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The New England Journal of Medicine Jan 2011
Topics: Antineoplastic Combined Chemotherapy Protocols; Benzamides; Breast Neoplasms; Female; Humans; Poly(ADP-ribose) Polymerase Inhibitors
PubMed: 21208102
DOI: 10.1056/NEJMe1012546 -
PloS One 2017Women with triple negative breast cancer (TNBC) have poor prognosis compared to other breast cancer subtypes. There were several reports indicating racial disparity in...
Women with triple negative breast cancer (TNBC) have poor prognosis compared to other breast cancer subtypes. There were several reports indicating racial disparity in breast cancer outcomes between African American (AA) and European American (EA) women. For example, the mortality rates of AA breast cancer patients were three times higher than of EA patients, even though, the incidence is lower in AA women. Our in vitro studies indicate that cancer stem-like cells (CSCs) derived from AA TNBC cell lines have significantly higher self-renewal potential (mammosphere formation) than CSCs derived from EA cell lines. TNBC tumors express high levels of Myc compared to luminal A or HER2 expressing breast cancers. We studied the effects of c-Myc overexpression on CSCs and chemotherapy in AA, and EA derived TNBC cell line(s). Overexpression of c-Myc in AA derived MDA-MB-468 (Myc/MDA-468) cells resulted in a significant increase in CSCs and with minimal changes in epithelial-to-mesenchymal transition (EMT) compared to the control group. In contrast, overexpression of c-Myc in EA derived MDA-MB-231(Myc/MDA-231) cells led to increased epithelial-to-mesenchymal transition (EMT), with a minimal increase in CSCs compared to the control group. Myc/MDA-468 cells were resistant to standard chemotherapeutic treatments such as iniparib (PARP inhibitor) plus cisplatin, / iniparib, cisplatin, paclitaxel and docetaxel. However, Myc/MDA-231 cells, which showed EMT changes responded to iniparib with cisplatin, but were resistant to other drugs, such as iniparib, cisplatin, paclitaxel and docetaxel. Collectively, our results indicate that intrinsic differences in the tumor biology may contribute to the breast cancer disparities.
Topics: Antineoplastic Agents; Cell Line, Tumor; Epithelial-Mesenchymal Transition; Genes, myc; Humans; Neoplastic Stem Cells; Signal Transduction; Triple Negative Breast Neoplasms; Wnt Proteins
PubMed: 28817737
DOI: 10.1371/journal.pone.0183578 -
Cancer Biology & Therapy Oct 2013To many investigators PARP1 is simply a substrate for caspase 3, and whose cleavage is thought indicative of apoptosis. However, in reality PARP1 plays a major role in...
To many investigators PARP1 is simply a substrate for caspase 3, and whose cleavage is thought indicative of apoptosis. However, in reality PARP1 plays a major role in the biology of the cell cycle and DNA repair. (1)(,) (2) PARP1 binds to damaged DNA where it becomes enzymatically activated and ADP ribosylates itself and other proteins. PARP facilitates DNA repair complex formation, e.g., with BRCA1/2, and the activation of the cell cycle regulatory enzymes ATM and ATR. (2) PARP inhibitors as a single agent have only shown any degree of efficacy in breast and ovarian cancer patients who lack BRCA1/2 function. (3)(,) (4) The present studies examined PARP1 inhibitor biology in a range of triple negative and non-triple negative breast cancer cell lines.
Topics: Antineoplastic Agents; Benzamides; Female; Humans; Phthalazines; Piperazines; Triple Negative Breast Neoplasms
PubMed: 24025256
DOI: 10.4161/cbt.26160 -
BMC Veterinary Research Jan 2020Dogs develop cancer spontaneously with age, with breed-specific risk underlying differences in genetics. Mammary tumors are reported as the most frequent neoplasia in... (Review)
Review
Dogs develop cancer spontaneously with age, with breed-specific risk underlying differences in genetics. Mammary tumors are reported as the most frequent neoplasia in intact female dogs. Their high prevalence in certain breeds suggests a genetic component, as it is the case in human familial breast cancer, distinctly in BRCA2-associated cancers. However, the molecular genetics of BRCA2 in the pathogenesis of canine cancer are still under investigation.Genetic variations of canine BRCA2 comprised single nucleotide polymorphisms, insertions and deletions. The BRCA2 level has been shown to be reduced in tumor gland samples, suggesting that low expression of BRCA2 is contributing to mammary tumor development in dogs. Additionally, specific variations of the BRCA2 gene affect RAD51 binding strength, critically damage the BRCA2-RAD51 binding and further provoke a defective repair. In humans, preclinical and clinical data revealed a synthetic lethality interaction between BRCA2 mutations and PARP inhibition. PARP inhibitors are successfully used to increase chemo- and radiotherapy sensitivity, although they are also associated with numerous side effects and acquired resistance. Cancer treatment of canine patients could benefit from increased chemo- and radiosensitivity, as their cancer therapy protocols usually include only low doses of drugs or radiation. Early investigations show tolerability of iniparib in dogs. PARP inhibitors also imply higher therapy costs and consequently are less likely to be accepted by pet owners.We summarized the current evidence of canine BRCA2 gene alterations and their association with mammary tumors. Mutations in the canine BRCA2 gene have the potential to be exploited in clinical therapy through the usage of PARP inhibitors. However, further investigations are needed before introducing PARP inhibitors in veterinary clinical practice.
