The Experts below are selected from a list of 17319 Experts worldwide ranked by ideXlab platform
Ursula A Matulonis - One of the best experts on this subject based on the ideXlab platform.
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choosing wisely selecting PARP Inhibitor combinations to promote anti tumor immune responses beyond brca mutations
Gynecologic Oncology, 2020Co-Authors: Jennifer Taylor Veneris, Joyce F Liu, Ursula A Matulonis, Panagiotis A KonstantinopoulosAbstract:Abstract PARP Inhibitors have transformed the management of advanced high-grade serous ovarian cancer. Despite the overwhelming success of PARP inhibition, particularly in BRCA-mutated ovarian cancer, several limitations and unanswered questions remain. With PARP Inhibitors now being used in earlier treatment settings, the issue of both de novo and acquired resistance mechanisms and appropriate post-PARP management are pressing concerns. In addition, the population appropriate to target with PARP Inhibitors and their use in patients without BRCA mutations is controversial and evolving. In this review we will discuss exciting PARP combinations and biologic rationale for the development and selection of PARP Inhibitor combinations.
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durable response in a woman with recurrent low grade endometrioid endometrial cancer and a germline brca2 mutation treated with a PARP Inhibitor
Gynecologic Oncology, 2018Co-Authors: A A Gockley, David L Kolin, Christopher S Awtrey, Neal I Lindeman, Ursula A Matulonis, Panagiotis A KonstantinopoulosAbstract:A 42-year-old woman with a germline BRCA2 mutation and recurrent low-grade endometrioid endometrial adenocarcinoma experienced clinical and radiographic response to the poly (ADP ribose) polymerase (PARP) Inhibitor, olaparib. Molecular and treatment factors are discussed.
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baseline clinical predictors of antitumor response to the PARP Inhibitor olaparib in germline brca1 2 mutated patients with advanced ovarian cancer
Oncotarget, 2017Co-Authors: Saeed Rafii, Michael Friedländer, Rajiv Kumar, Charlie Gourley, Elena Geuna, Joo Ern Ang, Tzyvia Rye, Leemay Chen, Ronnie Shapirafrommer, Ursula A MatulonisAbstract:// Saeed Rafii 1 , Charlie Gourley 2 , Rajiv Kumar 1 , Elena Geuna 1 , Joo Ern Ang 1 , Tzyvia Rye 2 , Lee-May Chen 3 , Ronnie Shapira-Frommer 4 , Michael Friedlander 5 , Ursula Matulonis 6 , Jacques De Greve 7 , Amit M. Oza 8 , Susana Banerjee 9 , L. Rhoda Molife 1 , Martin E. Gore 9 , Stan B. Kaye 1 and Timothy A. Yap 1 1 Drug Development Unit, The Institute of Cancer Research and The Royal Marsden NHS Foundation Trust, London, UK 2 University of Edinburgh Cancer Research UK Centre, Edinburgh, UK 3 University of California San Francisco, San Francisco, CA, USA 4 Sheba Medical Centre, Ramat Gan, Israel 5 Prince of Wales Cancer Centre, Randwick, Australia 6 Dana-Farber Cancer Institute, Boston, MA, USA 7 Oncologisch Centrum UZ Brussel, Brussels, Belgium 8 Princess Margaret Cancer Centre, University Health Network, Toronto, Canada 9 Gynae-Oncology Unit, Royal Marsden Hospital, London, UK Correspondence to: Timothy A. Yap, email: tyap@mdanderson.org Keywords: PARP Inhibitor, olaparib, BRCA, ovarian cancer, predictive biomarkers Received: October 25, 2016 Accepted: February 22, 2017 Published: April 10, 2017 ABSTRACT Background: The PARP Inhibitor olaparib was recently granted Food and Drug Administration (FDA) accelerated approval in patients with advanced BRCA1/2 mutation ovarian cancer. However, antitumor responses are observed in only approximately 40% of patients and the impact of baseline clinical factors on response to treatment remains unclear. Although platinum sensitivity has been suggested as a marker of response to PARP Inhibitors, patients with platinum-resistant disease still respond to olaparib. Results: 108 patients with advanced BRCA1/2 mutation ovarian cancers were included. The interval between the end of the most recent platinum chemotherapy and PARPi (PTPI) was used to predict response to olaparib independent of conventional definition of platinum sensitivity. RECIST complete response (CR) and partial response (PR) rates were 35% in patients with platinum-sensitive versus 13% in platinum-resistant (p<0.005). Independent of platinum sensitivity status, the RECIST CR/PR rates were 42% in patients with PTPI greater than 52 weeks and 18% in patients with PTPI less than 52 weeks (p=0.016). No association was found between baseline clinical factors such as FIGO staging, debulking surgery, BRCA1 versus BRCA2 mutations, prior history of breast cancer and prior chemotherapy for breast cancer, and the response to olaparib. Methods: We conducted an international multicenter retrospective study to investigate the association between baseline clinical characteristics of patients with advanced BRCA1/2 mutation ovarian cancers from eight different cancer centers and their antitumor response to olaparib. Conclusion: PTPI may be used to refine the prediction of response to PARP inhibition based on the conventional categorization of platinum sensitivity.
