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https://www.readbyqxmd.com/read/28069724/synthetic-lethality-exploitation-by-an-anti-trop-2-sn-38-antibody-drug-conjugate-immu-132-plus-parp-inhibitors-in-brca1-2-wild-type-triple-negative-breast-cancer
#1
Thomas M Cardillo, Robert M Sharkey, Diane L Rossi, Roberto Arrojo, Ali Mostafa, David M Goldenberg
PURPOSE: Both Poly(ADP-ribose) polymerase inhibitors (PARPi) and sacituzumab govitecan (IMMU-132) are currently under clinical evaluation in triple-negative breast cancer (TNBC). We sought to investigate the combined DNA-damaging effects of the topoisomerase I (Topo I)-inhibitory activity of IMMU-132 with PARPi disruption of DNA repair in TNBC. EXPERIMENTAL DESIGN: In vitro, human TNBC cell lines were incubated with IMMU-132 and various PARPi (olaparib, rucaparib, or talazoparib) to determine the effect on growth, double-stranded DNA (dsDNA) breaks, and cell-cycle arrest...
January 9, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/28028375/response-of-brca1-mutated-gallbladder-cancer-to-olaparib-a-case-report
#2
Yuan Xie, Yan Jiang, Xiao-Bo Yang, An-Qiang Wang, Yong-Chang Zheng, Xue-Shuai Wan, Xin-Ting Sang, Kai Wang, Da-Dong Zhang, Jia-Jia Xu, Fu-Gen Li, Hai-Tao Zhao
Gallbladder cancer (GBC), although considered as a relatively rare malignancy, is the most common neoplasm of the biliary tract system. The late diagnosis and abysmal prognosis present challenges to treatment. The overall 5-year survival rate for metastatic GBC patients is extremely low. BRCA1 and BRCA2 are the breast cancer susceptibility genes and their mutation carriers are at a high risk for cancer development, both in men and women. Olaparib, an oral poly ADP-ribose polymerase inhibitor, has been approved by the Food and Drug Administration and the European Commission for the treatment of ovarian cancer with any BRCA1/2 mutations...
December 14, 2016: World Journal of Gastroenterology: WJG
https://www.readbyqxmd.com/read/27993796/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
#3
U A Matulonis, G M Wulf, W T Barry, M Birrer, S N Westin, S Farooq, K M Bell-McGuinn, E Obermayer, C Whalen, T Spagnoletti, W Luo, H Liu, R C Hok, C Aghajanian, D B Solit, G B Mills, B S Taylor, H Won, M F Berger, S Palakurthi, J Liu, L C Cantley, E Winer
BACKGROUND: Based upon preclinical synergy in murine models, we performed a phase 1 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...
December 19, 2016: Annals of Oncology: Official Journal of the European Society for Medical Oncology
https://www.readbyqxmd.com/read/27958297/delivering-widespread-brca-testing-and-parp-inhibition-to-patients-with-ovarian-cancer
#4
REVIEW
Angela George, Stan Kaye, Susana Banerjee
The treatment of patients with ovarian cancer is rapidly changing following the success of poly [ADP-ribose] polymerase (PARP) inhibitors in clinical trials. Olaparib is the first PARP inhibitor to be approved by the EMA and FDA for BRCA-mutated ovarian cancer. Germ line BRCA mutation status is now established as a predictive biomarker of potential benefit from treatment with a PARP inhibitor; therefore, knowledge of the BRCA status of an individual patient with ovarian cancer is essential, in order to guide treatment decisions...
