Targeting NAD+ Biosynthesis Overcomes Panobinostat and Bortezomib-Induced Malignant
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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. -
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 -
Vorinostat—An Overview Aditya Kumar Bubna
E-IJD RESIDENTS' PAGE Vorinostat—An Overview Aditya Kumar Bubna Abstract From the Consultant Vorinostat is a new drug used in the management of cutaneous T cell lymphoma when the Dermatologist, Kedar Hospital, disease persists, gets worse or comes back during or after treatment with other medicines. It is Chennai, Tamil Nadu, India an efficacious and well tolerated drug and has been considered a novel drug in the treatment of this condition. Currently apart from cutaneous T cell lymphoma the role of Vorinostat for Address for correspondence: other types of cancers is being investigated both as mono-therapy and combination therapy. Dr. Aditya Kumar Bubna, Kedar Hospital, Mugalivakkam Key Words: Cutaneous T cell lymphoma, histone deacytelase inhibitor, Vorinostat Main Road, Porur, Chennai - 600 125, Tamil Nadu, India. E-mail: [email protected] What was known? • Vorinostat is a histone deacetylase inhibitor. • It is an FDA approved drug for the treatment of cutaneous T cell lymphoma. Introduction of Vorinostat is approximately 9. Vorinostat is slightly Vorinostat is a histone deacetylase (HDAC) inhibitor, soluble in water, alcohol, isopropanol and acetone and is structurally belonging to the hydroxymate group. Other completely soluble in dimethyl sulfoxide. drugs in this group include Givinostat, Abexinostat, Mechanism of action Panobinostat, Belinostat and Trichostatin A. These Vorinostat is a broad inhibitor of HDAC activity and inhibits are an emergency class of drugs with potential anti- class I and class II HDAC enzymes.[2,3] However, Vorinostat neoplastic activity. These drugs were developed with the does not inhibit HDACs belonging to class III. Based on realization that apart from genetic mutation, alteration crystallographic studies, it has been seen that Vorinostat of HDAC enzymes affected the phenotypic and genotypic binds to the zinc atom of the catalytic site of the HDAC expression in cells, which in turn lead to disturbed enzyme with the phenyl ring of Vorinostat projecting out of homeostasis and neoplastic growth. -
FARYDAK (Panobinostat) RATIONALE for INCLUSION in PA PROGRAM
FARYDAK (panobinostat) RATIONALE FOR INCLUSION IN PA PROGRAM Background Farydak (panobinostat) is the first histone deacetylase (HDAC) inhibitor approved to treat multiple myeloma in patients who have received at least two prior standard therapies, including bortezomib and an immunomodulatory agent. Farydak is to be used in combination with bortezomib, a type of chemotherapy, and dexamethasone, an anti-inflammatory medication. Multiple myeloma causes plasma cells to rapidly multiply and crowd out other healthy blood cells from the bone marrow. When the bone marrow has too many plasma cells, the cells may move to other parts of the body. Farydak works by inhibiting the activity of enzymes, known as histone deacetylases (HDACs). The inhibition of these enzymes may slow the over development of plasma cells in multiple myeloma patients or cause these dangerous cells to die (1). Regulatory Status FDA-approved indication: Farydak, a histone deacetylase inhibitor, in combination with bortezomib and dexamethasone, is indicated for the treatment of patients with multiple myeloma who have received at least 2 prior regimens, including bortezomib and an immunomodulatory agent (2). Farydak carries a Boxed Warning alerting patients and health care professionals that severe diarrhea and severe and fatal cardiac events, arrhythmias and electrocardiogram (ECG) changes have occurred in patients receiving Farydak. Arrhythmias may be exacerbated by electrolyte abnormalities. The most common laboratory abnormalities were low levels of phosphorus in the blood (hypophosphatemia), low potassium levels in the blood (hypokalemia), low levels of salt in the blood (hyponatremia), increased creatinine, low platelets (thrombocytopenia), low white blood cell counts (leukopenia) and low red blood cell counts (anemia). -
