Abstract 5126: Does genetic background in glioma influence the sensitivity of tumor cells to a PARP inhibitor in the presence of different DNA damaging agents

1081 Background: Patients with BRCA-positive HER2-negative breast cancer benefit from PARP inhibitor therapy, but additional benefit is still desired. PARP inhibition alone does not prevent all mechanisms for repairing damage to DNA such as homologous recombination repair. An attractive combination for treating such patients would be combining a topoisomerase I inhibitor with a PARP inhibitor given the dual mechanism this would provide for DNA damage and inhibited repair, leading to tumor cell death. This combination has been tried in multiple phase 1 studies, but myelotoxicity prevented the combination from being evaluated further. DAN-222 is a novel investigational polymeric nanoparticle conjugated with camptothecin, a topoisomerase I inhibitor, that provides significant accumulation of drug in tumor tissues via the enhanced permeability and retention (EPR) effect and significantly reduced bone marrow exposure compared to native chemotherapy. These observations underscore the potential advantages of DAN-222 alone as well as in combination with other agents such as PARP inhibitors in solid tumors. Here, we report the effects of DAN-222 monotherapy and in combination with a PARP inhibitor on the growth inhibition in an HRD+ TNBC breast cancer (MDA-MB-436) and an HRD- ovarian (OVCAR3) xenograft mouse model. Methods: HRD+ breast cancer tumor cells (MDA-MB-436) were implanted into female NCr nu/nu mice and HRD- ovarian cancer tumor cells (OVCAR3) were implanted into female CB.17 SCID mice. Mice were randomized to vehicle or treatment arms until tumors reached 2000 mm3 or day 45 (MDA-MB-436) or 1000mm3 or day 45 (OVCAR3). The groups evaluated include multiple dose levels of DAN-222 as monotherapy and those also combined with niraparib. Results: Results were consistent in both the HRD+ and HRD- tumor models with profound dose-response of DAN-222 monotherapy inhibiting tumor growth. Additionally, synergy was demonstrated when DAN-222 was combined with niraparib, clearly evident with low doses of both products when used in combination. The table below highlights the synergy of the combination of DAN-222 at 0.3 mg/kg and niraparib at 25 mg/kg above each agent alone on the tumor growth inhibition in the MDA-MB-436 xenograft. Conclusions: Combining a PARP inhibitor with a topoisomerase I inhibitor delivered via this polymeric nanoparticle delivery system (DAN-222) has synergistic efficacy in both HRD+ and HRD- xenograft tumor models. These data support continued development of DAN-222 to treat solid tumors and its combination use with PARP inhibitors.[Table: see text]

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Extent of radiosensitization by the PARP inhibitor olaparib depends on its dose, the radiation dose and the integrity of the homologous recombination pathway of tumor cells

Radiotherapy and Oncology ◽

10.1016/j.radonc.2015.03.028 ◽

2015 ◽

Vol 116 (3) ◽

pp. 358-365 ◽

Cited By ~ 61

Author(s):

Caroline V.M. Verhagen ◽

Rosemarie de Haan ◽

Floor Hageman ◽

Tim P.D. Oostendorp ◽

Annalisa L.E. Carli ◽

...

Keyword(s):

Radiation Dose ◽

Homologous Recombination ◽

Tumor Cells ◽

Parp Inhibitor ◽

Homologous Recombination Pathway ◽

Recombination Pathway

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Abstract LB-392: Loss of Rev7 causes PARP inhibitor resistance in BRCA1;p53-deficient mouse mammary tumor cells

10.1158/1538-7445.am2012-lb-392 ◽

2012 ◽

Author(s):

Guotai Xu ◽

Peter Bouwman ◽

Janneke Jaspers ◽

Mark Pieterse ◽

Ariena Kersbergen ◽

...

Keyword(s):

Tumor Cells ◽

Mammary Tumor ◽

Parp Inhibitor ◽

Deficient Mouse ◽

Mammary Tumor Cells ◽

Mouse Mammary Tumor ◽

Inhibitor Resistance ◽

Mouse Mammary Tumor Cells

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SDX-105 (Treanda™), Active in Non-Hodgkin’s Lymphoma Cells, Induces the Mitotic Catastrophe Death Pathway.

