Mukesh Nyati

Mukesh Nyati, PhD

Associate Professor

1301 Catherine St.
4326C Med Sci I
Ann Arbor, MI 48109-5637

734-936-9163

Biography

 Drs. Nyati and Lawrence in the laboratory

 

Dr. Mukesh Nyati has over twenty years of experience in basic and translational oncology. He is a tenured Associate Professor in the Department of Radiation Oncology at the University of Michigan, supervising junior faculty and post-doctoral fellows in the laboratory. His administrative responsibilities include the Cancer Biology Division’s daily operations and organizing weekly academic seminars as well as the Cancer Biology Course that prepares Radiation Oncology residents for their board exams. Dr. Nyati  actively participates in the peer review process for many journals and the grant review process for NIH, NCI, DOD, SBIR, and STTR. He served as a consultant for CTEP for clinical development of AT13387 and AZT9291.

Dr. Nyati is involved in three major type of research.

Basic Research

The main focus of his research is investigating the role of protein stability in cancer progression and treatment. Dr. Nyati has been studying EGFR, cMet and KRAS oncogenes and agents that either block their activity or induce selective degradation of these oncoproteins. His group also studies the roles of the EGFR protein independent of kinase activity in cell growth and DNA repair. He is also part of the efforts of the Protein Folding Disease Initiative Group (https://research.medicine.umich.edu/research-strengths/protein-folding-diseases-initiative/research-hubs/targeting-chaperones) where he is investigating roles of Hsp90 chaperone machinery in DNA repair. 

Clinical Research

In a clinic-laboratory collaboration with Drs. Avraham Eisbruch and Shruti Jolly, Dr. Nyati is working to understand how a specific antibody (cetuximab) that binds with EGFR  produces a clinical response in certain patients with head and neck squamous cell carcinoma but fails in other patients. Using patient samples taken before and during Cetuximab treatment, they are analyzing pharmacodynamic changes in EGFR and its associated signaling molecules, epigenetic markers, HPV status and immune response molecules. They then examine the relationships between each of these factors and the overall efficacy and toxicity of cetuximab treatment. The goal of this work is to identify patients most likely to respond to cetuximab therapy in combination with chemotherapy and/or radiotherapy early in the course of treatment.

Translational Research

Dr Nyati is working towards developing a novel agent that induces EGFR protein degradation by blocking EGFR dimer formation. Towards this, he developed a small peptide “Disruptin” that showed activity in TKI resistant lung tumor xenografts (Patent). He is currently developing small molecules that can degrade activated EGFR or mutant KRAS by blocking the protein-protein interactions that promote the stability of these oncoproteins. More info: http://innovation.medicine.umich.edu/portfolio_post/targeted-cancer-therapeutic/ .
Dr Nyati is also working with Dr Kyle Cuneo to develop a strategy to treat cetuximab-resistant, KRAS positive colorectal cancer patients.  

Tumor Cell

The photomicrograph shows that a cell surface receptor EGFR (red) can regulate the progression of cancer. The EGFR molecule forms a dimer upon binding with its ligand or forms a complex with Hsp90 (yellow). These interactions are required for EGFR protein stability. This image is from a tumor xenograft along with connective tissue (middle) and normal skin (top) that show higher EGFR and Hsp90 co-localization in tumors (lower half). Drs. Nyati and Lawrence found that a synthetic peptide (Disruptin) can inhibit both the dimerization of EGFR as well as its binding with Hsp90, which accelerate degradation of activated EGFR and kills EGFR driven tumor cells.

Dr. Nyati is also an avid photographer (see Medical Campus in Moonlight above) with photos published in a wide range of journals, calendars and newspapers. He has secured funding for research from a variety of sources and published articles in Nature, Science, PNAS, Cancer Research, and JBC. Dr. Nyati has trained students, post-doctoral fellows and residents in the laboratory setting. He is also a co-founder of Pi Squared Therapeutics, LLC, a start-up biotechnology company focused on selective targeting of protein stability of activated oncogenes by disrupting protein-protein interactions required for cancer cell survival. 