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) -
Use of Fluorescence to Guide Resection Or Biopsy of Primary Brain Tumors and Brain Metastases
Neurosurg Focus 36 (2):E10, 2014 ©AANS, 2014 Use of fluorescence to guide resection or biopsy of primary brain tumors and brain metastases *SERGE MARBACHER, M.D., M.SC.,1,5 ELISABETH KLINGER, M.D.,2 LUCIA SCHWYZER, M.D.,1,5 INGEBORG FISCHER, M.D.,3 EDIN NEVZATI, M.D.,1 MICHAEL DIEPERS, M.D.,2,5 ULRICH ROELCKE, M.D.,4,5 ALI-REZA FATHI, M.D.,1,5 DANIEL COLUCCIA, M.D.,1,5 AND JAVIER FANDINO, M.D.1,5 Departments of 1Neurosurgery, 2Neuroradiology, 3Pathology, and 4Neurology, and 5Brain Tumor Center, Kantonsspital Aarau, Aarau, Switzerland Object. The accurate discrimination between tumor and normal tissue is crucial for determining how much to resect and therefore for the clinical outcome of patients with brain tumors. In recent years, guidance with 5-aminolev- ulinic acid (5-ALA)–induced intraoperative fluorescence has proven to be a useful surgical adjunct for gross-total resection of high-grade gliomas. The clinical utility of 5-ALA in resection of brain tumors other than glioblastomas has not yet been established. The authors assessed the frequency of positive 5-ALA fluorescence in a cohort of pa- tients with primary brain tumors and metastases. Methods. The authors conducted a single-center retrospective analysis of 531 patients with intracranial tumors treated by 5-ALA–guided resection or biopsy. They analyzed patient characteristics, preoperative and postoperative liver function test results, intraoperative tumor fluorescence, and histological data. They also screened discharge summaries for clinical adverse effects resulting from the administration of 5-ALA. Intraoperative qualitative 5-ALA fluorescence (none, mild, moderate, and strong) was documented by the surgeon and dichotomized into negative and positive fluorescence. -
Phase I Trial of Carboplatin and Etoposide in Combination with Panobinostat in Patients with Lung Cancer
ANTICANCER RESEARCH 33: 4475-4482 (2013) Phase I Trial of Carboplatin and Etoposide in Combination with Panobinostat in Patients with Lung Cancer AHMAD A. TARHINI1,2, HARIS ZAHOOR1, BRIAN MCLAUGHLIN1, WILLIAM E GOODING2, JOHN C. SCHMITZ2, JILL M. SIEGFRIED2, MARK A. SOCINSKI1,2 and ATHANASSIOS ARGIRIS3 1University of Pittsburgh Medical Center, 2University of Pittsburgh Cancer Institute, UPMC Cancer Pavilion, Pittsburgh, PA, U.S.A.; 3University of Texas Health Science Center at San Antonio, San Antonio, TX, U.S.A. Abstract. A phase I trial consisting of panobinostat (a apoptosis in response to HDAC inhibitors may also be HDAC inhibitor), carboplatin and etoposide was condacted in mediated by acetylation of non-histone proteins (such as patients with lung cancer. Patients and Methods: Patients HSP-90, p53, HIF1-α, α-tubulin) (5). received carboplatin AUC5 on day 1 and etoposide 100 mg/m2 Panobinostat, a hydroxamic acid derivative, is an oral pan- on days 1, 2 and 3, every 21 days. Concurrent oral deacetylase inhibitor (6). It affects proteins involved in cell-cycle panobinostat was given 3 times weekly on a 2-weeks-on and 1- regulation (p53, p21), angiogenesis (HIF-1α), gene transcription week-off schedule during the 4-6 cycles of chemotherapy and (transcription factors), protein stabilization (Hsp90) and then continued as maintenance therapy. Results: Six evaluable cytoskeleton (α-tubulin), through inhibition of HDACs (7, 8). patients were treated at the first dose level of panobinostat Panobinostat exhibits increased histone acetylation and (10 mg). Dose-limiting toxicity occurred in two patients (33%) has potent antiproliferative activity against a broad range of during the first cycle. -