December 13, 2016: Nature Reviews. Clinical Oncology
https://www.readbyqxmd.com/read/27943283/prophylactic-window-therapy-with-the-clinical-parp-inhibitor-olaparib-delays-brca1-deficient-mammary-tumour-formation-in-mice
#5
Marieke van de Ven, Eline van der Burg, Hanneke van der Gulden, Sjoerd Klarenbeek, Peter Bouwman, Jos Jonkers
Women with heterozygous germline mutations in the BRCA1 tumour suppressor gene are strongly predisposed to developing early-onset breast cancer through loss of the remaining wild-type BRCA1 allele and inactivation of TP53. Although tumour prevention strategies in BRCA1-mutation carriers are still limited to prophylactic surgery, several therapeutic strategies have been developed to target the DNA repair defects (aka 'BRCAness') of BRCA1-deficient tumours. Especially DNA-damaging agents such as platinum drugs and poly(ADP-ribose) polymerase (PARP) inhibitors display strong activity against BRCA1-mutated tumours...
December 9, 2016: Journal of Pathology
https://www.readbyqxmd.com/read/27894958/poly-adp-ribose-polymerase-inhibitors-selectively-induce-cytotoxicity-in-tcf3-hlf-positive-leukemic-cells
#6
Jinhua Piao, Shiori Takai, Takahiro Kamiya, Takeshi Inukai, Kanji Sugita, Kazuma Ohyashiki, Domenico Delia, Mitsuko Masutani, Shuki Mizutani, Masatoshi Takagi
Poly (ADP-ribose) polymerase (PARP) is an indispensable component of the DNA repair machinery. PARP inhibitors are used as cutting-edge treatments for patients with homologous recombination repair (HRR)-defective breast cancers harboring mutations in BRCA1 or BRCA2. Other tumors defective in HRR, including some hematological malignancies, are predicted to be good candidates for treatment with PARP inhibitors. Screening of leukemia-derived cell lines revealed that lymphoid lineage-derived leukemia cell lines, except for those derived from mature B cells and KMT2A (MLL)-rearranged B-cell precursors, were relatively sensitive to PARP inhibitors...
February 1, 2017: Cancer Letters
https://www.readbyqxmd.com/read/27869446/-oncopathological-aspects-of-brca1-and-brca2-genes-inactivation-in-tumors-of-ovary-fallopian-tube-and-pelvic-peritoneum
#7
Petr Škapa, Pavel Dundr
Ovarian carcinoma represents a heterogeneous group of malignant epithelial tumors which could be divided into two fundamental groups: Type I (endometrioid carcinoma, clear cell carcinoma, low grade serous carcinoma, mucinous carcinoma and more rare seromucinous carcinoma and malignant Brenner tumor) and type II (high grade serous carcinoma - HGSC). HGSC is the most frequent ovarian carcinoma which may be etiologically linked to inactivation of tumor suppressor genes BRCA1/2 and TP53 and differs from type I carcinomas by higher aggressiveness, tendency to peritoneal spread and worse prognosis...
2016: Ceskoslovenská Patologie
https://www.readbyqxmd.com/read/27821315/current-perspectives-on-recommendations-for-brca-genetic-testing-in-ovarian-cancer-patients
#8
Ignace Vergote, Susana Banerjee, Anne-Marie Gerdes, Christi van Asperen, Christian Marth, Fatima Vaz, Isabelle Ray-Coquard, Dominique Stoppa-Lyonnet, Antonio Gonzalez-Martin, Jalid Sehouli, Nicoletta Colombo
Traditionally, BRCA genetic testing has been undertaken to identify patients and family members at future risk of developing cancer and patients have been referred for testing based on family history. However, the now recognised risk of ovarian cancer (OC) patients, even those with no known family history, harbouring a mutation in BRCA1/2, together with the first poly adenosine diphosphate ribose polymerase inhibitor (PARPi; olaparib [Lynparza]) being licenced for the treatment of BRCA-mutated OC, has led to reconsideration of referral criteria for OC patients...
