References

Indenos and Azas Overview

Cushman M. Design and Synthesis of Indenoisoquinoline Topoisomerase I Inhibitors for Cancer Chemotherapy. J. Med. Chem. 2021, 64, 24, 17572–17600.

Pommier Y, Cushman M. The indenoisoquinoline non-Camptothecin topoisomerase I inhibitors: update and perspectives. Mol Cancer Ther. 2009 May;8(5):1008-14. Epub 2009 Apr 21.

C-MYC Promoter G-Quadruplex Regulation

Bacolla A, Z Ye, Z Ahmed, J Tainer. Cancer mutational burden is shaped by G4 DNA, replication stress, and mitochondrial dysfunction. Prog Biophys Mol Biol. DOI: 10.1016/jbiomolbio.2019.03.004-0079-6107

Hui WWI, A Simeone, KG Zyner et al. Single-cell mapping of DNAG-quadruplex structures in human cancer cells. Nature (2021) 11:23641. DOI.org/10.1038/s41598-021-02943-3.

Kim N. The Interplay between G-quadruplex and Transcription. Cur Medicinal Chem 2019,26,2898-2917. DOI: 10.2174/0929867325666171229132619.

Kosiol N, S Juranek, P Brossart erttr al. G-quadruplexes: a promising target for cancer therapy. Mol Cancer (2021) 20-40. DOI: 10.1186/s12943-021-01328-4.

Neidle S, A Ahmed, R Angell, S Oxenford. The potent quadruplex-binding compound QN-302 shows anti-tumor activity in patient-derived in vivo models of pancreatic cancer. AACR Abstract 4069. April 2022. (Qualigen)

Paul R, T Das, M Debnath, et al. G-Quadruplex-Binding Small Molecule Induces Synthetic Lethality in Breast Cancer Cells by Inhibiting c-MYC and BCL2 Expression. ChemBioChem 2019,20,1-9. Doi: 10.1002/cbic.201900534.

Psaras AM, S Valiuska, V Noe et al. Facilitating G-quadruplex formation in the KRAS promoter with polypurine reverse Hoogsteen oligonucleotides. Can Res Abstract 675 (2022)82 (12_Supplement);675.

Siddiqui-Jain, CL Grand, DJ Bearss et al. Direct evidence for a G-quadruplex in a promoter region and its targeting with a small molecule to repress c-MYC transcription. PNAS (2002) 99(18) 11593-11598. DOI: 10.1073/pnas.182256799

Kiselev E, K Agama, Y Pommier, MCushman. Azaindenoisoquinolines as Topoisomerase I Inhibitors and Potential Anticancer Agents: A Systematic Study of Structure-Acftivity Relationships. J Med Chem 2012,55,1682-1697.

Thomas A and Y Pommier. Targeting Topoisomerase I in the Era of Precision Medicine. Clin Cancer Res. 2019,15:25(22):6581-6589. Doi://10.1158/1078-0432,CC%-19—1089.

7-Azas and Indenos in G-quadruplex C-Myc Inhibition

Beck DE, PVN Reddy, Y Pommier, M Cushman et al. Investigation of the Structure-Activity Relationships of Aza-A-Ring Indenoisoquinoline TopisomerSE I Poisons. J Med Chem 2016, 59,8,3840-3853.

Berroyer A, A Bacolla, J Tainer, N Kim. Cleavage-defective Topoisomerase I mutants sharply increase G-quadruplex-associated genomic instability. Microb Cell 2022; 9(3):52-68. DOI: 10.15698/mic2022.03.771.

Cushman M, D Nagarathnam, D Gopal, H M He, C M Lin, E Hamel. Synthesis and evaluation of analogs of (Z)-1-(4-methoxyphenyl)-2-(3,4,5-trimethoxyphenyl)ethene as potential cytotoxic and antimitotic agents. J Med Chem 1992,35,12,2293-2306.

Elsayed SA, Y Su, P Wang, MY Pommier, M Cushman et al. Design and Synthesis of Chlorinated and Fluorinated 7-Azaindenoisoquinolines as Potent Cytotoxic Anticancer Agents that Inhibit Topoisomerase 1. J Med Chem 2017,60,13,5364-5376.

Kiselev E, T Dexheimer, Y Pommier, M Cushman. Design, Synthesis, and Evaluation of Dibenzo(c,h) (1,6) napthyridines as Topoisomerase I Inhibitors ND Potential Anticancer Agents. J Med Chem 2010,53,24,8716-8726.

Kiselev, S Deguire, Y Pommier, M Cushman et al. 7-Azaindenoisoquinolines as Topoisomerase I Inhibitors and Potential Anticancer Agents. J Med Chem 2011, 54:6106-6116. Doi: 10.1021/jm200719v.

