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Expert Opinion on Drug Safety Mar 2023Several therapies directed at novel targets and also immunotherapies have recently shown promising results in advanced or metastatic TNBC. We aimed to compare the... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Several therapies directed at novel targets and also immunotherapies have recently shown promising results in advanced or metastatic TNBC. We aimed to compare the efficacy and safety of these new regimens for advanced or metastatic TNBC (mTNBC).
METHODS
The PubMed, Embase, and Cochrane Library electronic databases were searched for phase III randomized trials. We conducted a network meta-analysis to compare the efficacy and safety of new targeted and immunotherapy regimens. Trial quality was assessed using the GRADE method. The comparative outcomes were progression-free survival, overall survival, and G3-4 adverse drug events (ADEs).
RESULTS
Thirteen phase III randomized controlled trials were identified in the network meta-analysis. Olaparib significantly improved PFS in comparison with the pembrolizumab plus chemotherapy 1, atezolizumab plus nab-paclitaxel and pembrolizumab regimens. Sacituzumab yielded a significant improvement in OS over immunotherapies, veliparib, and chemotherapy alone, but no significantly superiority over pembrolizumab, olaparib, and talazoparib. The risk of ≥grade 3 ADEs associated with olaparib was significantly lower than the risks associated with the other regimens.
CONCLUSION
For mTNBC, sacituzumab had a better effect on overall survival, with comparatively high risk of SAE, whereas olaparib improved progression-free survival with a lower risk of SAE, particularly in those patients with BRCA mutations.
Topics: Humans; Network Meta-Analysis; Triple Negative Breast Neoplasms; Immunotherapy; Drug-Related Side Effects and Adverse Reactions; Antibodies, Monoclonal
PubMed: 35998294
DOI: 10.1080/14740338.2022.2116001 -
Frontiers in Surgery 2022Ferroptosis-related lncRNAs are promising biomarkers for predicting the prognosis of many cancers. However, a ferroptosis-related signature to predict the prognosis of...
PURPOSE
Ferroptosis-related lncRNAs are promising biomarkers for predicting the prognosis of many cancers. However, a ferroptosis-related signature to predict the prognosis of cutaneous melanoma (CM) has not been identified. The purpose of this study was to construct a ferroptosis-related lncRNA signature to predict prognosis and immunotherapy efficacy in CM.
METHODS
Ferroptosis-related differentially expressed genes (FDEGs) and lncRNAs (FDELs) were identified using TCGA, GTEx, and FerrDb datasets. We performed Cox and LASSO regressions to identify key FDELs, and constructed a risk score to stratify patients into high- and low-risk groups. The lncRNA signature was evaluated using the areas under the receiver operating characteristic curves (AUCs) and Kaplan-Meier analyses in the training, testing, and entire cohorts. Multivariate Cox regression analyses including the lncRNA signature and common clinicopathological characteristics were performed to identify independent predictors of overall survival (OS). A nomogram was developed for clinical use. We performed gene set enrichment analyses (GSEA) to identify significantly enriched pathways. Differences in the tumor microenvironment (TME) between the 2 groups were assessed using 7 algorithms. To predict the efficacy of immune checkpoint inhibitors (ICI), we analyzed the association between and expression and the risk score. Finally, differences in Tumor Mutational Burden (TMB) and molecular drugs Sensitivity between the 2 groups were performed.
RESULTS
We identified 5 lncRNAs (AATBC, AC145423.2, LINC01871, AC125807.2, and AC245041.1) to construct the risk score. The AUC of the lncRNA signature was 0.743 in the training cohort and was validated in the testing and entire cohorts. Kaplan-Meier analyses revealed that the high-risk group had poorer prognosis. Multivariate Cox regression showed that the lncRNA signature was an independent predictor of OS with higher accuracy than traditional clinicopathological features. The 1-, 3-, and 5-year survival probabilities for CM patients were 92.7%, 57.2%, and 40.2% with an AUC of 0.804, indicating a good accuracy and reliability of the nomogram. GSEA showed that the high-risk group had lower ferroptosis and immune response. TME analyses confirmed that the high-risk group had lower immune cell infiltration (e.g., CD8+ T cells, CD4+ memory-activated T cells, and M1 macrophages) and lower immune functions (e.g., immune checkpoint activation). Low-risk patients whose disease expressed or were likely to respond better to ICIs. The analysis demonstrated that the TMB had significantly difference between low- and high- risk groups. Chemotherapy drugs, such as sorafenib, Imatinib, ABT.888 (Veliparib), Docetaxel, and Paclitaxel showed Significant differences in the estimated IC50 between the two risk groups.
