Principal Investigator

Ming
You
Awardee Organization

Methodist Hospital Research Institute
United States

Fiscal Year
2022
Activity Code
R01
Early Stage Investigator Grants (ESI)
Not Applicable
Project End Date

Transfer Application - R01 CA223804 - Chemoimmunoprevention of EGFR-Driven Non-Small Cell Lung Cancer

Lung cancer is the leading cause of cancer mortality worldwide (1). More than 80% of lung cancers consist of non-small cell lung cancer (NSCLC) and activating mutations within EGFR occur in ~50% of Asian patients and ~20% of Western patients with NSCLC (1). Contrary to prevailing notions, EGFR mutations in NSCLC occur in both males and females and in both nonsmokers and nonsmokers (1). Thus, targeting EGFR against development of NSCLC will have significant impact to control this disease. In order to maximize efficacy of preventive approaches in NSCLC, the initial focus will be directed toward patients with premalignant lesions or those with previously treated lung cancer. Two promising therapeutic approaches in preventing development of NSCLC are with interventions designed to attenuate tumor development (chemoprevention) or modulate immune recognition of tumor (immunoprevention). This multi-PI proposal will test innovative chemoimmunopreventive strategies for lung cancer, combining the expertise from Dr. You's and Dr. Wang's research groups in chemoprevention and cancer immunotherapy, respectively. Prior work in Dr. You's laboratory has established retinoid X receptor (RXR) agonists (bexarotene and an analog UAB30) as potent chemopreventive agents in mouse models of lung cancer (2, Table 1). Dr. You's group was also the first to demonstrate remarkable efficacy of an immunopreventive multi-peptide EGFR vaccine against EGFR-driven lung tumorigenesis (3). Dr. Wang's prior work has established a novel immune checkpoint protein VISTA as a critical regulator of anti-tumor immunity (4-9), an important contribution given that blockade of immune checkpoint receptors has been identified as a major breakthrough in cancer treatment (10). Dr. Wang's group has shown that VISTA-blocking mAb enhances T cell-mediated tumor rejection in multiple preclinical mouse models (4-9). Given the established efficacy of these aforementioned approaches in controlling tumor growth, we hypothesize that combinatorial approaches of chemoimmunoprevention will enhance anti-tumor immunity within the tumor microenvironment (TME), which will inhibit lung tumor progression and recurrence. Three specific aims are proposed to test this hypothesis. Aim 1 will investigate the immune regulatory role of RXR agonists in preventing establishment of a tumor microenvironment that suppresses T cell activation against developing lung cancer. Aim 2 will determine the preventive efficacy of combined treatment of RXR agonists and a MHCII-restricted EGFR multi-peptide vaccine on EGFR-driven lung tumor progression. Aim 3 will test the hypothesis that blocking immune checkpoint proteins VISTA and PD-L1 will synergize with RXR agonists/EGFR vaccine to prevent acquired resistance and tumor recurrence. This proposal is highly significant because of the potential of chemoimmunoprevention to become a breakthrough preventive approach for lung cancer.

