There is a desperate need to develop agents that specifically and efficaciously treat NSCLC patients, which represent >80% of all lung cancers and whose 5 year survival rates are only ~15%. In the prior funding period, we discovered that not only were NAD(P)H:quinone oxidoreductase 1 (NQO1) levels elevated 5- to 40-fold in >80% NSCLC tumors vs associated normal tissue, but that catalase levels were inversely expressed comparatively, elevated in normal vs tumor tissue. NQO1, therefore, represents a perfect target to exploit for the therapeutic elimination of NSCLCs. Use of NQO1 'bioactivatable'drugs, such as ss-lapachone (ss-lap) and deoxynyboquinone (DNQ) that generate hydrogen peroxide as a mechanism to hyperactivate PARP1 and selectively kill tumors, are very attractive drugs to enable such a strategy. Previously, we generated nanoparticle micelles that efficaciously delivered ss-lap or ss-lap prodrugs to NSCLCs vs normal tissue, resulting in antitumor responses with significant 'apparent cures'in orthotopic NSCLC and other cancer models. We demonstrated significant radiosensitization of NSCLCs, as well as other solid cancers, via a PARP1 hyperactivation mechanism that allowed use of 6- to 10-fold lowered ss-lap doses in combination with nontoxic doses of ionizing radiation (IR) for curative effects in orthotopic NSCLC xenografts. Understanding the exact mechanism of DNA damage and cell death caused by NQO1 bioactivatable drugs allows the following novel next hypotheses and approaches: We hypothesize that sublethal ss-lap or DNQ87 doses can be used to elicit tumor-selective, NQO1-dependent DNA damage. Inhibition of specific DNA base excision (BER) or double strand break (DSB) repair processes will selectively suppress repair/recovery responses in NQO1+ NSCLC cells, causing synergistic antitumor effects. Tumor-specificity to DNA repair inhibitors will resul in dramatic NAD+/ATP losses and inhibition of glucose metabolism and DNA repair. This theory will be tested by completing the following Specific Aims (SAs): SA1: To elucidate the roles of specific DNA base, single or DSB repair pathways and glucose metabolism in recovery (resistance) of NQO1+ NSCLC cells after sublethal ss-lap or DNQ87 doses (Yrs. 1-5). SA2: To determine the antitumor efficacy of ss-lap- dC3-micelles or HPssCD-DNQ87, with or without DNA repair inhibitors, and/or with or without IR treatments (Yrs. 1- 5). Two distinct viable antitumor approaches will be tested in vitro (Aim 1) and in vivo (Aim 2). The first approach will augment specific DNA lesions that hyperactive PARP1 using nontoxic doses of ss-lap or DNQ87, a novel DNQ derivative developed by us by inhibiting BER or DSB repair. In the second approach, PARP1 will be blocked by clinically-relevant inhibitors that prevent DNA repair and will augment lethality of NQO1 bioactivatable drugs. Both approaches exploit the ability of NQO1 bioactivatable drugs to elicit specific tumor-selective DNA lesions, but should result in two completely different cell death mechanisms: programmed necrosis in the first strategy, while the second should cause classical apoptosis/senescence. In either case, use of NQO1 bioactivatable drugs will lend tumor-selectivity to DNA repair inhibitors, whose efficacy has been limited due to lack of specificity.
Patients with nonsmall cell lung cancer (NSCLC) have little hope of curative therapy, with five-year survival rates of only ~16%, little changed over the past few decades. This second competitive renewal of our grant continues to focus on drugs that exploit the enzyme, NQO1, which is selectively elevated in NSCLC. This grant continues to build on past accomplishments, including: (i) discovering a new class of compounds, deoxynyboquinones (DNQ), that work up to 100-fold better, but by the same mechanism of action, as ss-lapachone (ss-lap);(ii) Elucidating the radiation sensitizing mechanism of death, which is triggered by hyper-activating PARP1;(iii) developing novel ss-lap-prodrug nanoparticles that provided efficacy against NSCLC and pancreatic cancers in vivo. Recently, we discovered that blocking DNA repair/recovery processes can improve tumor- selectivity and efficacy, furthering our ultimate goal in developing efficacious, unique NQO1 bioactivatable drugs for eradication of NSCLCs.
|Huang, Xiumei; Motea, Edward A; Moore, Zachary R et al. (2016) Leveraging an NQO1 Bioactivatable Drug for Tumor-Selective Use of Poly(ADP-ribose) Polymerase Inhibitors. Cancer Cell 30:940-952|
|Madajewski, Brian; Boatman, Michael A; Chakrabarti, Gaurab et al. (2016) Depleting Tumor-NQO1 Potentiates Anoikis and Inhibits Growth of NSCLC. Mol Cancer Res 14:14-25|
|Kahanda, Dimithree; Chakrabarti, Gaurab; Mcwilliams, Marc A et al. (2016) Using DNA devices to track anticancer drug activity. Biosens Bioelectron 80:647-53|
|Li, Long-Shan; Reddy, Srilakshmi; Lin, Zhen-Hua et al. (2016) NQO1-Mediated Tumor-Selective Lethality and Radiosensitization for Head and Neck Cancer. Mol Cancer Ther 15:1757-67|
|da Cruz, Eduardo H G; Silvers, Molly A; Jardim, Guilherme A M et al. (2016) Synthesis and antitumor activity of selenium-containing quinone-based triazoles possessing two redox centres, and theirÂ mechanistic insights. Eur J Med Chem 122:1-16|
|Chakrabarti, Gaurab; Silvers, Molly A; Ilcheva, Mariya et al. (2015) Tumor-selective use of DNA base excision repair inhibition in pancreatic cancer using the NQO1 bioactivatable drug, Î²-lapachone. Sci Rep 5:17066|
|Moore, Z; Chakrabarti, G; Luo, X et al. (2015) NAMPT inhibition sensitizes pancreatic adenocarcinoma cells to tumor-selective, PAR-independent metabolic catastrophe and cell death induced by Î²-lapachone. Cell Death Dis 6:e1599|
|Chakrabarti, Gaurab; Moore, Zachary R; Luo, Xiuquan et al. (2015) Targeting glutamine metabolism sensitizes pancreatic cancer to PARP-driven metabolic catastrophe induced by ÃŸ-lapachone. Cancer Metab 3:12|
|Chakrabarti, Gaurab; Gerber, David E; Boothman, David A (2015) Expanding antitumor therapeutic windows by targeting cancer-specific nicotinamide adenine dinucleotide phosphate-biogenesis pathways. Clin Pharmacol 7:57-68|
|Ma, Xinpeng; Huang, Xiumei; Moore, Zachary et al. (2015) Esterase-activatable Î²-lapachone prodrug micelles for NQO1-targeted lung cancer therapy. J Control Release 200:201-11|
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