported to chemosensitize tumor cells to anti-cancer drugs. This study is designed to understand the underlying mechanisms of synergistic effect of fish oil and 5-fluorouracil by evaluation of tumor cell–associated markers such as apoptosis and DNA damage. The colon cancer was developed by administration of N,N-dimethylhydrazine dihydrochloride and dextran sulfate sodium salt. Further these animals were treated with 5-fluorouracil, fish oil, or a combination of both. In carcinogen-treated animals, a decrease in DNA damage and apoptotic index was observed. There was also a decrease in the expression of Fas, FasL, caspase 8, and Bax, and an increase in Bcl-2. In contrast, administration of 5-fluorouracil and fish oil as an adjuvant increased both DNA damage and apoptotic index by activation of both extrinsic and intrinsic apoptotic pathways as compared to the other groups. The increased pro-apoptotic effect by synergism of 5-fluorouracil and fish oil may be attributed to the incorporation of n-3 polyunsaturated fatty acids in membrane, which alters membrane fluidity in cancer cells. In conclusion, this study highlights that the induction of apoptotic pathway by fish oil may increase the susceptibility of tumors to chemotherapeutic regimens.


2021 ◽  
Vol 7 (1) ◽  
Author(s):  
Yuan-hui Li ◽  
Shuang Shen ◽  
Tong Shao ◽  
Meng-ting Jin ◽  
Dong-dong Fan ◽  
...  

AbstractMesenchymal stem cell (MSC) therapy has become a promising treatment for liver fibrosis due to its predominant immunomodulatory performance in hepatic stellate cell inhibition and fibrosis resolution. However, the cellular and molecular mechanisms underlying these processes remain limited. In the present study, we provide insights into the functional role of bone marrow-derived MSCs (BM-MSCs) in alleviating liver fibrosis by targeting intrahepatic Ly6Chi and Ly6Clo macrophage subsets in a mouse model. Upon chronic injury, the Ly6Chi subset was significantly increased in the inflamed liver. Transplantation of BM-MSCs markedly promoted a phenotypic switch from pro-fibrotic Ly6Chi subset to restorative Ly6Clo subpopulation by secreting paracrine cytokines IL-4 and IL-10 from the BM-MSCs. The Ly6Chi/Ly6Clo subset switch significantly blocked the source of fibrogenic TGF-β, PDGF, TNF-α, and IL-1β cytokines from Ly6Chi macrophages. Unexpectedly, BM-MSCs experienced severe apoptosis and produced substantial apoptotic bodies in the fibrotic liver during the 72 h period of transplantation. Most apoptotic bodies were engulfed by Ly6Clo macrophages, and this engulfment robustly triggered MMP12 expression for fibrosis resolution through the PtdSer-MerTK-ERK signaling pathway. This paper is the first to show previously unrecognized dual regulatory functions of BM-MSCs in attenuating hepatic fibrosis by promoting Ly6Chi/Ly6Clo subset conversion and Ly6Clo macrophage restoration through secreting antifibrogenic-cytokines and activating the apoptotic pathway.


Blood ◽  
2017 ◽  
Vol 129 (10) ◽  
pp. 1260-1269 ◽  
Author(s):  
Borja Saez ◽  
Matthew J. Walter ◽  
Timothy A. Graubert

Abstract Alternative splicing generates a diversity of messenger RNA (mRNA) transcripts from a single mRNA precursor and contributes to the complexity of our proteome. Splicing is perturbed by a variety of mechanisms in cancer. Recurrent mutations in splicing factors have emerged as a hallmark of several hematologic malignancies. Splicing factor mutations tend to occur in the founding clone of myeloid cancers, and these mutations have recently been identified in blood cells from normal, healthy elderly individuals with clonal hematopoiesis who are at increased risk of subsequently developing a hematopoietic malignancy, suggesting that these mutations contribute to disease initiation. Splicing factor mutations change the pattern of splicing in primary patient and mouse hematopoietic cells and alter hematopoietic differentiation and maturation in animal models. Recent developments in this field are reviewed here, with an emphasis on the clinical consequences of splicing factor mutations, mechanistic insights from animal models, and implications for development of novel therapies targeting the precursor mRNA splicing pathway.


