DOCSLIB.ORG

PARP Inhibitors Sensitize Ewing Sarcoma Cells to Temozolomide

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
PARP Inhibitors Sensitize Ewing Sarcoma Cells to Temozolomide Published OnlineFirst October 5, 2015; DOI: 10.1158/1535-7163.MCT-15-0587 Cancer Biology and Signal Transduction Molecular Cancer Therapeutics PARP Inhibitors Sensitize Ewing Sarcoma Cells to Temozolomide-Induced Apoptosis via the Mitochondrial Pathway Florian Engert1, Cornelius Schneider1, Lilly Magdalena Weib1,2,3, Marie Probst1,and Simone Fulda1,2,3 Abstract Ewing sarcoma has recently been reported to be sensitive to that subsequent to DNA damage-imposed checkpoint activa- poly(ADP)-ribose polymerase (PARP) inhibitors. Searching for tion and G2 cell-cycle arrest, olaparib/TMZ cotreatment causes synergistic drug combinations, we tested several PARP inhibi- downregulation of the antiapoptotic protein MCL-1, followed by tors (talazoparib, niraparib, olaparib, veliparib) together with activation of the proapoptotic proteins BAX and BAK, mitochon- chemotherapeutics. Here, we report that PARP inhibitors syner- drial outer membrane permeabilization (MOMP), activation of gize with temozolomide (TMZ) or SN-38 to induce apoptosis caspases, and caspase-dependent cell death. Overexpression of a and also somewhat enhance the cytotoxicity of doxorubicin, nondegradable MCL-1 mutant or BCL-2, knockdown of NOXA or etoposide, or ifosfamide, whereas actinomycin D and vincris- BAX and BAK, or the caspase inhibitor N-benzyloxycarbonyl-Val- tine show little synergism. Furthermore, triple therapy of ola- Ala-Asp-fluoromethylketone (zVAD.fmk) all significantly reduce parib, TMZ, and SN-38 is significantly more effective compared olaparib/TMZ-mediated apoptosis. These findings emphasize with double or monotherapy. Mechanistic studies revealed that the role of PARP inhibitors for chemosensitization of Ewing the mitochondrial pathway of apoptosis plays a critical role in sarcoma with important implications for further (pre)clinical mediating the synergy of PARP inhibition and TMZ. We show studies. Mol Cancer Ther; 14(12); 2818–30. Ó2015 AACR. Introduction accompanied by the release of mitochondrial intermembrane space proteins such as cytochrome c into the cytosol, which in Ewing sarcoma is the second most common pediatric primary turn results in caspase activation and apoptosis (5). MOMP is bone tumor in children and young adults (1). State-of-the-art tightly controlled by various factors including proteins of the BCL- treatment options for Ewing sarcoma patients include chemo- 2 family. BCL-2 family proteins consist of both antiapoptotic therapy consisting of vincristine, ifosfamide, doxorubicin, temo- members, for example BCL-2, BCL-x , and MCL-1, and proapop- zolomide (TMZ), actinomycin D, irinotecan, etoposide, and L totic molecules such as the multidomain proteins BAK and BAX cyclophosphamide (2). Despite aggressive treatment protocols, and BH3-only domain proteins, for example, BIM, BMF, PUMA, patients especially with advanced or relapsed diseases still harbor and NOXA (6). an overall poor survival (2). This highlights the unmet medical Characteristic for Ewing sarcoma is the existence of a chimeric need to develop innovative treatment strategies. fusion protein which is in >85% of cases generated by the Tumor response to cytotoxic therapies including chemotherapy translocation of the EWS gene on chromosome 22 and the FLI1 critically relies on intact