Olaparib and Temozolomide in SCLC
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Nanomedicines and Combination Therapy of Doxorubicin and Olaparib for Treatment of Ovarian Cancer
Nanomedicines and Combination Therapy of Doxorubicin and Olaparib for Treatment of Ovarian Cancer by Sina Eetezadi A thesis submitted in conformity with the requirements for the degree of Doctor of Philosophy Department of Pharmaceutical Sciences University of Toronto © Copyright by Sina Eetezadi 2016 Nanomedicines and Combination Therapy of Doxorubicin and Olaparib for Treatment of Ovarian Cancer Sina Eetezadi Doctor of Philosophy Department of Pharmaceutical Sciences University of Toronto 2016 Abstract Ovarian cancer is the fourth leading cause of death in women of developed countries, with dismal survival improvements achieved in the past three decades. Specifically, current chemotherapy strategies for second-line treatment of relapsed ovarian cancer are unable to effectively treat recurrent disease. This thesis aims to improve the therapeutic outcome associated with recurrent ovarian cancer by (1) creating a 3D cell screening method as an in vitro model of the disease (2) developing a nanomedicine of doxorubicin (DOX) that is more efficacious than PEGylated liposomal doxorubicin (PLD / Doxil®) and (3) evaluating additional strategies to enhance treatment efficacy such as mild hyperthermia (MHT) and combination therapy with inhibitors of the poly(ADP-ribose) polymerase enzyme family (PARP). Overall, this work demonstrates the use of 3D multicellular tumor spheroids (MCTS) as an in vitro drug testing platform which more closely reflects the clinical presentation of recurrent ovarian cancer relative to traditional monolayer cultures. With the use of this technology, it was found that tissue penetration of drug is not only an issue for large tumors, but also for invisible, microscopic lesions that result from metastasis or remain following cytoreductive surgery. A novel block-copolymer micelle formulation for DOX was developed and fulfilled the goal of ii controlling drug release while enhancing intratumoral distribution and MCTS bioavailability of DOX, which resulted in a significant improvement in growth inhibition, relative to PLD. -
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. -
The Ewing Family of Tumors Relies on BCL-2 and BCL-XL to Escape PARP Inhibitor Toxicity Daniel A.R
Published OnlineFirst October 22, 2018; DOI: 10.1158/1078-0432.CCR-18-0277 Cancer Therapy: Preclinical Clinical Cancer Research The Ewing Family of Tumors Relies on BCL-2 and BCL-XL to Escape PARP Inhibitor Toxicity Daniel A.R. Heisey1, Timothy L. Lochmann1, Konstantinos V. Floros1, Colin M. Coon1, Krista M. Powell1, Sheeba Jacob1, Marissa L. Calbert1, Maninderjit S. Ghotra1, Giovanna T. Stein2, Yuki Kato Maves3, Steven C. Smith4, Cyril H. Benes2, Joel D. Leverson5, Andrew J. Souers5, Sosipatros A. Boikos6, and Anthony C. Faber1 Abstract Purpose: It was recently demonstrated that the EWSR1-FLI1 revealed increased expression of the antiapoptotic protein t(11;22)(q24;12) translocation contributes to the hypersensi- BCL-2 in the chemotherapy-resistant cells, conferring apo- tivity of Ewing sarcoma to PARP inhibitors, prompting clinical ptotic resistance to olaparib. Resistance to olaparib was evaluation of olaparib in a cohort of heavily pretreated Ewing maintained in this chemotherapy-resistant model in vivo, sarcoma tumors. Unfortunately, olaparib activity was disap- whereas the addition of the BCL-2/XL inhibitor navitoclax pointing, suggesting an underappreciated resistance mecha- led to tumor growth inhibition. In 2 PDXs, olaparib and nism to PARP inhibition in patients with Ewing sarcoma. We navitoclax were minimally effective as monotherapy, yet sought to elucidate the resistance factors to PARP inhibitor induced dramatic tumor growth inhibition when dosed in therapy in Ewing sarcoma and identify a rational drug com- combination. We found that EWS-FLI1 increases BCL-2 bination capable of rescuing PARP inhibitor activity. expression; however, inhibition of BCL-2 alone by veneto- Experimental Design: We employed a pair of cell lines clax is insufficient to sensitize Ewing sarcoma cells to ola- derived from the same patient with Ewing sarcoma prior to parib, revealing a dual necessity for BCL-2 and BCL-XL in and following chemotherapy, a panel of Ewing sarcoma cell Ewing sarcoma survival. -
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 -
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) -
A Phase I Dose-Finding, Pharmacokinetics and Genotyping
