LB-100 (PP2A Inhibitor) and Azenosertib (WEE1 Inhibitor) in Metastatic Colorectal Cancer Patients
Ontology highlight
ABSTRACT:
DISEASE(S): Metastatic Colorectal Cancer,Colorectal Cancer,Colorectal Neoplasms
PROVIDER: 116295 | ecrin-mdr-crc |
REPOSITORIES: ECRIN MDR
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Project description:This Phase Ib trial studies the side effects and best dose of LB-100 when given with atezolizumab for the treatment of patients with metastatic microsatellite stable colorectal cancer. Immunotherapy with monoclonal antibodies, such as atezolizumab, may help the body’s immune system attack the cancer, and may interfere with the ability of the tumor to grow and spread. LB-100 has been shown to make anticancer drugs work better at killing cancer. LB-100 blocks a protein on the surface of cells called PP2A. Blocking this protein increases the stress signals for the tumor cells that express PP2A. Giving atezolizumab in combination with LB-100 may work better to treat metastatic colorectal cancer patients as the cancer cells that experience increased stress signals are more susceptible for the immunotherapy.
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Project description:This randomized phase II trial studies how giving a drug called levocetirizine to patients with colorectal cancer affects their tumor response to capecitabine and bevacizumab. Capecitabine is a chemotherapy drug that blocks tumor growth by disrupting DNA and RNA synthesis and repair (cell division and survival). Bevacizumab is a monoclonal antibody that blocks the ability of tumors to grow and spread by inhibiting the growth of blood vessels that feed them. Patients with colorectal cancer can develop a resistance to the effects of bevacizumab. Levocetirizine may decrease tumor resistance to bevacizumab. Giving bevacizumab, capecitabine, and levocetirizine dihydrochloride together may be an effective treatment for refractory colorectal cancer.
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Project description:The twenty-three Fanconi Anemia proteins cooperate in a DNA repair pathway, called the FA/BRCA pathway, required for the monoubiquitination of FANCD2 and the excision of interstrand DNA crosslinks (ICLs). The CCAR1 (cell division cycle and apoptosis regulator 1) protein is also a regulator of ICL repair, though its possible function in the FA/BRCA pathway remains unknown. Here, we demonstrate that CCAR1 plays a unique upstream role in the FA/BRCA pathway and is required for FANCA protein expression and FANCD2 monoubiquitination. Interestingly, loss of CCAR1 results in retention of a poison exon in the FANCA transcript, thereby leading to reduced FANCA protein expression. A unique domain of CCAR1, the so-called EF-hand domain, binds to the spliceosome SF3B complex and is required for its mRNA splicing activity. Taken together, CCAR1 is a unique splicing factor, required for normal splicing of the FANCA mRNA and perhaps other mRNAs involved in various cellular pathways.
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Project description:Kollarovic2016 - Cell fate decision at G1-S
transition
This model is described in the article:
To senesce or not to
senesce: how primary human fibroblasts decide their cell fate
after DNA damage.
Kollarovic G, Studencka M, Ivanova
L, Lauenstein C, Heinze K, Lapytsko A, Talemi SR, Figueiredo AS,
Schaber J.
Aging (Albany NY) 2016 Jan;
Abstract:
Excessive DNA damage can induce an irreversible cell cycle
arrest, called senescence, which is generally perceived as an
important tumour-suppressor mechanism. However, it is unclear
how cells decide whether to senesce or not after DNA damage. By
combining experimental data with a parameterized mathematical
model we elucidate this cell fate decision at the G1-S
transition. Our model provides a quantitative and conceptually
new understanding of how human fibroblasts decide whether DNA
damage is beyond repair and senesce. Model and data imply that
the G1-S transition is regulated by a bistable hysteresis
switch with respect to Cdk2 activity, which in turn is
controlled by the Cdk2/p21 ratio rather than cyclin abundance.
We experimentally confirm the resulting predictions that to
induce senescence i) in healthy cells both high initial and
elevated background DNA damage are necessary and sufficient,
and ii) in already damaged cells much lower additional DNA
damage is sufficient. Our study provides a mechanistic
explanation of a) how noise in protein abundances allows cells
to overcome the G1-S arrest even with substantial DNA damage,
potentially leading to neoplasia, and b) how accumulating DNA
damage with age increasingly sensitizes cells for
senescence.
