Anatoly Nikolaev Laboratory

Research

Overview

The mission of Nikolaev lab is to improve the outcomes of head and neck cancer and other malignancies by elucidating and targeting the key molecular and cellular pathways involved in loco-regional and distant tumor progression and resistance to chemo-radiation and immunotherapy.

Head and neck cancers are a heterogeneous group of malignancies that fall into at least two distinct groups:

1) HPV-positive oropharyngeal head and neck cancers thought to be driven by HPV infection and have a favorable overall prognosis. Specifically, the two HPV oncogenic proteins, E6 and E7, promote carcinogenesis by targeting cellular tumor suppressor proteins p53 and Rb, respectively. While these HPV-positive head and neck malignancies generally show a good response to chemo-radiation, distant metastatic failures sometimes do occur and represent a formidable challenge for subsequent therapy. Given the lack of FDA-approved HPV tumor-targeting drugs, the focus of our lab is to develop novel therapeutic agents targeting p53-HPV-E6 and Rb-HPV-E7 pathways.

2) HPV-negative oral cavity, laryngeal and hypo-pharyngeal head and neck malignancies with driver mutations in TP53 gene. These tumors are associated with cigarette smoking and believed to be a result of a chemical carcinogenesis leading to mutations in TP53 gene, along with other genetic changes, such as Cyclin D1 and EGFR amplifications. TP53 tumor suppressor is the most frequently mutated gene in these high-risk HPV-negative head and neck cancers. Mutations in TP53 are associated with reduced overall survival and increased resistance to first-line radiation and chemotherapy. Not only do the mutations in TP53 cause loss of its pro-apoptotic function, but also produce an oncogenic gain-of-function, which appears to be critical for tumor progression, resistance to conventional chemo-radiation, and poor response to immunotherapy agents. The exact molecular mechanism of mutant p53 gain-of-function remains poorly understood, but is believed to involve the metabolic switch from oxidative phosphorylation to glycolysis (Warburg Effect), activation of mevalonate pathway genes mediating cholesterol biosynthesis, and evasion of anti-tumor immune responses. Given the unmet medical need for improving the outcomes of high-risk HPV-negative head and neck cancer, the goal of our lab is to develop novel experimental therapeutics targeting mutant p53 gain-of-function, and the molecular pathways downstream. In particular, we are exploring the unique metabolic tumor vulnerabilities caused by the tumor addiction to glycolytic pathways stemming from the Warburg effect, and from activation of the mevalonate pathway genes. The links between the metabolic reprograming and tumor resistance to the therapies targeting immune checkpoint inhibitors are being explored utilizing immune co-culture systems and genetically engineered syngeneic mouse models of head and neck cancer with an intact immune system.

Diffuse intrinsic pontine glioma (DIPG) is a devastating pediatric brainstem malignancy with an overall survival of less than one year. Radiation therapy a primary treatment modality that causes a robust tumor regression and fast symptomatic recovery. Unfortunately, the tumors invariably recur within 1 year after radiation therapy, necessitating brainstem re-irradiation. The molecular pathogenesis of DIPG is poorly understood. Epigenetic effects of the H3K27M gain-of-function mutation in histone H3 gene are believed to drive global changes in gene expression leading to a stem cell like phenotype of DIPG. Additionally, TP53 gene mutations associated with H3K27M are believed to play a key role in radiation resistance. Given the devastating nature of this disease, there is an on-going unmet medical need in better understanding the molecular pathogenesis of DIPG and developing molecular therapeutics targeting the intrinsic tumor vulnerabilities of this terrible disease. Prior studies from our lab demonstrated that dual targeting of H3K27M/TP53 and oxidative stress pathways acts synergistically to enhance radiation sensitivity of DIPG by creating a DNA damage repair deficiency. Thus, our goal is to explore the efficacy of these molecular targeting agents in animal models of DIPG in combination with radiation, in hopes of translating these pre-clinical studies into phase 1-2 clinical trials for recurrent DIPG in the re-irradiation setting.

Selected Publications

1. Luo J, Nikolaev AY, Imai S, Chen D, Su F, Shiloh A, Guarente L, Gu W. Negative control of p53 by Sir2alpha promotes cell survival under stress. Cell. 2001 Oct 19;107(2):137-48
   
   
2. Li M, Chen D, Shiloh A, Luo J, Nikolaev AY, Qin J, Gu W. Deubiquitination of p53 by HAUSP is an important pathway for p53 stabilization. Nature. 2002 Apr 11;416(6881):648-53
   
   
3. Nikolaev AY, Li M, Puskas N, Qin J, Gu W. Parc: A Cytoplasmic Anchor for p53. Cell. 2003 Jan 10;112(1):29-40
   
   
4. Nikolaev AY and Gu W. PARC: A Potential Target for Cancer Therapy. Cell Cycle. 2003 May-Jun;2(3):169-71
   
   
5. Gu W, Luo J, Brooks CL, Nikolaev AY, Li M.  Dynamics of the p53 acetylation pathway. The Novartis Foundation Symposium. 2004. 259:205; discussion 205-7
   