CONCLUSION
Our novel ferroptosis-related lncRNA signature was able to accurately predict the prognosis and ICI outcomes of CM patients. These ferroptosis-related lncRNAs might be potential biomarkers and therapeutic targets for CM.
PubMed: 35937602
DOI: 10.3389/fsurg.2022.860806 -
Oncogene Sep 2022DNA repair gene mutations are frequent in castration-resistant prostate cancer (CRPC), suggesting eligibility for poly(ADP-ribose) polymerase inhibitor (PARPi)...
DNA repair gene mutations are frequent in castration-resistant prostate cancer (CRPC), suggesting eligibility for poly(ADP-ribose) polymerase inhibitor (PARPi) treatment. However, therapy resistance is a major clinical challenge and genes contributing to PARPi resistance are poorly understood. Using a genome-wide CRISPR-Cas9 knockout screen, this study aimed at identifying genes involved in PARPi resistance in CRPC. Based on the screen, we identified PARP1, and six novel candidates associated with olaparib resistance upon knockout. For validation, we generated multiple knockout populations/clones per gene in C4 and/or LNCaP CRPC cells, which confirmed that loss of PARP1, ARH3, YWHAE, or UBR5 caused olaparib resistance. PARP1 or ARH3 knockout caused cross-resistance to other PARPis (veliparib and niraparib). Furthermore, PARP1 or ARH3 knockout led to reduced autophagy, while pharmacological induction of autophagy partially reverted their PARPi resistant phenotype. Tumor RNA sequencing of 126 prostate cancer patients identified low ARH3 expression as an independent predictor of recurrence. Our results advance the understanding of PARPi response by identifying four novel genes that contribute to PARPi sensitivity in CRPC and suggest a new model of PARPi resistance through decreased autophagy.
Topics: Antineoplastic Agents; CRISPR-Cas Systems; Cell Line, Tumor; Drug Resistance, Neoplasm; Humans; Male; Poly(ADP-ribose) Polymerase Inhibitors; Prostatic Neoplasms, Castration-Resistant
PubMed: 35933519
DOI: 10.1038/s41388-022-02427-2 -
International Journal of Molecular... Jul 2022Prostate specific membrane antigen targeted radionuclide therapy (PSMA-TRT) is a promising novel treatment for prostate cancer (PCa) patients. However, PSMA-TRT cannot...
Prostate specific membrane antigen targeted radionuclide therapy (PSMA-TRT) is a promising novel treatment for prostate cancer (PCa) patients. However, PSMA-TRT cannot be used for curative intent yet, thus additional research on how to improve the therapeutic efficacy is warranted. A potential way of achieving this, is combining TRT with poly ADP-ribosylation inhibitors (PARPi), which has shown promising results for TRT of neuroendocrine tumor cells. Currently, several clinical trials have been initiated for this combination for PCa, however so far, no evidence of synergism is available for PCa. Therefore, we evaluated the combination of PSMA-TRT with three classes of PARPi in preclinical PCa models. In vitro viability and survival assays were performed using PSMA-expressing PCa cell lines PC3-PIP and LNCaP to assess the effect of increasing concentrations of PARPi veliparib, olaparib or talazoparib in combination with PSMA-TRT compared to single PARPi treatment. Next, DNA damage analyses were performed by quantifying the number of DNA breaks by immunofluorescent stainings. Lastly, the potential of the combination treatments was studied in vivo in mice bearing PC3-PIP xenografts. Our results show that combining PSMA-TRT with PARPi did not synergistically affect the in vitro clonogenic survival or cell viability. DNA-damage analysis revealed only a significant increase in DNA breaks when combining PSMA-TRT with veliparib and not in the other combination treatments. Moreover, PSMA-TRT with PARPi treatment did not improve tumor control compared to PSMA-TRT monotherapy. Overall, the data presented do not support the assumption that combining PSMA-TRT with PARPi leads to a synergistic antitumor effect in PCa. These results underline that extensive preclinical research using various PCa models is imperative to validate the applicability of the combination strategy for PCa, as it is for other cancer types.