Management of Multiple Myeloma: the Changing Paradigm
Management of Multiple Myeloma: The Changing Paradigm Relapsed/Refractory Disease Jeffrey A. Zonder, MD Karmanos Cancer Institute Objectives • Discuss use of standard myeloma therapies when used as therapy after relapse • Consider patient and disease factors which might impact therapy decisions. • Describe off-label options for patients who are not protocol candidates. Line ≠ Line ≠ Line ≠ … POLICE LINE – DO NOT CROSS POLICE LINE – DO NOT CROSS POLICE LINE – DO NOT CROSS POLICE LINE – DO NOT CROSS POLI LINE – DO NOT Define “Line” • A pre-defined course of therapy utilizing agents either simultaneously or sequentially – Len/Dex – Len/Dex ASCT – Vel/Dex ASCT Len/Dex – VDT-PACE ASCT TD ASCT VPT-PACE LD • Pts who have had the same # of “lines” of Rx may have had vastly different amounts of Rx What Is Relapsed/Refractory Disease? • Relapsed: recurrence after a response to therapy • Refractory: progression despite ongoing therapy What Do We Know About the Pt’s Myeloma? • What prior therapy has been used? • How well did it work? • Did the myeloma progress on active therapy? • High-risk cytogenetics/FISH/GEP? What Do We Know About the Patient? • Age • Other medical problems – Diabetes – Blood Clots • Lasting side effects from past therapies – Peripheral Neuropathy • Personal preferences and values Choosing Therapy for Relapsed/Refractory Myeloma Proteasome IMiDs Anthracyclines Alkylators Steroids HDACs Antibodies Inhibitors Thalidomide Bortezomib Doxil Melphalan Dex Panobinostat Elotuzumab Lenalidomide Carfilzomib Cytoxan Pred Vorinostat -
UC Irvine UC Irvine Previously Published Works
UC Irvine UC Irvine Previously Published Works Title ACTR-10. A RANDOMIZED, PHASE I/II TRIAL OF IXAZOMIB IN COMBINATION WITH STANDARD THERAPY FOR UPFRONT TREATMENT OF PATIENTS WITH NEWLY DIAGNOSED MGMT METHYLATED GLIOBLASTOMA (GBM) STUDY DESIGN Permalink https://escholarship.org/uc/item/2w97d9jv Journal Neuro-Oncology, 20(suppl_6) ISSN 1522-8517 Authors Kong, Xiao-Tang Lai, Albert Carrillo, Jose A et al. Publication Date 2018-11-05 DOI 10.1093/neuonc/noy148.045 Peer reviewed eScholarship.org Powered by the California Digital Library University of California Abstracts 3 dyspnea; grade 2 hemorrhage, non-neutropenic fever; and grade 1 hand- toxicities include: 1 patient with pre-existing vision dysfunction had Grade foot. CONCLUSIONS: Low-dose capecitabine is associated with a modest 4 optic nerve dysfunction; 2 Grade 4 hematologic events and 1 Grade 5 reduction in MDSCs and T-regs and a significant increase in CTLs. Toxicity event(sepsis) due to temozolamide-induced cytopenias. CONCLUSION: has been manageable. Four of 7 evaluable patients have reached 6 months 18F-DOPA-PET -guided dose escalation appears reasonably safe and toler- free of progression. Dose escalation continues. able in patients with high-grade glioma. ACTR-10. A RANDOMIZED, PHASE I/II TRIAL OF IXAZOMIB IN ACTR-13. A BAYESIAN ADAPTIVE RANDOMIZED PHASE II TRIAL COMBINATION WITH STANDARD THERAPY FOR UPFRONT OF BEVACIZUMAB VERSUS BEVACIZUMAB PLUS VORINOSTAT IN TREATMENT OF PATIENTS WITH NEWLY DIAGNOSED MGMT ADULTS WITH RECURRENT GLIOBLASTOMA FINAL RESULTS Downloaded from https://academic.oup.com/neuro-oncology/article/20/suppl_6/vi13/5153917 by University of California, Irvine user on 27 May 2021 METHYLATED GLIOBLASTOMA (GBM) STUDY DESIGN Vinay Puduvalli1, Jing Wu2, Ying Yuan3, Terri Armstrong2, Jimin Wu3, Xiao-Tang Kong1, Albert Lai2, Jose A. -