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phase i dose escalation study of the pi3kinase pathway Inhibitor bkm120 and the oral poly adp ribose polymerase PARP Inhibitor olaparib for the treatment of high grade serous ovarian and breast cancer
Annals of Oncology, 2016Co-Authors: Ursula A Matulonis, Gerburg M Wulf, William T Barry, Michael J Birrer, Shannon N Westin, Sarah Farooq, K M Bellmcguinn, Elizabeth Obermayer, Christin Whalen, Tatum SpagnolettiAbstract:ABSTRACT Background Based upon preclinical synergy in murine models, we carried out a phase I trial to determine the maximum tolerated dose (MTD), toxicities, pharmacokinetics, and biomarkers of response for the combination of BKM120, a PI3K Inhibitor, and olaparib, a PARP Inhibitor. Patients and methods Olaparib was administered twice daily (tablet formulation) and BKM120 daily on a 28-day cycle, both orally. A 3 + 3 dose-escalation design was employed with the primary objective of defining the combination MTD, and secondary objectives were to define toxicities, activity, and pharmacokinetic profiles. Eligibility included recurrent breast (BC) or ovarian cancer (OC); dose-expansion cohorts at the MTD were enrolled for each cancer. Results In total, 69 of 70 patients enrolled received study treatment; one patient never received study treatment because of ineligibility. Twenty-four patients had BC; 46 patients had OC. Thirty-five patients had a germlineBRCA mutation (gBRCAm). Two DLTs (grade 3 transaminitis and hyperglycemia) were observed at DL0 (BKM120 60 mg/olaparib and 100 mg b.i.d.). The MTD was determined to be BKM120 50 mg q.d. and olaparib 300 mg b.i.d. (DL8). Additional DLTs included grade 3 depression and transaminitis, occurring early in cycle 2 (DL7). Anticancer activity was observed in BC and OC and in gBRCAm and gBRCA wild-type (gBRCAwt) patients. Conclusions BKM120 and olaparib can be co-administered, but the combination requires attenuation of the BKM120 dose. Clinical benefit was observed in both gBRCAm and gBRCAwt pts. Randomized phase II studies will be needed to further define the efficacy of PI3K/PARP-Inhibitor combinations as compared with a PARP Inhibitor alone.
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cediranib a pan vegfr Inhibitor and olaparib a PARP Inhibitor in combination therapy for high grade serous ovarian cancer
Expert Opinion on Investigational Drugs, 2016Co-Authors: S P Ivy, Joyce F Liu, Ursula A Matulonis, J M Lee, Elise C KohnAbstract:ABSTRACTIntroduction: An estimated 22,000 women are diagnosed annually with ovarian cancer in the United States. Initially chemo-sensitive, recurrent disease ultimately becomes chemoresistant and may kill ~14,000 women annually. Molecularly targeted therapy with cediranib (AZD2171), a vascular endothelial growth factor receptor (VEGFR)-1, 2, and 3 signaling blocker, and olaparib (AZD2281), a poly(adenosine diphosphate [ADP]-ribose) polymerase (PARP) Inhibitor, administered orally in combination has shown anti-tumor activity in the treatment of high grade serous ovarian cancer (HGSOC). This combination has the potential to change the treatment of HGSOC.Areas covered: Preclinical and clinical studies of single agent cediranib and olaparib or their combination are reviewed. Data are presented from peer-reviewed published manuscripts, completed and ongoing early phase clinical trials registered in ClinicalTrials.gov, National Cancer Institute-sponsored clinical trials, and related recent abstracts.Expert opin...
Alan Ashworth - One of the best experts on this subject based on the ideXlab platform.
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PARP Inhibitor combination therapy.
Critical Reviews in Oncology Hematology, 2016Co-Authors: Amy Drean, Christopher J. Lord, Alan AshworthAbstract:In 2014, olaparib (Lynparza) became the first PARP (Poly(ADP-ribose) polymerase) Inhibitor to be approved for the treatment of cancer. When used as single agents, PARP Inhibitors can selectively target tumour cells with BRCA1 or BRCA2 tumour suppressor gene mutations through synthetic lethality. However, PARP inhibition also shows considerable promise when used together with other therapeutic agents. Here, we summarise both the pre-clinical and clinical evidence for the utility of such combinations and discuss the future prospects and challenges for PARP Inhibitor combinatorial therapies.