cell death programs in cancer cells, as gene on chromosome 11 (11;22)(q24;q12) (7). This fusion chemotherapeutics exert their anticancer effects to a large extent protein encodes the chimeric transcription factor EWS-FLI1 that by engaging programmed cell death (3). Apoptosis is mediated causes upregulation of a range of target genes including PARP1 via two well-defined pathways, that is the extrinsic (death recep- (7, 8), which promotes transcriptional activation by EWS-FLI1 in tor) pathway and the intrinsic (mitochondrial) pathway, which a positive feedback loop (9). Elevated PARP levels have been both eventually lead to activation of caspases as cell death effector detected in Ewing sarcoma specimens (8, 10), indicating that molecules (4). Engagement of the mitochondrial pathway results PARP may represent a promising target for therapeutic exploita- in mitochondrial outer membrane permeabilization (MOMP) tion in Ewing sarcoma. Indeed, Ewing sarcoma cells have been shown to be particularly sensitive to PARP inhibition (9, 10). 1Institute for Experimental Cancer Research in Pediatrics, Goethe- Several PARP inhibitors including talazoparib (BMN-673), nir- University, Frankfurt, Germany. 2German Cancer Consortium (DKTK), aparib (MK-4827), olaparib (AZD-2281), and veliparib (ABT- 3 Heidelberg, Germany. German Cancer Research Center (DKFZ), Hei- 888) are currently under investigation (11). delberg, Germany. Despite the sensitivity of Ewing sarcoma cells to PARP inhibi- Note: Supplementary data for this article are available at Molecular Cancer tors in vitro (9, 10, 12), PARP inhibitors as single therapy displayed Therapeutics Online (http://mct.aacrjournals.org/). limited efficacy in xenograft models of Ewing sarcoma and in Corresponding Author: Simone Fulda, Goethe-University, Komturstr. 3a, 60528 initial clinical trials (12–15), highlighting the need for combina- Frankfurt, Germany. Phone: 49-69-67866557; Fax: 49-69-6786659157; E-mail: tion therapies. PARP inhibitors have been documented to poten- [email protected] tiate DNA damage-mediated cytotoxicity caused in particular by doi: 10.1158/1535-7163.MCT-15-0587 topoisomerase I poisons, DNA methylating agents, or radiation in Ó2015 American Association for Cancer Research. several cancers including Ewing sarcoma, which has been related 2818 Mol Cancer Ther; 14(12) December 2015 Downloaded from mct.aacrjournals.org on September 24, 2021. © 2015 American Association for Cancer Research. Published OnlineFirst October 5, 2015; DOI: 10.1158/1535-7163.MCT-15-0587 Synergistic Apoptosis by PARP Inhibitors and Temozolomide A A4573 SK-ES-1 Talazoparib Talazoparib Niraparib Niraparib Olaparib Olaparib Veliparib Veliparib 100 100 90 90 80 80 70 70 60 60 50 50 40 40 30 30 Cell viability (% (% of viability control) Cell 20 Cell viability (% (% of viability Cell control) 20 10 10 0 0 0.1 1 10 100 1,000 10,000 100,000 0.1 1 10 100 1,000 10,000 100,000 Drug concentration (nmol/L) Drug concentration (nmol/L) B Talazoparib (nmol/L) Niraparib (nmol/L) Olaparib (nmol/L) Veliparib (nmol/L) A4573 CI values 0.5 1 2.5 5 7.5 25 50 75 100 300 600 1,600 2,200 2,800 25 < 0.1 Very strong synergism TMZ (µmol/L) 50 0.1–0.3 Strong synergism 100 0.3–0.7 Synergism 0.2 0.7–0.85 Moderate synergism SN38 (nmol/L) 0.4 0.85–0.9 Slight synergism 0.6 0.9–1.1 Nearly additive 25 1.1–1.2 Slightly antagonistic Etoposide (ng/mL) 50 1.2–1.45 Moderate antagonistic 75 >1.45 Antagonism 0.5 Not calculated Ifosfamide (µmol/L) 