Topics: Animals; Dog Diseases; Dogs; Female; Genes, BRCA2; Mammary Neoplasms, Animal; Mutation; Poly(ADP-ribose) Polymerase Inhibitors; Polymorphism, Single Nucleotide
PubMed: 32005245
DOI: 10.1186/s12917-020-2247-4 -
Annals of Oncology : Official Journal... Nov 2014Iniparib is a novel anticancer agent initially considered a poly (ADP-ribose) polymerase (PARP) inhibitor, but subsequently shown to act via non-selective protein... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Iniparib is a novel anticancer agent initially considered a poly (ADP-ribose) polymerase (PARP) inhibitor, but subsequently shown to act via non-selective protein modification through cysteine adducts. This randomized phase II study investigated the addition of iniparib to gemcitabine-cisplatin in metastatic non-small-cell lung cancer (NSCLC) patients.
PATIENTS AND METHODS
Patients with histologically confirmed stage IV NSCLC were randomized 2 : 1 to receive gemcitabine (1250 mg/m(2), days 1/8) and cisplatin (75 mg/m(2), day 1) with [gemcitabine/cisplatin/iniparib (GCI)] or without [gemcitabine/cisplatin (GC)] iniparib (5.6 mg/kg, days 1/4/8/11) every 3 weeks for six cycles. The primary end point was the overall response rate (ORR). Secondary objectives included progression-free survival (PFS), overall survival (OS), and safety. The study was not designed for formal efficacy comparison, the control arm being to benchmark results against the literature.
RESULTS
One hundred and nineteen patients were randomized (39 GC and 80 GCI). More GCI patients were male (80% GCI and 67% GC) and had PS 0 (61% GCI and 49% GC). The ORR was 25.6% [95% confidence interval (CI) 13.0%-42.1%] with GC versus 20.0% (95% CI 11.9%-30.4%) with GCI, which did not allow rejection of the null hypothesis (ORR with GCI ≤20%; P = 0.545). Median PFS was 4.3 (95% CI 2.8-5.6) months with GC and 5.7 (95% CI 4.6-6.6) months with GCI (hazard ratio 0.89, 95% CI 0.56-1.40). Median OS was 8.5 (95% CI 5.5 to not reached) months with GC, and 12.0 (95% CI 8.9-17.1) months with GCI (hazard ratio 0.78, 95% CI 0.48-1.27). More GCI patients received second-line treatment (51% GC and 68% GCI). Toxicity was similar in the two arms. Grade 3-4 toxicities included asthenia (28% GC and 8% GCI), nausea (3% GC and 14% GCI), and decreased appetite (10% in each).
CONCLUSIONS
Addition of iniparib to GC did not improve ORR over GC alone. The GCI safety profile was comparable to GC alone. Imbalances in PS and gender distribution may have impacted study results regarding PFS and OS.
TRIAL REGISTRATION
ClinicalTrial.gov Identifier NCT01086254.
Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Benzamides; Carcinoma, Non-Small-Cell Lung; Cisplatin; Deoxycytidine; Disease-Free Survival; Drug-Related Side Effects and Adverse Reactions; Female; Humans; Male; Middle Aged; Neoplasm Metastasis; Treatment Outcome; Gemcitabine
PubMed: 25139550
DOI: 10.1093/annonc/mdu384 -
Cancer Cell International 2015Advances in surgical and medical treatments for ovarian cancer have improved prognoses. Platinum drugs in particular are pivotal for the medical treatment of ovarian... (Review)
Review
Advances in surgical and medical treatments for ovarian cancer have improved prognoses. Platinum drugs in particular are pivotal for the medical treatment of ovarian cancer. However, previous studies have revealed that some histological subtypes, such as clear cell carcinoma, are resistant to medical treatment, including that with platinum drugs. Consequently, the clinical prognosis of advanced clear cell carcinoma is remarkably inferior, primarily because of its chemoresistant behavior. The prevalence of clear cell carcinoma is approximately 5 % in the West, but in Japan, its prevalence is particularly high, at approximately 25 %. Current medical treatments for advanced clear cell carcinoma are difficult to administer, and they have poor efficacy, warranting the development of novel target-based therapies. In this review, we describe medical treatments for clear cell carcinoma and discuss future prospects for therapy. In particular, we focus on the mechanism of platinum resistance in clear cell carcinoma, including the role of annexin A4, one of the most investigated factors of platinum resistance, as well as the mutant genes and overexpressed proteins such as VEGF, PI3K/AKT/mTOR signaling pathway, ARID1A, hepatocyte nuclear factor-1β, ZNF217. We also review targeted molecular therapeutics for epithelial ovarian cancer and discuss their role in clear cell carcinoma treatment. We review the drugs targeting angiogenesis (bevacizumab, sorafenib, and pazopanib), growth factors (gefitinib, erlotinib, lapatinib, trastuzumab, and AMG479), and signaling pathways (temsirolimus, dasatinib, and imatinib), and other drugs (oregovomab, volociximab, and iniparib). This current review summarizes and discusses the clinical significance of these factors in ovarian clear cell carcinoma as well as their potential mechanisms of action. It may provide new integrative understanding for future studies on their exact role in ovarian clear cell carcinoma.
PubMed: 26675567
DOI: 10.1186/s12935-015-0267-0 -
Breast Cancer Research and Treatment Nov 2015Iniparib is an investigational agent with antitumor activity of controversial mechanism of action. Two previous trials in advanced triple-negative breast cancer (TNBC)... (Randomized Controlled Trial)
Randomized Controlled Trial
SOLTI NeoPARP: a phase II randomized study of two schedules of iniparib plus paclitaxel versus paclitaxel alone as neoadjuvant therapy in patients with triple-negative breast cancer.
Iniparib is an investigational agent with antitumor activity of controversial mechanism of action. Two previous trials in advanced triple-negative breast cancer (TNBC) in combination with gemcitabine and carboplatin showed some evidence of efficacy that was not confirmed. This phase II randomized neoadjuvant study was designed to explore its activity and tolerability with weekly paclitaxel (PTX) as neoadjuvant treatment in TNBC patients. 141 patients with Stage II-IIIA TNBC were randomly assigned to receive PTX (80 mg/m(2), d1; n = 47) alone or in combination with iniparib, either once-weekly (PWI) (11.2 mg/kg, d1; n = 46) or twice-weekly (PTI) (5.6 mg/kg, d1, 4; n = 48) for 12 weeks. Primary endpoint was pathologic complete response (pCR) in the breast. pCR rate was similar among the three arms (21, 22, and 19 % for PTX, PWI, and PTI, respectively). Secondary efficacy endpoints were comparable: pCR in breast and axilla (21, 17, and 19 %); best overall response in the breast (60, 61, and 63 %); and breast conservation rate (53, 54, and 50 %). Slightly more patients in the PTI arm presented grade 3/4 neutropenia (4, 0, and 10 %). Grade 1/2 (28, 22, and 29 %), but no grade 3/4 neuropathy, was observed. There were no differences in serious adverse events and treatment-emergent adverse events leading to treatment discontinuation among the three arms. Addition of iniparib to weekly PTX did not add relevant antitumor activity or toxicity. These results do not support further evaluation of the combination of iniparib at these doses plus paclitaxel in early TNBC.
Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Benzamides; Combined Modality Therapy; Drug Administration Schedule; Female; Humans; Lymphatic Metastasis; Middle Aged; Neoadjuvant Therapy; Neoplasm Staging; Paclitaxel; Treatment Outcome; Triple Negative Breast Neoplasms
PubMed: 26536871
DOI: 10.1007/s10549-015-3616-8 -
Frontiers in Oncology 2014The repair of DNA double-strand breaks (DSBs) is a critical cellular mechanism that exists to ensure genomic stability. DNA DSBs are the most deleterious type of insult... (Review)
Review
The repair of DNA double-strand breaks (DSBs) is a critical cellular mechanism that exists to ensure genomic stability. DNA DSBs are the most deleterious type of insult to a cell's genetic material and can lead to genomic instability, apoptosis, or senescence. Incorrectly repaired DNA DSBs have the potential to produce chromosomal translocations and genomic instability, potentially leading to cancer. The prevalence of DNA DSBs in cancer due to unregulated growth and errors in repair opens up a potential therapeutic window in the treatment of cancers. The cellular response to DNA DSBs is comprised of two pathways to ensure DNA breaks are repaired: homologous recombination and non-homologous end joining. Identifying chemotherapeutic compounds targeting proteins involved in these DNA repair pathways has shown promise as a cancer therapy for patients, either as a monotherapy or in combination with genotoxic drugs. From the beginning, there have been a number of chemotherapeutic compounds that have yielded successful responses in the clinic, a number that have failed (CGK-733 and iniparib), and a number of promising targets for future studies identified. This review looks in detail at how the cell responds to these DNA DSBs and investigates the chemotherapeutic avenues that have been and are currently being explored to target this repair process.
PubMed: 24795863
DOI: 10.3389/fonc.2014.00086 -
Breast Cancer Research : BCR Aug 2011Inhibitors of poly(ADP-ribose) polymerase (PARP)-mediated DNA repair have shown promise in early clinical studies in the treatment of specific subgroups of breast... (Review)
Review
Inhibitors of poly(ADP-ribose) polymerase (PARP)-mediated DNA repair have shown promise in early clinical studies in the treatment of specific subgroups of breast cancer. Notably, phase II trials indicate that olaparib, an oral PARP inhibitor, has activity as a single agent in BRCA-related tumours, and that a combination of iniparib, an intravenous PARP inhibitor, and chemotherapy offers a survival advantage, compared with chemotherapy alone, in triple-negative breast cancer. Phase III data on the latter indication are expected in 2011. Intriguingly, iniparib does not increase toxicity when used as a chemo-potentiating agent, suggesting that it differs in its mechanism of action from other agents in this class. Overall, PARP inhibitors represent a potentially important new class of anti-cancer agents with two potential modes of action, as single agents causing synthetic lethality and as chemo-potentiating agents.
Topics: Antineoplastic Agents; Benzamides; Breast Neoplasms; Enzyme Inhibitors; Female; Genes, BRCA1; Genes, BRCA2; Humans; Phthalazines; Piperazines; Poly(ADP-ribose) Polymerase Inhibitors; Poly(ADP-ribose) Polymerases
PubMed: 21884642
DOI: 10.1186/bcr2877 -
Postepy Higieny I Medycyny... May 2012Poly-ADP-ribose polymerases (PARP) are involved in a number of processes that are vital for every living cell. Once activated by the presence of DNA damage they trigger... (Review)
Review
Poly-ADP-ribose polymerases (PARP) are involved in a number of processes that are vital for every living cell. Once activated by the presence of DNA damage they trigger poly-ADP-ribosylation of various proteins which are crucial for DNA repair, preserving of genom integrity, regulation of transcription, proliferation and apoptosis. PARP1, which is the best known enzyme of PARP protein family, plays a role in single-strand breaks (SSB) repair. Decrease of its activity results in accumulation of single strand DNA breaks (SSB) which leads as a consequence to double-strand breaks (DSBs). This disorder is particularly harmful to cells with deficiency of BRCA1/2 protein which is involved in repair of DNA double-strand breaks. This phenomenon is an example of "synthetic lethality" concept and contributes to research on application of PARP inhibitors in treatment of cancers associated with BRCA1/2 protein defect (breast or ovarian cancer). Noticed synergism between PARP inhibitors and genotoxic chemotherapy or radiotherapy determined another direction of research on application of these medicaments. After promising results of phase I and II trials with most commonly investigated PARP inhibitors--iniparib and olaparib--which recruited patients with triple negative breast cancer and ovarian cancer, further studies started. This paper presents theoretical basis of PARP inhibitors action as well as critical review of most important clinical trials of these medicaments.
Topics: Antineoplastic Agents; Breast Neoplasms; DNA Breaks, Double-Stranded; DNA Breaks, Single-Stranded; DNA Damage; DNA Repair; Enzyme Inhibitors; Female; Genes, BRCA1; Genes, BRCA2; Humans; Mutation; Ovarian Neoplasms; Poly(ADP-ribose) Polymerase Inhibitors; Poly(ADP-ribose) Polymerases
PubMed: 22706117
DOI: 10.5604/17322693.999033