Topics: Animals; Cell Line, Tumor; Humans; Male; Mice; Poly(ADP-ribose) Polymerase Inhibitors; Prostate; Prostatic Neoplasms; Radioisotopes
PubMed: 35887398
DOI: 10.3390/ijms23148037 -
Genes Jul 2022Chemotherapy treatment of cancer in children can influence formation of normal tissues, leading to irreversible changes in their structure and function. Tooth formation...
BACKGROUND
Chemotherapy treatment of cancer in children can influence formation of normal tissues, leading to irreversible changes in their structure and function. Tooth formation is susceptible to several types of chemotherapy that induce irreversible changes in the structure of enamel, dentin and dental root morphology. These changes can make the teeth more prone to fracture or to caries when they have erupted. Recent studies report successful treatment of brain tumors with the alkylating drug temozolomide (TMZ) in combination with veliparib (VLP) in a glioblastoma in vivo mouse model. Whether these drugs also affect tooth formation is unknown.
AIM
In this study the effect of TMZ/VLP on incisor formation was investigated in tissue sections of jaws from mice and compared with mice not treated with these drugs.
MATERIALS AND METHOD
The following aspects were studied using immunohistochemistry of specific protein markers including: (1) proliferation (by protein expression of proliferation marker Ki67) (2) a protein involved in ion transport (expression of tight junction (TJ) protein claudin-1) and (3) in of ions across the dental epithelium (expression of Na+, K+ 2Cl- cotransporter/NKCC1).
RESULTS
Chemotherapy with TMZ/VLP strongly reduced immunostaining for claudin-1 in distal parts of maturation ameloblasts. No gross changes were found in the treated mice, either in cell proliferation in the dental epithelium at the cervical loop or in the immunostaining pattern for NKCC1 in (non-ameloblastic) dental epithelium. The salivary glands in the treated mice contained strongly reduced immunostaining for NKCC1 in the basolateral membranes of acinar cells.
DISCUSSION/CONCLUSIONS
Based on the reduction of claudin-1 immunostaining in ameloblasts, TMZ/VLP may potentially influence forming enamel by changes in the structure of TJs structures in maturation ameloblasts, structures that are crucial for the selective passage of ions through the intercellular space between neighboring ameloblasts. The strongly reduced basolateral NKCC1 staining seen in fully-grown salivary glands of TMZ/VLP-treated mice suggests that TMZ/VLF could also influence ion transport in adult saliva by the salivary gland epithelium. This may cause treated children to be more susceptible to caries.
Topics: Animals; Benzimidazoles; Claudin-1; Mice; Models, Theoretical; Odontogenesis; Temozolomide
PubMed: 35885982
DOI: 10.3390/genes13071198 -
Journal of Clinical Oncology : Official... Jan 2023In VELIA trial, veliparib combined with carboplatin-paclitaxel, followed by maintenance (veliparib-throughout) was associated with improved progression-free survival...
PURPOSE
In VELIA trial, veliparib combined with carboplatin-paclitaxel, followed by maintenance (veliparib-throughout) was associated with improved progression-free survival (PFS) compared with carboplatin-paclitaxel alone in patients with high-grade ovarian carcinomas. We explored the prognostic value of the modeled cancer antigen (CA)-125 elimination rate constant K (KELIM), which is known to be an indicator of the intrinsic tumor chemosensitivity (the faster the rate of CA-125 decline, the higher the KELIM and the higher the chemosensitivity), and its association with benefit from veliparib.
PATIENTS AND METHODS
Individual KELIM values were estimated from longitudinal CA-125 kinetics. Patients were categorized as having favorable (≥ median) or unfavorable (< median) KELIM. The prognostic value of KELIM for veliparib-related PFS benefit was explored in cohorts treated with primary or interval debulking surgery, according to the surgery completeness, the disease progression risk group, and the homologous recombination (HR) status ( mutation, HR deficiency [HRD], or HR proficiency [HRP]).
