The Experts below are selected from a list of 1632 Experts worldwide ranked by ideXlab platform

Mansoor Raza Mirza - One of the best experts on this subject based on the ideXlab platform.

Kathleen N. Moore - One of the best experts on this subject based on the ideXlab platform.

  • Niraparib in the treatment of previously treated advanced ovarian, fallopian tube or primary peritoneal cancer.
    Future oncology (London England), 2020
    Co-Authors: Bobbie J. Rimel, Lauren Dockery, Leslie M. Randall, Kathleen N. Moore
    Abstract:

    Homologous recombination deficiency is a critical biologic feature of ovarian cancer. This weakness in DNA damage repair relies on functional poly(ADP-ribose) polymerase. Niraparib is a poly(ADP-ribose) polymerase inhibitor, orally available and initially approved for maintenance therapy in women with ovarian cancer by the US FDA in 2017 and by the EMA in 2017 for the same indication. Ovarian cancer represents the most lethal of gynecologic malignancies. The efficacy of Niraparib has changed the landscape of ovarian cancer treatment, but overall survival data is still to come. This review summarizes the data regarding Niraparib mechanism of action, toxicities, single agent efficacy and novel combinations in ovarian cancer.

  • engot ov44 first study a randomized double blind adaptive phase iii study of standard of care soc platinum based therapy dostarlimab followed by Niraparib dostarlimab maintenance as first line 1l treatment of stage 3 or 4 ovarian cancer oc
    Journal of Clinical Oncology, 2020
    Co-Authors: Anneclaire Hardybessard, Kathleen N. Moore, Mansoor Raza Mirza, Diane Provencher, B Asselain, Andres Redondo, Jacobus Pfisterer, Sandro Pignata, D Cibula, Anna K L Reyners
    Abstract:

    TPS6101Background: Despite surgery and CT (paclitaxel + carboplatin ± bevacizumab [bev]), 5-year survival rates remain low for patients (pts) with FIGO stage 3 or 4 OC. Niraparib is a poly (ADP-rib...

  • engot ov44 first study a randomized double blind adaptive phase iii study of platinum based therapy with dostarlimab tsr 042 Niraparib versus standard of care soc platinum based therapy as first line treatment of stage 3 4 non mucinous epithelial ova
    Journal of Clinical Oncology, 2019
    Co-Authors: Anneclaire Hardybessard, Kathleen N. Moore, Mansoor Raza Mirza, Diane Provencher, B Asselain, Andres Redondo, Jacobus Pfisterer, Sandro Pignata, D Cibula, Anna K L Reyners
    Abstract:

    TPS5600Background: Despite surgery and SOC therapy (paclitaxel and carboplatin ± bevacizumab[bev]), 5-year survival rates remain low for patients (pts) with FIGO stage 3/4 OC. Niraparib (ZEJULA) is...

  • efficacy and safety of Niraparib as maintenance treatment in older patients 70 years with recurrent ovarian cancer results from the engot ov16 nova trial
    Gynecologic Oncology, 2019
    Co-Authors: Michel Fabbro, Kathleen N. Moore, Anne Dørum, Anna V. Tinker, Sven Mahner, Isabel Bover, Susana Banerjee
    Abstract:

    Abstract Objective To analyze the safety and efficacy of Niraparib in patients aged ≥70 years with recurrent ovarian cancer in the ENGOT-OV16/NOVA trial. Methods The trial enrolled 2 independent cohorts with histologically diagnosed recurrent ovarian, fallopian tube, or peritoneal cancer who responded to platinum rechallenge, on the basis of germline breast cancer susceptibility gene mutation (gBRCAmut) status. Patients were randomized 2:1 to receive Niraparib (300 mg) or placebo once daily until disease progression. The primary endpoint was progression-free survival (PFS) by blinded independent central review. Adverse events (AEs) of special interest were based on the known safety profile of poly(ADP-ribose) polymerase inhibitors. Results Patients aged ≥70 years in the gBRCAmut cohort receiving Niraparib (n = 14) had not yet reached a median PFS compared with a median PFS of 3.7 months for the same age group in the placebo arm (hazard ratio [HR], 0.09 [95% confidence interval (CI), 0.01 to 0.73]). Non-gBRCAmut patients aged ≥70 years receiving Niraparib (n = 47) had a median PFS of 11.3 months compared with 3.8 months in the placebo arm (HR, 0.35 [95% CI, 0.18 to 0.71]). Median duration of follow-up in the Niraparib arm was 17.3 months in patients ≥70 years and 17.2 months in patients Conclusions For patients ≥70 years of age receiving Niraparib as maintenance treatment in the ENGOT-OV16/NOVA trial, PFS benefits and incidence of any grade or serious treatment-emergent AEs were comparable to results in the younger population. Use of Niraparib should be considered in this population.

