scholarly journals PARP Inhibitors and Haematological Malignancies—Friend or Foe?

Cancers ◽  
2021 ◽  
Vol 13 (21) ◽  
pp. 5328
Author(s):  
Kathryn A. Skelding ◽  
Lisa F. Lincz
Keyword(s):  
Gene Mutations ◽  
Standard Of Care ◽  
Parp Inhibitors ◽  
Haematological Malignancies ◽  
Brca Mutations ◽  
Dna Repair Mechanisms ◽  
Repair Mechanisms ◽  
Defective Dna Repair ◽  
Potential Use

Since their introduction several years ago, poly (ADP-ribose) polymerase (PARP) inhibitors (PARPi) have become the standard of care for breast and gynaecological cancers with BRCA gene mutations. Given that PARPi act by exploiting defective DNA repair mechanisms within tumour cells, they should be ideally suited to combatting haematological malignancies where these pathways are notoriously defective, even though BRCA mutations are rare. To date, despite promising results in vitro, few clinical trials in humans for haematological malignancies have been performed, and additional investigation is required. Paradoxically, secondary haematological malignancies have arisen in patients after treatment with PARPi, raising concerns about their potential use as therapies for any blood or bone marrow-related disorders. Here, we provide a comprehensive review of the biological, pre-clinical, and clinical evidence for and against treating individual haematological malignancies with approved and experimental PARPi. We conclude that the promise of effective treatment still exists, but remains limited by the lack of investigation into useful biomarkers unique to these malignancies.

scholarly journals Immune System and DNA Repair Defects in Ovarian Cancer: Implications for Locoregional Approaches

2019 ◽  
Vol 20 (10) ◽  
pp. 2569 ◽  
Author(s):  
Alberto Farolfi ◽  
Giorgia Gurioli ◽  
Paola Fugazzola ◽  
Salvatore Burgio ◽  
Claudia Casanova ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Dna Repair ◽  
Immune System ◽  
Tumor Infiltrating Lymphocytes ◽  
Parp Inhibitors ◽  
Therapeutic Implications ◽  
Dna Repair Mechanisms ◽  
Platinum Based Chemotherapy ◽  
Repair Mechanisms

In the last few years, substantial progress has been made in the treatment of ovarian cancer, with increased knowledge about the biology of the disease. Ovarian cancer is a neoplasm strongly linked to defects in DNA repair mechanisms, where deficiency in the homologous recombination (HR) system results in a better response of ovarian cancers to therapy, whether platinum-based chemotherapy, anthracyclines, or poly (ADP-ribose) polymerase (PARP) inhibitors. More recently, it has been demonstrated that different ovarian cancer histotypes may have different immunogenicity. Interestingly, defects in HR systems are associated more frequently with higher tumor infiltrating lymphocytes, providing a rationale for developing combination therapy with immune-modulating agents and PARP inhibitors. Again, locoregional therapies combining heat shock and chemotherapy delivery have been shown to induce an anticancer immune response in vitro. Thus, the potential for locoregional therapeutic approaches that may impact the immune system, perhaps in combination with immune-modulating agents or PARP inhibitors, needs to be further explored. With this premise, we reviewed the main biological and clinical data demonstrating a strict interplay between the immune system, DNA repair mechanisms, and intraperitoneal therapies in ovarian cancer, with a focus on potential future therapeutic implications.

scholarly journals Cellular Response against Oxidative Stress, a Novel Insight into Lupus Nephritis Pathogenesis

2021 ◽  
Vol 11 (8) ◽  
pp. 693
Author(s):  
Corina Daniela Ene ◽  
Simona Roxana Georgescu ◽  
Mircea Tampa ◽  
Clara Matei ◽  
Cristina Iulia Mitran ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Lupus Nephritis ◽  
Cellular Response ◽  
Molecular Mechanisms ◽  
Control Group ◽  
Dna Repair Mechanisms ◽  
Glycation End Products ◽  
Repair Mechanisms ◽  
Low Levels ◽  
Defective Dna Repair

