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Oncotarget Jun 2024Histone deacetylase inhibitors (HDACi) can modulate the acetylation status of proteins, influencing the genomic instability exhibited by cancer cells. Poly (ADP ribose)...
Histone deacetylase inhibitors (HDACi) can modulate the acetylation status of proteins, influencing the genomic instability exhibited by cancer cells. Poly (ADP ribose) polymerase (PARP) inhibitors (PARPi) have a direct effect on protein poly (ADP-ribosyl)ation, which is important for DNA repair. Decitabine is a nucleoside cytidine analogue, which when phosphorylated gets incorporated into the growing DNA strand, inhibiting methylation and inducing DNA damage by inactivating and trapping DNA methyltransferase on the DNA, thereby activating transcriptionally silenced DNA loci. We explored various combinations of HDACi and PARPi +/- decitabine (hypomethylating agent) in pancreatic cancer cell lines BxPC-3 and PL45 (wild-type BRCA1 and BRCA2) and Capan-1 (mutated BRCA2). The combination of HDACi (panobinostat or vorinostat) with PARPi (talazoparib or olaparib) resulted in synergistic cytotoxicity in all cell lines tested. The addition of decitabine further increased the synergistic cytotoxicity noted with HDACi and PARPi, triggering apoptosis (evidenced by increased cleavage of caspase 3 and PARP1). The 3-drug combination treatments (vorinostat, talazoparib, and decitabine; vorinostat, olaparib, and decitabine; panobinostat, talazoparib, and decitabine; panobinostat, olaparib, and decitabine) induced more DNA damage (increased phosphorylation of histone 2AX) than the individual drugs and impaired the DNA repair pathways (decreased levels of ATM, BRCA1, and ATRX proteins). The 3-drug combinations also altered the epigenetic regulation of gene expression (NuRD complex subunits, reduced levels). This is the first study to demonstrate synergistic interactions between the aforementioned agents in pancreatic cancer cell lines and provides preclinical data to design individualized therapeutic approaches with the potential to improve pancreatic cancer treatment outcomes.
Topics: Humans; Decitabine; Pancreatic Neoplasms; Drug Synergism; Cell Line, Tumor; Histone Deacetylase Inhibitors; Poly(ADP-ribose) Polymerase Inhibitors; Azacitidine; Apoptosis; Antineoplastic Combined Chemotherapy Protocols
PubMed: 38829622
DOI: 10.18632/oncotarget.28588 -
Therapeutic Advances in Medical Oncology 2024Despite several improvements in outcomes, metastatic prostate cancer remains deadly. Alterations in the homologous recombination repair (HRR) pathway are associated with... (Review)
Review
Despite several improvements in outcomes, metastatic prostate cancer remains deadly. Alterations in the homologous recombination repair (HRR) pathway are associated with more aggressive disease. Olaparib and rucaparib, two poly-ADP-ribose polymerase (PARP) inhibitors, have received approval from the authorities of several countries for their anti-tumoral effects in patients with metastatic castration-resistant prostate cancers harboring HRR gene alterations, in particular . More recently, it has been hypothesized that new hormonal therapies (NHTs) and PARP inhibitors (PARPi) could have synergistic actions and act independently of HRR deficiency. This review proposes to discuss the advantages and disadvantages of PARPi used as monotherapy or in combination with NHTs and whether there is a need for molecular selection.
PubMed: 38827177
DOI: 10.1177/17588359241242959 -
BioRxiv : the Preprint Server For... May 2024PARP1 and PARP2 recognize DNA breaks immediately upon their formation, generate a burst of local PARylation to signal their location, and are co-targeted by all current...
PARP1 and PARP2 recognize DNA breaks immediately upon their formation, generate a burst of local PARylation to signal their location, and are co-targeted by all current FDA-approved forms of PARP inhibitors (PARPi) used in the cancer clinic. Recent evidence indicates that the same PARPi molecules impact PARP2 differently from PARP1, raising the possibility that allosteric activation may also differ. We find that unlike for PARP1, destabilization of the autoinhibitory domain of PARP2 is insufficient for DNA damage-induced catalytic activation. Rather, PARP2 activation requires further unfolding of an active site α-helix absent in PARP1. Only one clinical PARPi, Olaparib, stabilizes the PARP2 active site α-helix, representing a structural feature with the potential to discriminate small molecule inhibitors. Collectively, our findings reveal unanticipated differences in local structure and changes in activation-coupled backbone dynamics between PARP1 and PARP2.
PubMed: 38826291
DOI: 10.1101/2024.05.20.594972 -
Scientific Reports Jun 2024Poly (ADP-ribose) polymerase inhibitors have been increasingly used in ovarian cancer treatment. However, the real-world safety data of these drugs in Japanese patients...