1 2 1 Doxo (ng/µL) 2.5 4 0.1 Vincristine (nmol/L) 0.25 0.4 0.1 AMD 0.25 (ng/mL) 0.4 Talazoparib (nmol/L) Niraparib (nmol/L) Olaparib (nmol/L) Veliparib (nmol/L) SK-ES-1 CI values 0.5 1 2.5 5 7.5 25 50 75 100 300 600 1,600 2,200 2,800 25 < 0.1 Very strong synergism TMZ (µmol/L) 50 0.1–0.3 Strong synergism 100 0.3–0.7 Synergism 0.2 0.7–0.85 Moderate synergism SN38 (nmol/L) 0.4 0.85–0.9 Slight synergism 0.6 0.9–1.1 Nearly additive 25 1.1–1.2 Slightly antagonistic Etoposide (ng/mL) 50 1.2–1.45 Moderate antagonistic 75 >1.45 Antagonism 0.5 Not calculated Ifosfamide (µmol/L) 1 2 1 Doxo (ng/µL) 2.5 4 0.1 Vincristine (nmol/L) 0.25 0.4 0.1 AMD 0.25 (ng/mL) 0.4 Figure 1. Screening for synergistic drug interactions of PARP inhibitors and chemotherapeutic drugs. A, A4573 and SK-ES-1 cells were treated for 72 hours with indicated concentrations of talazoparib, niraparib, olaparib, or veliparib. Cell viability was assessed by crystal violet assay and is shown as percentage of untreated control. B, A4573 and SK-ES-1 cells were treated for 72 hours with different PARP inhibitors (i.e., talazoparib, niraparib, olaparib, and veliparib) in combination with different cytostatic drugs (i.e., TMZ, SN-38, etoposide, ifosfamide, doxorubicin, vincristine, and actinomycin D). Cell viability was assessed by crystal violet assay. Synergistic, additive, or antagonistic drug interactions were calculated by combination index (CI). CI values were then used to generate a heatmap of drug interactions according to the subclassification provided by the software's manual. www.aacrjournals.org Mol Cancer Ther; 14(12) December 2015 2819 Downloaded from mct.aacrjournals.org on September 24, 2021. © 2015 American Association for Cancer Research. Published OnlineFirst October 5, 2015; DOI: 10.1158/1535-7163.MCT-15-0587 Engert et al. A4573 SK-ES-1 A 100 100 *** 100 *** 100 *** * 80 80 80 80 60 60 60 60 40 40 40 40 20 20 20 20 DNA fragmentation (%) fragmentation DNA DNA fragmentation (%) fragmentation DNA DNA fragmentation (%) fragmentation DNA DNA fragmentation (%) fragmentation DNA 0 0 0 0 Olaparib – + – + Olaparib – + – + Olaparib – + – + Olaparib – + – + TMZ – – + + SN-38 – – + + TMZ – – + + SN-38 – – + + B ** ** * ** 100 100 100 100 80 80 80 80 60 60 60 60 40 40 40 40 20 20 20 20 Cell viability (% of Cell viability control) Cell viability (% of Cell viability control) Cell viability (% of Cell viability control) 0 0 0 (% of Cell viability control) 0 Olaparib – + – + Olaparib – + – + Olaparib – + – + Olaparib – + – + TMZ – – + + SN-38 – – + + TMZ – – + + SN-38 – – + + C ****** 120 120 120 100 100 100 100 80 80 80 80 60 60 60 60 40 40 40 40 20 20 20 20 Colonies (% Colonies (% of control) Colonies (% Colonies (% of control) Colonies (% Colonies (% of control) Colonies (% Colonies (% of control) 00 0 0 Olaparib – + – + Olaparib – + – + Olaparib – + – + Olaparib – + – + TMZ – – + + SN-38 – – + + TMZ – – + + SN-38 – – + + – Olaparib + Olaparib – Olaparib + Olaparib – Olaparib + Olaparib – Olaparib + Olaparib – TMZ – TMZ – SN-38 – SN-38 + TMZ + TMZ + SN-38 + SN-38 D *** *** 100 100 ** * 80 80 60 60 40 40 20 20 Cell viability (% Cell viability of control) Cell viability (% of Cell viability control) 0 0 Olaparib – + – – – + + + Olaparib – + – – – + + + TMZ – – + – + + – + TMZ – – + – + + – + SN-38 – – – + + – + + SN-38 – – – + + – + + 2820 Mol Cancer Ther; 14(12) December 2015 Molecular Cancer Therapeutics Downloaded from mct.aacrjournals.org on September 24, 2021.