  • Effect of Niraparib on cardiac repolarization in patients with platinum-sensitive, recurrent epithelial ovarian, fallopian tube, and primary peritoneal cancer.
    Cancer chemotherapy and pharmacology, 2019
    Co-Authors: Kathleen N. Moore, John K. C. Chan, Angeles Alvarez Secord, Manish R. Patel, Timothy Callahan, Wei Guo, Zhi-yi Zhang
    Abstract:

    Anticancer drugs may cause cardiovascular toxicities, including QT interval prolongation. Niraparib, a potent and selective once-daily oral poly (ADP-ribose) polymerase inhibitor, is approved as a maintenance therapy in platinum-sensitive recurrent epithelial ovarian, fallopian tube, and primary peritoneal cancer (EOC). Here, we present the effects of Niraparib on cardiac repolarization, and the correlation between changes in baseline QT interval corrected by Fridericia’s formula (ΔQTcF) and Niraparib plasma concentrations. Patients with EOC from the NOVA study (subset of n = 15), the food effect NOVA substudy (n = 17), and a QTc substudy (n = 26) underwent intensive electrocardiographic (ECG) monitoring that included triplicate ECG testing on Day 1 at baseline (predose) and at 1, 1.5, 2, 3, 4, 6, and 8 h postdose concurrent with time-matched blood sampling for determination of Niraparib plasma concentrations. All patients received once-daily 300-mg Niraparib until disease progression or toxicity. Across the 3 substudies, the upper limit of the two-sided 90% confidence interval (CI) of ΔQTcF was ≤ 10 ms at every postdose timepoint, with a maximum upper limit of 4.3 ms, which indicates no clinically meaningful effect on QTc prolongation. No statistically significant relationship between ΔQTcF and Niraparib plasma concentration was observed (estimated slope: 0.0049; 95% CI: − 0.0020, 0.0117; P = 0.164). There were no clinically relevant changes in other ECG parameters that could be attributable to Niraparib. Niraparib administration at the recommended daily dose of 300 mg for EOC is not associated with clinically relevant alteration of ECGs, including QTc prolongation.

Jing Wang - One of the best experts on this subject based on the ideXlab platform.

  • Efficacy and pharmacodynamics of Niraparib in BRCA-mutant and wild-type intracranial triple-negative breast cancer murine models.
    Neuro-oncology advances, 2019
    Co-Authors: Maria J. Sambade, Kaiming Sun, Keith Mikule, Jing Wang, Amanda E.d. Van Swearingen, Marni B Mcclure, Allison M. Deal, Charlene Santos, Carey K. Anders
    Abstract:

    Background Despite the poor prognosis of triple-negative breast cancer (TNBC) brain metastases, there are no approved systemic therapies. We explored the DNA-damaging poly(ADP-ribose) polymerase inhibitor (PARPi) Niraparib in intracranial mouse models of breast cancer susceptibility protein (BRCA)-mutant TNBC. Methods Mice bearing intracranial human-derived TNBC cell lines (SUM149, MDA-MB-231Br, or MDA-MB-436) were treated with Niraparib and monitored for survival; intracranial tissues were analyzed for PAR levels and Niraparib concentration by mass spectrometry. RNASeq data of primary breast cancers using The Cancer Genome Atlas were analyzed for DNA damage signatures. Combined RAD51 and PARP inhibition in TNBC cell lines was assessed in vitro by colony-forming assays. Results Daily Niraparib increased median survival and decreased tumor burden in the BRCA-mutant MDA-MB-436 model, but not in the BRCA-mutant SUM149 or BRCA-wild-type MDA-MB-231Br models despite high concentrations in intracranial tumors. RAD51 inhibitor B02 was shown to sensitize all cell lines to PARP inhibition (PARPi). In the analysis of BRCA-mutant primary human TNBCs, gene expression predictors of PARPi sensitivity and DNA repair signatures demonstrate widespread heterogeneity, which may explain the differential response to PARPi. Interestingly, these signatures are significantly correlated to RAD51 expression including PARPi sensitivity (R 2 = 0.602, R 2= 0.758). Conclusions Niraparib penetrates intracranial tumor tissues in mouse models of TNBC with impressive single-agent efficacy in BRCA-mutant MDA-MB-436. Clinical evaluation of Niraparib to treat TNBC brain metastases, an unmet clinical need desperate for improved therapies, is warranted. Further compromising DNA repair through RAD51 inhibition may further augment TNBC's response to PARPi.

  • A comparative pharmacokinetic study of PARP inhibitors demonstrates favorable properties for Niraparib efficacy in preclinical tumor models.
    Oncotarget, 2018
    Co-Authors: Kaiming Sun, Sridhar Ramaswamy, Zhi-yi Zhang, Keith Mikule, Jeffrey Hanke, Grace Poon, Zebin Wang, Aparajitha Vaidyanathan, Gillian Smith, Jing Wang
    Abstract:

    Niraparib is an orally bioavailable and selective poly (ADP-ribose) polymerase (PARP)-1/-2 inhibitor approved for maintenance treatment of both BRCA mutant (mut) and BRCA wildtype (wt) adult patients with recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancers who have demonstrated a complete or partial response to platinum-based chemotherapy. In patients without germline BRCA mutations (non-gBRCAmut), Niraparib improved progression-free survival (PFS) by 5.4 months, whereas another PARP inhibitor (PARPi) olaparib supplied only 1.9 months of improvement in a similar patient population. Previous studies revealed higher cell membrane permeability and volume of distribution (VD) as unique features of Niraparib in comparison to other PARPi including olaparib. Here, we explore the potential correlation of these pharmacokinetic properties to preclinical antitumor effects in BRCAwt tumors. Our results show that at steady state, tumor exposure to Niraparib is 3.3 times greater than plasma exposure in tumor xenograft mouse models. In comparison, the tumor exposure to olaparib is less than observed in plasma. In addition, Niraparib crosses the blood-brain barrier and shows good sustainability in the brain, whereas sustained brain exposure to olaparib is not observed in the same models. Consistent with its favorable tumor and brain distribution, Niraparib achieves more potent tumor growth inhibition than olaparib in BRCAwt models and an intracranial tumor model at maximum tolerated doses (MTD). These findings demonstrate favorable pharmacokinetic profiles and potent antitumor effects of Niraparib in BRCAwt tumors, consistent with its broader clinical effect in patients with both BRCAmut and BRCAwt tumors.