Kiselev E, D Sooryakumar, K Agama, M Cushman, Y Pommier. Optimization of the Lactam Side Chair of 7-Azaindenoisoquinoline Topoisomerase I Inhibitors and Mechanism of Action Studies in Cancer Cells. J Med Chem 2014; 57:1289-1298. Doi: 10.1021/jm40147v1.

Liu W, C Lin, D Yang et al. Structures of 1:1 and 2:1 complexes of BMVC and MYC promoter G-quadruplex reveal a mechanism of ligand conformation adjustment for G4-recognition.

Wang P, MSA Elsayed, Y Pommier, M Cushman et al. Synthesis and Biological Evaluation of the First Triple Inhibitors of Human Topoisomerase 1, Tyrosyl-DNA Phosphodiesterase 1 (Tdpd1), and Tyrosyl-DNA Phosphodiesterase 2 (tdp2). J Med Chem 2017, 60,8,3275-3288.

Wang KB, D Yang, M Cushman, et al. Indenoisoquinoline Topoisomerase Inhibitors Strongly Bind and Stabilize the MYC Promoter G-Quadruplex and Downregulate MYC. J Am. Chem. Soc. 2019, 141, 28, 11059-11070. DOI: 10.1021/jacs.9b02679

Indenos work when Irinotecan Resistance

Candeil L,I Gourdier, D Peyron …Y Pommier et al. ABCG2 overexpression in colon cancer cells resistant to SN38 and in irinotecan‐treated metastases. International Journal of Cancer 2004;109: 848-854. DOI: https://doi.org/10.1002/ijc.20032.

Jandu H, K Aluzaite, L Fogh, et al. Molecular characterization of irinotecan (SN-38) resistant human breast cancer cell lines.
BMC Cancer (2016) 16:34.
DOI 10.1186/s 12885-016-2071-1

Jensen NF, Stenvang J, Beck MK, Hanáková B, Belling KC, Do KN, Viuff B, Nygård SB, Gupta R, Rasmussen MH, Tarpgaard LS, Hansen TP, Budinská E, Pfeiffer P, Bosman F, Tejpar S, Roth A, Delorenzi M, Andersen CL, Rømer MU, Brünner N, Moreira JM. Establishment and characterization of models of chemotherapy resistance in colorectal cancer: Towards a predictive signature of chemoresistance. Mol Oncol. 2015 Jun;9(6):1169-85. doi: 10.1016/j.molonc.2015.02.008. Epub 2015 Feb 24. PMID: 25759163

Veterinary Clinical Trials

Burton JH, C Mazcko, A LeBlanc, J H Doroshow, Y Pommier et al. NCI Comparative Oncology Program Testing of Non-Camptothecin Indenoisoquinoline Topoisomerase I Inhibitors In Naturally Occurring Canine Lymphoma. Clin Cancer Res;24(13);5830-40,2018.

Eiseman JL, Holleran J, McCormick D, et al… Plasma and Tumor pharmacokinetics of IV LMP 744, a novel Indenoisoquinoline topoisomerase I inhibitor, in a canine phase I study. Abstract # 4632 Presented at the AACR Annual Meeting 2015, Philadelphia, PA

Muzzio M, JH Beumer, J Holleran et al. Plasma pharmacokinetics of the indenoisoquinoline topoisomerase I inhibitor, NSC 743400, in rats and dogs. Cancer Chemother Pharmacol. 2015 May; 75(5): 1015–1023. doi: 10.1007/s00280-015-2722-y

Clinical Studies

Doroshow, J.H., J.J. Ji, A. Chen, et al. (2012). Proof of mechanism (POM) in the first-in-human trial of two novel indenoisoquinoline, non-camptothecin topoisomerase I (TOP1) inhibitors. J Clin Oncol. 30s:A3031.

Fox, B.M., Xiao, X. Antony, S., et al. (2003). Design, synthesis, and biological evaluation of cytotoxic 11-alkenylindenoisoquinoline topoisomerase I inhibitors and indenoisoquinoline-camptothecin hybrids. J Med Chem. 46:3275-3282.

Kummar S, A Chen, M Gutierrz et al. Clinical and pharmacologic evaluation of two dosing schedules of indenothecan (LMP400), a novel indenoisoquinoline, in patients with advanced solid tumors. Cancer Chemother Pharmacol (2016) 78:73-81.