Blood ◽

10.1182/blood.v104.11.4593.4593 ◽

2004 ◽

Vol 104 (11) ◽

pp. 4593-4593 ◽

Cited By ~ 1

Author(s):

Lorenzo M. Leoni ◽

Christina Niemeyer ◽

Heather Bendall ◽

Jack Reifert ◽

Brandi Bailey

Keyword(s):

Tumor Cells ◽

Mechanism Of Action ◽

Chromatin Condensation ◽

Alkylating Agents ◽

Mitotic Catastrophe ◽

Cross Resistance ◽

Pcr Analysis ◽

Dna Damaging Agents ◽

Anti Tumor Activity ◽

In Cells

Abstract SDX-105 (Treanda™) is an alkylating agent with a distinct mechanism of action that has been shown to be active in clinical trials in NHL and CLL patients refractory to traditional DNA-damaging agents. SDX-105 induces unique changes in gene expression in NHL cells and displays a lack of cross resistance with other 2-chloroethylamine alkylating agents. Quantitative PCR analysis confirmed that the G2/M checkpoint regulators Polo-like kinase 1 (PLK-1) and Aurora A kinase (AurkA) are down-regulated in the NHL cell line SU-DHL-1 after 8 hours of exposure to clinically relevant concentrations of SDX-105. No changes in these same genes were observed when cells were exposed to equi-toxic doses of chlorambucil or an active metabolite of cyclophosphamide. Because our previous studies demonstrated that SDX-105 treatment can activate apoptotic cell death pathways, we examined the ability of SDX-105 to induce cytotoxicity in cells unable to undergo ‘classical’ caspase-mediated apoptosis. Multi-drug resistant MCF-7/ADR cells and p53 deficient RKO-E6 colon adenocarcinoma cells were exposed for two or three days to either 50 μM SDX-105 alone or 50 μM SDX-105 and 20 μM pan-caspase inhibitor zVAD-fmk. Although zVAD-fmk was able to inhibit SDX-105 induced increases in Annexin-V-positive cells, microscopic analysis of nuclear morphology using the DNA stain DAPI in cells treated with either SDX-105 alone or in combination with zVAD-fmk showed increased incidence of micronucleation. Multi/micro-nucleation and abnormal chromatin condensation are both hallmarks of mitotic catastrophe and have been observed in tumor cells exposed to microtubule-binding drugs such as the vinca alkaloids and taxanes. Activation of mitotic catastrophe may amplify the cytotoxicity of SDX-105 and its activity in tumor cells where classical apoptotic pathways are inhibited. This may explain, at least in part, the potent anti-tumor activity of SDX-105 in tumor cells refractory to conventional 2-chloroethylamine DNA-damaging agents. Additional studies are ongoing to further elaborate the role of mitotic catastrophe in SDX-105’s mechanism of action. The capacity to induce mitotic catastrophe may explain the anti-tumor activity of SDX-105 in chemotherapy relapsed and resistant patients.

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AZD1775 Increases Sensitivity to Olaparib and Gemcitabine in Cancer Cells with p53 Mutations

Cancers ◽

10.3390/cancers10050149 ◽

2018 ◽

Vol 10 (5) ◽

pp. 149 ◽

Cited By ~ 21

Author(s):

Xiangbing Meng ◽

Jianling Bi ◽

Yujun Li ◽

Shujie Yang ◽

Yuping Zhang ◽

...