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Identification of miRNA modulators to PARP Inhibitor response.
DNA Repair, 2013Co-Authors: Sari Neijenhuis, Christopher J. Lord, Ilirjana Bajrami, Rowan Miller, Alan AshworthAbstract:Based on the principle of synthetic lethality, PARP Inhibitors have been shown to be very effective in killing cells deficient in homologous recombination (HR), such as those bearing mutations in BRCA1/2. However, questions regarding their wider use persist and other determinants of responsiveness to PARP Inhibitor remain to be fully explored. MicroRNAs (miRNAs) are small non-coding RNAs, which serve as post-transcriptional regulators of gene expression and are involved in a wide variety of cellular processes, including the DNA damage response (DDR). However, little is known about whether miRNAs might influence sensitivity to PARP Inhibitors. To investigate this, we performed a high throughput miRNA mimetic screen, which identified several miRNAs whose over-expression results in sensitization to the clinical PARP Inhibitor olaparib. In particular, our findings indicate that hsa-miR-107 and hsa-miR-222 regulate the DDR and sensitise tumour cells to olaparib by repressing expression of RAD51, thus impairing DSB repair by HR. Moreover, elevated expression of hsa-miR-107 has been observed in a subset of ovarian clear cell carcinomas, which correlates with PARP Inhibitor sensitivity and reduced RAD51 expression. Taken together, these observations raise the possibility that these miRNAs could be used as biomarkers to identify patients that may benefit from treatment with PARP Inhibitors.
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Biomarkers of PARP Inhibitor sensitivity.
Breast Cancer Research and Treatment, 2011Co-Authors: Nicholas C. Turner, Alan AshworthAbstract:The PARP Inhibitors represent one of the most exciting recent developments in cancer therapy. Substantial efficacy has been shown with PARP Inhibitors in the treatment of hereditary BRCA1/2 related Breast and Ovarian cancer as single agents [1–3] and in combination with temozolomide [4]. Similarly, encouraging activity has been shown in sporadic ovarian cancer with a PARP Inhibitor as a single agent [5], and in sporadic triple negative breast cancer in combination with gemcitabine/carboplatin chemotherapy [6]. Yet the picture is not universally positive. Negative studies have been reported in heavily pre-treated sporadic triple negative cancer, with PARP Inhibitor as a single agent [5] and no evidence of activity in combination with temozolomide [4]. To understand the reasons some studies have succeeded, and others failed, the development of biomarkers that will predict the sensitivity, or resistance, to PARP Inhibitors is required. There are two conceptually independent ways in which PARP Inhibitors are thought to act as anti-cancer agents. First, PARP Inhibitors work as single agents targeting homologous recombination (HR) deficient cancers through synthetic lethality. Second, PARP Inhibitors also act as chemotherapy or radiotherapy sensitizers in the absence of single agent activity. For example, PARP Inhibitors substantially increase the potency of temozolomide in vitro. Whether this translates to an increased therapeutic window in cancers with normal DNA repair in unclear; substantial bone marrow toxicity has been demonstrated with PARP Inhibitor and chemotherapy combinations. In reality many PARP Inhibitors are being developed assuming a combination of these two strategies, on the assumption that a combination of a PARP Inhibitor with chemotherapy may target HR deficient cancers more effectively than PARP Inhibitor alone.
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a high throughput rna interference screen for dna repair determinants of PARP Inhibitor sensitivity
DNA Repair, 2008Co-Authors: Christopher J. Lord, Nicholas C. Turner, Sarah Mcdonald, Sally Swift, Alan AshworthAbstract:Synthetic lethality is an attractive strategy for the design of novel therapies for cancer. Using this approach we have previously demonstrated that inhibition of the DNA repair protein, PARP1, is synthetically lethal with deficiency of either of the breast cancer susceptibility proteins, BRCA1 and BRCA2. This observation is most likely explained by the inability of BRCA deficient cells to repair DNA damage by homologous recombination (HR) and has led to the clinical trials of potent PARP Inhibitors for the treatment of BRCA mutation-associated cancer. To identify further determinants of PARP Inhibitor response, we took a high-throughput genetic approach. We tested each of the genes recognised as having a role in DNA repair using short-interfering RNA (siRNA) and assessed the sensitivity of siRNA transfected cells to a potent PARP Inhibitor, KU0058948. The validity of this approach was confirmed by the identification of known genetic determinants of PARP Inhibitor sensitivity, including genes involved in HR. Novel determinants of PARP Inhibitor response were also identified, including the transcription coupled DNA repair (TCR) proteins DDB1 and XAB2. These results suggest that DNA repair pathways other than HR may determine sensitivity to PARP Inhibitors and highlight the likelihood that ostensibly distinct DNA repair pathways cooperate to maintain genomic stability and cellular viability. Furthermore, the identification of these novel determinants may eventually guide the optimal use of PARP Inhibitors in the clinic.