RESULTS
The data from 854 of 1,140 enrolled patients were analyzed (primary debulking surgery, n = 700; interval debulking surgery, n = 154). Increasing KELIM values were associated with higher benefit from veliparib in HRD cancer, as were decreasing KELIM values in HRP cancer. The highest PFS benefit from veliparib was observed in patients with both favorable KELIM and mutation (hazard ratio, 0.28; 95% CI, 0.13 to 0.61) or wild-type HRD cancer (hazard ratio, 0.43; 95% CI, 0.26 to 0.70), consistent with the association between poly (adenosine diphosphate-ribose) polymerase inhibitor efficacy and platinum sensitivity. In contrast, seventy-four percent of patients with a mutation and unfavorable KELIM progressed within 18 months while on veliparib. The patients with HRP cancer and unfavorable KELIM might have benefited from the veliparib chemosensitizing effect.
CONCLUSION
In addition to HRD/ status, the tumor primary chemosensitivity observed during the first-line chemotherapy might be another complementary determinant of poly (adenosine diphosphate-ribose) polymerase inhibitor efficacy.
Topics: Female; Humans; Carboplatin; Ribose; Antineoplastic Combined Chemotherapy Protocols; Ovarian Neoplasms; Paclitaxel; Adenosine Diphosphate
PubMed: 35867965
DOI: 10.1200/JCO.22.00430 -
JCO Precision Oncology Jun 2022Genetic alterations in many components of the homologous recombination, DNA damage response, and repair (HR-DDR) pathway are involved in the hereditary cancer syndromes,...
PURPOSE
Genetic alterations in many components of the homologous recombination, DNA damage response, and repair (HR-DDR) pathway are involved in the hereditary cancer syndromes, including familial pancreatic cancer. HR-DDR genes beyond , , , and may also mutate and confer the HR-DDR deficiency in pancreatic ductal adenocarcinoma (PDAC).
METHODS
We conducted a study to examine the genetic alterations using a companion diagnostic 15-gene HR-DDR panel in PDACs. HR-DDR gene mutations were identified and characterized by whole-exome sequencing and whole-genome sequencing. Different HR-DDR gene mutations are associated with variable homologous recombination deficiency (HRD) scores.
RESULTS
Eight of 50 PDACs with at least one HR-DDR gene mutation were identified. One tumor with mutations is associated with a high HRD score. However, another tumor with a mutation is associated with a zero HRD score. Notably, four of eight PDACs in this study harbor a gene mutation. All four gene mutations were germline mutations. However, currently, is not the gene panel for germline tests.
CONCLUSION
The finding in this study thus supports including in the germline test of HR-DDR pathway genes.
Topics: Carcinoma, Pancreatic Ductal; DNA-Binding Proteins; Genes, BRCA2; Germ-Line Mutation; Humans; Pancreatic Neoplasms
PubMed: 35737913
DOI: 10.1200/PO.21.00404 -
Medical Principles and Practice :... 2022In mammalian cells, DNA damage response initiates repair by error-free homologous recombination (HRR) or by error-prone non-homologous end joining (NHEJ). DNA damage is... (Review)
Review
In mammalian cells, DNA damage response initiates repair by error-free homologous recombination (HRR) or by error-prone non-homologous end joining (NHEJ). DNA damage is detected by PARP proteins that facilitate this repair, both in normal cells and in cancer cells. Cells containing BRCA1/2 mutations have an HRR-deficient repair mechanism which may result in unrepaired one-ended double-strand breaks and stalled replication forks, considered as the most lethal cell damage. Here, we review the state of the art of the role of Poly (ADP-ribose) polymerase (PARP) inhibitors as a precision-targeted anticancer drug in BRCA1/2-mutated female breast cancer. Although knowledge is incomplete, it is assumed that the main role of the archetype PARP1 in the cell nucleus is to detect and adhere to single-strand breaks. This mediates possible damage repair, after which cells may continue replication; this process is called synthetic lethality. As for PARP clinical monotherapy, progression-free survival has been observed using the FDA- and EMA-approved drugs olaparib and talazoparib. In the case of combined drug therapy, a synergy has been demonstrated between veliparib and platinum drugs. Information regarding adverse effects is limited, but hematological effects have been described. However, there is need for multicenter trials, preferably conducted without commercial guidance and funding. Some of the available trials reported resistance to PARP inhibitors. In this review, we also describe the various causes of resistance to PARP inhibitors and research indicating how resistance can be overcome.