SCHLAFEN 11 (SLFN11) AND HRD BIOMARKERS

Ballestrero A, D Bedognetti, D Ferraioli..Pommier et al. Report of the first SLFN11 monothematic workshop: from function to role as a biomarker in cancer. J Trans Med 2017; 15:199-198. DoI 10.1186/s12967-017-1296-3.

Buettner R. Awakening of SCHLAFEN11 by immunohistochemistry: a new biomarker predicting response to chemotherapy. Virchows Archiv 2021. https://link.springer.com/article/10.1007/s00428-021003051-3.

Coussy F, R El-Botty…Y Pommier et al. BRCAness, SLFN11, and RBI loss predict response to topoisomerase 1 inhibitors in triple negative breast cancers. Sci.Transl. Med. 2020;12(531).pii: eaax2625. doi: 10.1126/scitranslmed.aax2625

Murai J and Y Pommier. Abstract 5875: Schlafen 11 (SLFN11) induces lethal S-phase arrest in response to DNA damage: A novel mechanism of how cancer cells are killed by DNA damaging agents. AACR 2017. DOI: 10.1158/1538-7445.AM2017-5975.

Murai J, SW Tang, E Leo…Y Pommier . SLFN11 Blocks Stress Replication Forks Independently of ATR. J Mol Cell 2018; 69(3):371-384.

Pommier Y, L Marzi, ZW Ohler..M Cushman et al. Abstract 4855: Indotecan (LMP400), Imidotecan (LMP776) and LMP744: a new class of non-camptothecin TOP1 inhibitors selective for cancer cells with homologous recombination deficiencies and high SLFN11 expression. 2018 Proceedings AACR . DOI: 10.1158-7445.AM2018-4855.

Brosnan EM and Carey K. Anders. Understanding patterns of brain metastasis in breast cancer and designing rational therapeutic strategies. Ann Transl Med. 2018 May; 6(9): 163. doi: 10.21037/atm.2018.04.35

Coussy F, R El-Botty…Y Pommier et al. BRCAness, SLFN11, and RBI loss predict response to topoisomerase 1 inhibitors in triple negative breast cancers. Sci.Transl. Med. 2020;12(531).doi: eaax2625. doi: 10.1126/scitranslmed.

Marzi L, L Szabova, M Gordon, Y Pommier et al. The Indenoisoquinoline TOP1 Inhibitors Selectively Target Homologous Recombination-Deficient and Schlafen 11-Positive Cancer Cells and Synergize with Olaparib. Amer Assoc Cancer Research 2019; DOI: 10.1158/1078-0432.CCR-19-0419.

Masayuki Sekine, Kosuke Yoshihara D Komata et al. Increased incidence of brain metastases in BRCA1-related ovarian cancers J Obstet Gyn Volume39, Issue1, 2013,292-29 https://doi.org/10.1111/j.1447-0756.2012.01961.x BRCA Gene Mutations: Cancer Risk and Genetic Testing Fact Sheet – NCI. https://www.cancer.gov › brca-fact-… Nov 19, 2020

Pommier Y, L Marzi, Z W Ohler et al. Indotecan (LMP400), Imidotecan (LMP776) and LMP744: A new class of non-camptothecin TOP1 Inhibitors selective for cancer cells with homologous recombination deficiencies and high SLFN11 expression. Cancer Res (2018)78 (13_Suppl): 4855. Htpps://doi.org.10.1158/1538-7445.AM2018-4855.

Fischietti M, F Eckerdt, R E Perez. SLFN11 negatively regulates non-canonical NFkB signaling to promote glioblastoma progression. Cancer Res Commun. 2022 September ; 2(9): 966–978. doi:10.1158/2767-9764.crc-22-0192

Reinhold WC, A Thomas, Y Pommier. DNA-Targeted Precision Medicine; Have we Been Caught Sleeping? Trends Cancer.2017;3(1): 2-6. DOI: 10.1016/j.trecan.2016.11.002

Tang SW, S Bilke, L Cao..Y Pommier et al. SLFN11 Is a Transcriptional Target of EWS-FLI1 and a Determinant of Drug Response in Ewing Sarcoma. Clin Can Res 2015;21(18):4184-93. Doi:10.1158/1078-0432.CCR-14-2112.Epub 2015 Mar 16.