Poly (ADP-ribose) polymerase inhibitors have been increasingly used in ovarian cancer treatment. However, the real-world safety data of these drugs in Japanese patients are limited. This retrospective study included 181 patients with ovarian cancer who received olaparib or niraparib at two independent hospitals in Japan between May 2018 and December 2022. Clinical information and blood sampling data were collected. Regarding patient backgrounds, the olaparib group had higher proportions of patients with serous carcinoma, BRCA positivity, homologous recombination deficiency, and those receiving maintenance therapy after recurrence treatment than the niraparib group. Regarding toxicity properties, the most common reasons for discontinuation in the olaparib group were anemia, fatigue, and nausea, while the reason in the niraparib was thrombocytopenia. Thrombocytopenia caused by niraparib treatment occurred earlier than anemia caused by olaparib treatment. Patients with a low body mass index or who had undergone several previous treatment regimens were more likely to discontinue treatment within the first 3 months. Although we analyzed blood collection data, predicting treatment interruptions due to blood toxicity was challenging. In this study, we revealed the characteristics of patients and the timing of interruptions for each drug, highlighting the importance of carefully managing adverse effects.
Topics: Humans; Female; Poly(ADP-ribose) Polymerase Inhibitors; Ovarian Neoplasms; Middle Aged; Aged; Japan; Retrospective Studies; Piperidines; Phthalazines; Piperazines; Indazoles; Adult; Aged, 80 and over; Thrombocytopenia; East Asian People
PubMed: 38824213
DOI: 10.1038/s41598-024-63600-z -
Scientific Reports Jun 2024Coconut (Cocos nucifera) leaves, an unutilized resource, enriched with valuable bioactive compounds. Spectral analysis of purified pentane fraction of coconut leaves...
Coconut (Cocos nucifera) leaves, an unutilized resource, enriched with valuable bioactive compounds. Spectral analysis of purified pentane fraction of coconut leaves revealed the presence of a squalene analog named 4,4'-diapophytofluene or in short 4,4'-DPE (CH). Pure squalene standard (PSQ) showed cytotoxicity after 8 µg/ml concentration whereas 4,4'-DPE exhibited no cytotoxic effects up to 16 µg/ml concentration. On senescence-induced WI38 cells, 4,4'-DPE displayed better percentage of cell viability (164.5% at 24 h, 159.4% at 48 h and 148% at 72 h) compared to PSQ and BSQ (bio-source squalene) with same time duration. Similar trend of result was found in HaCaT cells. SA-β-gal assay showed that number of β-galactosidase positive cells were significantly decreased in senescent cells (WI38 and HaCaT) after treated with 4,4'-DPE than PSQ, BSQ. Percentage of ROS was increased to 60% in WI38 cells after olaparib treatment. When PSQ, BSQ and 4,4'-DPE were applied separately on these oxidative-stress-induced cells for 48 h, the overall percentage of ROS was decreased to 39.3%, 45.6% and 19.3% respectively. This 4,4'-DPE was found to be more effective in inhibiting senescence by removing ROS as compared to squalene. Therefore, this 4,4'-DPE would be new potent senotherapeutic agent for pharmaceuticals and dermatological products.
Topics: Humans; Plant Leaves; Squalene; Cellular Senescence; Antioxidants; Keratinocytes; Fibroblasts; Cocos; Cell Survival; Cell Line; Plant Extracts; Reactive Oxygen Species; Oxidative Stress
PubMed: 38824160
DOI: 10.1038/s41598-024-63547-1 -
The Oncologist May 2024The National Cancer Institute-Children's Oncology Group Pediatric Molecular Analysis for Therapy Choice (MATCH) precision oncology platform trial enrolled children aged...
BACKGROUND
The National Cancer Institute-Children's Oncology Group Pediatric Molecular Analysis for Therapy Choice (MATCH) precision oncology platform trial enrolled children aged 1-21 years with treatment-refractory solid tumors and predefined actionable genetic alterations. Patients with tumors harboring alterations in DNA damage repair (DDR) genes were assigned to receive olaparib.
METHODS
Tumor and blood samples were submitted for centralized molecular testing. Tumor and germline sequencing were conducted in parallel. Olaparib was given twice daily for 28-day cycles starting at a dose 30% lower than the adult recommended phase 2 dose (RP2D). The primary endpoint was the objective response.
RESULTS
Eighteen patients matched (1.5% of those screened) based on the presence of a deleterious gene alteration in BRCA1/2, RAD51C/D, or ATM detected by tumor sequencing without germline subtraction or analysis of loss of heterozygosity (LOH). Eleven (61%) harbored a germline mutation, with only one exhibiting LOH. Six patients enrolled and received the olaparib starting dose of 135 mg/m2/dose. Two participants were fully evaluable; 4 were inevaluable because <85% of the prescribed dose was administered during cycle 1. There were no dose-limiting toxicities or responses. Minimal hematologic toxicity was observed.
CONCLUSION
Most DDR gene alterations detected in Pediatric MATCH were germline, monoallelic, and unlikely to confer homologous recombination deficiency predicting sensitivity to olaparib monotherapy. The study closed due to poor accrual.