2019 ◽  
Vol 20 (16) ◽  
pp. 3951 ◽  
Author(s):  
Marzia Del Re ◽  
Stefania Crucitta ◽  
Giulia Gianfilippo ◽  
Antonio Passaro ◽  
Iacopo Petrini ◽  
...  

Liquid biopsy has emerged as an alternative source of nucleic acids for the management of Epidermal Growth Factor Receptor (EGFR)-mutant non-Small Cell Lung Cancer (NSCLC). The use of circulating cell-free DNA (cfDNA) has been recently introduced in clinical practice, resulting in the improvement of the identification of druggable EGFR mutations for the diagnosis and monitoring of response to targeted therapy. EGFR-dependent (T790M and C797S mutations) and independent (Mesenchymal Epithelial Transition [MET] gene amplification, Kirsten Rat Sarcoma [KRAS], Phosphatidyl-Inositol 4,5-bisphosphate 3-Kinase Catalytic subunit Alpha isoform [PI3KCA], and RAF murine sarcoma viral oncogene homolog B1 [BRAF] gene mutations) mechanisms of resistance to EGFR tyrosine kinase inhibitors (TKIs) have been evaluated in plasma samples from NSCLC patients using highly sensitive methods (i.e., digital droplet PCR, Next Generation Sequencing), allowing for the switch to other therapies. Therefore, liquid biopsy is a non-invasive method able to detect the molecular dynamic changes that occur under the pressure of treatment, and to capture tumor heterogeneity more efficiently than is allowed by tissue biopsy. This review addresses how liquid biopsy may be used to guide the choice of treatment strategy in EGFR-mutant NSCLC.


2019 ◽  
Vol 39 (5) ◽  
Author(s):  
Dongxu Zhang ◽  
Houxian Liu ◽  
Binbin Yang ◽  
Jiasheng Hu ◽  
Yue Cheng

Abstract The present study aims to evaluate the anticancer effect of L-securinine on androgen-independent prostate cancer (AIPC) DU145 cells. L-securinine (2.5, 5, and 10 μM) treatment for 24, 48 and 72 h displayed strong growth inhibitory effect on DU145 cells in a concentration and time-dependent fashion but has less toxicity toward normal androgen-dependent LNCaP cells. Hoechst 332582 staining of DU145 cells and Annexin V-FITC/ PI dual-labeling followed by flow cytometry assay identified that this growth inhibition by L-securinine would be due to the induction of apoptosis. Moreover Transwell assay revealed that L-securinine significantly inhibited the cell migration/invasion ability of DU145 cells. Furthermore, results of western blotting showed that the involvement of mitochondrial apoptotic pathway in the L-securinine-induced apoptosis of DU145 cell, as evidenced by an increase in the protein expression of Bax, cleaved caspase-9, cleaved caspase-3, cytosolic cytochrome c, and cleaved PARP, together with a unchanged cleaved caspase-8 and decreased Bcl-2 protein expression. Also, L-securinine-induced antimetastatic activity in DU145 cells was associated with decreased protein expression of MMP-2 and MMP-9 and concurrent reduction of VEGF. In addition, further studies revealed that L-securinine may inhibit the protein expression of AGTR1, p-MEK1/2, p-ERK1/2, p-STAT3, PAX2, and p-PAX2, while the expression of ERK1/2, MEK1/2, and STAT3 protein retains intact. These findings suggest that L-securinine may be a promising chemopreventive agent against AIPC.