Publications

  • Li C, Wang Y, Gao S, Hu M, You M. The Chemoprevention Effects of Two Herbal Mixtures on Chemically Induced Lung Tumorigenesis in Mice. Pharmaceuticals (Basel, Switzerland). 2023 Nov 30;16. (12). PMID: 38139793
  • Zhang Q, Chen X, Palen K, Johnson B, Bui D, Xiong D, Pan J, Hu M, Wang Y, You M. Cancer chemoprevention with PV-1, a novel Prunella vulgaris-containing herbal mixture that remodels the tumor immune microenvironment in mice. Frontiers in immunology. 2023 Nov 24;14:1196434. doi: 10.3389/fimmu.2023.1196434. eCollection 2023. PMID: 38077406
  • Pan J, Zhang Q, Palen K, Wang L, Qiao L, Johnson B, Sei S, Shoemaker RH, Lubet RA, Wang Y, You M. Potentiation of Kras peptide cancer vaccine by avasimibe, a cholesterol modulator. EBioMedicine. 2019 Nov;49:72-81. Epub 2019 Oct 31. PMID: 31680003
  • Xie X, Zhang J, Shi Z, Liu W, Hu X, Qie C, Chen W, Wang Y, Wang L, Jiang J, Liu J. The Expression Pattern and Clinical Significance of the Immune Checkpoint Regulator VISTA in Human Breast Cancer. Frontiers in immunology. 2020 Oct 29;11:563044. doi: 10.3389/fimmu.2020.563044. eCollection 2020. PMID: 33250890
  • Pagliuca S, Gurnari C, Zhang K, Kewan T, Bahaj W, Mori M, Nautiyal I, Rubio MT, Ferraro F, Maciejewski JP, Wang L, Visconte V. Comprehensive Transcriptomic Analysis of VISTA in Acute Myeloid Leukemia: Insights into Its Prognostic Value. International journal of molecular sciences. 2022 Nov 28;23. (23). PMID: 36499220
  • Okeke EB, Louttit C, Fry C, Najafabadi AH, Han K, Nemzek J, Moon JJ. Inhibition of neutrophil elastase prevents neutrophil extracellular trap formation and rescues mice from endotoxic shock. Biomaterials. 2020 Apr;238:119836. Epub 2020 Feb 3. PMID: 32045782
  • Louttit C, Park KS, Moon JJ. Bioinspired nucleic acid structures for immune modulation. Biomaterials. 2019 Oct;217:119287. Epub 2019 Jun 19. PMID: 31247511
  • Pan J, Chen Y, Zhang Q, Khatun A, Palen K, Xin G, Wang L, Yang C, Johnson BD, Myers CR, Sei S, Shoemaker RH, Lubet RA, Wang Y, Cui W, You M. Inhibition of lung tumorigenesis by a small molecule CA170 targeting the immune checkpoint protein VISTA. Communications biology. 2021 Jul 23;4(1):906. PMID: 34302042
  • Fan Y, Stronsky SM, Xu Y, Steffens JT, van Tongeren SA, Erwin A, Cooper CL, Moon JJ. Multilamellar Vaccine Particle Elicits Potent Immune Activation with Protein Antigens and Protects Mice against Ebola Virus Infection. ACS nano. 2019 Oct 22;13(10):11087-11096. Epub 2019 Sep 12. PMID: 31497947
  • Huang M, Xiong D, Pan J, Zhang Q, Wang Y, Myers CR, Johnson BD, Hardy M, Kalyanaraman B, You M. Prevention of Tumor Growth and Dissemination by In Situ Vaccination with Mitochondria-Targeted Atovaquone. Advanced science (Weinheim, Baden-Wurttemberg, Germany). 2022 Apr;9(12):e2101267. Epub 2022 Mar 4. PMID: 35243806
  • Zhang Q, Xiong D, Pan J, Wang Y, Hardy M, Kalyanaraman B, You M. Chemoprevention of Lung Cancer with a Combination of Mitochondria-Targeted Compounds. Cancers. 2022 May 21;14. (10). PMID: 35626143
  • Lee Y, Sugihara K, Gillilland MG 3rd, Jon S, Kamada N, Moon JJ. Hyaluronic acid-bilirubin nanomedicine for targeted modulation of dysregulated intestinal barrier, microbiome and immune responses in colitis. Nature materials. 2020 Jan;19(1):118-126. Epub 2019 Aug 19. PMID: 31427744
