Xiumei Huang, PhD
Associate Professor of Radiation Oncology
- xiuhuang@iu.edu
- Phone
- 317-278-6449
- Address
-
980 West Walnut Street
R3 C511
Indianapolis, IN 46202 - PubMed:
Bio
Dr. Xiumei Huang is an Associate Professor with tenure in the Department of Radiation Oncology and a full member of the Indiana University Simon Comprehensive Cancer Center.
Dr. Huang received her Ph.D. training in neuroscience from Sanford Burnham Prebys Medical Discovery Institute (La Jolla, CA) in 2010. She completed her postdoctoral training in chemotherapy, radiotherapy, and immunotherapy for cancer at UT Southwestern Medical Center/Simmons Comprehensive Cancer Center (Dallas, TX). In January 2018, Dr. Huang joined the Indiana University School of Medicine as a tenure-track Assistant Professor. She was then promoted to Associate Professor with tenure in July 2024.
Dr. Huang's lab is currently invovled in three broad areas of research. The first area focuses on understanding the mechanisms of tumor-selective radiosensitization of Non-Small Cell Lung Cancer (NSCLC), Triple Negative Breast Cancer (TNBC) and Pancreatic Ductal Adenocarcinoma (PDA) using novel NQO1 bioactivatable drugs. The second area centers on screening novel NQO1 bioactivatable drugs and uncovering the mechanisms underlying their synergy with PARP inhibitors. Lastly, the third area investigates the mechanisms by which NQO1 bioactivatable drugs stimulate innate and adaptive immunity to overcome immune checkpoint blockade resistance.
Grant Support
Current Support
NIH R01CA240952-05 (Huang, PI), Targeting NQO1+ tumor to trigger innate and adaptive immunity.
Completed Support
NIH 1R01CA224493-05 (Huang, PI), Tumor-selective radiosensitization of NSCLC using NQO1 bioactivatable drugs.
NIH 5R01CA221158-06 (Huang & Motea, MPI), Tumor-selective use of PARP inhibitors against NQO1+ non-small cell lung cancer.
Patents
a) Title: “Tumor-selective combination therapy” (Immunotherapy). Inventors: Fu, Huang, Boothman, Hergenrother, Li and Jiang. US patent application #: 17440787, 5/26/2022. (Submitted through IU and led by Dr. Huang)
b) Title: “Tumor-selective combination therapy”. Inventors: Hergenrother, Boothman, Bair, Cao, Gao, Huang, Luo, Ma, Moore, Parkinson. US patent #: 10576096, 02/04/2020.
Current Lab Members Related Link: Huang Lab
Postdoctoral fellows:
Lingxiang Jiang, Ph.D.
Soumya Tumbath, Ph.D.
Key Publications
Selected publications:
Corresponding author’s publications
- Tumbath S, Jiang L, Li X, Zhang T, Zahid KR, Zhao Y, Zhou H, Yin Z, Lu T, Jiang S, Chen Y, Chen X, Fu YX and Huang X#. β-Lapachone Promotes the Recruitment and Polarization of Tumor associated Neutrophils (TANs) towards An Antitumor (N1) Phenotype in NQO1-positive Cancers. OncoImmunology, 2024, 13:1, 2363000.
- Wang J, Su X, Jiang L, Boudreau MW, Chatkewitz LE, Kilgore JA, Zahid KR, Williams NS, Chen Y, Liu S, Hergenrother PJ# and Huang X#. Augmented Concentration of Isopentyl-Deoxynyboquinone in Tumors Selectively Kills NAD(P)H Quinone Oxidoreductase 1-Positve Cancer Cells through Programmed Necrotic and Apoptotic Mechanisms. Cancers, 2023, 15:5844.
- Jiang L, Liu Y, Tumbath S, Boudreau MW, Chatkewitz LE, Wang J, Su X, Zahid KR, Li K, Chen Y, Yang K, Hergenrother PJ# and Huang X#. IP-DNQ induces mitochondrial dysfunction and G2/M phase cell cycle arrest to selectively kill NQO1-positive pancreatic cancer cells. Antioxidants & Redox Signaling, 2023 Nov 11.
- Jiang L, Liu Y, Su X, Wang J, Tumbath S, Zhao Y, Kilgore JA, Williams NS, Chen Y, Wang X, Mendonca MS, Lu T, Fu YX and Huang X#. KP372-1-induced AKT Hyperactivation Blocks DNA Repair to Synergize with PARP inhibitor Rucaparib via Inhibiting FOXO3a/GADD45α Pathway. Frontiers in Oncology, 2022, 12:976292.
