The PARP1 inhibitor BMN 673 exhibits immunoregulatory effects in a  Brca1 −/−  murine model of ovarian cancer

Huang, Jing; Wang, Lei; Cong, Zhongyi; Amoozgar, Zohreh; Kiner, Evgeny; Xing, Deyin; Oršulić, Sandra; Matulonis, Ursula A.; Goldberg, Michael S.

doi:10.1016/j.bbrc.2015.05.083

Cited by 129 publications

(98 citation statements)

References 24 publications

(26 reference statements)

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“…Applying this information to mouse models, researchers found that treatment with BMN673 increased the proportion of cytotoxic immune cells (CD8+ T cells, B cells and NK cells) while simultaneously decreasing the proportion of immunosuppressive cells [Huang et al 2015]. It was concluded that the improved survival noted in mice treated with BMN 673 was, in part, a result of the immunomodulatory effects of PARP inhibition.…”

Section: Parp Inhibitors and Immune Checkpoint Inhibitorsmentioning

confidence: 99%

PARP inhibitors in ovarian cancer: evidence, experience and clinical potential

Evans

Matulonis

2017

Ther Adv Med Oncol

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Abstract:Inhibitors of poly(ADP-ribose) polymerase (PARP) are considered one of the most active and exciting new therapies for the treatment of ovarian cancer. The anticancer activity of PARP inhibitors is based on the DNA repair vulnerability of many ovarian cancer cells, and multiple mechanisms of action of PARP inhibitors have been identified. As single agents, PARP inhibitors have demonstrated their greatest activity in ovarian cancer cells that harbor mutations in BRCA genes. Additionally, recent phase III studies have shown that single-agent PARP inhibitor activity extends beyond BRCA-related cancers and can benefit patients with ovarian cancers that do not have known BRCA mutations, especially when clinical characteristics such as platinum sensitivity and high-grade serous histology are present. PARP inhibitors have also been combined with chemotherapy, however, overlapping myelosuppression observed with PARP inhibitor and chemotherapy combinations has hampered development of these combinations. Contrariwise, PARP inhibitor and biologic agent combinations, specifically antiangiogenic agents, appear well tolerated and show promising activity in both BRCA mutated (BRCAm) and BRCA wild-type (BRCAwt) cancers. Currently, multiple clinical trials are underway examining the antitumor activity of PARP inhibitor combination therapy.

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Section: Parp Inhibitors and Immune Checkpoint Inhibitorsmentioning

confidence: 99%

PARP inhibitors in ovarian cancer: evidence, experience and clinical potential

Evans

Matulonis

2017

Ther Adv Med Oncol

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“…Several recent pre-clinical studies suggest that PARP inhibition enhances immunogenicity in models of ovarian and breast cancer and that combining the two results in synergistic effects [73][74][75]. TOPACIO, a multicenter, open-label phase 1/2 study evaluated the PARP inhibitor niraparib plus pembrolizumab in metastatic TNBC and advanced ovarian cancer and during the dose-finding portion of the trial, none of the eight evaluable patients progressed: 4/8 had objective response and 4/8 had stable disease [71].…”

Section: Targeting Homologous Recombination Deficiency To Enhance Brementioning

confidence: 99%

Homologous recombination deficiency and host anti-tumor immunity in triple-negative breast cancer

Telli

Stover

Loi

et al. 2018

Breast Cancer Res Treat

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Purpose Triple-negative breast cancer (TNBC) is associated with worse outcomes relative to other breast cancer subtypes. Chemotherapy remains the standard-of-care systemic therapy for patients with localized or metastatic disease, with few biomarkers to guide benefit. Methods We will discuss recent advances in our understanding of two key biological processes in TNBC, homologous recombination (HR) DNA repair deficiency and host anti-tumor immunity, and their intersection. Results Recent advances in our understanding of homologous recombination (HR) deficiency, including FDA approval of PARP inhibitor olaparib for BRCA1 or BRCA2 mutation carriers, and host anti-tumor immunity in TNBC offer potential for new and biomarker-driven approaches to treat TNBC. Assays interrogating HR DNA repair capacity may guide treatment with agents inducing or targeting DNA damage repair. Tumor infiltrating lymphocytes (TILs) are associated with improved prognosis in TNBC and recent efforts to characterize infiltrating immune cell subsets and activate host anti-tumor immunity offer promise, yet challenges remain particularly in tumors lacking pre-existing immune infiltrates. Advances in these fields provide potential biomarkers to stratify patients with TNBC and guide therapy: induction of DNA damage in HR-deficient tumors and activation of existing or recruitment of host anti-tumor immune cells. Importantly, these advances provide an opportunity to guide use of existing therapies and development of novel therapies for TNBC. Efforts to combine therapies that exploit HR deficiency to enhance the activity of immune-directed therapies offer promise. Conclusions HR deficiency remains an important biomarker target and potentially effective adjunct to enhance immunogenicity of 'immune cold' TNBCs.

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“…Suh et al demonstrated that treatment of afatinib and lapatinib, which are EGFR and HER2 inhibitors, suppressed both the PD-L1 expression and expression of cytokines, such as CCL2, CCL21, and CXCL1, in the TME [100]. Moreover, studies suggested that PARP inhibitor BMN673 increased the proportion of cytotoxic immune cells while simultaneously decreasing the proportion of immunosuppressive cells in BRCA-deficient ovarian cancer mouse [101]. Based on the promising results, there are several ongoing trials combining PARP and immune checkpoint inhibitors [102].…”

Section: Targeted Therapymentioning

confidence: 99%

Complex interplay between tumor microenvironment and cancer therapy

Shen

Kang

2018

Front. Med.

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Tumor microenvironment (TME) is comprised of cellular and non-cellular components that exist within and around the tumor mass. The TME is highly dynamic and its importance in different stages of cancer progression has been well recognized. A growing body of evidence suggests that TME also plays pivotal roles in cancer treatment responses. TME is significantly remodeled upon cancer therapies, and such change either enhances the responses or induces drug resistance. Given the importance of TME in tumor progression and therapy resistance, strategies that remodel TME to improve therapeutic responses are under developing. In this review, we provide an overview of the essential components in TME and the remodeling of TME in response to anti-cancer treatments. We also summarize the strategies that aim to enhance therapeutic efficacy by modulating TME.

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The PARP1 inhibitor BMN 673 exhibits immunoregulatory effects in a Brca1 −/− murine model of ovarian cancer

Cited by 129 publications

References 24 publications

PARP inhibitors in ovarian cancer: evidence, experience and clinical potential

PARP inhibitors in ovarian cancer: evidence, experience and clinical potential

Homologous recombination deficiency and host anti-tumor immunity in triple-negative breast cancer

Complex interplay between tumor microenvironment and cancer therapy

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