2019 ◽  
Vol 2 (2) ◽  
pp. 100-109 ◽  
Author(s):  
Manni Wang ◽  
Liu Yu ◽  
Xiawei Wei ◽  
Yuquan Wei

AbstractEarly studies shed light on the immune suppression of immune checkpoint molecules in the cancer microenvironment, with later studies applying immune checkpoint blockade (ICB) in treatment of various malignancies. Despite the encouraging efficacy of ICBs in a substantial subset of cancer patients, the treatment response varies. Gene mutations of both tumor cells and immune cells in the tumor microenvironment have recently been identified as potential predictors of the ICB response. Recent developments in gene expression profiling of tumors have allowed identification of a panel of mutated genes that may affect tumor cell response to ICB treatment. In this review, we discuss the association of the ICB response with gene expression and mutation profiles in tumor cells, which it is hoped will help to optimize the clinical application of ICBs in cancer patients.


Cells ◽  
2019 ◽  
Vol 8 (9) ◽  
pp. 1038 ◽  
Author(s):  
Yang ◽  
Li ◽  
Gu ◽  
Li ◽  
Cui

We have previously observed the predominant expression of nucleoporin 62-like (Nup62l) mRNA in the pharyngeal region of zebrafish, which raises the question whether Nup62l has important implications in governing the morphogenesis of pharyngeal arches (PA) in zebrafish. Herein, we explored the functions of Nup62l in PA development. The disruption of Nup62l with a CRISPR/Cas9-dependent gene knockout approach led to defective PA, which was characterized by a thinned and shortened pharyngeal region and a significant loss of pharyngeal cartilages. During pharyngeal cartilage formation, prechondrogenic condensation and chondrogenic differentiation were disrupted in homozygous nup62l-mutants, while the specification and migration of cranial neural crest cells (CNCCs) were unaffected. Mechanistically, the impaired PA region of nup62l-mutants underwent extensive apoptosis, which was mainly dependent on activation of p53-dependent apoptotic pathway. Moreover, aberrant activation of a series of apoptotic pathways in nup62l-mutants is closely associated with the inactivation of Wnt/β-catenin signaling. Thus, these findings suggest that the regulation of Wnt/β-catenin activity by Nup62l is crucial for PA formation in zebrafish.


Blood ◽  
1991 ◽  
Vol 77 (6) ◽  
pp. 1153-1156 ◽  
Author(s):  
K Sugimoto ◽  
H Toyoshima ◽  
R Sakai ◽  
K Miyagawa ◽  
K Hagiwara ◽  
...  

Abstract p53 is currently considered to be a tumor suppressor gene product, and its alterations are suggested to be involved in several human malignancies. Here we show evidence of the possible involvement of p53 gene mutations in lymphoid leukemias studied by reverse transcriptase- polymerase chain reaction, single strand conformation polymorphism analysis, and nucleotide sequencing. Fourteen patients with various leukemias were examined and two with acute lymphoblastic leukemia and one with Waldenstrom's macroglobulinemia were identified to have mutations in the coding region of the p53 gene. These mutations included point mutation, triplet deletion, and single nucleotide insertion. Furthermore, expression of the wild-type p53 mRNA was not detected in the samples from these three patients. In one of them, chromosome 17p was deleted, suggesting the absence of the nonmutated p53 gene, whereas in the other two patients, chromosome 17p seemed to be intact by cytogenetic analysis. Our results suggest that alterations of the p53 gene may have a role in the genesis of some leukemias.


Sarcoma ◽  
2002 ◽  
Vol 6 (1) ◽  
pp. 27-42 ◽  
Author(s):  
R. J. Olsen ◽  
S. R. Tarantolo ◽  
S. H. Hinrichs