  • Abstract 5826: Enhanced anti-tumor effects of selinexor and Niraparib in preclinical models of ovarian cancer
    Experimental and Molecular Therapeutics, 2018
    Co-Authors: Hua Chang, Sarah Wang, Keith Mikule, Mansoor Raza Mirza, Trinayan Kashyap, Sophie Debler, Thaddeus J. Unger, Jing Wang, Sharon Shacham, Yosef Landesman
    Abstract:

    Introduction: Selinexor (KPT-330) is a first-in-class oral exportin-1 (XPO1/ CRM1) inhibitor that induces cell cycle arrest and apoptosis in cancer cells through reactivation of tumor suppressor proteins and inhibition of DNA damage repair genes. Here, we studied selinexor in combination with Niraparib, an inhibitor of the DNA damage repair proteins PARP1 and 2, in preclinical models of ovarian cancer. Given that both compounds can inhibit DNA damage repair responses, we hypothesized the combination of selinexor and Niraparib would enhance cancer cell death by accumulation of DNA damage that cannot be resolved in ovarian cancer. Methods: Selinexor and Niraparib alone and in combination were tested in vitro on the BRCA wildtype ovarian cancer cell line A2780. Total RNA and protein were extracted from cell lysates and analyzed by qPCR and immunoblots. In vivo, a subcutaneous A2780 xenograft mouse model was treated with selinexor [10 mg/kg, once per week (M) for three weeks] or Niraparib [37.5 mg/kg, once-daily for five days per week (M-F) for three weeks] as single agents or in combination. Tumor growth and body weights were measured for 21 days. Tumors were harvested at the end of the study and analyzed by immunohistochemistry (IHC). Results: Selinexor and Niraparib as single agents inhibited A2780 cell proliferation (selinexor IC50: 200nM; Niraparib IC50: 800nM). The combination of selinexor and Niraparib showed synergistic cytotoxicity in A2780 cells. Increased expression of phospho (S139) H2A.X with the combination confirmed induction of DNA damage. In vivo, the combination enhanced tumor inhibition (51.0% in combination versus 24.3% and 29.6% in selinexor and Niraparib respectively) and improved median survival compared to vehicle or each agent alone (18 days in combination group versus 11, 14 and 16 days in vehicle, selinexor, and Niraparib groups, respectively). IHC analysis showed enhanced nuclear p53 and p21 staining in selinexor treated tumors as well as in tumors treated with the combination. Increased apoptosis was observed in tumor samples treated with both selinexor and Niraparib as compared to vehicle control or each agent alone. Conclusions: Selinexor plus Niraparib demonstrated enhanced anti-tumor activity in preclinical models of human ovarian cancer. Since both drugs could inhibit DNA damage repair pathway, the drug combination efficiently accumulated DNA damage, which was associated with reduced cell proliferation, and induced apoptosis. This combination therapy warrants further investigation as a treatment option for patients with ovarian cancer. Citation Format: Hua Chang, Trinayan Kashyap, Sophie Debler, Thaddeus J. Unger, Sarah Wang, Keith Mikule, Jing Wang, Mansoor R. Mirza, Sharon Shacham, Yosef Landesman. Enhanced anti-tumor effects of selinexor and Niraparib in preclinical models of ovarian cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5826.

  • Abstract 1724: Evaluation of Niraparib in combination with anti-PD1/anti-PD-L1 in preclinical models
    Immunology, 2018
    Co-Authors: Sarah Wang, Bin Feng, Sridhar Ramaswamy, Kaiming Sun, Yonghong Xiao, Keith Mikule, Jeffrey Hanke, Jing Wang
    Abstract:

