Chromatin Stability as a Target for Cancer Treatment
In this essay, I propose that DNA-binding anti-cancer drugs work more via chromatin disruption than DNA damage.
Role of Chromatin Damage and Chromatin Trapping of FACT in Mediating the Anticancer Cytotoxicity of DNA-Binding Small-Molecule Drugs
DNA-targeting small molecules have been widely used for cancer treatment for many years
Mechanism of FACT removal from transcribed genes by anticancer drugs curaxins
Human FACT (facilitates chromatin transcription) is a multifunctional protein complex that has histone chaperone activity and facilitates nucleosome survival and transcription through chromatin.
The FACT inhibitor CBL0137 Synergizes with Cisplatin in Small-Cell Lung Cancer by Increasing NOTCH1 Expression and Targeting TumorInitiating Cells
Lung cancer is the leading cause of cancer-related deaths in the world, with more than 1.3 million fatalities annuall
TRAIN (Transcription of Repeats Activates INterferon) in response to chromatin destabilization induced by small molecules in mammalian cells
The effect of CBL0137 on gene expression may be due to its binding to DNA and the unfolding of chromatin or due to the functional inhibition of FACT.
Level of FACT defines the transcriptional landscape and aggressive phenotype of breast cancer cells.
Although breast cancer (BrCa) may be detected at an early stage, there is a shortage of markers that predict tumor aggressiveness and a lack of targeted therapies. Histone chaperone FACT, expressed in a limited number of normal cells, is overexpressed in different types of cancer, including BrCa. Recently, we found that FACT expression in BrCa correlates with markers of aggressive BrCa, which prompted us to explore the consequences of FACT inhibition in BrCa cells with varying levels of FACT.
FACT is a sensor of DNA torsional stress in eukaryotic cells
Transitions of B-DNA to alternative DNA structures (ADS) can be triggered by negative torsional strain, which occurs during replication and transcription, and may lead to genomic instability. However, how ADS are recognized in cells is unclear.
Preclinical Validation of a Single-Treatment Infusion Modality That Can Eradicate Extremity Melanomas
Isolated limb perfusion (ILP) with the chemotherapeutic agent melphalan is an effective treatment option for extremity in-transit melanoma but is toxic and technically challenging to deliver locoregionally. CBL0137 is an experimental clinical drug with broad anticancer activity in animal models, owing to its ability to bind DNA in a nongenotoxic manner and inactivate the FACT chromatin modulator essential for tumor cell viability.
Pharmacological Targeting of the Histone Chaperone Complex FACT Preferentially Eliminates Glioblastoma Stem Cells and Prolongs Survival in Preclinical Models
The nearly universal recurrence of glioblastoma (GBM) is driven in part by a treatment-resistant subpopulation of GBM stem cells (GSC). To identify improved therapeutic possibilities, we combined the EGFR/HER2 inhibitor lapatinib with a novel small molecule, CBL0137, which inhibits FACT (facilitates chromatin transcription), a histone chaperone complex predominantly expressed in undifferentiated cells.
Anticancer drug candidate CBL0137, which inhibits histone chaperone FACT, is efficacious in preclinical orthotopic models of temozolomide- responsive and -resistant glioblastoma
Glioblastoma (GBM) is the most prevalent and aggressive primary brain tumor, with a dismal 5-year survival rate of about 5%. Standard-of-care therapies, including surgery, radiation, and temozolomide chemotherapy, have brought median sur vival to almost 15 months. However, this figure has stalled.
Therapeutic targeting of the MYC signal by inhibition of FACT in neuroblastoma
Amplification of the MYCN oncogene predicts treatment resistance in childhood neuroblastoma. We used a MYC target gene signature that predicts poor neuroblastoma prognosis to identify the histone chaperone FACT (facilitates chromatin transcription) as a crucial mediator of the MYC signal and a therapeutic target in the disease.
Quinacrine Overcomes Resistance to Erlotinib by Inhibiting FACT, NF-kB, and Cell-Cycle Progression in Non–Small Cell Lung Cancer
Erlotinib is a tyrosine kinase inhibitor approved for the treatment of patients with advanced non–small cell lung cancer (NSCLC). In these patients, erlotinib prolongs survival but its benefit remains modest because many tumors express wild-type (wt) EGFR or develop a second-site EGFR mutation.