- Zahid KR, Raza U, Tumbath S, Jiang L, Xu W and Huang X#. Neutrophils: Musketeers against immunotherapy. Frontiers in Oncology, 2022, 12:975981.
- Zhao W, Jiang L, Fang T, Fang F, Liu Y, Zhao Y, You Y, Zhou H, Su X, Wang J, Liu S, Chen Y, Wan J and Huang X#. β-lapachone selectively kills hepatocellular carcinoma cells by targeting NQO1 to induce extensive DNA damage and PARP1 hyperactivation. Frontiers in Oncology, 2021, 11:747282.
- Su X, Wang J, Jiang L, Chen Y, Lu T, Mendonca MS and Huang X#. PCNA inhibition enhances the cytotoxicity of β-lapachone in NQO1-Positive cancer cells by augmentation of oxidative stress-induced DNA damage. Cancer Letters, 2021, 519:304-314.
- Li X, Liu Z, Zhang A, Han C, Shen A, Jiang L, Boothman DA, Qiao J, Wang Y, Huang X# and Fu YX#. NQO1 targeting prodrug triggers innate sensing and overcomes checkpoint blockade resistance. Nature Communications, 2019, 19;10(1):3251. (#Co-corresponding authors).
First or Co-first author's publications
- Motea EA*, Huang X*, Singh N, Kilgore JA, Williams NS, Xie X, Gerber DE, Beg MS, Bey EA and Boothman DA. NQO1-dependent, Tumor-selective Radiosensitization of Non-small Cell Lung Cancers. Clinical Cancer Research, 2019, 25(8): 2601-2609. (*Co-first authors).
- Huang X, Motea EA, Moore ZR, Yao J, Dong Y, Chakrabarti G, Kilgore JA, Silvers MA, Patidar PL, Cholka A, Fattah F, Cha Y, Anderson GG, Kusko R, Peyton M, Yan J, Xie XJ, Sarode V, Williams NS, Minna JD, Beg M, Gerber DE, Bey EA, and Boothman DA. Leveraging an NQO1 bioactivatable drug for tumor-selective use of Poly(ADP-ribose) polymerase (PARP) inhibitors. Cancer Cell, 2016, 30: 940-952.
- Ma X*, Huang X*, Moore Z, Huang G, Kilgore JA, Wang Y, Hammer S, Williams NS, Boothman DA, Gao J. Esterase-activatable β-lapachone prodrug micelles for NQO1-targeted lung cancer therapy. Journal of Controlled Release, 2015, 200: 201-211. (*Co-first authors).
- Chen Y*, Huang X*, Zhang YW, Rockenstein E, Bu G, Masliah E, Golde TE, Xu H. Alzheimer’s β-secretase (BACE1) regulates the cAMP/PKA/CREB pathway independently of β-amyloid. The Journal of Neuroscience, 2012, 32(33): 11390-11395. (*Co-first authors).
- Huang X, Dong Y, Bey EA, Kilgore JA, Bair JS, Li LS, Patel M, Parkinson EI, Wang Y, Williams NS, Gao J, Hergenrother PJ, Boothman DA. An NQO1 substrate with potent antitumor activity that selectively kills by PARP1-induced programmed necrosis. Cancer Research, 2012,72(12): 3038-3047.
- Huang X, Chen Y, Zhang H, Ma Q, Zhang YW, Xu H. Salubrinal attenuates amyloid β-induced neuronal death and microglial activation by inhibition of the NF-κB pathway. Neurobiology of Aging, 2012, 33(5): 1007.e9-1007.e17.
- Chen Y*, Huang X*, Thompson R, Zhao YB. Clinical features and efficacy of escitalopram treatment for geriatric depression. Journal of International Medical Research, 2011, 39(5): 1946-1953. (*Co-first authors).
- Huang X, Chen Y, Li WB, Cohen SN, Liao FF, Li L, Xu H, Zhang YW. The Rps23rg gene family originated through retroposition of the ribosomal protein s23 mRNA and encodes proteins that decrease Alzheimer's β-amyloid level and tau phosphorylation. Human Molecular Genetics, 2010, 19(19): 3835-3843.
| Year | Degree | Institution |
|---|---|---|
| 2010 | PhD | Sanford Burnham Prebys Medical Discovery Institute |
| 2007 | MS | Xiamen University |
| 2001 | BS | Soochow University |
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.