Topics: Animals; Breast Neoplasms; Female; Humans; Poly(ADP-ribose) Polymerase Inhibitors; Poly(ADP-ribose) Polymerases; Risk Reduction Behavior
PubMed: 35636395
DOI: 10.1159/000525281 -
Journal of Chemotherapy (Florence,... Apr 2023BRCA1/2 mutations and homologous recombination deficiency (HRD) predispose to increased sensitivity to poly(ADP-ribose)polymerase (PARP) inhibitor treatment. Our aim was... (Meta-Analysis)
Meta-Analysis
BRCA1/2 mutations and homologous recombination deficiency (HRD) predispose to increased sensitivity to poly(ADP-ribose)polymerase (PARP) inhibitor treatment. Our aim was to evaluate the PARP inhibitors effect on progression free survival (PFS) in a subpopulation with homologous recombination proficient status (HRD-BRCA-). A systematic literature search was performed for all studies reporting on the effect of PARP inhibitors regarding PFS in the HRD-BRCA- subpopulation, in patients with epithelial ovarian, tubal or primary peritoneal cancers (EOC). Five studies were included, enrolling a population of 3413 patients, with 1070 of them being HRD-BRCA-. PARP inhibitors were effective in the treatment of EOC, regardless of HRD and BRCA status or line of therapy. The estimated pooled effect hazard ratio (HR), assessing PFS for PARP inhibitors compared with control, was 0.76 (95% CI: 0.65-0.88, = 46%) in the HRD-BRCA- subpopulation. Comparing both subpopulations with HRD positive status (HRD+ BRCA+, HRD+ BRCA-) versus the HRD-BRCA-subpopulation, we have found statistically significant differences in the effect on PFS (P < 0.05 for every interaction test) favouring HRD positive subpopulations (HRD+ BRCA+, HRD+ BRCA-). In the HRD-BRCA- subpopulation of patients, PARP inhibitors used as the second- or later-line of therapy showed more pronounced effect then when given as first line treatment (P = 0.04). Treatment of EOC with PARP inhibitors showed a significant effect regarding PFS in the HRD-BRCA- subpopulation, although a much higher benefit was evident for patients with HRD+ status (HRD+ BRCA+ and HRD+ BRCA-). In the HRD- subpopulation second line PARP inhibitor treatment showed greater benefit compared to first line PARP inhibitor treatment.
Topics: Female; Humans; Poly(ADP-ribose) Polymerase Inhibitors; BRCA1 Protein; BRCA2 Protein; Ovarian Neoplasms; Homologous Recombination
PubMed: 35550005
DOI: 10.1080/1120009X.2022.2073161 -
Expert Opinion on Investigational Drugs Jun 2022Poly (ADP-ribose) polymerase inhibitors (PARPis) are an exciting class of agents that have shown efficacy, particularly for BRCA-mutant triple-negative breast cancer... (Review)
Review
PARP inhibitors as single agents and in combination therapy: the most promising treatment strategies in clinical trials for BRCA-mutant ovarian and triple-negative breast cancers.
INTRODUCTION
Poly (ADP-ribose) polymerase inhibitors (PARPis) are an exciting class of agents that have shown efficacy, particularly for BRCA-mutant triple-negative breast cancer (TNBC) and high-grade serous ovarian cancer (HGSOC). However, most patients who receive PARPi as their standard of care therapy inevitably develop resistance and this underscores the need to identify additional targets that can circumvent such resistance. Combination treatment strategies have been developed in preclinical and clinical studies to address the challenges of efficacy and resistance.
AREAS COVERED
This review examines completed or ongoing clinical trials of PARPi mono- and combination therapies. PARPi monotherapy in HER2 negative breast (HR+ and TNBC subtypes) and ovarian cancer is a focal point. The authors propose potential strategies that might overcome resistance to PARPi and discuss key questions and future directions.
EXPERT OPINION
While the advent of PARPis has significantly improved the treatment of tumors with defects in DNA damage and repair pathways, careful patient selection will be essential to enhance these treatments. The identification of molecular biomarkers to predict disease response and progression is an endeavor.
Topics: Carcinoma, Ovarian Epithelial; DNA Damage; Female; Humans; Ovarian Neoplasms; Poly(ADP-ribose) Polymerase Inhibitors; Triple Negative Breast Neoplasms
PubMed: 35435784
DOI: 10.1080/13543784.2022.2067527