November 4, 2016: European Journal of Cancer
https://www.readbyqxmd.com/read/27793035/performance-of-multiplicom-s-brca-mastr-dx-kit-on-the-detection-of-brca1-and-brca2-mutations-in-fresh-frozen-ovarian-and-breast-tumor-samples
#9
Cindy Badoer, Céline Garrec, Dirk Goossens, Gillian Ellison, John Mills, Mélina Dzial, Hakim El Housni, Sarah Berwouts, Paola Concolino, Virginie Guibert-Le Guevellou, Capucine Delnatte, Jurgen Del Favero, Ettore Capoluongo, Stéphane Bézieau
Next-generation sequencing (NGS) has enabled new approaches for detection of mutations in the BRCA1 and BRCA2 genes responsible for hereditary breast and ovarian cancer (HBOC). The search for germline mutations in the BRCA1 and BRCA2 genes is of importance with respect to oncogenetic and surgical (bilateral mastectomy, ovariectomy) counselling. Testing tumor material for BRCA mutations is of increasing importance for therapeutic decision making as the poly ADP ribose polymerase (PARP) inhibitor, olaparib, is now available to treat patients with specific forms of ovarian cancer and BRCA mutations...
October 25, 2016: Oncotarget
https://www.readbyqxmd.com/read/27708239/foxc1-identifies-basal-like-breast-cancer-in-a-hereditary-breast-cancer-cohort
#10
Jeff Johnson, Michael Choi, Farnaz Dadmanesh, Bingchen Han, Ying Qu, Yi Yu-Rice, Xiao Zhang, Sanjay Bagaria, Clive Taylor, Armando E Giuliano, Farin Amersi, Xiaojiang Cui
Breast cancers arising in the setting of the hereditary breast cancer genes BRCA1 and BRCA2 are most commonly classified as basal-like breast cancer (BLBC) or luminal breast cancer, respectively. BLBC is an aggressive subtype of breast cancer associated with liver and lung metastases and poorer prognosis than other subtypes and for which chemotherapy is the only systemic therapy. Multiple immunohistochemical markers are used to identify the basal-like subtype, including the absence of estrogen receptor alpha, progesterone receptor, and human epidermal growth factor receptor 2...
September 30, 2016: Oncotarget
https://www.readbyqxmd.com/read/27663600/sequence-specific-pharmacokinetic-and-pharmacodynamic-phase-i-ib-study-of-olaparib-tablets-and-carboplatin-in-women-s-cancer
#11
Jung-Min Lee, Cody J Peer, Minshu Yu, Lauren Amable, Nicolas Gordon, Christina M Annunziata, Nicole Houston, Andrew K L Goey, Tristan M Sissung, Bernard Parker, Lori Minasian, Victoria Chiou, Robert F Murphy, Brigitte C Widemann, William D Figg, Elise C Kohn
PURPOSE: Our preclinical studies showed the PARP inhibitor, olaparib prior to carboplatin attenuated carboplatin cytotoxicity. We evaluated sequence-specific pharmacokinetic/pharmacodynamic (PK/PD) effects, safety and activity of the combination. PATIENTS AND METHODS: Eligible patients had metastatic or recurrent women's cancer. Olaparib tablets were introduced (100 or 200mg bid, days1-7) in a 3+3 dose escalation with carboplatin AUC4 or 5 q21 days, up to eight cycles, followed by olaparib maintenance...
September 23, 2016: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/27634150/update-on-poly-adp-ribose-polymerase-inhibition-for-ovarian-cancer-treatment
#12
REVIEW
Anselmo Papa, Davide Caruso, Martina Strudel, Silverio Tomao, Federica Tomao
BACKGROUND: Despite standard treatment for epithelial ovarian cancer (EOC), that involves cytoreductive surgery followed by platinum-based chemotherapy, and initial high response rates to these, up to 80 % of patients experience relapses with a median progression-free survival of 12-18 months. There remains an urgent need for novel targeted therapies to improve clinical outcomes in ovarian cancer. Of the many targeted therapies currently under evaluation, the most promising strategies developed thus far are antiangiogenic agents and Poly(ADP-ribose) polymerase (PARP) inhibitors...