Load more

Recommended publications
  • Genetic Screens in Isogenic Mammalian Cell Lines Without Single Cell Cloning
    ARTICLE https://doi.org/10.1038/s41467-020-14620-6 OPEN Genetic screens in isogenic mammalian cell lines without single cell cloning Peter C. DeWeirdt1,2, Annabel K. Sangree1,2, Ruth E. Hanna1,2, Kendall R. Sanson1,2, Mudra Hegde 1, Christine Strand 1, Nicole S. Persky1 & John G. Doench 1* Isogenic pairs of cell lines, which differ by a single genetic modification, are powerful tools for understanding gene function. Generating such pairs of mammalian cells, however, is labor- 1234567890():,; intensive, time-consuming, and, in some cell types, essentially impossible. Here, we present an approach to create isogenic pairs of cells that avoids single cell cloning, and screen these pairs with genome-wide CRISPR-Cas9 libraries to generate genetic interaction maps. We query the anti-apoptotic genes BCL2L1 and MCL1, and the DNA damage repair gene PARP1, identifying both expected and uncharacterized buffering and synthetic lethal interactions. Additionally, we compare acute CRISPR-based knockout, single cell clones, and small- molecule inhibition. We observe that, while the approaches provide largely overlapping information, differences emerge, highlighting an important consideration when employing genetic screens to identify and characterize potential drug targets. We anticipate that this methodology will be broadly useful to comprehensively study gene function across many contexts. 1 Genetic Perturbation Platform, Broad Institute of MIT and Harvard, 75 Ames Street, Cambridge, MA 02142, USA. 2These authors contributed equally: Peter C. DeWeirdt,
    [Show full text]
  • The Role of PARP1 in Monocyte and Macrophage
    cells Review The Role of PARP1 in Monocyte and Macrophage Commitment and Specification: Future Perspectives and Limitations for the Treatment of Monocyte and Macrophage Relevant Diseases with PARP Inhibitors Maciej Sobczak 1, Marharyta Zyma 2 and Agnieszka Robaszkiewicz 1,* 1 Department of General Biophysics, Faculty of Biology and Environmental Protection, University of Lodz, Pomorska 141/143, 90-236 Lodz, Poland; [email protected] 2 Department of Immunopathology, Medical University of Lodz, 7/9 Zeligowskiego, Bldg 2, Rm177, 90-752 Lodz, Poland; [email protected] * Correspondence: [email protected]; Tel.: +48-42-6354449; Fax: +48-42-6354449 or +48-42-635-4473 Received: 4 August 2020; Accepted: 4 September 2020; Published: 6 September 2020 Abstract: Modulation of PARP1 expression, changes in its enzymatic activity, post-translational modifications, and inflammasome-dependent cleavage play an important role in the development of monocytes and numerous subtypes of highly specialized macrophages. Transcription of PARP1 is governed by the proliferation status of cells at each step of their development. Higher abundance of PARP1 in embryonic stem cells and in hematopoietic precursors supports their self-renewal and pluri-/multipotency, whereas a low level of the enzyme in monocytes determines the pattern of surface receptors and signal transducers that are functionally linked to the NFκB pathway. In macrophages, the involvement of PARP1 in regulation of transcription, signaling, inflammasome activity, metabolism, and redox balance supports macrophage polarization towards the pro-inflammatory phenotype (M1), which drives host defense against pathogens. On the other hand, it seems to limit the development of a variety of subsets of anti-inflammatory myeloid effectors (M2), which help to remove tissue debris and achieve healing.
    [Show full text]
  • AHFS Pharmacologic-Therapeutic Classification System
    AHFS Pharmacologic-Therapeutic Classification System Abacavir 48:24 - Mucolytic Agents - 382638 8:18.08.20 - HIV Nucleoside and Nucleotide Reverse Acitretin 84:92 - Skin and Mucous Membrane Agents, Abaloparatide 68:24.08 - Parathyroid Agents - 317036 Aclidinium Abatacept 12:08.08 - Antimuscarinics/Antispasmodics - 313022 92:36 - Disease-modifying Antirheumatic Drugs - Acrivastine 92:20 - Immunomodulatory Agents - 306003 4:08 - Second Generation Antihistamines - 394040 Abciximab 48:04.08 - Second Generation Antihistamines - 394040 20:12.18 - Platelet-aggregation Inhibitors - 395014 Acyclovir Abemaciclib 8:18.32 - Nucleosides and Nucleotides - 381045 10:00 - Antineoplastic Agents - 317058 84:04.06 - Antivirals - 381036 Abiraterone Adalimumab; -adaz 10:00 - Antineoplastic Agents - 311027 92:36 - Disease-modifying Antirheumatic Drugs - AbobotulinumtoxinA 56:92 - GI Drugs, Miscellaneous - 302046 92:20 - Immunomodulatory Agents - 302046 92:92 - Other Miscellaneous Therapeutic Agents - 12:20.92 - Skeletal Muscle Relaxants, Miscellaneous - Adapalene 84:92 - Skin and Mucous Membrane Agents, Acalabrutinib 10:00 - Antineoplastic Agents - 317059 Adefovir Acamprosate 8:18.32 - Nucleosides and Nucleotides - 302036 28:92 - Central Nervous System Agents, Adenosine 24:04.04.24 - Class IV Antiarrhythmics - 304010 Acarbose Adenovirus Vaccine Live Oral 68:20.02 - alpha-Glucosidase Inhibitors - 396015 80:12 - Vaccines - 315016 Acebutolol Ado-Trastuzumab 24:24 - beta-Adrenergic Blocking Agents - 387003 10:00 - Antineoplastic Agents - 313041 12:16.08.08 - Selective
    [Show full text]
  • R&D Briefing 76