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a synthetic lethal sirna screen identifying genes mediating sensitivity to a PARP Inhibitor
The EMBO Journal, 2008Co-Authors: Nicholas C. Turner, Rachel Brough, Christopher J. Lord, Sally Swift, Elizabeth Iorns, Richard Elliott, Sydonia Rayter, Andrew Tutt, Alan AshworthAbstract:Inhibitors of poly (ADP-ribose)-polymerase-1 (PARP) are highly lethal to cells with deficiencies in BRCA1, BRCA2 or other components of the homologous recombination pathway. This has led to PARP Inhibitors entering clinical trials as a potential therapy for cancer in carriers of BRCA1 and BRCA2 mutations. To discover new determinants of sensitivity to these drugs, we performed a PARP-Inhibitor synthetic lethal short interfering RNA (siRNA) screen. We identified a number of kinases whose silencing strongly sensitised to PARP Inhibitor, including cyclin-dependent kinase 5 (CDK5), MAPK12, PLK3, PNKP, STK22c and STK36. How CDK5 silencing mediates sensitivity was investigated. Previously, CDK5 has been suggested to be active only in a neuronal context, but here we show that CDK5 is required in non-neuronal cells for the DNA-damage response and, in particular, intra-S and G2/M cell-cycle checkpoints. These results highlight the potential of synthetic lethal siRNA screens with chemical Inhibitors to define new determinants of sensitivity and potential therapeutic targets.
Gerburg M Wulf - One of the best experts on this subject based on the ideXlab platform.
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abstract 4490 PARP Inhibitor efficacy depends on cd8 t cell recruitment via the sting pathway in brca deficient models of triple negative breast cancer
Cancer Research, 2019Co-Authors: Constantia Pantelidou, Mateus Oliveira Taveira, Anita Mehta, Olmo Sonzogni, Dan Wang, Aditi Kothari, Tanvi Visal, Jennifer L Guerriero, Gerburg M Wulf, Geoffrey I ShapiroAbstract:Combinatorial clinical trials of PARP Inhibitors with immunotherapies are ongoing, yet the immunomodulatory effects of PARP inhibition have been incompletely studied. Here, we sought to dissect the mechanisms underlying PARP Inhibitor-induced changes in the tumor microenvironment of BRCA1-deficient triple-negative breast cancer (TNBC). We demonstrate that the PARP Inhibitor olaparib induces CD8+ T cell infiltration and activation in vivo, and that depletion of CD8+ T cells severely compromises anti-tumor efficacy. Olaparib-induced T cell recruitment is mediated through activation of the STING/TBK1/IRF3 pathway in tumor and dendritic cells and is more pronounced in HR-deficient compared to HR-proficient TNBC cells. CRISPR-knockout of STING in cancer cells prevents type I IFN production and is sufficient to abolish PARP Inhibitor-induced T cell infiltration in vivo. These findings elucidate a novel mechanism of action of PARP Inhibitors and provide mechanistic rationale for combining PARP inhibition with immunotherapies for the treatment of TNBC. Citation Format: Constantia Pantelidou, Olmo Sonzogni, Mateus De Oliveira Taveira, Anita K. Mehta, Dan Wang, Aditi Kothari, Michelle K. Li, Tanvi H. Visal, Jennifer L. Guerriero, Gerburg M. Wulf, Geoffrey I. Shapiro. PARP Inhibitor efficacy depends on CD8+ T-cell recruitment via the STING pathway in BRCA-deficient models of triple-negative breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4490.