CLINICALTRIALS.GOV IDENTIFIER
NCT03233204. IRB approved: initial July 24, 2017.
PubMed: 38815151
DOI: 10.1093/oncolo/oyae096 -
Acta Oncologica (Stockholm, Sweden) May 2024In this manuscript we describe the academic French multicentric molecular analysis platforms including PROFILER, promoted by Centre Léon Berard, and the multicentric... (Review)
Review
BACKGROUND AND PURPOSE
In this manuscript we describe the academic French multicentric molecular analysis platforms including PROFILER, promoted by Centre Léon Berard, and the multicentric personalized medicine trials MOST, MOST Plus and MEGAMOST.
PATIENTS/MATERIAL AND METHODS
MOST, MOST Plus and MEGAMOST comprise 14 cohorts with different targeted agents and immunotherapies.
RESULTS AND INTERPRETATION
PROFILER has recruited 5,991 patients in 10 years, MOST and MOST Plus 875 patients since 2014 and MEGAMOST 172 patients since 2020, and are still ongoing. We provide a description of the local, national and international implications of these initiatives, and we review the results of the sorafenib and olaparib cohorts.
Topics: Humans; Precision Medicine; France; Neoplasms; Sorafenib; Phthalazines; Piperazines; Molecular Targeted Therapy; Clinical Trials as Topic; Immunotherapy; Antineoplastic Agents
PubMed: 38807312
DOI: 10.2340/1651-226X.2024.32745 -
Cell Death & Disease May 2024In ovarian tumors, the omental microenvironment profoundly influences the behavior of cancer cells and sustains the acquisition of stem-like traits, with major impacts...
In ovarian tumors, the omental microenvironment profoundly influences the behavior of cancer cells and sustains the acquisition of stem-like traits, with major impacts on tumor aggressiveness and relapse. Here, we leverage a patient-derived platform of organotypic cultures to study the crosstalk between the tumor microenvironment and ovarian cancer stem cells. We discovered that the pro-tumorigenic transcription factor FOXM1 is specifically induced by the microenvironment in ovarian cancer stem cells, through activation of FAK/YAP signaling. The microenvironment-induced FOXM1 sustains stemness, and its inactivation reduces cancer stem cells survival in the omental niche and enhances their response to the PARP inhibitor Olaparib. By unveiling the novel role of FOXM1 in ovarian cancer stemness, our findings highlight patient-derived organotypic co-cultures as a powerful tool to capture clinically relevant mechanisms of the microenvironment/cancer stem cells crosstalk, contributing to the identification of tumor vulnerabilities.
Topics: Humans; Tumor Microenvironment; Forkhead Box Protein M1; Female; Ovarian Neoplasms; Neoplastic Stem Cells; Cell Line, Tumor; Signal Transduction; YAP-Signaling Proteins; Focal Adhesion Kinase 1; Mice; Gene Expression Regulation, Neoplastic; Animals; Phthalazines; Piperazines
PubMed: 38806454
DOI: 10.1038/s41419-024-06767-7 -
Journal of Investigative Medicine High... 2024Urothelial carcinoma of the upper urinary tract (UTUC) presents a significant clinical challenge, often requiring aggressive surgical intervention for optimal...
Urothelial carcinoma of the upper urinary tract (UTUC) presents a significant clinical challenge, often requiring aggressive surgical intervention for optimal management. We present a case of an 84-year-old woman with recurrent high-grade papillary UTUC of the left renal pelvis, refractory to prior endourologic interventions, who underwent neoadjuvant treatment with pembrolizumab and enfortumab vedotin (Pembro/EV) due to contraindications to cisplatin therapy. Following a favorable response to neoadjuvant therapy, the patient underwent laparoscopic left radical nephroureterectomy, achieving a pathologic complete response. We discuss the utility of Pembro/EV in the perioperative management of patients with UTUC, particularly in those ineligible for cisplatin-based therapy. In addition, we highlight the potential role of somatic mutation testing and the integration of novel therapeutic agents such as olaparib in personalized treatment strategies for UTUC. This case underscores the importance of exploring innovative treatment approaches and optimizing patient selection for kidney preservation strategies in the management of UTUC. Further research and clinical trials are warranted to elucidate the full therapeutic potential of Pembro/EV and other emerging therapies in this setting.
Topics: Humans; Female; Antibodies, Monoclonal, Humanized; Aged, 80 and over; Carcinoma, Transitional Cell; Neoadjuvant Therapy; Antibodies, Monoclonal; Antineoplastic Combined Chemotherapy Protocols; Nephroureterectomy; Kidney Neoplasms; Kidney Pelvis; Antineoplastic Agents, Immunological
PubMed: 38804541
DOI: 10.1177/23247096241257333 -
Advances in Radiation Oncology Jul 2024
PubMed: 38799106
DOI: 10.1016/j.adro.2024.101528