  • Maisel BA, Yi M, Peck AR, Sun Y, Hooke JA, Kovatich AJ, Shriver CD, Hu H, Nevalainen MT, Tanaka T, Simone N, Wang LL, Rui H, Chervoneva I. Spatial Metrics of Interaction between CD163-Positive Macrophages and Cancer Cells and Progression-Free Survival in Chemo-Treated Breast Cancer. Cancers. 2022 Jan 8;14. (2). PMID: 35053472
  • Hu W, Wang G, Wang Y, Riese MJ, You M. Uncoupling Therapeutic Efficacy from Immune-Related Adverse Events in Immune Checkpoint Blockade. iScience. 2020 Sep 20;23(10):101580. doi: 10.1016/j.isci.2020.101580. eCollection 2020 Oct 23. PMID: 33083746
  • Xiong D, Wang Y, You M. A gene expression signature of TREM2hi macrophages and γδ T cells predicts immunotherapy response. Nature communications. 2020 Oct 8;11(1):5084. PMID: 33033253
  • Roy D, Gilmour C, Patnaik S, Wang LL. Combinatorial blockade for cancer immunotherapy: targeting emerging immune checkpoint receptors. Frontiers in immunology. 2023 Oct 19;14:1264327. doi: 10.3389/fimmu.2023.1264327. eCollection 2023. PMID: 37928556
  • Son S, Nam J, Zenkov I, Ochyl LJ, Xu Y, Scheetz L, Shi J, Farokhzad OC, Moon JJ. Sugar-Nanocapsules Imprinted with Microbial Molecular Patterns for mRNA Vaccination. Nano letters. 2020 Mar 11;20(3):1499-1509. Epub 2020 Feb 10. PMID: 32023415
  • Scheetz L, Park KS, Li Q, Lowenstein PR, Castro MG, Schwendeman A, Moon JJ. Engineering patient-specific cancer immunotherapies. Nature biomedical engineering. 2019 Oct;3(10):768-782. Epub 2019 Aug 12. PMID: 31406259
  • Huang M, Xiong D, Pan J, Zhang Q, Sei S, Shoemaker RH, Lubet RA, Montuenga LM, Wang Y, Slusher BS, You M. Targeting Glutamine Metabolism to Enhance Immunoprevention of EGFR-Driven Lung Cancer. Advanced science (Weinheim, Baden-Wurttemberg, Germany). 2022 Sep;9(26):e2105885. Epub 2022 Jul 21. PMID: 35861366
  • Xu W, Dong J, Zheng Y, Zhou J, Yuan Y, Ta HM, Miller HE, Olson M, Rajasekaran K, Ernstoff MS, Wang D, Malarkannan S, Wang L. Immune-Checkpoint Protein VISTA Regulates Antitumor Immunity by Controlling Myeloid Cell-Mediated Inflammation and Immunosuppression. Cancer immunology research. 2019 Sep;7(9):1497-1510. Epub 2019 Jul 24. PMID: 31340983
  • Lee SB, Pan J, Xiong D, Palen K, Johnson B, Lubet RA, Shoemaker RH, Green JE, Fernando RI, Sei S, You M, Wang Y. Striking efficacy of a vaccine targeting TOP2A for triple-negative breast cancer immunoprevention. NPJ precision oncology. 2023 Oct 25;7(1):108. PMID: 37880313
  • Xu C, Nam J, Hong H, Xu Y, Moon JJ. Positron Emission Tomography-Guided Photodynamic Therapy with Biodegradable Mesoporous Silica Nanoparticles for Personalized Cancer Immunotherapy. ACS nano. 2019 Oct 22;13(10):12148-12161. Epub 2019 Sep 30. PMID: 31556987
  • Weerappuli PD, Louttit C, Kojima T, Brennan L, Yalavarthi S, Xu Y, Ochyl LJ, Maeda ML, Kim HS, Knight JS, Takayama S, Moon JJ. Extracellular Trap-Mimicking DNA-Histone Mesostructures Synergistically Activate Dendritic Cells. Advanced healthcare materials. 2019 Nov;8(22):e1900926. Epub 2019 Oct 15. PMID: 31614077
  • Zhang K, Zakeri A, Alban T, Dong J, Ta HM, Zalavadia AH, Branicky A, Zhao H, Juric I, Husich H, Parthasarathy PB, Rupani A, Drazba JA, Chakraborty AA, Ching-Cheng Huang S, Chan T, Avril S, Wang LL. VISTA promotes the metabolism and differentiation of myeloid-derived suppressor cells by STAT3 and polyamine-dependent mechanisms. Cell reports. 2024 Jan 23;43(1):113661. Epub 2024 Jan 3. PMID: 38175754