The interaction of reactive oxygen species (ROS) with lipids, proteins, nucleic acids and hydrocarbonates promotes acute and chronic tissue damage, mediates immunomodulation and triggers autoimmunity in systemic lupus erythematous (SLE) patients. The aim of the study was to determine the pathophysiological mechanisms of the oxidative stress-related damage and molecular mechanisms to counteract oxidative stimuli in lupus nephritis. Our study included 38 SLE patients with lupus nephritis (LN group), 44 SLE patients without renal impairment (non-LN group) and 40 healthy volunteers as control group. In the present paper, we evaluated serum lipid peroxidation, DNA oxidation, oxidized proteins, carbohydrate oxidation, and endogenous protective systems. We detected defective DNA repair mechanisms via 8-oxoguanine-DNA-glycosylase (OGG1), the reduced regulatory effect of soluble receptor for advanced glycation end products (sRAGE) in the activation of AGE-RAGE axis, low levels of thiols, disulphide bonds formation and high nitrotyrosination in lupus nephritis. All these data help us to identify more molecular mechanisms to counteract oxidative stress in LN that could permit a more precise assessment of disease prognosis, as well as developing new therapeutic targets.

Liability to Chromosome Damage in Lymphocytes of “Cancer Family” Subjects: A Study of Spontaneous and Induced Chromosomal Fragility

1987 ◽  
Vol 2 (1) ◽  
pp. 9-17 ◽  
Author(s):  
Lidia Larizza ◽  
Luisa Doneda ◽  
Miria Stefanini ◽  
Giuseppa Francone ◽  
Valter Gualandri ◽  
...  
Keyword(s):  
Chromosomal Instability ◽  
Fragile Sites ◽  
Chromosome 1 ◽  
Chromosome Damage ◽  
Tumor Patients ◽  
Dna Repair Mechanisms ◽  
Chromosomal Fragility ◽  
Repair Mechanisms ◽  
Heterochromatin Polymorphism ◽  
Defective Dna Repair

Spontaneous chromosomal fragility was detected in seven tumor patients and one healthy member from two families with a high recurrence of cancer. Major chromosome lesions, such as terminal deletions and rearranged chromosomes, were found at levels significantly higher than those reported for control individuals. The prevalence of these aberrations in comparison to minor ones (chromosome gaps and chromatid breaks) in this group ofpatients seems to indicate that the fragility observed is the end-point of a process of chromosomal instability, which may have already been brought to expression. Study of other parameters of genetic instability in the most unstable karyotypes showed that the chromosome damage observed was neither paralleled by abnormal SCE frequency nor sustained by defective DNA repair mechanisms or expression of inherited or constitutional fragile sites. As all the subjects investigated here had previously been shown to display intraindividual variations in the C-banded region of chromosome 1, it is possible that spontaneous fragility and acquired C-heterochromatin polymorphism may be markers that, combined with chromosomal instability, create genetic predisposition to cancer.

scholarly journals Defective DNA repair mechanisms in prostate cancer: impact of olaparib

2017 ◽  
Vol Volume11 ◽  
pp. 547-552 ◽  
Author(s):  
Francesca De Felice ◽  
Vincenzo Tombolini ◽  
Francesco Marampon ◽  
Angela Musella ◽  
Claudia Marchetti
Keyword(s):  
Prostate Cancer ◽  
Dna Repair ◽  
Dna Repair Mechanisms ◽  
Repair Mechanisms ◽  
Defective Dna Repair