www.nature.com/scientificreports OPEN A phase I dose‑fnding, pharmacokinetics and genotyping study of olaparib and lurbinectedin in patients with advanced solid tumors Andres Poveda1*, Ana Oaknin2, Ignacio Romero3, Angel Guerrero‑Zotano3, Lorena Fariñas‑Madrid2, Victor Rodriguez‑Freixinos4, Pedro Mallol5, Raquel Lopez‑Reig6,7 & Jose Antonio Lopez‑Guerrero6,7,8 The poly (ADP‑Ribose) polymerase (PARP) inhibitor olaparib has shown antitumor activity in patients with ovarian or breast cancer with or without BRCA1/2 mutations. Lurbinectedin is an ecteinascidin that generates DNA double‑strand breaks. We hypothesized that the combination of olaparib and lurbinectedin maximizes the DNA damage increasing the efcacy. A 3 + 3 dose‑escalation study examined olaparib tablets with lurbinectedin every 21 days. The purpose of this phase I study is to determine the dose‑limiting toxicities (DLTs) of the combination, to investigate the maximum tolerated dose (MTD), the recommended phase II dose (RP2D), efcacy, pharmacokinetics, in addition to genotyping and translational studies. In total, 20 patients with ovarian and endometrial cancers were included. The most common adverse events were asthenia, nausea, vomiting, constipation, abdominal pain, neutropenia, anemia. DLT grade 4 neutropenia was observed in two patients in dose level (DL) 5, DL4 was defned as the MTD, and the RP2D was lurbinectedin 1.5 mg/m2 + olaparib 250 mg twice a day (BID). Mutational analysis revealed a median of 2 mutations/case, 53% of patients with mutations in the homologous recombination (HR) pathway. None of the patients reached a complete or partial response; however, 60% of stable disease was achieved. In conclusion, olaparib in combination with lurbinectedin was well tolerated with a disease control rate of 60%. -
BC Cancer Benefit Drug List September 2021
Page 1 of 65 BC Cancer Benefit Drug List September 2021 DEFINITIONS Class I Reimbursed for active cancer or approved treatment or approved indication only. Reimbursed for approved indications only. Completion of the BC Cancer Compassionate Access Program Application (formerly Undesignated Indication Form) is necessary to Restricted Funding (R) provide the appropriate clinical information for each patient. NOTES 1. BC Cancer will reimburse, to the Communities Oncology Network hospital pharmacy, the actual acquisition cost of a Benefit Drug, up to the maximum price as determined by BC Cancer, based on the current brand and contract price. Please contact the OSCAR Hotline at 1-888-355-0355 if more information is required. 2. Not Otherwise Specified (NOS) code only applicable to Class I drugs where indicated. 3. Intrahepatic use of chemotherapy drugs is not reimbursable unless specified. 4. For queries regarding other indications not specified, please contact the BC Cancer Compassionate Access Program Office at 604.877.6000 x 6277 or [email protected] DOSAGE TUMOUR PROTOCOL DRUG APPROVED INDICATIONS CLASS NOTES FORM SITE CODES Therapy for Metastatic Castration-Sensitive Prostate Cancer using abiraterone tablet Genitourinary UGUMCSPABI* R Abiraterone and Prednisone Palliative Therapy for Metastatic Castration Resistant Prostate Cancer abiraterone tablet Genitourinary UGUPABI R Using Abiraterone and prednisone acitretin capsule Lymphoma reversal of early dysplastic and neoplastic stem changes LYNOS I first-line treatment of epidermal -
Dual Oncogenic and Tumor Suppressor Roles of the Promyelocytic Leukemia Gene in Hepatocarcinogenesis Associated with Hepatitis B Virus Surface Antigen
www.impactjournals.com/oncotarget/ Oncotarget, Vol. 7, No. 19 Dual oncogenic and tumor suppressor roles of the promyelocytic leukemia gene in hepatocarcinogenesis associated with hepatitis B virus surface antigen Yih-Lin Chung1, and Mei-Ling Wu2 1Department of Radiation Oncology, Koo Foundation Sun-Yat-Sen Cancer Center, Taipei, Taiwan 2Department of Pathology and Laboratory Medicine, Koo Foundation Sun-Yat-Sen Cancer Center, Taipei, Taiwan Correspondence to: Yih-Lin Chung, email: [email protected] Keywords: hepatitis B virus, hepatocarcinogenesis, PML, tumor suppressor, oncogene Received: November 05, 2015 Accepted: March 18, 2016 Published: April 6, 2016 ABSTRACT Proteasome-mediated degradation of promyelocytic leukemia tumor suppressor (PML) is upregulated in many viral infections and cancers. We previously showed that PML knockdown promotes early-onset hepatocellular carcinoma (HCC) in hepatitis B virus surface antigen (HBsAg)-transgenic mice. Here we report the effects of PML restoration on late-onset HBsAg-induced HCC. We compared protein expression patterns, genetic mutations and the