253 Phase 1 correlative study of ARQ761, a β-lapachone analogue that promotes NQ01-mediated programmed cancer cell necrosis

Gerber, David E.; Arriaga, Yull; Beg, Muhammad Shaalan; Dowell, Jonathan E.; Schiller, J.H.; Frankel, Andrea; Leff, Richard D.; Meek, Claudia; Bolluyt, J.; Fatunde, Oluwatomilade; Martinez, Roberta; Vo, Phuc Hong; Fattah, Farjana J.; Sarode, Venetia; Zhou, Yangyang; Yuexia, Xie; McLeod, Marcus; Schwartz, Betty; Boothman, David A.

doi:10.1016/s0959-8049(14)70379-x

Cited by 11 publications

(10 citation statements)

References 0 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…6A,B and SF7A ). Importantly, there was no significant increase in Methemoglobinemia after drug combination, which is the dose-limiting toxicity noted in ß-lap (ARQ761), pre-clinically or clinically 48 . During and well after treatment (up to day 12), we noted significant tumor regression in 5 of 8 mice following MeOX + ß-lap, where regression was not observed after any of the other treatments ( Fig.…”

Section: Resultsmentioning

confidence: 94%

Tumor-selective use of DNA base excision repair inhibition in pancreatic cancer using the NQO1 bioactivatable drug, β-lapachone

Chakrabarti

Silvers

Ilcheva

et al. 2015

Sci Rep

View full text Add to dashboard Cite

Base excision repair (BER) is an essential pathway for pancreatic ductal adenocarcinoma (PDA) survival. Attempts to target this repair pathway have failed due to lack of tumor-selectivity and very limited efficacy. The NAD(P)H:Quinone Oxidoreductase 1 (NQO1) bioactivatable drug, ß-lapachone (ARQ761 in clinical form), can provide tumor-selective and enhanced synergy with BER inhibition. ß-Lapachone undergoes NQO1-dependent futile redox cycling, generating massive intracellular hydrogen peroxide levels and oxidative DNA lesions that stimulate poly(ADP-ribose) polymerase 1 (PARP1) hyperactivation. Rapid NAD+/ATP depletion and programmed necrosis results. To identify BER modulators essential for repair of ß-lapachone-induced DNA base damage, a focused synthetic lethal RNAi screen demonstrated that silencing the BER scaffolding protein, XRCC1, sensitized PDA cells. In contrast, depleting OGG1 N-glycosylase spared cells from ß-lap-induced lethality and blunted PARP1 hyperactivation. Combining ß-lapachone with XRCC1 knockdown or methoxyamine (MeOX), an apyrimidinic/apurinic (AP)-modifying agent, led to NQO1-dependent synergistic killing in PDA, NSCLC, breast and head and neck cancers. OGG1 knockdown, dicoumarol-treatment or NQO1- cancer cells were spared. MeOX + ß-lapachone exposure resulted in elevated DNA double-strand breaks, PARP1 hyperactivation and TUNEL+ programmed necrosis. Combination treatment caused dramatic antitumor activity, enhanced PARP1-hyperactivation in tumor tissue, and improved survival of mice bearing MiaPaca2-derived xenografts, with 33% apparent cures. Significance: Targeting base excision repair (BER) alone has limited therapeutic potential for pancreatic or other cancers due to a general lack of tumor-selectivity. Here, we present a treatment strategy that makes BER inhibition tumor-selective and NQO1-dependent for therapy of most solid neoplasms, particularly for pancreatic cancer.

show abstract

Section: Resultsmentioning

confidence: 94%

Tumor-selective use of DNA base excision repair inhibition in pancreatic cancer using the NQO1 bioactivatable drug, β-lapachone

Chakrabarti

Silvers

Ilcheva

et al. 2015

Sci Rep

View full text Add to dashboard Cite

show abstract

“…However, this combination has the potential to cause methemoglobinemia at high concentrations, which is dose-limiting in preclinical and clinical studies (17, 25). Since radiotherapy is used to treat a majority of HNC, radiosensitization using sub-lethal doses of β-lap was explored using relative cell survival assays.…”

Section: Resultsmentioning

confidence: 99%

NQO1-Mediated Tumor-Selective Lethality and Radiosensitization for Head and Neck Cancer