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phase i dose escalation study of the pi3kinase pathway Inhibitor bkm120 and the oral poly adp ribose polymerase PARP Inhibitor olaparib for the treatment of high grade serous ovarian and breast cancer
Annals of Oncology, 2016Co-Authors: Ursula A Matulonis, Gerburg M Wulf, William T Barry, Michael J Birrer, Shannon N Westin, Sarah Farooq, K M Bellmcguinn, Elizabeth Obermayer, Christin Whalen, Tatum SpagnolettiAbstract:ABSTRACT Background Based upon preclinical synergy in murine models, we carried out a phase I trial to determine the maximum tolerated dose (MTD), toxicities, pharmacokinetics, and biomarkers of response for the combination of BKM120, a PI3K Inhibitor, and olaparib, a PARP Inhibitor. Patients and methods Olaparib was administered twice daily (tablet formulation) and BKM120 daily on a 28-day cycle, both orally. A 3 + 3 dose-escalation design was employed with the primary objective of defining the combination MTD, and secondary objectives were to define toxicities, activity, and pharmacokinetic profiles. Eligibility included recurrent breast (BC) or ovarian cancer (OC); dose-expansion cohorts at the MTD were enrolled for each cancer. Results In total, 69 of 70 patients enrolled received study treatment; one patient never received study treatment because of ineligibility. Twenty-four patients had BC; 46 patients had OC. Thirty-five patients had a germlineBRCA mutation (gBRCAm). Two DLTs (grade 3 transaminitis and hyperglycemia) were observed at DL0 (BKM120 60 mg/olaparib and 100 mg b.i.d.). The MTD was determined to be BKM120 50 mg q.d. and olaparib 300 mg b.i.d. (DL8). Additional DLTs included grade 3 depression and transaminitis, occurring early in cycle 2 (DL7). Anticancer activity was observed in BC and OC and in gBRCAm and gBRCA wild-type (gBRCAwt) patients. Conclusions BKM120 and olaparib can be co-administered, but the combination requires attenuation of the BKM120 dose. Clinical benefit was observed in both gBRCAm and gBRCAwt pts. Randomized phase II studies will be needed to further define the efficacy of PI3K/PARP-Inhibitor combinations as compared with a PARP Inhibitor alone.
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abstract ct338 combination of a pi3k and a PARP Inhibitor to treat high grade serous ovarian or triple negative breast cancer
Cancer Research, 2014Co-Authors: Gerburg M Wulf, Ashish Juvekar, Costas A Lyssiotis, Sina Yadegarynia, Hui Liu, Baek Kim, Eric Winter, Ralph Scully, John M Asara, Lewis C CantleyAbstract:Proceedings: AACR Annual Meeting 2014; April 5-9, 2014; San Diego, CA Clinical trials have shown promising responses of BRCA-linked breast and ovarian cancers to PARP Inhibitor therapy, but remissions are often short-lived and incomplete. The PI3K pathway is frequently activated in these malignancies. Recently, we reported in vivo synergy of a PI3K- and a PARP-Inhibitor in a mouse model of BRCA1-related breast cancer. While the PARP-Inhibitor olaparib alone attenuated tumor growth modestly, a dramatic reduction in tumor growth was observed when olaparib was combined with the PI3K-Inhibitor BKM120. In BRCA1-mutant HCC1937 BC cells, PI3K- (but not akt-) inhibition increased indicators of DNA damage, such as poly-ADP-ribosylation and γH2AX, suggesting a critical role of PI3K activity for the maintenance of genomic stability. Here, we report on the molecular mechanism underlying this synergy, on treatment outcomes in an improved mouse model system and the development of an early-phase clinical study. Pre-clinical modeling was done in BRCA1-mutant HCC1937 cells and in a mouse model based on the syngenic transplantation of tumors derived on the K14-Cre BRCA1f/fp53f/f background. Metabolic profiling in vitro and in vivo showed that PI3K-inhibition decreased flux through glycolysis and specifically through the non-oxidative pentose-phosphate pathway, the main source of ribose-5-phosphate required for the de novo synthesis of nucleotides in HCC1937 cells. Within 3 hours and preceding cell cycle changes, BKM120 caused a decrease in nucleotide pools that was further exacerbated by the addition of olaparib. Nucleotide shortage led to to replication stress with the appearance of γH2AX and increased poly-ADP-ribosylation. Tumors with complete loss of BRCA1 and p53 proved particularly vulnerable to this treatment strategy. We were able to induce complete and durable remissions of murine tumors arising on the K14-Cre BRCA1f/fp53f/f background with a 28-day course of BKM120 and Olaparib. These preclinical data have served as the rationale for a phase I, multi-center study ([NCT01623349][1]) combining the oral PARP Inhibitor olaparib with the oral PI3-kinase Inhibitor BKM120 in patients with recurrent HGSC or recurrent TNBC. The study is being conducted through the Stand Up to Cancer (SU2C)'s Targeting PI3-kinase in Women's Cancers Dream Team. It has a 3 + 3 design, escalating if 0/3 or 1/6 participants have a DLT during the first cycle of therapy. The study objectives are to determine the recommended phase II dose (RP2D) of daily continuous oral olaparib (using the tablet formulation) and BKM120, assess toxicities, safety, and preliminary activity of this combination, and determine pharmacokinetic profiles of both agents as well as translational endpoints. The study serves as an example for the development of a clinical trials concept for TNBC and HGSC based on a close collaboration of basic and clinical scientists through the SU2C mechanism. Citation Format: Gerburg M. Wulf, Ashish Juvekar, Costas A. Lyssiotis, Hai Hu, Sina Yadegarynia, Hui Liu, Baek Kim, Eric Winter, Ralph Scully, John Asara, Lewis C. Cantley, Ursula Matulonis. Combination of a PI3K- and a PARP-Inhibitor to treat high-grade serous ovarian or triple-negative breast cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr CT338. doi:10.1158/1538-7445.AM2014-CT338 [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT01623349&atom=%2Fcanres%2F74%2F19_Supplement%2FCT338.atom
Constantia Pantelidou - One of the best experts on this subject based on the ideXlab platform.
