Boothman, DA Abstract In non-small cell lung cancer (NSCLC), >80% tumors have elevated NQO1 levels 5- to 200-fold above associated normal tissues, while Catalase levels are expressed at extremely low levels in NSCLCs compared to all normal tissue in the body. We showed that unique and novel NQO1 bioactivatable drugs, -lapachone (ARQ761 in clinical trials) and a new drug, isobutyldeoxynyboquinone (IB-DNQ), are `bioactivated' by NQO1, resulting in massive H2O2-induced, apyrimidinic/apurinic (AP) site- and DNA single-strand break-mediated hyperactivation of poly(ADP- ribosyl) polymerase 1 (PARP1) that causes dramatic NAD+/ATP losses. -Lapachone is also an excellent radiosensitizer against cancer cells overexpressing NQO1. We hypothesize that exposure of NQO1+ NSCLC cancers with low dose ionizing radiation (IR), followed immediately with nontoxic NQO1 bioactivatable drugs (-lapachone or IB-DNQ for 2 h) will cause an elevated level of DNA lesions that hyperactivate PARP activity in cells that over-express NQO1. Low doses of IR or - lapachone, which are not able alone to cause a significant level of DNA lesions to hyperactivate PARP, will be used together. Since IR causes DSBs that are quickly repaired, this agent must be delivered before or at the same time as NQO1 bioactivatable drugs,18,19 which then must be applied for at least 2 h for maximal DNA lesion formation, PARP hyperactivation and metabolic alterations7,8,12 that inhibit DSB repair and cause synergistic lethality of NQO1+ NSCLC cells.
Three aims will be performed:
Aim 1 : To define DNA repair inhibitory effects (on homologous recombination (HR) and non- homologous end joining (NHEJ)) after IR + -lapachone. (Yrs 0-5). Premise: Nonlethal, low doses of IR or -lap can be used to cause DSBs and PARP hyperactivation that depletes NAD+/ATP levels and inhibits DSB repair (NHEJ and HR) to enhance efficacy against NSCLC.
Aim 2 : To define the inhibition of carbon metabolism (glycolytic and TCA cycle inhibition due to NAD+/ATP losses) after IR + -lapachone (Yrs 0-5). Premise: PARP hyperactivation causes dramatic NAD+/ATP losses that greatly suppress glycolysis (via GAPDH inhibition) and TCA cycling by LDH inhibition and other NAD(P)H-dependent pathways to maximize efficacy against NQO1+ NSCLC.
Aim 3 : To elucidate the most efficacious use of IR + NQO1 bioactivatable drug combination against NQO1+ NSCLCs. (Yrs 0-5). Premise: IR + NQO1 bioactivatable drugs will induce DSBs + DNA lesions that hyperactivate PARP, lead to dramatic NAD+/ATP losses, inhibit DSB repair, greatly suppress glycolysis and TCA cycle metabolism that induces tumor-selective programmed necrosis. An outstanding research team will explore the effects of IR + NQO1 bioactivatable drugs on DSB repair, metabolism and efficacy against NSCLC xenograft models, leading to a clinical trial in 3-5 years.

Public Health Relevance

/ Lay statement Nonsmall cell lung cancers have inherent cancer vulnerabilities, such as the need to over-express specific enzymes, such as NAD(P)H:quinone Oxidoreductase 1 (NQO1), for their survival. We are developing tumor-selective therapies using unique compounds that are over-metabolized by NQO1 in a manner that ultimately kills lung cancers (specifically NSCLC), but have no affects on normal tissue. We will develop cancer- selective strategies of therapy using ionizing radiation and unique NQO1 bioactivatable drugs, such as -lapachone (in clinical trials as ARQ761 now at UTSW and Johns Hopkins University) and isobutyldeoxynyboquinone (IB-DNQ), where we believe a clinical trial will begin within 5 years.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA224493-02
Application #
9624419
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Buchsbaum, Jeffrey
Project Start
2018-01-10
Project End
2022-12-31
Budget Start
2019-01-01
Budget End
2019-12-31
Support Year
2
Fiscal Year
2019
Total Cost
Indirect Cost
Name
Indiana University-Purdue University at Indianapolis
Department
Biochemistry
Type
Schools of Medicine
DUNS #
603007902
City
Indianapolis
State
IN
Country
United States
Zip Code
46202