Exploiting NQO1 bioactivatable drugs for selective therapy of human cancers with elevated levels of NQO1
Role of specific RNA termination factors (rprD1B, RPRD1A, XRN2) in genetic instability and exploiting their loss for cancer-selective therapy
NIH/NCI, 5 R01 CA102792-15, PI: Boothman, DA, 08/01/03-04/30/18
The aims of this grant are to exploit naturally elevated levels of NQO1 enzyme specifically in non-small cell lung cancer (NSCLC) patients using newly developed NSCLC animal models and novel targeted and non-targeted nanoparticle delivery methods. Researchers in the Boothman lab are developing novel pH-sensitive imaging of particles and drug and examining preclinical antitumor efficacy and pharmacology of these novel drug delivery vehicles. The lab is also developing novel prodrugs that are activated by tumor esterases. Overlap: None.
NIH/NCI, 1 R01 CA201489-02, PI: Boothman, DA, 07/01/2016-06/30/2021
This grant focuses on the lab’s discovery that Kub5/Hera (K-H) regulates RNAPII at specific genetic promoters that include CDK1. Loss of K-H expression results in CDK1-BRCA1p-HR function loss, and hypersensitizes cells to PARP inhibitors. Aim 1 focuses on determining the structure/function of K-H regulation of the CTD domain of RNPII binding to specific promoter regions of CDK1. Aim 2 studies examine the therapeutic index of K-H-deficient breast cancers that are, in turn, hypersensitive to PARP inhibitors. Overlap: None.
NIH/NCI, 1 R01 CA221158-01, PI: Boothman, DA, 07/01/2017-0630/2022
The goals of this grant are to explore the efficacy of Isobutyldeoxuynyboquinone (IB-DNQ), a novel NQO1 bioactivatable drug for use with PARP inhibitors (Aim 1), as a producer of bystander effects (aim 2) and for efficacy against NSCLCs (Aim 3). Overlap: None.
NIH/NCI, 1R01 R01CA224493, PI: Boothman, DA, 12/01/2017-11/30/2022
To examine the mechanism of action of the IR + NQO1 bioactvatable drug synergy, DNA double strand break repair (Aim 1), changes in carbon metabolism (Aim2) and overall efficacy (Aim 3) are examined. Overlap: None.
NIH/NCI, U01CA215848, PI: Melissa Kemp, GA Tech, 09/1/2017-08/31/2022
Co-Is: Boothman, DA (UTSW) and Furdui, C (WFCC). The goals of this grant are to understand the systems biology of NAD+ metabolism and then alter NAD+ enzymes to improve therapy of NQO1 bioactivatable drugs for the treatment of NQO1 elevated head and neck cancer. Overlap: None.
14-65-25-BOOT AACR/PanCan/Rising Tide for Clinical Cancer/Gateway Foundation Clinical Trials Continuation Grant, 07/01/2015-06/30/2018 (NCE)
The goal of this clinical trial is to exploit elevated levels of NQO1 in pancreatic cancer patients using ARQ761, a prodrug of ß-lapachone.
Yan Y, Zhou K, Xiong H, Miller JB, Liu L, Motea EA, Boothman DA, and Siegwart DJ. Aerosol delivery of stabilized polyester-siRNA nanoparticles to silence gene expression in orthotopic lung tumors. 2017: Biomaterials, 118: 84-93, 2017. 10.1016/j.biomaterials.2016.12.001
Zhou Y, Dong Y, Huang G, Wang Y, Huang X, Zhang F, Boothman DA, Gao J, Liang W. Lysosome-oriented, dual-stage pH-responsive polymeric micelles for β-Lapachone delivery. 2017; J Mater Chem B Mat Biol Med. 4(46): 7429-7440.
Beg MS, Huang X, Silvers MA, Gerber DE, Bolluyt J, Sarode V, Fattah F, Deberardinis RJ, Merritt ME, Xie, X. J. Leff, R. Laheru, D. Boothman, DA. Using a novel NQO1 bioactivatable drug, beta-lapachone (ARQ761), to enhance chemotherapeutic effects by metabolic modulation in pancreatic cancer. 2017; J. Surg Oncol. 116(1): 83-88. 10.1002/jso.24624
Lewis JE, Constantini F, Mims J, Chen X, Furdui CM, Boothman DA and Kemp ML. Genome-scale modeling of NADPH-driven ß-lapachone sensitization in head and neck squamous cell carcinoma. Antioxidant and Redox Signaling, IN PRESS, 10.1089/ars.2017.7048, Access #:28762750156.
Silvers MA, Deja S, Singh N, Egnatchik RA, Sudderth J, Luo X, Beg MS, Burgess S, DeBerardinis RJ, Boothman DA and Merritt ME. The NQO1 bioactivatable drug, beta-Lapachone, alters the redox state of NQO1+ pancreatic cancer cells, causing perturbation in central carbon metabolism. 2017: J Biological Chemistry, 292 (44): 18203-18216
Patidar PL, Motea, EA, Fattah, FJ, Morales JC, and Boothman DA. A proteomic approach reveals a novel role for Kub5/Hera (K-H) in DNA mismatch repair to maintain genomic stability. 2016; Nucleic Acids Research, 44(4): 1718-1731.
da Cruz EHG, Silvers MA, Jardim GAM, Resende JM, Cavalcanti BC, Bomfim IS, Pessoa C, de Simone CA, Botteselle GV, Braga AL, Nair DK, Namboothiri INN, Boothman DA, and da Silva Júnior EN, Synthesis and antitumor activity of selenium-containing quinone- based triazoles possessing two redox centres, and their mechanistic insights. 2016; European Journal of Medicinal Chemistry, 122: 1-16, doi: 10.1016/j.ejmech.2016.06.019.