    Niraparib is an orally available and selective poly(ADP-ribose) polymerase (PARP)-1/-2 inhibitor approved for maintenance treatment of adult patients with recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in complete or partial response to platinum-based chemotherapy. PARP inhibition may enhance the immune response in tumors treated with anti-PD-1 therapy via generation of cytosolic DNA that activates T cells through the stimulator of interferon gene (STING) pathway, rendering tumors immunologically “hot” with an increase in infiltrating lymphocytes. In this study, we explored the responses and mechanism of action of Niraparib and anti-PD-1/anti-PD-L1 combination therapy in preclinical models. Out of a cohort of 14 immune-competent mouse tumor models, the combination treatment demonstrated enhanced anti-tumor activity in eight tumor models derived from BRCA-proficient and BRCA-deficient genetic backgrounds. Substantial increases compared to monotherapies in anti-tumor activity was observed in 5 models, indicative of synergy between Niraparib and anti-PD-1/anti-PD-L1 therapy. The combination triggered durable responses that were coincident with induction of immune memories in a BRCA-deficient ovarian syngeneic model. Mechanistically, Niraparib treatment increased the number of infiltrating CD8+ and CD4+ cells within the intratumoral region. The enhanced immune cell infiltration was accompanied by elevated interferon-stimulated gene expression. Pathway analyses using transcriptome profiling identified interferon response gene signatures as the significantly differentially-upregulated gene sets following Niraparib treatment. Consistently, Niraparib treatment activated the STING pathway in vitro in BRCA-deficient MDA-MB-436 human triple negative breast cancer cells. STING pathway markers including p-STING(Ser366), p-TBK1(Ser172) and p-NFκB p65 were elevated following Niraparib treatment and was accompanied by an increase in IFNB mRNA expression. In summary, our data suggested that Niraparib treatment in combination with anti-PD-1/anti-PD-L1 therapy enhanced immune cell infiltration, interferon-stimulated gene expression and tumor responses. Citation Format: Sarah Wang, Kaiming Sun, Yonghong Xiao, Bin Feng, Keith Mikule, Sridhar Ramaswamy, Jeffrey Hanke, Jing Wang. Evaluation of Niraparib in combination with anti-PD1/anti-PD-L1 in preclinical models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1724.

  • abstract 1724 evaluation of Niraparib in combination with anti pd1 anti pd l1 in preclinical models
    Cancer Research, 2018
    Co-Authors: Sarah Wang, Bin Feng, Sridhar Ramaswamy, Kaiming Sun, Yonghong Xiao, Keith Mikule, Jeffrey Hanke, Jing Wang
    Abstract:

    Niraparib is an orally available and selective poly(ADP-ribose) polymerase (PARP)-1/-2 inhibitor approved for maintenance treatment of adult patients with recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in complete or partial response to platinum-based chemotherapy. PARP inhibition may enhance the immune response in tumors treated with anti-PD-1 therapy via generation of cytosolic DNA that activates T cells through the stimulator of interferon gene (STING) pathway, rendering tumors immunologically “hot” with an increase in infiltrating lymphocytes. In this study, we explored the responses and mechanism of action of Niraparib and anti-PD-1/anti-PD-L1 combination therapy in preclinical models. Out of a cohort of 14 immune-competent mouse tumor models, the combination treatment demonstrated enhanced anti-tumor activity in eight tumor models derived from BRCA-proficient and BRCA-deficient genetic backgrounds. Substantial increases compared to monotherapies in anti-tumor activity was observed in 5 models, indicative of synergy between Niraparib and anti-PD-1/anti-PD-L1 therapy. The combination triggered durable responses that were coincident with induction of immune memories in a BRCA-deficient ovarian syngeneic model. Mechanistically, Niraparib treatment increased the number of infiltrating CD8+ and CD4+ cells within the intratumoral region. The enhanced immune cell infiltration was accompanied by elevated interferon-stimulated gene expression. Pathway analyses using transcriptome profiling identified interferon response gene signatures as the significantly differentially-upregulated gene sets following Niraparib treatment. Consistently, Niraparib treatment activated the STING pathway in vitro in BRCA-deficient MDA-MB-436 human triple negative breast cancer cells. STING pathway markers including p-STING(Ser366), p-TBK1(Ser172) and p-NFκB p65 were elevated following Niraparib treatment and was accompanied by an increase in IFNB mRNA expression. In summary, our data suggested that Niraparib treatment in combination with anti-PD-1/anti-PD-L1 therapy enhanced immune cell infiltration, interferon-stimulated gene expression and tumor responses. Citation Format: Sarah Wang, Kaiming Sun, Yonghong Xiao, Bin Feng, Keith Mikule, Sridhar Ramaswamy, Jeffrey Hanke, Jing Wang. Evaluation of Niraparib in combination with anti-PD1/anti-PD-L1 in preclinical models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1724.

Keith Mikule - One of the best experts on this subject based on the ideXlab platform.

  • Efficacy and pharmacodynamics of Niraparib in BRCA-mutant and wild-type intracranial triple-negative breast cancer murine models.
    Neuro-oncology advances, 2019
    Co-Authors: Maria J. Sambade, Kaiming Sun, Keith Mikule, Jing Wang, Amanda E.d. Van Swearingen, Marni B Mcclure, Allison M. Deal, Charlene Santos, Carey K. Anders
    Abstract:

