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Boothman Lab

The research lab of David A. Boothman is working to understand and exploit cell stress responses in cancer versus normal cells. Three ongoing projects in the laboratory focus on: 1) EMT, migration and metastasis and the influences of, or changes in, metabolism during TGFß1-driven EMT; 2) DNA double strand break (DSB) repair and the specific roles of RNA termination factors in R-loop resolution and DSB repair; and 3) NQO1-mediated programmed necrosis for improved therapy of cancers that have elevated levels of NAD(P)H:quinone oxidoreductase 1 (NQO1), including cancers of the lung (NSCLC), pancreas (PDAC), breast and prostate.

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Active Research

Researchers in the Boothman laboratory focus on understanding cell stress responses and exploiting these for tumor-selective therapies. Research in the lab center on tTwo active projects. One is focused onexploiting elevated levels of the NAD(P)H:quinone oxidoreductase 1 (NQO1) for treatment of pancreatic, lung, breast, prostate, head and neck and ATRT (pediatric) cancers using unique NQO1 bioactivatable drugs. The other is studying and exploiting the functions of RNA termination factors (Kub5-Hera (RPRD1B), p15RS (RPRD1A), XRN2 and others) in carcinogenesis and for leveraging tumor vs normal tissue differences for therapy.

Exploiting NQO1 bioactivatable drugs for selective therapy of human cancers with elevated levels of NQO1

NQO01 is elevated in a vast majority of human solid cancers, specifically in nonsmall cell lung, pancreatic, breast and prostate cancers. This labhas developed two classes of NQO1 bioactivatable drugs, ß-lapachone and deoxynyboquinone derivatives that are bioactivated by NQO1 to produce massive levels of hydrogen peroxide and huge pools of NAD+. The DNA damage created by H2O2 leads to the hyperactivation of PARP1, which degrades NAD+ leaving cells deficient in NAD+, creating losses of carbon metabolic pools and NAD+ loss-dependent programmed necrosis cell death. This group of researchers has learned how to use these drugs in combination with base excision repair (BER) inhibitors, PARP inhibitors and ionizing radiation.

Role of specific RNA termination factors (rprD1B, RPRD1A, XRN2) in genetic instability and exploiting their loss for cancer-selective therapy

The lab has discovered that the specific loss of RNA termination factors leads to the creation of R-loops, which cause the formation of complex DNA double strand breaks (DSBs), leading to genetic instability. Studies here further showed that these same RNA termination factors (RPRD1A, RPRD1B or XRN2) are directly involved in DSB repair. Therefore loss of specific RNA termination factors can lead to the formation of DSBs that remain unrepaired causing enhanced genetic instability. Understanding the mechanism of these RNA termination factors in DSB repair has led to new ways to specifically treat cancers that have losses in these specific proteins. Recently, researchers found that loss of Kub5-Hera (K-H)/RPRD1B led to loss of CDK1 expression, loss of BRCA1 activation, leasing to a BRCAness phenotype. These cancer cells are hypersensitive to ionizing radiation or PARP inhibitors.

Research Funding

  • Use of ß-lapachone for non-small cell lung cancer 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.

  • RPRD1B/Kub5/Hera, an RNA Pol II determinant that controls PARPi IR sensitivity
    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.

  • Tumor-selective use of PARP inhibitors against NQO1 nonsmall cell lung cancer
    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.

  • Tumor-selective radiosensitization of NSCLC using NQO1 bioactivatable drugs
    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.

  • Model-based Prediction of Redox-Modulated Responses to Cancer Treatments
    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.

  • Exploiting elevated levels of NQO1 in human pancreatic cancers for therapy using ARQ761
    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.

Recent Publications

  • 2017

    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

  • 2016
    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.

  • 2015
    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

41390-Singh, Naveen

Naveen Singh, PHD

Postdoctoral Fellow in Biochemistry & Molecular Biology

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Additional Research Team Members

Other research team members in the Boothman Lab include Jayne Silver, Laboratory Manager.