Zoppoli G, M Regairaz, E Leo, …et al and Yves Pommier. Putative DNA/RNA helicase Schlafen-11 (SLFN11) sensitizes cancer cells to DNA-damaging agents. PNAS September 11, 2012. 109 (37) 15030-15035;

Glioblastoma and Pontine Gliomas

Cenci T, M Martini, N Montano et al. Prognostic Releance of c-Muc and BMI1 Expression in Patients with Glioblatoma. Amer J Clin Pathology,2012, 138 (3), 390-396. Htpps://doi.org/10.1309/AJCPRXHNJQLO09QA

Fatma H, S Maurya, H Siddique. Epigenetic modifications of c-MYC: Role in cancer cell reprogramming, progression and chemoresistance. Sem in Cancer Biol (2022) 83,166-176. https://doi.org/10.1016/j.semcancer.2020.11.008

Kool M, J Koster,J Bunt et al. Integrated Genomics Identifi3e Five Medulloblatoma Subtypes with Distinct Genetic PROFILES, Pathway Signatures and Clinicopathological Features. PloSONE 3(8):e3088.

Kool M, A Korshunov, M Remke et al. Molecular subgroups of medulloblaoma: an international meta-analysis of transcriptome, genetic aberrations, and clinical data of WNT,SHH,Group 3, and Group 4 medulloblastomas. Acta Neuropathol (2012) 123:473-484. Doi: 10.1007/s00401-012-0958-8

Xie Y,T Bergstrom, Y Jiang et al. The Human Glioblastoma Cell Culture Resource: Validated Cell Models Representing All Molecular Subtypes. EBioMedicine 2(2015) 1351-1363 .Doi.org/10.1016/j.ebiom.2015.08.026

PHARMOKINETICS OF INDENENOS

Beumer J, Holleran J, Doroshow J, et al… Phase I pharmokinetics and pharmacodynamics of a novel indenoisoquinoline topoisomerase I (Top1) inhibitor, LMP 400, administered on a daily x 5 schedule. Cancer Research 74: A 464, 2014.

Guo J, Holleran J, Schmitz J, Czambel K, Beumer JH, Eiseman JL. Pharmacokinetics and pharmacodynamics of indenoisoquinoline LMP400 (Indotecan) in BALB/c female mice bearing CT26 colon tumors. Annual Meeting American Association for Cancer Research, Philadelphia, PA, April 18-22 2015. Published: Proceedings of the American Association for Cancer Research 2015; 57: 4513.*Proceedings of the American Association for Cancer Research. Cancer Res August 1, 2015 75:4513; doi:10.1158/1538-7445.AM2015-4513.

Muzzio M, S Hu, JL Holleran, JH Beumer et al. Plasma Pharmacokinetic of the indenoioquinoline topoisomerase I inhibitor, NSC743400, in rats and dogs. Cancer Chemother Pharmacol. 2015 :75(5):1015-1023. DOI: 10.1007/s00280-015-2722-y.

Kummar S, A Chen, M Gutierrz et al. Clinical and pharmacologic evaluation of two dosing schedules of indenothecan (LMP400), a novel indenoisoquinoline, in patients with advanced solid tumors. Cancer Chemother Pharmacol (2016) 78:73-81.

INDENOS IN CANCER

Adam C. New anticancer agents may better control tumor growth in nearly every cancer type (2019, July 8) retrieved 11 February 2020 from https://phys.org/news/2019-07-anticancer-agents-tumor-growthcancer.html

Allen-Petersen BL, RC Sears. Mission Possible: Advances in MYC Therapeutic Targeting in Cancer. BioDrugs 2019 33:539-553.

Carabet LA, PS Rennie, A Cherkasov. Therapeutic Inhibition of Myc in Cancer. Structural Bases and Computer-Aided Drug Discovery Approaches. Int J Mol Sci. 2019 Jan; 20(1): 120. doi: 10.3390/ijms20010120

Heestand GM, M Schwaederie, Z Gatalica et al. Topoisomerase expression and amplification in solid tumors: Analysis of 24,262 patients. Eur J Cancer 2017;83:80-87. Doi:10.1016/j.ejca.2017.06.019.

Howard Y. Chang, Lei S. Qi, Reversing the Central Dogma: RNA-guided control of DNA in epigenetics and genome editing. Molecular Cell, Volume 83, Issue 3, 2023, Pages 442-451, ISSN 1097-2765,
https://doi.org/10.1016/j.molcel.2023.01.010. (https://www.sciencedirect.com/science/article/pii/S1097276523000308)

Chen BJ, YL Wu, Y Tanaka, W Zhang. Small Molecules Targeting c-Myc Oncogene: Promising Anti-Cancer Therapeutics. Int J Biol Sci 2014; 10(10):1084-1096. doi:10.7150/ijbs.10190

Chen H, H Liu, G Qing. Targeting oncogenic Myc as a strategy for cancer treatment. Signal Transduction and Targeted Therapy (2018) 3:5 ; https://doi.org/10.1038/s41392-018-0008-7

Dang CV, Reddy EP, Shokat KM, Soucek L (August 2017). “Drugging the ‘undruggable’ cancer targets”. Nature Reviews. Cancer. 17 (8): 502–508. doi:10.1038/nrc.2017.36. PMC 5945194. PMID 28643779.