    Background Despite the poor prognosis of triple-negative breast cancer (TNBC) brain metastases, there are no approved systemic therapies. We explored the DNA-damaging poly(ADP-ribose) polymerase inhibitor (PARPi) Niraparib in intracranial mouse models of breast cancer susceptibility protein (BRCA)-mutant TNBC. Methods Mice bearing intracranial human-derived TNBC cell lines (SUM149, MDA-MB-231Br, or MDA-MB-436) were treated with Niraparib and monitored for survival; intracranial tissues were analyzed for PAR levels and Niraparib concentration by mass spectrometry. RNASeq data of primary breast cancers using The Cancer Genome Atlas were analyzed for DNA damage signatures. Combined RAD51 and PARP inhibition in TNBC cell lines was assessed in vitro by colony-forming assays. Results Daily Niraparib increased median survival and decreased tumor burden in the BRCA-mutant MDA-MB-436 model, but not in the BRCA-mutant SUM149 or BRCA-wild-type MDA-MB-231Br models despite high concentrations in intracranial tumors. RAD51 inhibitor B02 was shown to sensitize all cell lines to PARP inhibition (PARPi). In the analysis of BRCA-mutant primary human TNBCs, gene expression predictors of PARPi sensitivity and DNA repair signatures demonstrate widespread heterogeneity, which may explain the differential response to PARPi. Interestingly, these signatures are significantly correlated to RAD51 expression including PARPi sensitivity (R 2 = 0.602, R 2= 0.758). Conclusions Niraparib penetrates intracranial tumor tissues in mouse models of TNBC with impressive single-agent efficacy in BRCA-mutant MDA-MB-436. Clinical evaluation of Niraparib to treat TNBC brain metastases, an unmet clinical need desperate for improved therapies, is warranted. Further compromising DNA repair through RAD51 inhibition may further augment TNBC's response to PARPi.

  • Niraparib activates interferon signaling and potentiates anti-PD-1 antibody efficacy in tumor models
    Scientific reports, 2019
    Co-Authors: Zebin Wang, Bin Feng, Kaiming Sun, Yonghong Xiao, Keith Mikule, Xiao Yan, Ningping Feng, Christopher P. Vellano, Lorenzo Federico, Joseph R. Marszalek
    Abstract:

    PARP inhibitors have been proven clinically efficacious in platinum-responsive ovarian cancer regardless of BRCA1/2 status and in breast cancers with germline BRCA1/2 mutation. However, resistance to PARP inhibitors may preexist or evolve during treatment in many cancer types and may be overcome by combining PARP inhibitors with other therapies, such as immune checkpoint inhibitors, which confer durable responses and are rapidly becoming the standard of care for multiple tumor types. This study investigated the therapeutic potential of combining Niraparib, a highly selective PARP1/2 inhibitor, with anti-PD-1 immune checkpoint inhibitors in preclinical tumor models. Our results indicate that Niraparib treatment increases the activity of the type I (alpha) and type II (gamma) interferon pathways and enhances the infiltration of CD8+ cells and CD4+ cells in tumors. When coadministered in immunocompetent models, the combination of Niraparib and anti-PD-1 demonstrated synergistic antitumor activities in both BRCA-proficient and BRCA-deficient tumors. Interestingly, mice with tumors cured by Niraparib monotherapy completely rejected tumor growth upon rechallenge with the same tumor cell line, suggesting the potential establishment of immune memory in animals treated with Niraparib monotherapy. Taken together, our findings uncovered immunomodulatory effects of Niraparib that may sensitize tumors to immune checkpoint blockade therapies.

  • A comparative pharmacokinetic study of PARP inhibitors demonstrates favorable properties for Niraparib efficacy in preclinical tumor models.
    Oncotarget, 2018
    Co-Authors: Kaiming Sun, Sridhar Ramaswamy, Zhi-yi Zhang, Keith Mikule, Jeffrey Hanke, Grace Poon, Zebin Wang, Aparajitha Vaidyanathan, Gillian Smith, Jing Wang
    Abstract:

    Niraparib is an orally bioavailable and selective poly (ADP-ribose) polymerase (PARP)-1/-2 inhibitor approved for maintenance treatment of both BRCA mutant (mut) and BRCA wildtype (wt) adult patients with recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancers who have demonstrated a complete or partial response to platinum-based chemotherapy. In patients without germline BRCA mutations (non-gBRCAmut), Niraparib improved progression-free survival (PFS) by 5.4 months, whereas another PARP inhibitor (PARPi) olaparib supplied only 1.9 months of improvement in a similar patient population. Previous studies revealed higher cell membrane permeability and volume of distribution (VD) as unique features of Niraparib in comparison to other PARPi including olaparib. Here, we explore the potential correlation of these pharmacokinetic properties to preclinical antitumor effects in BRCAwt tumors. Our results show that at steady state, tumor exposure to Niraparib is 3.3 times greater than plasma exposure in tumor xenograft mouse models. In comparison, the tumor exposure to olaparib is less than observed in plasma. In addition, Niraparib crosses the blood-brain barrier and shows good sustainability in the brain, whereas sustained brain exposure to olaparib is not observed in the same models. Consistent with its favorable tumor and brain distribution, Niraparib achieves more potent tumor growth inhibition than olaparib in BRCAwt models and an intracranial tumor model at maximum tolerated doses (MTD). These findings demonstrate favorable pharmacokinetic profiles and potent antitumor effects of Niraparib in BRCAwt tumors, consistent with its broader clinical effect in patients with both BRCAmut and BRCAwt tumors.