    The Impact of Recent Regulatory Developments on the Mexican Therapeutic Landscape Access to innovative medicines is key to El acceso a medicamentos innovadores es clave para improving overall population health, reducing mejorar la salud de toda la población, para reducir los hospitalisation time and decreasing morbidity and tiempos de hospitalización, la morbilidad y la mortalidad mortality. An efficient regulatory process can be de un país. Un proceso regulatorio eficiente tiene un reflected in measurable positive health impacts; impacto positivo medible en la salud, y por el contrario, conversely, activities that slow or impede acciones que retrasan o impiden la eficiencia regulatoria y regulatory efficiency and predictability can be su predictibilidad pueden ser perjudiciales. La parálisis detrimental. Recent developments in the Mexican reciente del Sistema regulatorio mexicano respecto a la regulatory system for the assessments of evaluación de nuevos medicamentos innovadores innovative new products have had a negative conlleva un impacto negativo en la salud de la población impact on Mexican public health. mexicana. This Briefing addresses the impact of suspending Este informe analiza el impacto de la suspensión de las the activities of the New Molecules Committee actividades del Comité de Moléculas Nuevas (NMC, por (NMC) on the Mexican therapeutic landscape. sus siglas en inglés) sobre el horizonte terapéutico de First, we compared the way that “new medicines” México. En primer lugar, comparamos la definición de are defined within the context of the Mexican nuevos medicamentos según el contexto regulatorio regulatory system, with definitions used by mexicano con las definiciones adoptadas por otras comparable regulators and health organisations. agencias reguladoras u organizaciones de salud del We have also investigated the extent to which mundo.
    [Show full text]
  • Cancer Drug Pharmacology Table
    CANCER DRUG PHARMACOLOGY TABLE Cytotoxic Chemotherapy Drugs are classified according to the BC Cancer Drug Manual Monographs, unless otherwise specified (see asterisks). Subclassifications are in brackets where applicable. Alkylating Agents have reactive groups (usually alkyl) that attach to Antimetabolites are structural analogues of naturally occurring molecules DNA or RNA, leading to interruption in synthesis of DNA, RNA, or required for DNA and RNA synthesis. When substituted for the natural body proteins. substances, they disrupt DNA and RNA synthesis. bendamustine (nitrogen mustard) azacitidine (pyrimidine analogue) busulfan (alkyl sulfonate) capecitabine (pyrimidine analogue) carboplatin (platinum) cladribine (adenosine analogue) carmustine (nitrosurea) cytarabine (pyrimidine analogue) chlorambucil (nitrogen mustard) fludarabine (purine analogue) cisplatin (platinum) fluorouracil (pyrimidine analogue) cyclophosphamide (nitrogen mustard) gemcitabine (pyrimidine analogue) dacarbazine (triazine) mercaptopurine (purine analogue) estramustine (nitrogen mustard with 17-beta-estradiol) methotrexate (folate analogue) hydroxyurea pralatrexate (folate analogue) ifosfamide (nitrogen mustard) pemetrexed (folate analogue) lomustine (nitrosurea) pentostatin (purine analogue) mechlorethamine (nitrogen mustard) raltitrexed (folate analogue) melphalan (nitrogen mustard) thioguanine (purine analogue) oxaliplatin (platinum) trifluridine-tipiracil (pyrimidine analogue/thymidine phosphorylase procarbazine (triazine) inhibitor)
    [Show full text]
  • Horizon Scanning Status Report June 2019
    Statement of Funding and Purpose This report incorporates data collected during implementation of the Patient-Centered Outcomes Research Institute (PCORI) Health Care Horizon Scanning System, operated by ECRI Institute under contract to PCORI, Washington, DC (Contract No. MSA-HORIZSCAN-ECRI-ENG- 2018.7.12). The findings and conclusions in this document are those of the authors, who are responsible for its content. No statement in this report should be construed as an official position of PCORI. An intervention that potentially meets inclusion criteria might not appear in this report simply because the horizon scanning system has not yet detected it or it does not yet meet inclusion criteria outlined in the PCORI Health Care Horizon Scanning System: Horizon Scanning Protocol and Operations Manual. Inclusion or absence of interventions in the horizon scanning reports will change over time as new information is collected; therefore, inclusion or absence should not be construed as either an endorsement or rejection of specific interventions. A representative from PCORI served as a contracting officer’s technical representative and provided input during the implementation of the horizon scanning system. PCORI does not directly participate in horizon scanning or assessing leads or topics and did not provide opinions regarding potential impact of interventions. Financial Disclosure Statement None of the individuals compiling this information have any affiliations or financial involvement that conflicts with the material presented in this report. Public Domain Notice This document is in the public domain and may be used and reprinted without special permission. Citation of the source is appreciated. All statements, findings, and conclusions in this publication are solely those of the authors and do not necessarily represent the views of the Patient-Centered Outcomes Research Institute (PCORI) or its Board of Governors.