Soft tissue sarcomas comprise a heterogeneous group of aggressive tumors that have a relatively poor prognosis. Although conventional therapeutic regimens can effectively cytoreduce the overall tumor mass, they fail to consistently achieve a curative outcome. Alternative gene-based approaches that counteract the underlying neoplastic process by eliminating the clonal aberrations that potentiate malignant behavior have been proposed. As compared to the accumulation of gene alterations associated with epithelial carcinomas, sarcomas are frequently characterized by the unique presence of a single chromosomal translocation in each histological subtype. Similar to the Philadelphia chromosome associated with CML, these clonal abnormalities result in the fusion of two independent unrelated genes to generate a unique chimeric protein that displays aberrant activity believed to initiate cellular transformation. Secondary gene mutations may provide an additional growth advantage that further contributes to malignant progression. The recent clinical success of the tyrosine kinase inhibitor, STI571, suggests that therapeutic approaches specifically directed against essential survival factors in sarcoma cells may be effective. This review summarizes published approaches targeting a specific molecular mechanism associated with sarcomagenesis. The strategy and significance of published translational studies in six distinct areas are presented. These include: (1) the disruption of chimeric transcription factor activity; (2) inhibition of growth stimulatory post-translational modifications; (3) restoration of tumor suppressor function; (4) interference with angiogenesis; (5) induction of apoptotic pathways; and (6) introduction of toxic gene products. The potential for improving outcomes in sarcoma patients and the conceptual obstacles to be overcome are discussed.


Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 2536-2536
Author(s):  
Rasim Gucalp ◽  
Karl Insogna ◽  
Mimi Hu ◽  
Ilya Glezerman ◽  
Sophie Leboulleux ◽  
...  

Abstract Background Hypercalcemia of malignancy (HCM) is a serious complication in patients with advanced cancer, including those with hematologic malignancies. HCM is commonly treated with intravenous (IV) bisphosphonates, but HCM may persist or relapse despite bisphosphonate therapy. Denosumab (XGEVA®) is a fully human monoclonal antibody that binds to RANK ligand (RANKL) to inhibit osteoclast-mediated bone resorption. Methods In this single-arm, open-label study, patients with solid tumors or hematologic malignancies who had HCM (corrected serum calcium [CSC] >12.5 mg/dL) despite IV bisphosphonate treatment ≥7 and ≤30 days before screening received subcutaneous denosumab 120 mg on days 1, 8, 15, and 29, then every 4 weeks thereafter. The primary endpoint was the proportion of patients who had a treatment response (defined as CSC ≤11.5 mg/dL) within 10 days of denosumab initiation. Key secondary endpoints included the proportion of patients with a treatment response at each study visit and the proportion of patients with a complete response (defined as CSC ≤10.8 mg/dL) by day 10 or at each study visit. This ad hoc analysis summarizes results for patients with hematologic malignancies. Results The study enrolled 33 patients, of whom 9 had hematologic malignancies (5 myeloma, 2 non-Hodgkin lymphoma, 2 chronic lymphocytic leukemia [CLL] with Richter's transformation). Key baseline characteristics are shown in the Table. By day 10, 21 of the 33 patients in the study (64%) had a treatment response. Also by day 10, all 9 patients (100%) with hematologic malignancies had a treatment response, and 5 of 9 (56%) had a complete response. Eight of the 9 hematologic malignancy patients (89%) had a complete response over the course of the study. The most frequently reported serious adverse events (SAEs) in the overall study population were worsening of hypercalcemia (n=5, 15%) and dyspnea (n=3, 9%). In patients with hematologic malignancies, disease progression was reported in 2 patients (22%), and worsening of hypercalcemia was reported in 1 patient (11%); all other SAEs occurred in only 1 patient each. Two patients, including 1 with CLL, had isolated episodes of CSC levels ≤8.0 mg/dL; none had CSC <7.0 mg/dL. No osteonecrosis of the jaw was reported. Conclusions In this ad hoc analysis from a study of patients with persistent or relapsed HCM despite recent IV bisphosphonate treatment, 100% of patients with hematologic malignancies responded to denosumab within 10 days. No unexpected safety findings were identified. Disclosures: Off Label Use: This abstract describes the use of denosumab for the treatment of hypercalcemia of malignancy, which is investigational and not an approved indication for denosumab. Hu:Amgen Inc.: Research Funding. Glezerman:Amgen Inc.: Research Funding. Misiorowski:Amgen Inc.: Research Funding. Zorsky:Galena Biopharma: Equity Ownership; RxI: Equity Ownership. Tosi:Novartis: Research Funding. Ying:Amgen Inc.: Employment. Braun:Amgen Inc.: Employment, Equity Ownership. Jain:Amgen Inc.: Employment.


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