Keyword(s):

Dna Damage ◽

Cancer Cells ◽

Tumor Cells ◽

Gynecologic Cancer ◽

Cell Cycle Checkpoints ◽

Ovarian Cancer Cells ◽

Tumor Suppressor P53 ◽

New Approach ◽

Dna Damaging Agents ◽

Recurrent Gynecologic Cancer

Tumor suppressor p53 is responsible for enforcing cell cycle checkpoints at G1/S and G2/M in response to DNA damage, thereby allowing both normal and tumor cells to repair DNA before entering S and M. However, tumor cells with absent or mutated p53 are able to activate alternative signaling pathways that maintain the G2/M checkpoint, which becomes uniquely critical for the survival of such tumor cells. We hypothesized that abrogation of the G2 checkpoint might preferentially sensitize p53-defective tumor cells to DNA-damaging agents and spare normal cells with intact p53 function. The tyrosine kinase WEE1 regulates cdc2 activity at the G2/M checkpoint and prevents entry into mitosis in response to DNA damage or stalled DNA replication. AZD1775 is a WEE1 inhibitor that overrides and opens the G2/M checkpoint by preventing WEE1-mediated phosphorylation of cdc2 at tyrosine 15. In this study, we assessed the effect of AZD1775 on endometrial and ovarian cancer cells in the presence of two DNA damaging agents, the PARP1 inhibitor, olaparib, and the chemotherapeutic agent, gemcitabine. We show that AZD1775 alone is effective as a therapeutic agent against some p53 mutated cell models. Moreover, the combination of AZD1775 with olaparib or gemcitabine is synergistic in cells with mutant p53 and constitutes a new approach that should be considered in the treatment of advanced and recurrent gynecologic cancer.

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Potentiation of 177Lu-octreotate peptide receptor radionuclide therapy of human neuroendocrine tumor cells by PARP inhibitor

Oncotarget ◽

10.18632/oncotarget.25266 ◽

2018 ◽

Vol 9 (37) ◽

pp. 24693-24706 ◽

Cited By ~ 9

Author(s):

Nupur K. Purohit ◽

Rashmi G. Shah ◽

Samuel Adant ◽

Michael Hoepfner ◽

Girish M. Shah ◽

...

Keyword(s):

Neuroendocrine Tumor ◽

Tumor Cells ◽

Radionuclide Therapy ◽

Parp Inhibitor ◽

Peptide Receptor Radionuclide Therapy ◽

Peptide Receptor

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Opening a Door to PARP Inhibitor-Induced Lethality in HR-Proficient Human Tumor Cells

Cancer Cell ◽

10.1016/j.ccell.2020.01.005 ◽

2020 ◽

Vol 37 (2) ◽

pp. 139-140

Author(s):

Elodie Hatchi ◽

David M. Livingston

Keyword(s):

Tumor Cells ◽

Parp Inhibitor ◽

Human Tumor ◽

Human Tumor Cells

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Assessment of γH2AX levels in circulating tumor cells in patients treated with veliparib in combination with doxorubicin and cyclophosphamide in metastatic breast cancer.

Journal of Clinical Oncology ◽

10.1200/jco.2013.31.15_suppl.2582 ◽

2013 ◽

Vol 31 (15_suppl) ◽

pp. 2582-2582

Author(s):

Antoinette R. Tan ◽

Deborah Toppmeyer ◽

Serena Tsan-Lai Wong ◽

Hongxia Lin ◽

Murugesan Gounder ◽

...

Keyword(s):