    [Show full text]
  • New Drug Update: the Next Step in Personalized Medicine
    New Drug Update: The Next Step in Personalized Medicine Jordan Hill, PharmD, BCOP Clinical Pharmacy Specialist WVU Medicine Mary Babb Randolph Cancer Center Objectives • Review indications for new FDA approved anti- neoplastic medications in 2017 • Outline place in therapy of new medications • Become familiar with mechanisms of action of new medications • Describe adverse effects associated with new medications • Summarize dosing schemes and appropriate dose reductions for new medications First-in-Class Approvals • FLT3 inhibitor – midostaurin • IDH2 inhibitor – enasidenib • Anti-CD22 antibody drug conjugate – inotuzumab ozogamicin • CAR T-cell therapy - tisagenlecleucel “Me-too” Approvals • CDK 4/6 inhibitor – ribociclib and abemaciclib • PD-L1 inhibitors • Avelumab • Durvalumab • PARP inhibitor – niraparib • ALK inhibitor – brigatinib • Pan-HER inhibitor – neratinib • Liposome-encapsulated combination of daunorubicin and cytarabine • PI3K inhibitor – copanlisib Drugs by Malignancy AML Breast Bladder ALL FL Lung Ovarian 0 1 2 3 Oral versus IV 46% 54% Oral IV FIRST-IN CLASS FLT3 Inhibitor - midostaurin Journal of Hematology & Oncology 2017;10:93 Midostaurin (Rydapt®) • 717 newly diagnosed FLT3+ AML Patients • Induction and consolidation chemotherapy and placebo maintenance versus chemotherapy + midostaurin and Treatment maintenance midostaurin • OS: 74.7 mo versus 25.6 mo (P=0.009) Efficacy • EFS: 8.2 mo versus 3.0 mo (P=0.002) • Higher grade > 3 anemia, rash, and nausea Safety N Engl J Med 2017;377:454-64 Midostaurin (Rydapt®) • Approved indications: FLT3+ AML, mast cell leukemia, systemic mastocytosis • AML dose: 50 mg twice daily with food on days 8-21 • Of each induction cycle (+ daunorubicin and cytarabine) • Of each consolidation cycle (+ high dose cytarabine) • ADEs: nausea, myelosuppression, mucositis, increases in LFTs, amylase/lipase, and electrolyte abnormalities • Pharmacokinetics: hepatic metabolism, substrate of CYP 3A4; < 5% excretion in urine RYDAPT (midostaurin) [package insert].
    [Show full text]
  • Olaparib and Temozolomide in SCLC
    Olaparib and temozolomide in SCLC Anna Farago, MD, PhD and Benjamin Drapkin, MD, PhD March 16, 2018 Disclosures Farago: • Consulting fees from: PharmaMar, AbbVie, Takeda, Merrimack, Loxo Oncology • Honorarium from: Foundation Medicine • Research funding (to institution) from: AstraZeneca, AbbVie, Novartis, PharmaMar, Loxo Oncology, Ignyta, Merck, Bristol-Myers Squibb Drapkin: • Research funding (to institution) from: AstraZeneca, AbbVie, Novartis Bedside to Bench… and Back PARP inhibition in SCLC • PARP1 regulates base excision repair, homologous recombination, and non-homologous end joining. Inhibition of PARP enzymatic activity blocks PARP-mediated DNA repair.1 • PARP1 is highly expressed in SCLC compared to other cancers.2, 3 • SCLC cell lines are sensitive to PARP inhibitors. PARP sensitivity is not associated with BRCA1/2 mutations or HR defects.4,5 • “Trapping” of PARP complexes to sites of DNA single stranded breaks by PARP inhibitors can cause failure of repair and induction of double strand breaks.6 1. Sonnenblick et al., 2015 • PARP inhibitors synergize with agents that increase prevalence of 2. Byers et al., 2012 3. Cardnell et al., 2013 7,8 single stranded breaks in tumor models, including SCLC models. 4. Stewart et al., 2017 5. George et al., 2015 6. Hopkins et al., 2015 7. Murai et al., 2014 8. Lok et al., 2016 Farago et al., Presented at AACR annual meeting 2017 Rationale for olaparib + temozolomide in relapsed SCLC • Catalytic inhibitor of PARP1 and • Alkylating agent that induces Olaparib PARP2 Temozolomide single strand DNA breaks • Moderate PARP-trapping activity1 • FDA-approved in newly • FDA-approved as monotherapy for diagnosed glioblastoma patients with BRCA-mutated multiforme and refractory advanced ovarian cancer and for anaplastic astrocytoma patients with germline BRCA-mutated • Single agent activity in SCLC2 breast cancer • STOMP UK trial: Maintenance olaparib vs placebo following first-line chemotherapy.
