Xiumei Huang

Indiana University School of Medicine, USA

Title: Novel NQO1 bioactivatable drug for cancer chemotherapy and immunotherapy

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Biography

Dr. Xiumei Huang is an Assistant Professor in the Department of Radiation Oncology and full member of Indiana University Simon Comprehensive Cancer Center. Prior to her appointment at Indiana University in November 2017, she received her Ph.D. training in neuroscience from Sanford Burnham Prebys Medical Discovery Institute (La Jolla, CA). Dr. Huang received her postdoctoral training in chemotherapy, radiotherapy and immunotherapy for cancer at UT Southwestern Medical Center/Simmons Comprehensive Cancer Center (Dallas, TX). Overall, Dr. Huang’s lab has three broad areas of research ongoing: (1) understanding the mechanism of tumor-selective, radiosensitization of Non-Small Cell Lung Cancer (NSCLC), Triple Negative Breast Cancer (TNBC) or Pancreatic Ductal Adenocarcinoma (PDA) using a novel NQO1 bioactivatable drug; (2) screening novel NQO1 bioactivatable drugs and uncovering the mechanisms underlying the synergy between these drugs and PARP inhibitors; (3) investigating the mechanism by which NQO1 bioactivatable drugs stimulate innate and adaptive immunity

Abstract

Cancer is the second leading cause of death worldwide. Most current treatments for solid cancers are associated with certain side effects due to relatively low tumor-specificity-inducing normal cell toxicity. Thus, there is a critical need to develop novel highly potent tumor-selective therapies to enhance antitumor activity and reduce the toxicity to normal cells. NAD(P)H:quinone oxidoreductase 1 (NQO1) is a promising therapeutic target due to its elevation in most solid cancers, with low levels in normal tissues. We developed a novel deoxynyboquinone (DNQ) derivative – Isobutyl-deoxynyboquinone (IB-DNQ), which is a highly efficient NQO1 substrate with considerable potency and selectivity to kill cancer cells. However, the molecular mechanism of antitumor activity of IB-DNQ and its effect on cancer cell metabolism remain unknown. Here, we found that IB-DNQ killed cancer cells in an NQO1-dependent manner independent of tumor oncogenic driver mutations with a 10-fold greater potency than the prototypic NQO1 bioactivatable drug, ?-lapachone. IB-DNQ treatment induced extensive reactive oxygen-induced DNA damage, PARP1 hyperactivation, severe NAD+/ATP depletion and programmed necrosis. Further mechanistic studies indicated that IB-DNQ suppressed NAD+-sensitive carbon metabolism, inhibiting glycolysis, lactate production and the Krebs cycle. In addition, IB-DNQ caused extremely low side effects of methemoglobinemia with three-fold improvement of the maximum tolerated dose (MTD) compared to DNQ and showed significant antitumor efficacy and prolonged survival in mice bearing orthotopic human non-small cell lung cancer (NSCLC) and pancreatic cancer xenografts. IB-DNQ treatment induced tumor-selective innate sensing leading to T cell dependent tumor suppression and increased PD-L1 expression in the tumor microenvironment. IB-DNQ or PD-1 blockade treatment alone led to tumor rejection in mice bearing small but not large established tumors. However, combination therapy of IB-DNQ with anti-PD-L1 eradicated well-established and checkpoint blockade refractory tumors. Together, our findings provide preclinical proof-of-concept for IB-DNQ as a potent chemotherapeutic agent for the treatment of NQO1-positive cancers.