  • Long-term treatment with the PARP inhibitor Niraparib does not increase the mutation load in cell line models and tumour xenografts.
    British journal of cancer, 2018
    Co-Authors: Ádám Póti, Yonghong Xiao, Keith Mikule, Keith Wilcoxen, Kinga Berta, Orsolya Pipek, Gregory T. Klus, Thomas Ried, István Csabai, Zoltan Szallasi
    Abstract:

    Poly-ADP ribose polymerase (PARP) inhibitor-based cancer therapy selectively targets cells with deficient homologous recombination repair. Considering their long-term use in maintenance treatment, any potential mutagenic effect of PARP inhibitor treatment could accelerate the development of resistance or harm non-malignant somatic cells. We tested the mutagenicity of long-term treatment with the PARP inhibitor Niraparib using whole-genome sequencing of cultured cell clones and whole-exome sequencing of patient-derived breast cancer xenografts. We observed no significant increase in the number and alteration in the spectrum of base substitutions, short insertions and deletions and genomic rearrangements upon Niraparib treatment of human DLD-1 colon adenocarcinoma cells, wild-type and BRCA1 mutant chicken DT40 lymphoblastoma cells and BRCA1-defective SUM149PT breast carcinoma cells, except for a minor increase in specific deletion classes. We also did not detect any contribution of in vivo Niraparib treatment to subclonal mutations arising in breast cancer-derived xenografts. The results suggest that long-term inhibition of DNA repair with PARP inhibitors has no or only limited mutagenic effect. Mutagenesis due to prolonged use of PARP inhibitors in cancer treatment is therefore not expected to contribute to the genetic evolution of resistance, generate significant immunogenic neoepitopes or induce secondary malignancies.

  • Abstract 5826: Enhanced anti-tumor effects of selinexor and Niraparib in preclinical models of ovarian cancer
    Experimental and Molecular Therapeutics, 2018
    Co-Authors: Hua Chang, Sarah Wang, Keith Mikule, Mansoor Raza Mirza, Trinayan Kashyap, Sophie Debler, Thaddeus J. Unger, Jing Wang, Sharon Shacham, Yosef Landesman
    Abstract:

    Introduction: Selinexor (KPT-330) is a first-in-class oral exportin-1 (XPO1/ CRM1) inhibitor that induces cell cycle arrest and apoptosis in cancer cells through reactivation of tumor suppressor proteins and inhibition of DNA damage repair genes. Here, we studied selinexor in combination with Niraparib, an inhibitor of the DNA damage repair proteins PARP1 and 2, in preclinical models of ovarian cancer. Given that both compounds can inhibit DNA damage repair responses, we hypothesized the combination of selinexor and Niraparib would enhance cancer cell death by accumulation of DNA damage that cannot be resolved in ovarian cancer. Methods: Selinexor and Niraparib alone and in combination were tested in vitro on the BRCA wildtype ovarian cancer cell line A2780. Total RNA and protein were extracted from cell lysates and analyzed by qPCR and immunoblots. In vivo, a subcutaneous A2780 xenograft mouse model was treated with selinexor [10 mg/kg, once per week (M) for three weeks] or Niraparib [37.5 mg/kg, once-daily for five days per week (M-F) for three weeks] as single agents or in combination. Tumor growth and body weights were measured for 21 days. Tumors were harvested at the end of the study and analyzed by immunohistochemistry (IHC). Results: Selinexor and Niraparib as single agents inhibited A2780 cell proliferation (selinexor IC50: 200nM; Niraparib IC50: 800nM). The combination of selinexor and Niraparib showed synergistic cytotoxicity in A2780 cells. Increased expression of phospho (S139) H2A.X with the combination confirmed induction of DNA damage. In vivo, the combination enhanced tumor inhibition (51.0% in combination versus 24.3% and 29.6% in selinexor and Niraparib respectively) and improved median survival compared to vehicle or each agent alone (18 days in combination group versus 11, 14 and 16 days in vehicle, selinexor, and Niraparib groups, respectively). IHC analysis showed enhanced nuclear p53 and p21 staining in selinexor treated tumors as well as in tumors treated with the combination. Increased apoptosis was observed in tumor samples treated with both selinexor and Niraparib as compared to vehicle control or each agent alone. Conclusions: Selinexor plus Niraparib demonstrated enhanced anti-tumor activity in preclinical models of human ovarian cancer. Since both drugs could inhibit DNA damage repair pathway, the drug combination efficiently accumulated DNA damage, which was associated with reduced cell proliferation, and induced apoptosis. This combination therapy warrants further investigation as a treatment option for patients with ovarian cancer. Citation Format: Hua Chang, Trinayan Kashyap, Sophie Debler, Thaddeus J. Unger, Sarah Wang, Keith Mikule, Jing Wang, Mansoor R. Mirza, Sharon Shacham, Yosef Landesman. Enhanced anti-tumor effects of selinexor and Niraparib in preclinical models of ovarian cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5826.

Kaiming Sun - One of the best experts on this subject based on the ideXlab platform.