Morales M, Richard P, Patidar P, Motea E, Manley J and Boothman DA. XRN2, functions in R-loop resolution, DNA double strand break repair and MRN-ATM signaling. 2016; PLoS Genetics, 12(7): e1006107. 10.1371/journal.pgen.1006107.
Li LS, Reddy S, Lin ZH, Liu S, Park H, Chun SG, Bornmann WG, Thibodeaux J, Yan J, Chakrabarti G, Xie XJ, Sumer BD, Boothman DA, and Yordy JS. NQO1-mediated tumor-selective lethality and radiosensitization for head and neck cancer. 2016; Mol. Cancer Ther., 15(7): 1757-1767.
Huang X, Motea EA, Moore ZR, Yao J, Dong Y, Chakrabarti G, Kilgore J, Silvers MA, Patidar PL, Cholka A, Fattah F, Cha Y, Anderson GG, Kusko R, Peyton M, Jan J, Xie X-J, Sarode V, Williams N, Minna JD, Beg M, Gerber DE, Bey EA, and Boothman, DA. Leveraging an NQO1 bioactivatable drug for tumor-selective use of poly(ADP-ribose) polymerase (PARP) inhibitors. 2016: Cancer Cell, 30 (6): 940–952. 10.1016/j.ccell.2016.11.006.
Tang KJ, Constanzo JD, Venkateswaran N, Melegari M, Ilcheva M, Morales JC, Skoulidis F, Heymach JV, Boothman DA, Scaglioni PP. Focal Adhesion Kinase regulates the DNA damage response and its inhibition radiosensitizes mutant KRAS lung cancer. 2016; Clinical Cancer Research, 22(23): 5851-5863.
Moore Z, Chakrabarti G, Xiuquan L, Ali A, Deberardinis R, Brekken R, and Boothman DA. NAMPT inhibition sensitizes pancreatic adenocarcinoma cells to tumor-selective, PAR-independent metabolic catastrophe and cell death induced by ß-lapachone. 2015; Cell Death & Disease, 6: e1599-08.
Ma X, Huang X, Moore Z, Huang G, Kilgore JA, Wang Y, Hammer S, Williams NS, Boothman DA, Gao J. Esterase-activatable β-lapachone prodrug micelles for NQO1-targeted lung cancer. 2015; J Control Release. 200: 201-211. pii: S0168-3659(14)00824-4.
Jiang L, Xiao L, Sugiura H, Huang X, Ali A, Kuro-o M, Deberardinis R, and Boothman DA. Metabolic reprogramming during TGFβ1-induced epithelial-to-mesenchymal transition. 2015; Oncogene, 34(30): 3908-16. onc2014321 [pli] 10.1038/onc.2014.321
Chakrabarti G, Gerber DE, and Boothman DA. Expanding antitumor therapeutic windows by targeting cancer-specific nicotinamide adenine dinucleotide phosphate-biogenesis pathways. 2015; Clinical Pharmacology: Advances and Applications. 7: 57-68.
Ma X, Moore ZR, Huang G, Huang X, Boothman DA, Gao, J. Nanotechnology-enabled delivery of NQO1 bioactivatable drugs. 2015; J Controlled Rel. 23: 7-8, 672-680.
Chakrabarti G, Moore ZR, Luo X, Ilcheva M, Ali A, Padanad M, Zhou Y, Xie Y, Burma, S, Scaglioni PP, Kimmelman AC, Lyssiotis CA, DeBerardinis RJ, Cantley LC, and Boothman DA. Targeting glutamine metabolism sensitizes pancreatic cancer to PARP1-driven metabolic catastrophe induced by ß-lapachone. 2015; Cancer & Metabolism, 3:12-24.
Wang M, Topalovski M, Toombs JE, Wright C, Moore Z, Castrillon DH, Boothman DA, Yanagisawa H, and Brekken RA. Matricellular protein Fibulin5 promotes pancreatic cancer progression by suppressing microenvironment ROS. Cancer Research, 75 (23): 5058-5059. 10.1158/0008-5472.CAN-15-0744
Chakrabarti G, Silvers MA, Ilcheva M, Liu Y, Moore ZR, Lou X, Gao J, Anderson D, Liu L, Sarode V, Gerber GE, Burma S, Deberardinis RJ, Gerson SL, Boothman DA. Inhibiting base excision repair augments NQO1-bioactivatable drugs efficacy against pancreatic cancer. 2015; Scientific Reports, 5: 16066-75.
Madajewski B, Boatman MA, Chakrabarti G, Weed SA, Rojanasakul Y, Boothman DA, and Bey EA. Depleting tumor-NQO1 expression levels increases anoikis sensitization and inhibits non-small cell lung cancer. 2015; Molecular Cancer Research, 14 (1): 14-25 doi:1158/1541-7786.MCR-15-0189.
Gerber DE, Boothman DA, Fattah FJ, Dong Y, Zhu H, Skelton RA, Priddy L L, Vo P, Dowell JE, Sarode V, Leff R, Meeks C, Xie Y, Schiller JH. Phase 1 study of romidepsin plus erlotinib in advanced non-small cell lung cancer. 2015; Lung Cancer, 90 (3): 534-541.
Faculty Research Team
Additional Research Team Members
Other research team members in the Boothman Lab include Jayne Silver, Laboratory Manager.