Gabay M, Y. L. (2014). MYC Activation Is a Hallmark of Cancer Initiation and Maintenance., Cold Spring Harb Perspect Med 2014;4:a014241).

Madden SK, AD de Araujo, M Gerhardt, et al. Taking the Myc out of cancer: toward therapeutic strategies to directly inhibit c-Myc. Molecular Cancer (2021)20:3. DOI: 10.1186/212943-020-01291-6

Sollazzo MR, MS Benassi, P Picci et al. Increased C-MYC Oncogene Expression in Ewing’s Sarcoma: Correlation with Ki67 Proliferation Index.

Thomas A and Y Pommier. Targeting Topoisomerase I in the Era of Precision Medicine. Clin Cancer Res. 2019,15:25(22):6581-6589. Doi://10.1158/1078-0432,CC%-19—1089.

GLIOBLASTOMA AND PONTINE GLIOMAS

Bisht P , V U Kumar , R P. Role of PARP Inhibitors in Glioblastoma and Perceiving Challenges as Well as Strategies for Successful Clinical Development. Frontiers in Pharmacology 2022; vol 13. doi: 10.3389/fphar.2022.939570

Anthony Chalmers, Garth Cruickshank, Laurence Dunn, et al. Actr-16. Results of the oparatic trial: a phase i dose escalation study of olaparib in combination with temozolomide (tmz) in patients with relapsed glioblastoma (GBM) . Neuro-Oncology, Volume 19, Issue suppl_6, November 2017, Page vi4, https://doi.org/10.1093/neuonc/nox168.012

Gupta SK , A C Mladek , B L Carlson . Preclinical Discordant In Vitro and In Vivo Chemopotentiating Effects of the PARP Inhibitor Veliparib in Temozolomide-Sensitive versus -Resistant Glioblastoma Multiforme Xenografts.Clin Can Res 2014;.CCR-13-3446 Cancer Therapy: DOI: 10.1158/1078-0432

Hanna C, Kurian KM, Williams K, Watts C, Jackson A, Carruthers R, Strathdee K, Cruickshank G, Dunn L, Erridge S, Godfrey L, Jefferies S, McBain C, Sleigh R, McCormick A, Pittman M, Halford S, Chalmers AJ. Pharmacokinetics, safety, and tolerability of olaparib and temozolomide for recurrent glioblastoma: results of the phase I OPARATIC trial. Neuro Oncol. 2020 Dec 18;22(12):1840-1850. doi: 10.1093/neuonc/noaa104. PMID: 32347934; PMCID: PMC7746945.

Halford SF, G Cruickshank, L Dunn, Sara Erridge, Anthony J. Chalmerset al. Results of the OPARATIC trial: A phase I dose escalation study of olaparib in combination with temozolomide (TMZ) in patients with relapsed glioblastoma (GBM). Journal of Clinical Oncology 2017 35:15_suppl, 2022-2022’

Patrizii M, M Bartucci, S R Pine et al. Utility of Glioblastoma Patient-Derived Orthotopic Xenografts in Drug Discovery and Personalized Therapy. Front Oncol 2018;8: 23; doi8:10.3389/fpmc.2018.00023

Peng H, Wa Y, Wang P, Huang C, Liu Z and Wu C (2022) A Risk Model Developed Based on Homologous Recombination Deficiency Predicts Overall Survival in Patients With Lower Grade Glioma. Front. Genet. 13:919391. doi: 10.3389/fgene.2022.919391

Sim, H.-W.; Galanis, E.; Khasraw, M. PARP Inhibitors in Glioma: A Review of Therapeutic Opportunities. Cancers 2022, 14, 1003. https://doi.org/10.3390/ cancers14041003.

Teo WT, K Sekar, P Seshachalam, et al. Relevance of a TCGA-derived Glioblastoma Subtype Gene-Classifier among Patient Populations. Scientific Reports 9,7442 (2019)

References

Indenos and Azas Overview

C-MYC Promoter G-Quadruplex Regulation

7-Azas and Indenos in G-quadruplex C-Myc Inhibition

Indenos work when Irinotecan Resistance

Veterinary Clinical Trials

Clinical Studies

SCHLAFEN 11 (SLFN11) AND HRD BIOMARKERS

Glioblastoma and Pontine Gliomas

PHARMOKINETICS OF INDENENOS

INDENOS IN CANCER

GLIOBLASTOMA AND PONTINE GLIOMAS

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