  • Efficacy and pharmacodynamics of Niraparib in BRCA-mutant and wild-type intracranial triple-negative breast cancer murine models.
    Neuro-oncology advances, 2019
    Co-Authors: Maria J. Sambade, Kaiming Sun, Keith Mikule, Jing Wang, Amanda E.d. Van Swearingen, Marni B Mcclure, Allison M. Deal, Charlene Santos, Carey K. Anders
    Abstract:

    Background Despite the poor prognosis of triple-negative breast cancer (TNBC) brain metastases, there are no approved systemic therapies. We explored the DNA-damaging poly(ADP-ribose) polymerase inhibitor (PARPi) Niraparib in intracranial mouse models of breast cancer susceptibility protein (BRCA)-mutant TNBC. Methods Mice bearing intracranial human-derived TNBC cell lines (SUM149, MDA-MB-231Br, or MDA-MB-436) were treated with Niraparib and monitored for survival; intracranial tissues were analyzed for PAR levels and Niraparib concentration by mass spectrometry. RNASeq data of primary breast cancers using The Cancer Genome Atlas were analyzed for DNA damage signatures. Combined RAD51 and PARP inhibition in TNBC cell lines was assessed in vitro by colony-forming assays. Results Daily Niraparib increased median survival and decreased tumor burden in the BRCA-mutant MDA-MB-436 model, but not in the BRCA-mutant SUM149 or BRCA-wild-type MDA-MB-231Br models despite high concentrations in intracranial tumors. RAD51 inhibitor B02 was shown to sensitize all cell lines to PARP inhibition (PARPi). In the analysis of BRCA-mutant primary human TNBCs, gene expression predictors of PARPi sensitivity and DNA repair signatures demonstrate widespread heterogeneity, which may explain the differential response to PARPi. Interestingly, these signatures are significantly correlated to RAD51 expression including PARPi sensitivity (R 2 = 0.602, R 2= 0.758). Conclusions Niraparib penetrates intracranial tumor tissues in mouse models of TNBC with impressive single-agent efficacy in BRCA-mutant MDA-MB-436. Clinical evaluation of Niraparib to treat TNBC brain metastases, an unmet clinical need desperate for improved therapies, is warranted. Further compromising DNA repair through RAD51 inhibition may further augment TNBC's response to PARPi.

  • Niraparib activates interferon signaling and potentiates anti-PD-1 antibody efficacy in tumor models
    Scientific reports, 2019
    Co-Authors: Zebin Wang, Bin Feng, Kaiming Sun, Yonghong Xiao, Keith Mikule, Xiao Yan, Ningping Feng, Christopher P. Vellano, Lorenzo Federico, Joseph R. Marszalek
    Abstract:

    PARP inhibitors have been proven clinically efficacious in platinum-responsive ovarian cancer regardless of BRCA1/2 status and in breast cancers with germline BRCA1/2 mutation. However, resistance to PARP inhibitors may preexist or evolve during treatment in many cancer types and may be overcome by combining PARP inhibitors with other therapies, such as immune checkpoint inhibitors, which confer durable responses and are rapidly becoming the standard of care for multiple tumor types. This study investigated the therapeutic potential of combining Niraparib, a highly selective PARP1/2 inhibitor, with anti-PD-1 immune checkpoint inhibitors in preclinical tumor models. Our results indicate that Niraparib treatment increases the activity of the type I (alpha) and type II (gamma) interferon pathways and enhances the infiltration of CD8+ cells and CD4+ cells in tumors. When coadministered in immunocompetent models, the combination of Niraparib and anti-PD-1 demonstrated synergistic antitumor activities in both BRCA-proficient and BRCA-deficient tumors. Interestingly, mice with tumors cured by Niraparib monotherapy completely rejected tumor growth upon rechallenge with the same tumor cell line, suggesting the potential establishment of immune memory in animals treated with Niraparib monotherapy. Taken together, our findings uncovered immunomodulatory effects of Niraparib that may sensitize tumors to immune checkpoint blockade therapies.

  • A comparative pharmacokinetic study of PARP inhibitors demonstrates favorable properties for Niraparib efficacy in preclinical tumor models.
    Oncotarget, 2018
    Co-Authors: Kaiming Sun, Sridhar Ramaswamy, Zhi-yi Zhang, Keith Mikule, Jeffrey Hanke, Grace Poon, Zebin Wang, Aparajitha Vaidyanathan, Gillian Smith, Jing Wang
    Abstract:

    Niraparib is an orally bioavailable and selective poly (ADP-ribose) polymerase (PARP)-1/-2 inhibitor approved for maintenance treatment of both BRCA mutant (mut) and BRCA wildtype (wt) adult patients with recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancers who have demonstrated a complete or partial response to platinum-based chemotherapy. In patients without germline BRCA mutations (non-gBRCAmut), Niraparib improved progression-free survival (PFS) by 5.4 months, whereas another PARP inhibitor (PARPi) olaparib supplied only 1.9 months of improvement in a similar patient population. Previous studies revealed higher cell membrane permeability and volume of distribution (VD) as unique features of Niraparib in comparison to other PARPi including olaparib. Here, we explore the potential correlation of these pharmacokinetic properties to preclinical antitumor effects in BRCAwt tumors. Our results show that at steady state, tumor exposure to Niraparib is 3.3 times greater than plasma exposure in tumor xenograft mouse models. In comparison, the tumor exposure to olaparib is less than observed in plasma. In addition, Niraparib crosses the blood-brain barrier and shows good sustainability in the brain, whereas sustained brain exposure to olaparib is not observed in the same models. Consistent with its favorable tumor and brain distribution, Niraparib achieves more potent tumor growth inhibition than olaparib in BRCAwt models and an intracranial tumor model at maximum tolerated doses (MTD). These findings demonstrate favorable pharmacokinetic profiles and potent antitumor effects of Niraparib in BRCAwt tumors, consistent with its broader clinical effect in patients with both BRCAmut and BRCAwt tumors.