September 15, 2016: Journal of Translational Medicine
https://www.readbyqxmd.com/read/27559053/drug-driven-synthetic-lethality-bypassing-tumor-cell-genetics-with-a-combination-of-asidna-and-parp-inhibitors
#13
Wael Jdey, Sylvain Thierry, Christophe Russo, Flavien Devun, Muthana Al Abo, Patricia Noguiez-Hellin, Jian-Sheng Sun, Emmanuel Barillot, Andrei Zinovyev, Inna Kuperstein, Yves Pommier, Marie Dutreix
PURPOSE: Cancer treatments using tumor defects in DNA repair pathways have shown promising results but are restricted to small subpopulations of patients. The most advanced drugs in this field are PARP inhibitors (PARPi), which trigger synthetic lethality in tumors with homologous recombination (HR) deficiency. Using AsiDNA, an inhibitor of HR and nonhomologous end joining, together with PARPi should allow bypassing the genetic restriction for PARPi efficacy. EXPERIMENTAL DESIGN: We characterized the DNA repair inhibition activity of PARPi (olaparib) and AsiDNA by monitoring repair foci formation and DNA damage...
August 24, 2016: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/27428646/parp-inhibitors-in-clinical-use-induce-genomic-instability-in-normal-human-cells
#14
Shuhei Ito, Conleth G Murphy, Ekaterina Doubrovina, Maria Jasin, Mary Ellen Moynahan
Poly(ADP-ribose) polymerases (PARPs) are the first proteins involved in cellular DNA repair pathways to be targeted by specific inhibitors for clinical benefit. Tumors harboring genetic defects in homologous recombination (HR), a DNA double-strand break (DSB) repair pathway, are hypersensitive to PARP inhibitors (PARPi). Early phase clinical trials with PARPi have been promising in patients with advanced BRCA1 or BRCA2-associated breast, ovary and prostate cancer and have led to limited approval for treatment of BRCA-deficient ovary cancer...
2016: PloS One
https://www.readbyqxmd.com/read/27426307/combined-inhibition-of-pi3k-and-parp-is-effective-in-the-treatment-of-ovarian-cancer-cells-with-wild-type-pik3ca-genes
#15
Dong Wang, Chengbo Li, Yuan Zhang, Min Wang, Nan Jiang, Lin Xiang, Ting Li, Thomas M Roberts, Jean J Zhao, Hailing Cheng, Pixu Liu
OBJECTIVE: Combined inhibition of PI3K and PARP has been shown to be effective in the treatment of preclinical models of breast cancer and prostate cancer independent of BRCA or PIK3CA mutational status. However, the knowledge about this combination treatment in ovarian cancer is limited. The aim of this study was to evaluate the therapeutic effect of PI3K inhibitor BKM120 and PARP inhibitor Olaparib on ovarian cancer cell lines bearing wild-type PIK3CA genes. METHODS: We exposed three wild-type PIK3CA ovarian cancer cell lines to a PI3K inhibitor BKM120 and/or a PARP inhibitor Olaparib...
September 2016: Gynecologic Oncology
https://www.readbyqxmd.com/read/27425647/tankyrase-as-a-novel-molecular-target-in-cancer-and-fibrotic-diseases
#16
Vijaya Lakshmi Tiruveedi, Swarna Bale, Amit Khurana, Chandraiah Godugu
Tankyrases belong to a group of enzymes called poly ADP ribosyl polymerases (PARPs). With the advent of a new class of small molecule inhibitors of PARP for clinical use like OLAPARIB; that gained accelerated approval by the USFDA in treating ovarian and breast cancers, the horizons of the PARPs as a novel target in various disease conditions has risen. Tankyrases (PARP 5) are yet another class of PARPs that perform poly ADP ribosylation on different substrate proteins aiding in progression of many diseases like cancer, fibrosis, diabetes and neurological disorders even...
July 15, 2016: Current Drug Targets
https://www.readbyqxmd.com/read/27385701/olaparib-for-the-treatment-of-brca-mutated-advanced-ovarian-cancer
#17
REVIEW
Marklie Munroe, Jill Kolesar
PURPOSE: The pharmacology, clinical efficacy, safety, dosage and administration, and role in therapy of olaparib, a first-in-class treatment for advanced treatment-refractory ovarian cancer, are reviewed. SUMMARY: Olaparib (Lynparza, AstraZeneca) is an oral inhibitor of poly(ADP-ribose) polymerase (PARP) proteins that play a key role in DNA repair and genomic stability. Olaparib is indicated for use in treating certain patients with advanced, recurrent ovarian cancer who have mutations of the breast cancer 1 gene (BRCA1) or breast cancer 2 gene (BRCA2)...