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2024-09-02 | BIOMD0000000632 | BioModels
Project description:The cell division protein SepF aligns polymers formed by the key cell division protein FtsZ during synthesis of the (Fts)Z-ring at midcell, the first stage in cytokinesis. In addition, SepF acts as a membrane anchor for the Z-ring. SepF is conserved in Gram-positive and cyanobacteria. Recently, it was shown that SepF overproduction in Mycobacterium smegmatis blocks cell division. Here we investigated this in more detail using the Gram-positive model system Bacillus subtilis. Surprisingly, overproduction of SepF does not interfere with assembly of the Z-ring, but blocks assembly of the late cell division proteins responsible for septum synthesis. Transposon mutagenesis suggested that SepF overproduction inactivates the WalKR two-component system involved in cell division. Indeed, SepF overproduction impairs WalK localization, possibly because septal WalK localization requires late cell division proteins. Unexpectedly, transcriptome analysis showed that WalKR activity was not affected. Another surprise was that the cell division phenotype occurs when SepF does not bind to FtsZ. Further analyses provided an explanation for the contradictory transposon and transcriptome results, and suggested that SepF competes with other cell division proteins for binding to FtsZ. Our data show that an imbalance in early cell division proteins can interfere with recruitment of late cell division proteins.
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Project description:Critical DNA repair pathways become deranged during cancer development. This vulnerability may be exploited with DNA-targeting chemotherapy. Topoisomerase II inhibitors induce double-strand breaks which are detrimental to the cell, if not repaired. This repair process requires high-fidelity functional homologous recombination or error-prone non-homologous recombination. If either of these pathways is targeted, the compensatory pathway may rescue the cells and induce treatment resistance. c-Abl is a protein tyrosine kinase that is involved in cell differentiation, cell division, cell adhesion, and stress response including DNA damage induced stress. Here we used a low dose topoisomerase II inhibitor mitoxantrone to induce DNA damage and c-Abl kinase inhibitor imatinib in combination and studied the drug effects at transcriptomic level. The microarray data suggests that DNA repair, particularly homologous recombination, is downregulated together with alterations in cell cycle regulation. The data prompted to further validation assays on functional level which are shown in the original publication.
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2016-03-13 | MSV000079577 | MassIVE
Project description:Inhibition of protein synthesis by cycloheximide blocks subsequent division of a mammalian cell, but only if the cell is exposed to the drug before the "restriction point" (i.e. within the first several hours after birth). If exposed to cycloheximide after the restriction point, a cell proceeds with DNA synthesis, mitosis and cell division and halts in the next cell cycle. If cycloheximide is later removed from the culture medium, treated cells will return to the division cycle, showing a complex pattern of division times post-treatment, as first measured by Zetterberg and colleagues. We simulate these physiological responses of mammalian cells to transient inhibition of growth, using a set of nonlinear differential equations based on a realistic model of the molecular events underlying progression through the cell cycle. The model relies on our earlier work on the regulation of cyclin-dependent protein kinases during the cell division cycle of yeast. The yeast model is supplemented with equations describing the effects of retinoblastoma protein on cell growth and the synthesis of cyclins A and E, and with a primitive representation of the signaling pathway that controls synthesis of cyclin D.
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Project description:Efficacy and safety of anticancer drugs are traditionally studied using cancer cell lines and animal models. Recently, a potential anticancer agent, JQ1, an inhibitor of bromodomain and extra terminal (BET) protein, has been shown to promote apoptosis of cancerous cells by arresting them in G1 phase of the cell cycle. However, the effect of JQ1 on normal cells is poorly understood. In this study, we investigated the safety of JQ1 by using human umbilical cord mesenchymal stem cells (MSCs) as an in vitro model system. Our results indicated that JQ1 induced cell cycle arrest in G1 phase of MSCs, but did not promote apoptosis. Microarray analysis of MSCs treated with JQ1 indicated that it down-regulated genes involved not only in cell cycle regulation but also DNA replication, mitosis, and cell division. Although many studies have suggested the potential of JQ1 as an anticancer agent, our findings suggest that it caused a deleterious effect on normal cells and may not be safe for anticancer therapy. Human umbilical cord derived MSCs were cultured in vitro and treated with either 100 nM or 500 nM JQ1 for 24 hrs. Gene expression of treated cells was compared to untreated cultured cells.
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