effects of pharmacologically targeting PML in wild-type, PML-/-, PML+/+HBsAgtg/o and PML-/-HBsAgtg/o mice. PML-/- mice exhibited somatic mutations in DNA repair genes and developed severe steatosis and proliferative disorders, but not HCC. PML-/-HBsAgtg/o mice exhibited early mutations in cancer driver genes and developed hyperplasia, fatty livers and indolent adipose- like HCC. In PML+/+HBsAg-transgenic mice, HBsAg expression declined over time, and HBsAg-associated PML suppression was concomitantly relieved. Nevertheless, these mice accumulated mutations in genes contributing to oxidative stress pathways and developed aggressive late-onset angiogenic trabecular HCC. PML inhibition using non-toxic doses of arsenic trioxide selectively killed long-term HBsAg-affected liver cells in PML+/+HBsAgtg/o mice with falling HBsAg and rising PML levels, but not normal liver cells or early-onset HCC cells in PML-/-HBsAgtg/0 mice. -
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]. -
Neuro-Oncology 22(12), 1840–1850, 2020 | Doi:10.1093/Neuonc/Noaa104 | Advance Access Date 29 April 2020
applyparastyle "fig//caption/p[1]" parastyle "FigCapt" applyparastyle "fig" parastyle "Figure" 1840 Neuro-Oncology 22(12), 1840–1850, 2020 | doi:10.1093/neuonc/noaa104 | Advance Access date 29 April 2020 Pharmacokinetics, safety, and tolerability of olaparib and temozolomide for recurrent glioblastoma: results of the phase I OPARATIC trial Catherine Hanna, Kathreena M Kurian, Karin Williams, Colin Watts, Alan Jackson, Ross Carruthers, Karen Strathdee, Garth Cruickshank, Laurence Dunn, Sara Erridge, Lisa Godfrey, Sarah Jefferies, Catherine McBain, Rebecca Sleigh, Alex McCormick, Marc Pittman, Sarah Halford, and Anthony J. Chalmers Institute of Cancer Sciences, University of Glasgow, Glasgow, UK (C.H., K.W., R.C., K.S., A.J.C.); Brain Tumour Research Centre, University of Bristol, Bristol, UK (K.M.K.); Institute of Cancer and Genomic Sciences, University of Birmingham, Birmingham, UK (C.W., G.C.); Division of Informatics, Imaging and Data Sciences, University of Manchester, Manchester, UK (A.J.); Institute of Neuroscience and Psychology, University of Glasgow, Glasgow, UK (L.D.); Edinburgh Centre for Neuro-Oncology, NHS Lothian, Edinburgh, UK (S.E.); Cancer Research UK Centre for Drug Development, London, UK (L.G., M.P., S.H.); Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK (S.J.); The Christie NHS Foundation Trust, Manchester, UK (C.M.); LGC Group, Cambridgeshire, UK (R.S.); AstraZeneca, Macclesfield, UK (A.M.). Corresponding Author: Anthony J. Chalmers, Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, University of Glasgow, Glasgow G61 1QH, UK ([email protected]). Abstract Background. The poly(ADP-ribose) polymerase (PARP) inhibitor olaparib potentiated radiation and temozolomide (TMZ) chemotherapy in preclinical glioblastoma models but brain penetration was poor. -
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, -
Phenotype-Based Drug Screening Reveals Association Between Venetoclax Response and Differentiation Stage in Acute Myeloid Leukemia
Acute Myeloid Leukemia SUPPLEMENTARY APPENDIX Phenotype-based drug screening reveals association between venetoclax response and differentiation stage in acute myeloid leukemia Heikki Kuusanmäki, 1,2 Aino-Maija Leppä, 1 Petri Pölönen, 3 Mika Kontro, 2 Olli Dufva, 2 Debashish Deb, 1 Bhagwan Yadav, 2 Oscar Brück, 2 Ashwini Kumar, 1 Hele Everaus, 4 Bjørn T. Gjertsen, 5 Merja Heinäniemi, 3 Kimmo Porkka, 2 Satu Mustjoki 2,6 and Caroline A. Heckman 1 1Institute for Molecular Medicine Finland, Helsinki Institute of Life Science, University of Helsinki, Helsinki; 2Hematology Research Unit, Helsinki University Hospital Comprehensive Cancer Center, Helsinki; 3Institute of Biomedicine, School of Medicine, University of Eastern Finland, Kuopio, Finland; 4Department of Hematology and Oncology, University of Tartu, Tartu, Estonia; 5Centre for Cancer Biomarkers, De - partment of Clinical Science, University of Bergen, Bergen, Norway and 6Translational Immunology Research Program and Department of Clinical Chemistry and Hematology, University of Helsinki, Helsinki, Finland ©2020 Ferrata Storti Foundation. This is an open-access paper. doi:10.3324/haematol. 2018.214882 Received: December 17, 2018. Accepted: July 8, 2019. Pre-published: July 11, 2019. Correspondence: CAROLINE A. HECKMAN - [email protected] HEIKKI KUUSANMÄKI - [email protected] Supplemental Material Phenotype-based drug screening reveals an association between venetoclax response and differentiation stage in acute myeloid leukemia Authors: Heikki Kuusanmäki1, 2, Aino-Maija