    [Show full text]
  • TALZENNA (Talazoparib) RATIONALE for INCLUSION in PA PROGRAM
    TALZENNA (talazoparib) RATIONALE FOR INCLUSION IN PA PROGRAM Background Talzenna (talazoparib) is an inhibitor of poly (ADP-ribose) polymerase (PARP) enzymes, including PARP1 and PARP2 which play a role in DNA repair. Talazoparib-induced cytotoxicity may involve inhibition of PARP enzymatic activity and increased formation of PARP-DNA complexes resulting in DNA damage, decreased cell proliferation, and apoptosis. Talazoparib anti-tumor activity was observed in human patient-derived xenograft breast cancer tumor models that expressed mutated or wild-type BRCA 1 and 2 (1). Regulatory Status FDA-approved indication: Talzenna is a poly (ADP-ribose) polymerase (PARP) inhibitor indicated for the treatment of adult patients with deleterious or suspected deleterious germline BRCA- mutated (gBRCAm) HER2-negative locally advanced or metastatic breast cancer. Select patients based on an FDA-approved companion diagnostic for Talzenna (1). Myelodysplastic Syndrome/Acute Myeloid Leukemia (MDS/AML) can occur in patients treated with Talzenna. Talzenna should not be started until patients have adequately recovered from hematological toxicity caused by previous chemotherapy. Complete blood counts should be monitored for cytopenia at baseline and monthly thereafter. If MDS/AML is confirmed, Talzenna should be discontinued (1). Talzenna can also cause myelosuppression, consisting of anemia, leukopenia/neutropenia, and/or thrombocytopenia. Talzenna should not be started until patients have adequately recovered from hematological toxicity caused by previous chemotherapy (1). Talzenna can cause fetal harm when administered to a pregnant woman. Females of reproductive potential should be advised to use effective contraception during treatment and for at least 7 months following the last dose of Talzenna. Male patients with female partners of reproductive potential or who are pregnant should be advised to use effective contraception during treatment and for at least 4 months following the last dose of Talzenna (1).
    [Show full text]
  • PFIZER INC. (Exact Name of Registrant As Specified in Its Charter)
    UNITED STATES SECURITIES AND EXCHANGE COMMISSION Washington, D.C. 20549 FORM 10-K (Mark One) ☒ ANNUAL REPORT PURSUANT TO SECTION 13 OR 15(d) OF THE SECURITIES EXCHANGE ACT OF 1934 For the fiscal year ended December 31, 2019 ☐ TRANSITION REPORT PURSUANT TO SECTION 13 OR 15(d) OF THE SECURITIES EXCHANGE ACT OF 1934 For the transition period from to Commission file number 1-3619 PFIZER INC. (Exact name of registrant as specified in its charter) Delaware 13-5315170 (State or other jurisdiction of incorporation or organization) (I.R.S. Employer Identification Number) 235 East 42nd Street, New York, New York 10017 (Address of principal executive offices) (zip code) (212) 733-2323 (Registrant’s telephone number, including area code) Securities registered pursuant to Section 12(b) of the Act: Title of each class Trading Symbol(s) Name of each exchange on which registered Common Stock, $.05 par value PFE New York Stock Exchange 0.000% Notes due 2020 PFE20A New York Stock Exchange 0.250% Notes due 2022 PFE22 New York Stock Exchange 1.000% Notes due 2027 PFE27 New York Stock Exchange Securities registered pursuant to Section 12(g) of the Act: None Indicate by check mark if the registrant is a well-known seasoned issuer, as defined in Rule 405 of the Securities Act. Yes ☒ No ☐ Indicate by check mark if the registrant is not required to file reports pursuant to Section 13 or Section 15(d) of the Act. Yes ☐ No ☒ Indicate by check mark whether the registrant (1) has filed all reports required to be filed by Section 13 or 15(d) of the Securities Exchange Act of 1934 during the preceding 12 months (or for such shorter period that the registrant was required to file such reports), and (2) has been subject to such filing requirements for the past 90 days.
