scholarly journals Whole Blood Transcriptome Profiling Identifies DNA Replication and Cell Cycle Regulation as Early Marker of Response to Anti-PD-1 in Patients with Urothelial Cancer

Cancers ◽  
2021 ◽  
Vol 13 (18) ◽  
pp. 4660
Author(s):  
Sandra van Wilpe ◽  
Victoria Wosika ◽  
Laura Ciarloni ◽  
Sahar Hosseinian Ehrensberger ◽  
Rachel Jeitziner ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Dna Replication ◽  
Whole Blood ◽  
Clinical Benefit ◽  
Cell Cycle Regulation ◽  
Urothelial Cancer ◽  
Transcriptome Profiling ◽  
Ki 67 ◽  
Cycle Regulation ◽  
Blood Transcriptome

Although immune checkpoint inhibitors improve median overall survival in patients with metastatic urothelial cancer (mUC), only a minority of patients benefit from it. Early blood-based response biomarkers may provide a reliable way to assess response weeks before imaging is available, enabling an early switch to other therapies. We conducted an exploratory study aimed at the identification of early markers of response to anti-PD-1 in patients with mUC. Whole blood RNA sequencing and phenotyping of peripheral blood mononuclear cells were performed on samples of 26 patients obtained before and after 2 to 6 weeks of anti-PD-1. Between baseline and on-treatment samples of patients with clinical benefit, 51 differentially expressed genes (DEGs) were identified, of which 37 were upregulated during treatment. Among the upregulated genes was PDCD1, the gene encoding PD-1. STRING network analysis revealed a cluster of five interconnected DEGs which were all involved in DNA replication or cell cycle regulation. We hypothesized that the upregulation of DNA replication/cell cycle genes is a result of T cell proliferation and we were able to detect an increase in Ki-67+ CD8+ T cells in patients with clinical benefit (median increase: 1.65%, range −0.63 to 7.06%, p = 0.012). In patients without clinical benefit, no DEGs were identified and no increase in Ki-67+ CD8+ T cells was observed. In conclusion, whole blood transcriptome profiling identified early changes in DNA replication and cell cycle regulation genes as markers of clinical benefit to anti-PD-1 in patients with urothelial cancer. Although promising, our findings require further validation before implementation in the clinic.

scholarly journals Targeting Non-Oncogene Addiction for Cancer Therapy

Biomolecules ◽  
2021 ◽  
Vol 11 (2) ◽  
pp. 129
Author(s):  
Hae Ryung Chang ◽  
Eunyoung Jung ◽  
Soobin Cho ◽  
Young-Jun Jeon ◽  
Yonghwan Kim
Keyword(s):  
Cell Cycle ◽  
Dna Replication ◽  
Cancer Therapy ◽  
Cell Cycle Regulation ◽  
Synthetic Lethality ◽  
Current Knowledge ◽  
Cancer Therapies ◽  
Oncogene Addiction ◽  
Clinical Biomarkers ◽  
Cycle Regulation

While Next-Generation Sequencing (NGS) and technological advances have been useful in identifying genetic profiles of tumorigenesis, novel target proteins and various clinical biomarkers, cancer continues to be a major global health threat. DNA replication, DNA damage response (DDR) and repair, and cell cycle regulation continue to be essential systems in targeted cancer therapies. Although many genes involved in DDR are known to be tumor suppressor genes, cancer cells are often dependent and addicted to these genes, making them excellent therapeutic targets. In this review, genes implicated in DNA replication, DDR, DNA repair, cell cycle regulation are discussed with reference to peptide or small molecule inhibitors which may prove therapeutic in cancer patients. Additionally, the potential of utilizing novel synthetic lethal genes in these pathways is examined, providing possible new targets for future therapeutics. Specifically, we evaluate the potential of TONSL as a novel gene for targeted therapy. Although it is a scaffold protein with no known enzymatic activity, the strategy used for developing PCNA inhibitors can also be utilized to target TONSL. This review summarizes current knowledge on non-oncogene addiction, and the utilization of synthetic lethality for developing novel inhibitors targeting non-oncogenic addiction for cancer therapy.

scholarly journals Erratum to: Effects of flavonoids on expression of genes involved in cell cycle regulation and DNA replication in human fibroblasts

2016 ◽  
Vol 424 (1-2) ◽  
pp. 211-211
Author(s):  
Marta Moskot ◽  
Joanna Jakóbkiewicz-Banecka ◽  
Elwira Smolińska ◽  
Ewa Piotrowska ◽  
Grzegorz Węgrzyn ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Dna Replication ◽  
Cell Cycle Regulation ◽  
Human Fibroblasts ◽  
Expression Of Genes ◽  
Cycle Regulation

Modulation of Gene Expression Profile and In Vivo Anti-Myeloma Activity Induced by Valproic Acid, a Histone Deacytylase Inhibitor.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 4790-4790
Author(s):  
Paola Neri ◽  
Teresa Calimeri ◽  
Mariateresa Di Martino ◽  
Marco Rossi ◽  
Orietta Eramo ◽  
...  
Keyword(s):  
Gene Expression ◽  
Cell Cycle ◽  
Valproic Acid ◽  
Dna Replication ◽  
Gene Expression Profile ◽  
Cell Cycle Regulation ◽  
Cycle Regulation ◽  
Anti Tumor Activity