  • Abstract 1724: Evaluation of Niraparib in combination with anti-PD1/anti-PD-L1 in preclinical models
    Immunology, 2018
    Co-Authors: Sarah Wang, Bin Feng, Sridhar Ramaswamy, Kaiming Sun, Yonghong Xiao, Keith Mikule, Jeffrey Hanke, Jing Wang
    Abstract:

    Niraparib is an orally available and selective poly(ADP-ribose) polymerase (PARP)-1/-2 inhibitor approved for maintenance treatment of adult patients with recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in complete or partial response to platinum-based chemotherapy. PARP inhibition may enhance the immune response in tumors treated with anti-PD-1 therapy via generation of cytosolic DNA that activates T cells through the stimulator of interferon gene (STING) pathway, rendering tumors immunologically “hot” with an increase in infiltrating lymphocytes. In this study, we explored the responses and mechanism of action of Niraparib and anti-PD-1/anti-PD-L1 combination therapy in preclinical models. Out of a cohort of 14 immune-competent mouse tumor models, the combination treatment demonstrated enhanced anti-tumor activity in eight tumor models derived from BRCA-proficient and BRCA-deficient genetic backgrounds. Substantial increases compared to monotherapies in anti-tumor activity was observed in 5 models, indicative of synergy between Niraparib and anti-PD-1/anti-PD-L1 therapy. The combination triggered durable responses that were coincident with induction of immune memories in a BRCA-deficient ovarian syngeneic model. Mechanistically, Niraparib treatment increased the number of infiltrating CD8+ and CD4+ cells within the intratumoral region. The enhanced immune cell infiltration was accompanied by elevated interferon-stimulated gene expression. Pathway analyses using transcriptome profiling identified interferon response gene signatures as the significantly differentially-upregulated gene sets following Niraparib treatment. Consistently, Niraparib treatment activated the STING pathway in vitro in BRCA-deficient MDA-MB-436 human triple negative breast cancer cells. STING pathway markers including p-STING(Ser366), p-TBK1(Ser172) and p-NFκB p65 were elevated following Niraparib treatment and was accompanied by an increase in IFNB mRNA expression. In summary, our data suggested that Niraparib treatment in combination with anti-PD-1/anti-PD-L1 therapy enhanced immune cell infiltration, interferon-stimulated gene expression and tumor responses. Citation Format: Sarah Wang, Kaiming Sun, Yonghong Xiao, Bin Feng, Keith Mikule, Sridhar Ramaswamy, Jeffrey Hanke, Jing Wang. Evaluation of Niraparib in combination with anti-PD1/anti-PD-L1 in preclinical models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1724.

  • abstract 1724 evaluation of Niraparib in combination with anti pd1 anti pd l1 in preclinical models
    Cancer Research, 2018
    Co-Authors: Sarah Wang, Bin Feng, Sridhar Ramaswamy, Kaiming Sun, Yonghong Xiao, Keith Mikule, Jeffrey Hanke, Jing Wang
    Abstract:

    Niraparib is an orally available and selective poly(ADP-ribose) polymerase (PARP)-1/-2 inhibitor approved for maintenance treatment of adult patients with recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in complete or partial response to platinum-based chemotherapy. PARP inhibition may enhance the immune response in tumors treated with anti-PD-1 therapy via generation of cytosolic DNA that activates T cells through the stimulator of interferon gene (STING) pathway, rendering tumors immunologically “hot” with an increase in infiltrating lymphocytes. In this study, we explored the responses and mechanism of action of Niraparib and anti-PD-1/anti-PD-L1 combination therapy in preclinical models. Out of a cohort of 14 immune-competent mouse tumor models, the combination treatment demonstrated enhanced anti-tumor activity in eight tumor models derived from BRCA-proficient and BRCA-deficient genetic backgrounds. Substantial increases compared to monotherapies in anti-tumor activity was observed in 5 models, indicative of synergy between Niraparib and anti-PD-1/anti-PD-L1 therapy. The combination triggered durable responses that were coincident with induction of immune memories in a BRCA-deficient ovarian syngeneic model. Mechanistically, Niraparib treatment increased the number of infiltrating CD8+ and CD4+ cells within the intratumoral region. The enhanced immune cell infiltration was accompanied by elevated interferon-stimulated gene expression. Pathway analyses using transcriptome profiling identified interferon response gene signatures as the significantly differentially-upregulated gene sets following Niraparib treatment. Consistently, Niraparib treatment activated the STING pathway in vitro in BRCA-deficient MDA-MB-436 human triple negative breast cancer cells. STING pathway markers including p-STING(Ser366), p-TBK1(Ser172) and p-NFκB p65 were elevated following Niraparib treatment and was accompanied by an increase in IFNB mRNA expression. In summary, our data suggested that Niraparib treatment in combination with anti-PD-1/anti-PD-L1 therapy enhanced immune cell infiltration, interferon-stimulated gene expression and tumor responses. Citation Format: Sarah Wang, Kaiming Sun, Yonghong Xiao, Bin Feng, Keith Mikule, Sridhar Ramaswamy, Jeffrey Hanke, Jing Wang. Evaluation of Niraparib in combination with anti-PD1/anti-PD-L1 in preclinical models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1724.