Multi-analyte interrogation based treatment of advanced refractory cancers.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e15624-e15624
Author(s):  
Dadasaheb B Akolkar ◽  
Timothy Crook ◽  
Darshana Patil ◽  
Anantbhushan Ranade ◽  
Amit Bhatt ◽  
...  
Keyword(s):  
Treatment Options ◽  
Objective Response ◽  
Gene Mutations ◽  
Progression Free Survival ◽  
Standard Of Care ◽  
Response To Treatment ◽  
Patient Specific ◽  
Solid Organ ◽  
Systemic Treatments

e15624 Background: Treatment of advanced refractory cancers face challenges in non-availability of systemic therapy regimens with evidenced benefit. Post failure of two to three lines of systemic treatments, patients with such cancers are usually considered for palliation or clinical trials. Prior attempts at label-agnostic treatment regimens (precision medicine) in such populations were largely based on a single-indication-single-drug paradigm which had limited application. We hypothesized that advanced refractory malignancies have latent vulnerabilities which can be identified by an integrational multi-analyte interrogation of the tumor, and can be targeted using patient-specific combination regimens to yield clinical benefit. Methods: Fresh tumor tissue and blood samples were obtained from 158 patients with solid organ cancers where the disease had progressed following failure of at least two lines of standard of care systemic treatment options. These samples were used for Encyclopedic Tumor Analysis (ETA) which interrogated gene mutations, gene overexpression, pathway dysregulation, immunohistochemistry as well as in vitro chemosensitivity profiling of viable tumor cells. Integration of datasets from the multi-analyte ETA was used to generate patient-specific therapy recommendations. Patients who received ETA-guided treatments were followed up and response to treatment was retrospectively evaluated from radiological scans. Results: All patients received ETA-guided individualized treatments which were combinations of cytotoxic, targeted and endocrine agents. No two patients received the same treatment regimen. Complete or Partial Response (CR or PR) was observed in 76 patients yielding an Objective Response Rate (ORR) of 48.1%. 67 patients showed Stable Disease (SD), thus yielding a Disease Control Rate (DCR) of 90.5%. Median Progression Free Survival (PFS) was 117 days (Range 27 – 379 days). There were no Grade IV therapy related Adverse Events or therapy related deaths. Conclusions: Viable efficacious combination treatment options can be made available for patients with advanced refractory malignancies via ETA, despite perceived non-availability or non-viability of standard of care treatment options.

scholarly journals DNA methyltransferase inhibitors induce a BRCAness phenotype that sensitizes NSCLC to PARP inhibitor and ionizing radiation

2019 ◽  
Vol 116 (45) ◽  
pp. 22609-22618 ◽  
Author(s):  
Rachel Abbotts ◽  
Michael J. Topper ◽  
Christopher Biondi ◽  
Daniel Fontaine ◽  
Reena Goswami ◽  
...  
Keyword(s):  
Ionizing Radiation ◽  
Dna Methyltransferase ◽  
Parp Inhibitor ◽  
Nonsmall Cell Lung Cancer ◽  
Parp Inhibitors ◽  
End Joining ◽  
Brca Mutations ◽  
Dna Methyltransferase Inhibitors

A minority of cancers have breast cancer gene (BRCA) mutations that confer sensitivity to poly (ADP-ribose) polymerase (PARP) inhibitors (PARPis), but the role for PARPis in BRCA-proficient cancers is not well established. This suggests the need for novel combination therapies to expand the use of these drugs. Recent reports that low doses of DNA methyltransferase inhibitors (DNMTis) plus PARPis enhance PARPi efficacy in BRCA-proficient AML subtypes, breast, and ovarian cancer open up the possibility that this strategy may apply to other sporadic cancers. We identify a key mechanistic aspect of this combination therapy in nonsmall cell lung cancer (NSCLC): that the DNMTi component creates a BRCAness phenotype through downregulating expression of key homologous recombination and nonhomologous end-joining (NHEJ) genes. Importantly, from a translational perspective, the above changes in DNA repair processes allow our combinatorial PARPi and DNMTi therapy to robustly sensitize NSCLC cells to ionizing radiation in vitro and in vivo. Our combinatorial approach introduces a biomarker strategy and a potential therapy paradigm for treating BRCA-proficient cancers like NSCLC.