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Targeting immunosuppressive macrophages overcomes PARP Inhibitor resistance in BRCA1-associated triple-negative breast cancer
Nature Cancer, 2020Co-Authors: Anita K. Mehta, Emily M. Cheney, Christina A. Hartl, Constantia Pantelidou, Madisson Oliwa, Jessica A. Castrillon, Jia-ren Lin, Katie E. Hurst, Mateus Oliveira Taveira, Nathan T. JohnsonAbstract:Despite objective responses to poly(ADP-ribose) polymerase (PARP) inhibition and improvements in progression-free survival (PFS) compared to standard chemotherapy in patients with BRCA -associated triple-negative breast cancer (TNBC), benefits are transitory. Using high-dimensional single-cell profiling of human TNBC, here we demonstrate that macrophages are the predominant infiltrating immune cell type in breast cancer susceptibility (BRCA)-associated TNBC. Through multi-omics profiling, we show that PARP Inhibitors enhance both anti- and pro-tumor features of macrophages through glucose and lipid metabolic reprogramming, driven by the sterol regulatory element-binding protein 1 (SREBF1, SREBP1) pathway. Combining PARP Inhibitor therapy with colony-stimulating factor 1 receptor (CSF1R)-blocking antibodies significantly enhanced innate and adaptive antitumor immunity and extended survival in mice with BRCA-deficient tumors in vivo, and this was mediated by CD8^+ T cells. Collectively, our results uncover macrophage-mediated immune suppression as a liability of PARP Inhibitor treatment and demonstrate that combined PARP inhibition and macrophage-targeting therapy induces a durable reprogramming of the tumor microenvironment (TME), thus constituting a promising therapeutic strategy for TNBC. Mehta et al. show that PARP inhibition induces CSF1R-dependent immune-suppressive macrophages, and that its blockade restores PARP Inhibitor efficacy and stimulates CD8^+ T cell-dependent antitumor immunity in triple-negative breast cancer.
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860 targeting immunosuppressive macrophages overcomes PARP Inhibitor resistance in brca1 associated triple negative breast cancer
Journal for ImmunoTherapy of Cancer, 2020Co-Authors: Anita Mehta, Emily M. Cheney, Christina A. Hartl, Constantia Pantelidou, Madisson Oliwa, Jessica A. Castrillon, Jia-ren Lin, Mateus Oliveira Taveira, Katie Hurst, Nathan T. JohnsonAbstract:Background Despite objective responses to PARP inhibition and improvements in progression-free survival compared to standard chemotherapy in patients with BRCA-associated triple-negative breast cancer (TNBC), benefits are transitory. Methods Using high dimensional single-cell profiling of human TNBC, here we demonstrate that macrophages are the predominant infiltrating immune cell type in BRCA-associated TNBC. Through multi-omics profiling we show that PARP Inhibitors enhance both anti- and pro-tumor features of macrophages through glucose and lipid metabolic reprogramming driven by the sterol regulatory element-binding protein 1 (SREBP-1) pathway. Results Combined PARP Inhibitor therapy with CSF-1R blocking antibodies significantly enhanced innate and adaptive anti-tumor immunity and extends survival in BRCA-deficient tumors in vivo and is mediated by CD8+ T-cells. Conclusions Collectively, our results uncover macrophage-mediated immune suppression as a liability of PARP Inhibitor treatment and demonstrate combined PARP inhibition and macrophage targeting therapy induces a durable reprogramming of the tumor microenvironment, thus constituting a promising therapeutic strategy for TNBC.
