The research lab of Xiumei Huang, Ph.D. is working on uncovering how NAD(P)H:quinone oxidoreductase 1 (NQO1) bioactivatable drugs alone, or in synergy with ionizing radiation, poly(ADP-ribose) polymerase (PARP) inhibitors or immune checkpoint inhibitors (PD-1/PD-L1, etc.), trigger immunogenic cell death (ICD) and induce damage-associated molecular patterns (DAMPs) release and phagocytes/APCs (antigen-presenting cells) recruitment, which enhance cross-talk between tumor cells and immune cells to stimulate anti-cancer immunity. The goal is to develop novel antitumor therapies to treat cancers with elevated (> 100-fold) levels of NQO1.
Active Research
Overall, the Huang lab has three broad areas of research ongoing. The first area focuses on 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. The second area focuses on screening novel NQO1 bioactivatable drugs and uncovering the mechanisms underlying the synergy between these drugs and PARP inhibitors. The third area focuses on investigating the mechanism by which NQO1 bioactivatable drugs stimulate innate and adaptive immunity.
NQO1 bioactivatable drugs as radiosensitizer
Ionizing radiation (IR) is a prime therapeutic tool for treating NSCLC/PDA, including both low dose fractionated and high dose ablative regimen. However, long-term side effects and/or late-term consequences of IR still plague this regimen for NSCLC/PDA therapy. Thus, novel strategies to increase tumor-selectivity are required to improve lower doses of IR therapies. We previously showed that sublethal dose of β-lapachone significantly increased the efficacy of IR therapy (Motea et al., Clinical Cancer Research, 2019), however, the underlying mechanism is not completely delineated, and efficacy against NSCLC/PDA is not demonstrated. Our current work is focused on elucidating the inhibitory effects of IR + NQO1 bioactivatable drugs on DNA repair (homologous recombination (HR) and non-homologous end joining (NHEJ)) and carbon metabolism (glycolytic and TCA cycle).
Synergistic effects of NQO1 bioactivatable drugs and PARP inhibitors
PARP inhibitors, similar to other DNA repair blockers, lack tumor-selectivity, are typically toxic to normal tissue, and are only efficacious against a small subset of vulnerable (e.g., BRCA1/2-deficient) cancers by synthetic lethality. NQO1 bioactivatable drug, β-lapachone (ARQ761, ArQule, in clinical form), capitalizes on elevated NQO1:CAT ratios in recalcitrant pancreatic, non-small-cell lung cancer and breast cancer to elicit tumor-selective programmed necrosis. We previously showed that combination treatment with β-lapachone and a PARP inhibitor causes unrepaired DNA damage and induces apoptosis, which leads to a synergistic therapeutic effect in orthotopic PDA and NSCLC (Huang et al., Cancer Cell, 2016). We have developed a new NQO1 bioactivatable drug, Isobutyldeoxynyboquinone (IB-DNQ), which is a ten times more potent anti-cancer drug compared to β-lapachone that kills NQO1 over-expressing cancer cells. Our current work is focused on uncovering the novel mechanism of IB-DNQ in synergy with PARP inhibitors to kill NQO1+ NSCLC, PDA and TNBC.
Targeting NQO1+ tumor to trigger innate and adaptive immunity
Patients with well-established solid tumors generate complicated immunosuppressive networks and are generally refractory to immunotherapy. Current therapies for solid cancers lack rationale to exploit cancer-specific targets, and are subject to inherent resistance mechanisms and ineffective against non-cycling cancer cells. Lack of proper innate sensing inside tumor microenvironment (TME) limits T cell-targeted immunotherapy. Our previous studies demonstrate that β-lapachone-induced high mobility group box 1 (HMGB1) release activates the host TLR4/MyD88/type I interferon pathway and Batf3 dendritic cell-dependent cross-priming to bridge innate and adaptive immune responses against the NQO1+ tumor, and targeting NQO1 potently triggers innate sensing within TME that synergizes with immunotherapy to overcome adaptive resistance (Li et al., Nature Communications, 2019). However, the underlying mechanism of cross-talk between tumor cells and immune cells is not yet fully understood. Our current work is focused on elucidating the role of β-lapachone-induced tumor-derived cytosolic DNA in innate immune sensing and the mechanism of cross-talk between tumor cells and immune cells, and determining how β-lapachone synergizes with immune checkpoint blockade therapy.
Current Research Funding
NIH R01CA240952-01 (Huang, PI), Targeting NQO1+ tumor to trigger innate and adaptive immunity.
NIH 1R01CA224493-02 (Huang, PI), Tumor-selective radiosensitization of NSCLC using NQO1 bioactivatable drugs.
NIH 5R01CA221158-03 (Huang & Motea, MPI), Tumor-selective use of PARP inhibitors against NQO1+ non-small cell lung cancer.