    [Show full text]
  • Patent Application Publication ( 10 ) Pub . No . : US 2019 / 0192440 A1
    US 20190192440A1 (19 ) United States (12 ) Patent Application Publication ( 10) Pub . No. : US 2019 /0192440 A1 LI (43 ) Pub . Date : Jun . 27 , 2019 ( 54 ) ORAL DRUG DOSAGE FORM COMPRISING Publication Classification DRUG IN THE FORM OF NANOPARTICLES (51 ) Int . CI. A61K 9 / 20 (2006 .01 ) ( 71 ) Applicant: Triastek , Inc. , Nanjing ( CN ) A61K 9 /00 ( 2006 . 01) A61K 31/ 192 ( 2006 .01 ) (72 ) Inventor : Xiaoling LI , Dublin , CA (US ) A61K 9 / 24 ( 2006 .01 ) ( 52 ) U . S . CI. ( 21 ) Appl. No. : 16 /289 ,499 CPC . .. .. A61K 9 /2031 (2013 . 01 ) ; A61K 9 /0065 ( 22 ) Filed : Feb . 28 , 2019 (2013 .01 ) ; A61K 9 / 209 ( 2013 .01 ) ; A61K 9 /2027 ( 2013 .01 ) ; A61K 31/ 192 ( 2013. 01 ) ; Related U . S . Application Data A61K 9 /2072 ( 2013 .01 ) (63 ) Continuation of application No. 16 /028 ,305 , filed on Jul. 5 , 2018 , now Pat . No . 10 , 258 ,575 , which is a (57 ) ABSTRACT continuation of application No . 15 / 173 ,596 , filed on The present disclosure provides a stable solid pharmaceuti Jun . 3 , 2016 . cal dosage form for oral administration . The dosage form (60 ) Provisional application No . 62 /313 ,092 , filed on Mar. includes a substrate that forms at least one compartment and 24 , 2016 , provisional application No . 62 / 296 , 087 , a drug content loaded into the compartment. The dosage filed on Feb . 17 , 2016 , provisional application No . form is so designed that the active pharmaceutical ingredient 62 / 170, 645 , filed on Jun . 3 , 2015 . of the drug content is released in a controlled manner. Patent Application Publication Jun . 27 , 2019 Sheet 1 of 20 US 2019 /0192440 A1 FIG .
    [Show full text]
  • Targeting NAD+ Biosynthesis Overcomes Panobinostat and Bortezomib-Induced Malignant
    Author Manuscript Published OnlineFirst on April 1, 2020; DOI: 10.1158/1541-7786.MCR-19-0669 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Targeting NAD+ biosynthesis overcomes panobinostat and bortezomib-induced malignant glioma resistance Esther P. Jane, 1, 2 Daniel R. Premkumar, 1, 2, 3 Swetha Thambireddy, 1 Brian Golbourn, 1 Sameer Agnihotri, 1, 2, 3 Kelsey C. Bertrand, 4 Stephen C. Mack, 4 Max I. Myers, 1 Ansuman Chattopadhyay, 5 D. Lansing Taylor, 6, 7, 8 Mark E. Schurdak, 6, 7, 8 Andrew M. Stern, 7, 8 and Ian F. Pollack 1, 2, 3 Department of Neurosurgery 1, University of Pittsburgh School of Medicine 2, University of Pittsburgh Cancer Institute Brain Tumor Center 3, Texas Children's Hospital, Baylor College of Medicine 4, University of Pittsburgh Molecular Biology Information Service 5, University of Pittsburgh Cancer Institute 6, University of Pittsburgh Drug Discovery Institute 7, Department of Computational and Systems Biology, University of Pittsburgh School of Medicine 8, Pittsburgh, Pennsylvania, U.S.A. Disclosure of Potential Conflict of Interest The authors have declared that no conflict of interest exists. 1 Downloaded from mcr.aacrjournals.org on October 2, 2021. © 2020 American Association for Cancer Research. Author Manuscript Published OnlineFirst on April 1, 2020; DOI: 10.1158/1541-7786.MCR-19-0669 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Keywords: Panobinostat, bortezomib, synergy, resistance, glioma,
    [Show full text]