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abstract 4490 PARP Inhibitor efficacy depends on cd8 t cell recruitment via the sting pathway in brca deficient models of triple negative breast cancer
Cancer Research, 2019Co-Authors: Constantia Pantelidou, Mateus Oliveira Taveira, Anita Mehta, Olmo Sonzogni, Dan Wang, Aditi Kothari, Tanvi Visal, Jennifer L Guerriero, Gerburg M Wulf, Geoffrey I ShapiroAbstract:Combinatorial clinical trials of PARP Inhibitors with immunotherapies are ongoing, yet the immunomodulatory effects of PARP inhibition have been incompletely studied. Here, we sought to dissect the mechanisms underlying PARP Inhibitor-induced changes in the tumor microenvironment of BRCA1-deficient triple-negative breast cancer (TNBC). We demonstrate that the PARP Inhibitor olaparib induces CD8+ T cell infiltration and activation in vivo, and that depletion of CD8+ T cells severely compromises anti-tumor efficacy. Olaparib-induced T cell recruitment is mediated through activation of the STING/TBK1/IRF3 pathway in tumor and dendritic cells and is more pronounced in HR-deficient compared to HR-proficient TNBC cells. CRISPR-knockout of STING in cancer cells prevents type I IFN production and is sufficient to abolish PARP Inhibitor-induced T cell infiltration in vivo. These findings elucidate a novel mechanism of action of PARP Inhibitors and provide mechanistic rationale for combining PARP inhibition with immunotherapies for the treatment of TNBC. Citation Format: Constantia Pantelidou, Olmo Sonzogni, Mateus De Oliveira Taveira, Anita K. Mehta, Dan Wang, Aditi Kothari, Michelle K. Li, Tanvi H. Visal, Jennifer L. Guerriero, Gerburg M. Wulf, Geoffrey I. Shapiro. PARP Inhibitor efficacy depends on CD8+ T-cell recruitment via the STING pathway in BRCA-deficient models of triple-negative breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4490.
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PARP Inhibitor efficacy depends on cd8 t cell recruitment via intratumoral sting pathway activation in brca deficient models of triple negative breast cancer
Cancer Discovery, 2019Co-Authors: Constantia Pantelidou, Anita K. Mehta, Olmo Sonzogni, Dan Wang, Aditi Kothari, Tanvi Visal, Mateus De Oliveria Taveira, Jocelin Pinto, Jessica A. CastrillonAbstract:Combinatorial clinical trials of PARP Inhibitors with immunotherapies are ongoing, yet the immunomodulatory effects of PARP inhibition have been incompletely studied. Here, we sought to dissect the mechanisms underlying PARP Inhibitor-induced changes in the tumor microenvironment of BRCA1-deficient triple-negative breast cancer (TNBC). We demonstrate that the PARP Inhibitor olaparib induces CD8+ T cell infiltration and activation in vivo, and that CD8+ T cell depletion severely compromises anti-tumor efficacy. Olaparib-induced T cell recruitment is mediated through activation of the cGAS/STING pathway in tumor cells with paracrine activation of dendritic cells and is more pronounced in HR-deficient compared to HR-proficient TNBC cells and in vivo models. CRISPR-knockout of STING in cancer cells prevents proinflammatory signaling and is sufficient to abolish olaparib-induced T cell infiltration in vivo. These findings elucidate an additional mechanism of action of PARP Inhibitors and provide rationale for combining PARP inhibition with immunotherapies for the treatment of TNBC.
Kelly E Mccann - One of the best experts on this subject based on the ideXlab platform.
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abstract 4124 the combination of PARP Inhibitor talazoparib with low dose temozolomide results in increased cell lethality in brca1 2 wild type melanoma small cell lung cancer ovarian and colon cancer cell lines and mouse xenografts via the formation
Cancer Research, 2020Co-Authors: Kelly E Mccann, Erika Von Euw, Neil A Obrien, Dennis J SlamonAbstract:Background: Previous studies of PARP Inhibitors have shown efficacy in tumors with defects in homologous recombination repair, particularly in persons with ovarian and breast cancers with germline deleterious BRCA1/2 mutations (gBRCA1/2+). There is much interest in expanding the use of PARP Inhibitors beyond these populations, with one strategy being the creation of DNA damage with cytotoxic chemotherapy with concomitant inhibition of its repair with a PARP Inhibitor. Murai, et al, have also shown that PARP is trapped on the DNA at the site of damage in the presence of a PARP Inhibitor. In April 2016, my colleague Dr Zev Wainberg presented Phase I safety and efficacy data at AACR (abstract CT011) with PARP Inhibitor talazoparib in combination with alkylating agent temozolomide in cancer patients without gBRCA1/2+, demonstrating this to be a promising combination. Methods: We evaluated the molecular mechanisms underlying cancer cell lethality with talazoparib plus temozolomide in melanoma, small cell lung, ovarian, and colorectal cancer cell lines and mouse xenografts. We determined growth-adjusted IC50s for talazoparib in multiple histologies to choose cell lines of low and high sensitivity to the PARP Inhibitor as monotherapy. We studied percent growth inhibition of talazoparib, temozolomide, and combination therapy at increasing doses. We investigated cell