Curaxin CBL0137 eradicates drug resistant cancer stem cells
Pancreatic ductal adenocarcinoma (PDA) continues to be one of the deadliest cancers due to the absence of effective treatment. Curaxins are a class of small molecules with anti-cancer activity demonstrated in different models of cancer in mice.
Facilitates Chromatin Transcription Complex is an «Accelerator» of Tumor Transformation and Potential Marker and Target of Aggressive Cancers
The facilitates chromatin transcription (FACT) complex is involved in chromatin remodeling during transcription, replication, and DNA repair. FACT was previously considered to be ubiquitously expressed and not associated with any disease.
Targeting FACT Complex Suppresses Mammary Tumorigenesis in Her2neu Transgenic Mice
Development of safe and effective tumor-preventive treatments for high-risk patient populations and therapies for early-stage cancer remains a critical need in oncology. We have recently discovered compound with anticancer activity, Curaxin-137, which modulates several important signaling pathways involved in even the very early stages of cancer.
Expression of FACT in mammalian tissues suggests its role in maintaining of undifferentiated state of cells
The Facilitates Chromatin Transcription (FACT) chromatin remodeling complex, comprised of two subunits, SSRP1 and SPT16, is involved in transcription, replication and DNA repair. We recently showed that curaxins, small molecules with anti-cancer activity, target FACT and kill tumor cells in a FACT-dependent manner.
Cancer Drug Discovery Faces the FACT
In this issue of Science Translational Medicine, Gasparian et al. use a clever cell-based screen to identify a family of DNA-binding small molecules—curaxins—that inhibit tumor cell growth and division. The curaxins’ mechanism of action pinpoints a new chromatin-remodeling factor as a therapeutic target for cancer.
Anticancer Compounds that Simultaneously Suppress NF-kB and Activate p53 by Targeting FACT
Targeted cancer therapies offer the possibility of personalized therapies with reduced toxicity, but their impact is limited by the development of drug resistance and subsequent proliferation of tumor cells that are refractory to further treatment. Combination therapies might help overcome the resistance problem because a tumor cell is less likely to be simultaneously resistant to multiple drugs that act by distinct mechanisms, but the potential for negative drug interactions and increased toxicities causes concern in the clinic.
Gurova New hopes from old drugs revisiting DNA-binding small molecules as anticancer agents
Most of the anticancer chemotherapeutic drugs that are broadly and successfully used today are DNA-damaging agents. Targeting of DNA has been proven to cause relatively potent and selective destruction of tumor cells.
Anti-malaria drug blocks proteotoxic stress response anti-cancer implications
The number of physical conditions and chemical agents induce accumulation of misfolded
proteins creating proteotoxic stress. This leads to activation of adaptive pro-survival pathway, known as heat shock response (HSR), resulting in expression of additional chaperones.
9-Aminoacridine-based anticancer drugs target the PI3KAKTmTOR, NF-kB and p53 pathways
Acquisition of a transformed phenotype involves deregulation of several signal transduction pathways contributing to unconstrained cell growth. Understanding the interplay of different cancer-related signaling pathways is important for development of efficacious multitargeted anticancer drugs.
Small molecules that reactivate p53 in renal cell carcinoma reveal a NF-kB dependent mechanism of p53 supression in tumors
Renal cell carcinomas (RCC) commonly retain wild-type but func tionally inactive p53, which is repressed by an unknown dominant mechanism. To help reveal this mechanism, we screened a diverse chemical library for small molecules capable of restoring p53 dependent transactivation in RCC cells carrying a p53-responsive reporter.
p53 pathway in renal cell carcinoma is repressed by a dominant mechanism
Renal cell carcinoma (RCC) rarely acquires mutations in p53 tumor suppressor gene, suggesting that p53 signaling in this tumor type might be repressed by some other mechanism. In fact, all four RCC-derived cell lines we tested maintained wild-type p53 but were not capable of transactivating p53-responsive reporters and endogenous p53-responsive genes.