   
6. Nikolaev AY, Papanikolaou NA, Li M, Qin J, Gu W.  Identification of a novel BRMS1-homologue protein p40 as a component of the mSin3A/p33ING1b/HDAC1 deacetylase complex. Biochem Biophys Res Commun. 2004. 323(4):1216-22
   
   
7. Abida W, Nikolaev A, Zhao W, Zhang W, Gu W. FBXO11 promotes the Neddylation of p53 and inhibits its transcriptional activity. J. Biol. Chem., 2007;282(3):1797-804
   
   
8. Ly A, Nikolaev A, Suresh G, Zheng Y, Tessier-Lavigne M, Stein E. DSCAM is a netrin receptor that collaborates with DCC in mediating responses to netrin-1. Cell, Vol 133, 1241-1254, 27 June 2008
   
   
9. Nikolaev A,McLaughlinT, O’Leary D, and Tessier-Lavigne M. APP binds DR6 to trigger axon pruning and neuron death via distinct caspases.                             Nature, Vol 457, 981-990, 19 February 2009
   
   
10. Nikolaev A, Blake C, Carlson DL. Association between hyperprolactinemia and granulomatous mastitis. Breast J., 2015 Dec 26
     
11. Nikolaev A and Benda R. Palliative radiation therapy for symptomatic control of inoperable renal cell carcinoma. Urology Case Reports, Vol 4, 51-52, January 2016
    
    
12. Nikolaev A, Yang ES. The Impact of DNA Repair Pathways in Cancer Biology and Therapy. Cancers (Basel). 2017 Sep 19;9(9)
     
13. Nikolaev A, Fiveash JB, Yang ES. Combined Targeting of Mutant p53 and Jumonji Family Histone Demethylase Augments Therapeutic Efficacy of Radiation in H3K27M DIPG. Int J Mol Sci. 2020 Jan 13; 21(2)
     
14. Ling Z, Nikolaev A, Xing C, L Della Manna D, and Yang ES. CHK1/2 Inhibitor Prexasertib Suppresses NOTCH Signaling and Enhances Cytotoxicity of Cisplatin and Radiation in Head and Neck Squamous Cell Carcinoma. Mol Cancer Ther. 2020 Jun;19(6):1279-1288. 

Published Abstracts and Posters

1. Nikolaev A, Bonner JA, et al. Pharmacological Reactivation of Mutant p53 Sensitizes Tumor Cells to Radiation by Triggering Caspase-Independent Ferroptosis Pathway. International Journal of Radiation Oncology, 2019, Vol 105, Issue 1, Page S75
    
2. Nikolaev A, Fiveash JB, et al. Differential effects of Jumonji family demethylase and EZH2 methyl-transferase inhibition on radiation sensitivity of H3 K27M mutant DIPG. AACR 2019 Proceedings: Abstracts 2749-5314
    
3. Nikolaev A. Drug Targeting p53 Sensitizes Cancer Cells to Radiotherapy in Head and Neck Cancer. ACRO 2019 Oncology Practice Update
   
   
4. Nikolaev A, Bonner JA, et al. A Computational Approach to Discovery of Novel Mutant p53 Reactivating Molecules As Targeted Radio-Sensitizing Agents for Head and Neck Cancer. International Journal of Radiation Oncology, 2018, Vol 102, Issue 3, Pages S185–S186
   
   
5. Nikolaev A, Benda RK, et al. SBRT Dose Escalation for Distinct Histopathological Types of Early-Stage NSCLC: Relevance for Loco-Regional Control. International Journal of Radiation Oncology, 2017, Vol 99, Issue 2, Pages E486–E487
   
   
6. Nikolaev A, Benda RK, et al. Significance of tumor cell histology for local control of early-stage non-small cell lung cancer treated with stereotactic body radiation therapy: a stratified retrospective analysis. International Journal of Radiation Oncology, 2016, Vol 96, Issue 2 Page E424

Book Chapters

1. Combining Chk1/2 inhibition with radiation in head and neck cancer
   Anatoly Nikolaev, and Eddy S. Yang.
   Book title: Improving the Therapeutic Ratio in Head and Neck Cancer
   Editor: Randall Kimple. 2020 Elsevier. ISSN: 2468-3183
   
   
2. Fiveash J.B., Nikolaev A., Conry R.M. (2020) Integrating Systemic Therapy into the Management of Brain Metastases. In: Yamada Y., Chang E., Fiveash J., Knisely J. (eds) Radiotherapy in Managing Brain Metastases. Springer, Cham
   First Online 31 May 2020
   
   
3. Radiobiology of hypo-fractionation.
   Anatoly Nikolaev, and Chistopher Willey.
   In preparation