cycle dynamics at 24 hours and 48 hours; PARP Inhibitors have been shown to activate the G2/M cell cycle checkpoint, which could confound growth arrest and DNA repair studies. We performed western blot analysis to identify phosphorylated histone H2AX as a marker of DNA double-strand breaks. We used FACS to determine apoptotic fractions and to correlate phospho-H2AX formation with cell cycle phase. We used confocal microscopy to correlate phospho-H2AX with nuclear PARP. We used mouse xenografts to demonstrate sensitivity of tumors to temozolomide, talazoparib, and combination therapy. Results: The combination of temozolomide with talazoparib results in the formation of DNA double-strand breaks during S-phase, which results in increased cell lethality in BRCA1/2 wild-type cell lines and mouse xenografts of melanoma, colorectal, ovarian, and small cell lung histologies even when those cell lines are not sensitive to either talazoparib or temozolomide alone. We were unable to demonstrate colocalization of PARP and phospho-H2AX due to PARP9s high expression in the nucleus during S-phase. We were also not able to demonstrate PARP-trapping by western blot at doses utilized in human patients, but this is likely due to lack of assay sensitivity. Conclusions: Taking into consideration both the molecular data demonstrating efficacy of talazoparib plus temozolomide therapy in BRCA1/2 wild-type cell lines and mouse xenografts and the Phase I trial data showing safety and efficacy with this combination, PARP Inhibitors likely have utility beyond treatment of gBRCA1/2+ patients. Use of the alkylating agent might be particularly important, as it is recognized during S-phase and trapping of PARP on the DNA could result in collapse of a stalled replication fork into a DNA double-strand break. Citation Format: Kelly Elizabeth McCann, Erika von Euw, Neil O9Brien, Dennis Slamon. The combination of PARP Inhibitor talazoparib with low-dose temozolomide results in increased cell lethality in BRCA1/2 wild-type melanoma, small cell lung cancer, ovarian, and colon cancer cell lines and mouse xenografts via the formation of DNA double-strand breaks during S-phase [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4124.
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Advances in the use of PARP Inhibitor therapy for breast cancer.
Drugs in context, 2018Co-Authors: Kelly E Mccann, Sara A. HurvitzAbstract:Poly-ADP-ribose polymerase 1 (PARP-1) and PARP-2 are DNA damage sensors that are most active during S-phase of the cell cycle and that have wider-reaching roles in DNA repair than originally described. BRCA1 and BRCA2 (Breast Cancer) proteins are involved in homologous recombination repair (HRR), which requires a homologous chromosome or sister chromatid as a template to faithfully repair DNA double-strand breaks. The small-molecule NAD+ mimetics, olaparib, niraparib, rucaparib, veliparib, and talazoparib, inhibit the catalytic activity of PARP-1 and PARP-2 and are currently being studied in later-stage clinical trials. PARP Inhibitor clinical trials have predominantly focused on patients with breast and ovarian cancer with deleterious germline BRCA1 and BRCA2 mutations (gBRCA1/2+) but are now expanding to include cancers with known, suspected, or more-likely-than-not defects in homologous recombination repair. In ovarian cancer, this group also includes women whose cancers are responsive to platinum therapy. Olaparib was FDA-approved in January 2018 for the treatment of gBRCA1/2+ metastatic breast cancers. gBRCA1+ predisposes women to develop triple-negative breast cancers, while women with gBRCA2+ tend to develop hormone-receptor-positive, human epidermal growth factor receptor 2 negative breast cancers. Although PARP Inhibitor monotherapy strategies seem most effective in cancers with homologous recombination repair defects, combination strategies may allow expansion into a wider range of cancers. By interfering with DNA repair, PARP Inhibitors essentially sensitize cells to DNA-damaging chemotherapies and radiation therapy. Certainly, one could also consider expanding the utility of PARP Inhibitors beyond gBRCA1/2+ cancers by causing DNA damage with cytotoxic agents in the presence of a DNA repair Inhibitor. Unfortunately, in numerous phase I clinical trials utilizing a combination of cytotoxic chemotherapy at standard doses with dose-escalation of PARP Inhibitors, there has generally been failure to reach monotherapy dosages of PARP Inhibitors due to myelosuppressive toxicities. Strategies utilizing angiogenesis Inhibitors and immune checkpoint Inhibitors are generally not hindered by additive toxicities, though the utility of combining PARP Inhibitors with treatments that have not been particularly effective in breast cancers somewhat tempers enthusiasm. Finally, there are combination strategies that may serve to mitigate resistance to PARP Inhibitors, namely, upregulation of the intracellular PhosphoInositide-3-kinase, AK thymoma (protein kinase B), mechanistic target of rapamycin (PI3K-AKT-mTOR) pathway, or perhaps are more simply meant to interfere with a cell growth pathway heavily implicated in breast cancers while administering relatively well-tolerated PARP Inhibitor therapy.