The Relevance of Photomutagenicity Testing as a Predictor of Photocarcinogenicity

1998 ◽  
Vol 17 (5) ◽  
pp. 551-558 ◽  
Author(s):  
Lutz Müller ◽  
Peter Kasper
Keyword(s):  
Oxidative Damage ◽  
Mammalian Cells ◽  
Active Oxygen Species ◽  
Gene Mutations ◽  
Oxygen Species ◽  
Chromosomal Damage ◽  
Hairless Mice ◽  
Molecular Events ◽  
Repair Mechanisms

Today's lifestyle is associated with frequent and intense exposure to ultraviolet radiation (UVR). The tumorigenic effects of UVR are well known. Specifically, the premutagenic lesions of UVB (290-320 nm) are known to be the most important molecular events in UVR tumorigenicity. The less carcinogenic UVA (320-400 nm) mainly generates oxidative damage in the DNA via photody-namic generation of active oxygen species involving endogenous or exogenous photosen sitizers. Several pharmaceuticals are known to act as photosensitizers. Photoinstable phenothiazines, furocoumarins, and fluoroquinolones were shown to be very efficient inducers of chromosomal damage in mammalian cells in culture. Photocar cinogenicity testing in hairless mice of furocoumarins and several fluoroquinolones demonstrated a higher incidence and a shorter latent period for skin tumors compared to UVR alone. These data show a good correlation between the photomutagenic and photocarcinogenic potential of these compounds. Although mammalian cells possess effective repair mechanisms for oxidative damage, photoproducts, and dimers, these repair mechanisms can be overloaded. Eventually, unrepaired damage leads to gene mutations or chromosomal damage in exposed cells and to tumors in the skin. Therefore, in vitro photomutageni-city testing in mammalian cells may be an early and easy-to-measure predictor of the photocarcinogenic potential of a pharmaceutical.

scholarly journals Pin1 plays a key role in the response to treatment and clinical outcome in triple negative breast cancer

2020 ◽  
Vol 12 ◽  
pp. 175883592090604 ◽  
Author(s):  
Catherine Knowlson ◽  
Paula Haddock ◽  
Victoria Bingham ◽  
Stephen McQuaid ◽  
Paul B. Mullan ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Clinical Outcome ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Treatment Options ◽  
Standard Of Care ◽  
Parp Inhibitors ◽  
Response To Treatment ◽  
Increased Sensitivity

Background: Triple negative breast cancer (TNBC) is the subset of breast cancer associated with the poorest outcome, and currently lacks targeted treatments. Standard of care (SoC) chemotherapy often consists of DNA damaging chemotherapies ± taxanes, with a range of responses observed. However, we currently lack biomarkers to predict this response and lack alternate treatment options. Methods: Pin1 expression was modulated in vitro and proliferation and treatment response was studied. Pin1 expression was analysed in patient samples and correlated with clinical outcome. Results: In this study, we have shown that the prolyl isomerase, Pin1, which is highly expressed in TNBC, plays a key role in pathogenesis of the disease. Knockdown of Pin1 in TNBC resulted in cell death while the opposite is seen in normal cells. We revealed for the first time that loss of Pin1 leads to increased sensitivity to Taxol but only in the absence of functional BRCA1. Conversely, loss of Pin1 results in decreased sensitivity to DNA-damaging agents independent of BRCA1 status. Analysis of Pin1 gene or IHC-based expression in over 200 TNBC patient samples revealed a novel role for Pin1 as a TNBC-specific biomarker, with high expression associated with improved outcome in the context of SoC chemotherapy. Preliminary data indicated this may be extended to other treatment options (e.g. Cisplatin/Parp Inhibitors) that are gaining traction for the treatment of TNBC. Conclusions: This study highlights the important role played by Pin1 in TNBC and highlights the context-dependent functions in modulating cell growth and response to treatment.

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