Breast Cancer ◽

Dna Damage ◽

Metastatic Breast Cancer ◽

Tumor Cells ◽

Circulating Tumor Cells ◽

Brca Mutation ◽

Parp Inhibitor ◽

Metastatic Breast ◽

Chemotherapeutic Agents ◽

Response To Treatment

2582 Background: Veliparib (V) is a potent PARP inhibitor that delays repair of DNA damage induced by chemotherapeutic agents. In metastatic breast cancer pts, we evaluated V with doxorubicin (A) and cyclophosphamide (C) given both on day 1 with V at 100 mg po BID for 7 days post-chemotherapy every 21 days, to increase DNA damage. We report use of γH2AX, (phosphorylated histone protein), a marker of DNA double-strand breaks, in circulating tumor cells (CTCs) to assess DNA damage. We evaluated number of CTCs and percentage of γH2AX-positive CTCs pre- and post-treatment. Methods: Eligibility included prior A ≤ 300 mg/m2 and EF ≥ 50%. Further A was omitted after a cumulative dose of 420 mg/m2. Primary objective was to assess DNA damage response to treatment by measuring γH2AX-positive CTCs during cycle 1 on days 1 (pre-treatment), 2, 7, and 14. Cell Search System was used to enumerate CTCs. γH2AX was quantitated using a validated assay. Results: Eleven pts enrolled. Median age was 53 (34 – 73); median ECOG PS 1 (0 – 2); there were 1 ER-negative/HER2+, 4 triple-negative (BRCA2+, n =1), and 6 ER+/PR+/HER2-negative (BRCA2+, n =2) tumors. Most common drug-related toxicities were grade (gr) 4 neutropenia, gr 2 anemia and thrombocytopenia, and gr 1 nausea and vomiting. In BRCA2+ pts, there were 2 PRs and 1 SD. In BRCA wt or unknown status, 5 pts had SD ≥ 3 mo and there were 3 PDs. CTCs (≥ 8) were detected in 10/11 pts on days 1 and 2. Day 7 samples were not obtainable in 2 pts. On day 7, 1/8 pts had 0 CTCs and rest had ≥ 3 CTCs. A decrease in CTCs (p < 0.0001) occurred from day 1 (median: 22, range, 8-1216) to day 7 (median: 5, range 3-37). At baseline, 7 pts had ≥ 10% γH2AX-positive CTCs. Fraction of CTCs positive for γH2AX increased to ≥ 50% by day 7 in 6/7 pts and persisted to day 14 in 5 pts. Conclusions: The toxicity profile of V 100 mg BID days 1-7 with AC (60/600 mg/m2) on day 1 on a 21-day cycle was expected. Objective antitumor activity was seen in BRCA mutation carriers. CTCs decreased and percentage of γH2AX-positive CTCs increased after combination treatment with a PARP inhibitor and chemotherapy. This observation is notable and we plan to extend dosing of V to 14 days. This work is supported by NCI U01-CA132194. Clinical trial information: NCT00740805.

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Research progress of PARP inhibitor monotherapy and combination therapy for endometrial cancer.

Current Drug Targets ◽

10.2174/1389450122666210617111304 ◽

2021 ◽

Vol 22 ◽

Author(s):

Ke Shen ◽

Li Yang ◽

Fei-Yan Li ◽

Feng Zhang ◽

Lei-Lei Ding ◽

...

Keyword(s):

Endometrial Cancer ◽

Homologous Recombination ◽

Tumor Cells ◽

Checkpoint Inhibitors ◽

Parp Inhibitor ◽

Parp Inhibitors ◽

Cell Cycle Checkpoint ◽

Research Progress ◽

Homologous Recombination Repair ◽

Recombination Repair

: Endometrial cancer is one of the three most common malignant tumors in the female reproductive system. Advanced and recurrent endometrial cancers have poor prognoses and lack effective treatments. Poly(ADP-ribose) polymerase (PARP) inhibitors have been applied to many different types of tumors, and they can selectively kill tumor cells that are defective in homologous recombination repair. Endometrial cancer is characterized by mutations in homologous recombination repair genes; accordingly, PARP inhibitors have achieved positive results in off-label treatments of endometrial cancer cases. Clinical trials of PARP inhibitors as monotherapies and within combination therapies for endometrial cancer are ongoing. For this review, we searched PubMed with "endometrial cancer" and "PARP inhibitor" as keywords, and we used "olaparib", "rucaparib", "niraparib" and "talazoparib" as search terms in clinicaltrials.gov for ongoing trials. The literature search ended in October 2020, and only English-language publications were selected. Multiple studies confirm that PARP inhibitors play an important role in killing tumor cells with defects in homologous recombination repair. Its combination with immune checkpoint inhibitors, PI3K/AKT/mTOR pathway inhibitors, cell cycle checkpoint inhibitors, and other drugs can improve the treatment of endometrial cancer.

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