Abstract Valproic acid (VPA) is a well-tolerated anticonvulsant drug that has been recently recognized as powerful histone deacetylase (HDCA) inhibitor. VPA induces hyperacetylation of histone H3 and H4 and inhibits both class I and II HDCACs. Recently it has been shown that VPA exerts in vitro and in vivo anti-tumor activity against solid cancers and its in vitro anti-Multiple Myeloma (MM) activity has been previously reported. However, the molecular mechanisms are still unclear. Here we have investigated molecular changes induced by VPA as well as its in vivo activity in murine models of MM. We first studied the in vitro activity of VPA against IL-6 independent as well as IL-6 dependent MM cells. A time- and dose-dependent decrease in proliferation and survival of MM cell lines was observed (IC50 in the range of 1–3 mM). Gene expression profile following treatment with VPA at 2 and 5 mM showed down-regulation of genes involved in cell cycle regulation, DNA replication and transcription as well as up-regulation of genes implicated in apoptosis and chemokine pathways. The signaling pathway analysis performed by Ingenuity Systems Software identified the cell growth, cell cycle, cell death as well as DNA replication and repair as the most important networks modulated by VPA treatment. We next evaluated the in vivo activity of VPA using two xenograft models of human MM. A cohort of SCID mice bearing subcutaneous MM1s or OPM1 were treated i.p. daily with VPA (200 mg/kg, and 300 mg/kg, n=5 mice, respectively), or vehicle alone (n=5 mice) for 16 consecutive days. Tumors were measured every 2 days, and survival was calculated using the Kaplan Mayer method. Following VPA treatment, we found a significant (p=0.006) inhibition of tumor growth in mice bearing subcutaneous MM-1s cells treated with VPA at 200 mg/kg compared to control group, which translated into a significant (p= 0.002) survival advantage in the VPA treated animals. Similar results were obtained in animals bearing subcutaneous OPM1 cells. Flow cytometry analysis performed on retrieved tumor tissues from animals showed reduction of G2-M and S phase in tumor specimens following VPA treatment, versus untreated tumors, strongly suggesting in vivo effects of VPA on cell cycle regulation. Taken together, our data demonstrate the in vitro and in vivo anti-tumor activity of VPA, delineate potential molecular targets triggered by this agent and provide a preclinical rationale for its clinical evaluation, both as a single agent or in combination, to improve patient outcome in MM.

Association of cyclin D2 downregulation with adverse prognostic factors and survival: Analysis of D-type cyclins, cyclin E1, p27, and ki-67 mRNA in breast carcinomas.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. e22208-e22208
Author(s):  
Helena Brizova ◽  
Marcela Mrhalova ◽  
Roman Kodet
Keyword(s):  
Cell Cycle ◽  
Cyclin D1 ◽  
Cell Cycle Regulation ◽  
Mrna Level ◽  
Breast Carcinomas ◽  
Time To Event ◽  
Cyclin D2 ◽  
Ki 67 ◽  
Quantitative Level ◽  
Cycle Regulation

e22208 Background: In a normal mammary gland D-type and E1 cyclins play a significant role in the cell cycle control. Not surprisingly, they are considered to have an oncogenic potential and belong among the most commonly overexpressed genes in breast cancer. Besides, cyclin D2 overexpression is associated with an inhibition of cyclin D1 phosphorylation and with an increase of the p27 inhibitor. Such a complex cell cycle regulation is realized at the quantitative level and results in the proliferation activity control. Therefore, we analyzed the molecules involved in the cell cycle regulation together with the proliferation marker Ki-67 at the quantitative level. Methods: We examined cyclin D1, D2, D3, E1, and p27 and Ki-67 mRNA level by qRT-PCR in 95 fresh frozen invasive ductal breast carcinomas and in 15 non-neoplastic breast tissues. In patients with the carcinoma we correlated the mRNA levels with the ERBB-2 positivity, estrogen and progesterone receptor status, proliferation rate, cyclin D1 protein expression, CCDN1 gene amplification, grade, lymph node status, tumor size and age at diagnosis. We looked for a correlation with overall survival and time to event in 70 patients with available long term follow-up data. Results: The only significant association found in this analysis related to cyclin D2. In comparison with non-neoplastic controls we observed cyclin D2 mRNA down-regulation in breast carcinomas and it was inversely correlated with a higher tumor grade and its greater size, which are considered as parameters related to a less favorable prognosis. Moreover, cyclin D2 mRNA down-regulation together with cyclin D1 and D3 up-regulation revealed a significant association with decreased overall survival and time to event in multivariate analysis. Conclusions: The data indicate that down-regulated cyclin D2 mRNA correlates with a greater malignant potential of breast carcinoma. Thus, establishing cyclin D2 mRNA level may be used as a prognostically relevant investigation and along with other prognostically related data it has a potential in helping to identify patients with an adverse prognosis. Support CZ.2.16/3.1.00/24022 and 00064203.

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