2016 ASCO TRC102 + Temodar Phase 1 Poster
Phase I Trial of TRC102 (methoxyamine HCL) in Combination with Temozolomide in Patients with Relapsed Solid Tumors Robert S. Meehan1, Alice P. Chen1, Geraldine Helen O'Sullivan Coyne1, Jerry M. Collins1, Shivaani Kummar1, Larry Anderson1, Kazusa Ishii1, Jennifer Zlott1, 1 1 2 1 1 2 2 1,3 #2556 Larry Rubinstein , Yvonne Horneffer , Lamin Juwara , Woondong Jeong , Naoko Takebe , Robert J. Kinders , Ralph E. Parchment , James H. Doroshow 1Division of Cancer Treatment and Diagnosis, National Cancer Institute, Bethesda, Maryland 20892 2Frederick National Laboratory for Cancer Research, Frederick, Maryland 21702; 3Center for Cancer Research, NCI, Bethesda, Maryland 20892 Introduction Patient Characteristics Adverse Events Response • Base excision repair (BER), one of the pathways of DNA damage repair, has been implicated in No. of Patients 34 C3D1 chemoresistance. Age (median) 60 Adverse Event Grade 2 Grade 3 Grade 4 Baseline C3D1 Baseline Range 39-78 Neutrophil count decreased 1 3 2 • TRC102 is a small molecule amine that covalently binds to abasic sites generated by BER, Race Platelet count decreased 2 1 2 resulting in DNA strand breaks and apoptosis; therefore, co-adminstraion of TRC102 is Caucasian 24 African American 6 Lymphocyte count decreased 6 5 anticipated to enhance the antitumor activity of temozolomide (TMZ), which methylates DNA Asian 2 Anemia 9 3 1 at N-7 and O-6 positions of guanine. Hispanic 2 Hypophosphatemia 2 2 Tumor Sites • We conducted a phase 1 trial of TRC102 in combination with TMZ to determine the safety, tolerability, GI 11 Fatigue 3 1 and maximum tolerated dose (MTD) of the combination (Clinicaltrials.gov identifier: NCT01851369) H&N 4 Hypophosphatemia 1 Lung 7 Hemolysis 1 1 1 • First enrollment: 7/16/2013. -
In Patients with Metastatic Melanoma Nageatte Ibrahim1,2, Elizabeth I
Cancer Medicine Open Access ORIGINAL RESEARCH A phase I trial of panobinostat (LBH589) in patients with metastatic melanoma Nageatte Ibrahim1,2, Elizabeth I. Buchbinder1, Scott R. Granter3, Scott J. Rodig3, Anita Giobbie-Hurder4, Carla Becerra1, Argyro Tsiaras1, Evisa Gjini3, David E. Fisher5 & F. Stephen Hodi1 1Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts 2Currently at Merck & Co.,, Kenilworth, New Jersey 3Department of Pathology, Brigham and Women’s Hospital, Boston, Massachusetts 4Department of Biostatistics & Computational Biology, Dana-Farber Cancer Institute, Boston, Massachusetts 5Department of Dermatology, Massachusetts General Hospital, Boston, Massachusetts Keywords Abstract HDAC, immunotherapy, LBH589, melanoma, MITF, panobinostat Epigenetic alterations by histone/protein deacetylases (HDACs) are one of the many mechanisms that cancer cells use to alter gene expression and promote Correspondence growth. HDAC inhibitors have proven to be effective in the treatment of specific Elizabeth I. Buchbinder, Dana-Farber Cancer malignancies, particularly in combination with other anticancer agents. We con- Institute, 450 Brookline Avenue, Boston, ducted a phase I trial of panobinostat in patients with unresectable stage III or 02215, MA. Tel: 617 632 5055; IV melanoma. Patients were treated with oral panobinostat at a dose of 30 mg Fax: 617 632 6727; E-mail: [email protected] daily on Mondays, Wednesdays, and Fridays (Arm A). Three of the six patients on this dose experienced clinically significant thrombocytopenia requiring dose Funding Information interruption. Due to this, a second treatment arm was opened and the dose Novartis Pharmaceuticals Corporation was changed to 30 mg oral panobinostat three times a week every other week provided clinical trial support, additional (Arm B). -
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].