Reddy

Lin

et al. 2016

Molecular Cancer Therapeutics

View full text Add to dashboard Cite

Ionizing radiation (IR) is a key therapeutic regimen for many head and neck cancers (HNCs). However, the 5-year overall survival rate for locally-advanced HNCs is ∼50% and better therapeutic efficacy is needed. NAD(P)H:quinone oxidoreductase 1 (NQO1) is over-expressed in many cancers, and β-lapachone (β-lap), an unique NQO1 bioactivatable drug, exploits this enzyme to release massive reactive oxygen species (ROS) levels that synergizes with IR to kill by programmed necrosis. β-Lap represents a novel therapeutic opportunity in HNC leading to tumor-selective lethality that will enhance the efficacy of ionizing radiation. Immunohistochemical staining and western blot assays were used to assess the expression levels of NQO1 in HNC cells and tumors. Forty-five percent of endogenous HNCs express elevated NQO1 levels. In addition, multiple HNC cell lines and tumors demonstrated elevated levels of NQO1 expression and activity and were tested for anticancer lethality and radiosensitization by β-lap using long-term survival assays. The combination of nontoxic β-lap doses and IR significantly enhanced NQO1-dependenttumor cell lethality, increased ROS, TUNEL positive cells, DNA damage, NAD+ and adenosine triphosphate (ATP) consumption, and resulted in significantantitumor efficacy and prolonged survival in two xenograft murine HNC models, demonstrating β-Lap radiosensitization of HNCs through a NQO1-dependent mechanism. This translational study offers a potential biomarker-driven strategy using NQO1 expression to select tumors susceptible to β-lap-induced radiosensitization.

show abstract

“…Other toxicities normally associated with conventional cytotoxic regimens such as nausea, neutropenia, and thrombocytopenia were not observed. Single‐agent clinical activity has been seen starting at the first dose level studied (195 mg/m 2 ) …”

Section: Introductionmentioning

confidence: 99%

“…A histo‐score (H‐score) was assigned based on intensity of NQO1 expression and prevalence of positive tumor cells. An H‐Score of ≥200 (range 0‐300) has been determined to be the cut off in defining NQO1 expression as positive or negative . Future studies will validate the NQO1:catalase ratio in patient tumors as a biomarker of response, and determine patterns of expression across multiple tumor types (including pancreas, non‐small lung, triple negative breast, and bladder cancers), changes in expression with treatment and the relationship of NQO1 expression with molecular biomarkers (eg, KRAS).…”

Section: Introductionmentioning

confidence: 99%

“…Single-agent clinical activity has been seen starting at the first dose level studied (195 mg/m 2 ). 30 NQO1 expression is being developed as a companion diagnostic with ARQ761 and is used as an integral biomarker on clinical trials. Archival formalin-fixed, paraffin embedded tissue was tested for NQO1 expression using an immunohistochemistry (IHC) assay.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Using a novel NQO1 bioactivatable drug, beta‐lapachone (ARQ761), to enhance chemotherapeutic effects by metabolic modulation in pancreatic cancer

Beg

Huang

Silvers

et al. 2017

Journal of Surgical Oncology

View full text Add to dashboard Cite

Novel, tumor-selective therapies are needed to increase the survival rate of pancreatic cancer patients. K-Ras-mutant-driven NAD(P)H:quinone oxidoreductase 1 (NQO1) is over-expressed in pancreatic tumor vs associated normal tissue, while catalase expression is lowered compared to levels in associated normal pancreas tissue. ARQ761 undergoes a robust, futile redox cycle in NQO1+ cancer cells, producing massive hydrogen peroxide (H2O2) levels; normal tissues are spared by low NQO1 and high catalase expression. DNA damage created by ARQ761 in pancreatic cancer cells ‘hyperactivates’ PARP1, causing metabolic catastrophe and NAD+-keresis cell death. NQO1: catalase levels (high in tumor, low in normal tissue) are an attractive therapeutic window to treat pancreatic cancer. Based on a growing body of literature, we are leading a clinical trial to evaluate the combination of ARQ761 and chemotherapy in patients with pancreatic cancer.

show abstract

253 Phase 1 correlative study of ARQ761, a β-lapachone analogue that promotes NQ01-mediated programmed cancer cell necrosis

Cited by 11 publications

References 0 publications

Tumor-selective use of DNA base excision repair inhibition in pancreatic cancer using the NQO1 bioactivatable drug, β-lapachone

Tumor-selective use of DNA base excision repair inhibition in pancreatic cancer using the NQO1 bioactivatable drug, β-lapachone

NQO1-Mediated Tumor-Selective Lethality and Radiosensitization for Head and Neck Cancer

Using a novel NQO1 bioactivatable drug, beta‐lapachone (ARQ761), to enhance chemotherapeutic effects by metabolic modulation in pancreatic cancer

Contact Info

Product

Resources

About