July 15, 2016: American Journal of Health-system Pharmacy: AJHP
https://www.readbyqxmd.com/read/27381626/mechanisms-of-therapy-resistance-in-patient-derived-xenograft-models-of-brca1-deficient-breast-cancer
#18
Petra Ter Brugge, Petra Kristel, Eline van der Burg, Ute Boon, Michiel de Maaker, Esther Lips, Lennart Mulder, Julian de Ruiter, Catia Moutinho, Heidrun Gevensleben, Elisabetta Marangoni, Ian Majewski, Katarzyna Jóźwiak, Wigard Kloosterman, Markus van Roosmalen, Karen Duran, Frans Hogervorst, Nick Turner, Manel Esteller, Edwin Cuppen, Jelle Wesseling, Jos Jonkers
BACKGROUND: Although BRCA1-deficient tumors are extremely sensitive to DNA-damaging drugs and poly(ADP-ribose) polymerase (PARP) inhibitors, recurrences do occur and, consequently, resistance to therapy remains a serious clinical problem. To study the underlying mechanisms, we induced therapy resistance in patient-derived xenograft (PDX) models of BRCA1-mutated and BRCA1-methylated triple-negative breast cancer. METHODS: A cohort of 75 mice carrying BRCA1-deficient breast PDX tumors was treated with cisplatin, melphalan, nimustine, or olaparib, and treatment sensitivity was determined...
November 2016: Journal of the National Cancer Institute
https://www.readbyqxmd.com/read/27324108/a-phase-ii-study-of-olaparib-in-breast-cancer-patients-biological-evaluation-from-a-window-of-opportunity-trial
#19
Giandomenico Roviello, Manuela Milani, Angela Gobbi, Martina Dester, Maria Rosa Cappelletti, Giovanni Allevi, Sergio Aguggini, Andrea Ravelli, Francesca Gussago, Alessandra Cocconi, Laura Zanotti, Chiara Senti, Carla Strina, Alberto Bottini, Daniele Generali
The OLTRE trial (ClinicalTrials.gov number: NCT02681562) is an open-label, 'window of opportunity' Phase II controlled trial to evaluate the biological activity of olaparib in locally advanced triple-negative breast cancer compared with other subtypes of locally advanced breast cancer patients carrying germinal BRCA mutation receiving olaparib with the same treatment approach. The primary end point is to investigate the correlation between baseline gene and protein expression profile in order to identify possible predictive markers of response to olaparib...
October 2016: Future Oncology
https://www.readbyqxmd.com/read/27323902/a-phase-i-followed-by-a-randomized-phase-ii-trial-of-two-cycles-carboplatin-olaparib-followed-by-olaparib-monotherapy-versus-capecitabine-in-brca1-or-brca2-mutated-her2-negative-advanced-breast-cancer-as-first-line-treatment-revival-study-protocol-for-a-randomized
#20
Philip C Schouten, Gwen M H E Dackus, Serena Marchetti, Harm van Tinteren, Gabe S Sonke, Jan H M Schellens, Sabine C Linn
BACKGROUND: Preclinical studies in breast cancer models showed that BRCA1 or BRCA2 deficient cell lines, when compared to BRCA proficient cell lines, are extremely sensitive to PARP1 inhibition. When combining the PARP1 inhibitor olaparib with cisplatin in a BRCA1-mutated breast cancer mouse model, the combination induced a larger response than either of the two compounds alone. Several clinical studies have investigated single agent therapy or combinations of both drugs, but no randomized clinical evidence exists for the superiority of carboplatin-olaparib versus standard of care therapy in patients with BRCA1- or BRCA2--mutated metastatic breast cancer...
June 21, 2016: Trials
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