Areas of Interest

  • Signal transduction
  • Protein degradation
  • Radiation sensitization
  • Experimental therapeutics

Honors & Awards

2014  Panelist in the first “Protein Folding Symposium”, organized at the Univ of Michigan, Ann Arbor
2013  Co-chair on receptor tyrosine kinase in Head and Neck Cancer SPORE Workshop, Rockville, MD
2010  Program committee member for the 2010 AACR Annual Meeting 
2010  International examiner to review a PhD thesis entitled "Preclinical studies on the antagonistic effect of Zigerone, a phenolic alkanone against gamma radiation" for this University of Manipal, India. 
2010  Panelist during AHNS Research workshop on the Biology, Prevention & Treatment of Head and Neck Cancer in Arlington, Virginia on CTEP committee member on AT13387 project team.

Credentials

  • Post-doctoral Fellowship, University of Michigan, 1999-2001, Ann Arbor, MI
  • Post-doctoral Fellowship, Indian Institute of Science, 1997-1998, Bangalore, India
  • PhD, University of Rajasthan, 1991-1996, Jaipur, India
  • MS, University of Ajmer, 1989-1991, Ajmer, India
  • BS, University of Ajmer, 1986-1989, Ajmer, India

Grants

  • (PI: Nyati), 3/1/2017-2/28/2018, University of Michigan Rogel Center: Collaborative Research in Cancer Experimental Therapeutics: Development of active-EGFR dimer disruptor to induce degradation of phosphorylated-EGFR as a novel approach for drug resistant EGFR driven tumors. Role: Principal Investigator.
  • (PI: Nyati), 09/01/2013-8/30/2018,University of Michigan Fast Forward Program: Modulate chaperone machinery to enhance EGFR protein ubiquitination and degradation, Role: Co-Principal Investigator
  • (PI: Nyati), 12/1/2016-11/30/2017 BMRC Bridge Funds, University of Michigan: Induction of tumor specific EGFR degradation by blocking EGFR-dimerization.  Role: Principal Investigator.
  • (PI: Nyati), 4/1/2017-3/31/2018 Pilot Grant, (part of NIH U01 CA216449-01, PI Ted Lawrence): Sensitization to Chemoradiation by Therapeutic Targeting of the Hsp90. Role: Principal Investigator.

Published Articles via PubMed

Published Articles or Reviews

Selected from 44 publications

  • Elaimy AL, Ahsan A, Marsh K, Pratt WB, Ray D, Lawrence TS, Nyati MK. ATM is the primary kinase responsible for phosphorylation of Hsp90α after ionizing radiation. Oncotarget, 7(50):82450-82457, 2016
  • Ray D, Cuneo KC, Rehemtulla A, Lawrence TS, Nyati MK. Inducing Oncoprotein Degradation to Improve Targeted Cancer Therapy. Neoplasia, 17(9):697-703, 2015.
  • Ahsan A, Ray D, Ramanand SG, Hegde A, Whitehead C, Rehemtulla A, Morishima Y, Pratt WB, Osawa Y, Lawrence TS, Nyati MK. Destabilization of the epidermal growth factor receptor (EGFR) by a peptide that inhibits EGFR binding to heat shock protein 90 and receptor dimerization. Journal of Biological Chemistry, 288:26879-86, 2013. PMCID:PMC3772236 
  • Ahsan A, Ramanand SG, Bergin IL, Zhao L, Whitehead CE, Rehemtulla A, Ray D, Pratt WB, Lawrence TS, Nyati MK. Efficacy of an EGFR-specific peptide against EGFR-dependent cancer cell lines and tumor xenografts. Neoplasia, 16:105-14, 2014. PMCID:PMC3978391.

Web Sites

Locations