Radiation therapy (RT) is an integral therapeutic modality for treating non-small cell lung cancer (NSCLC). However, lung cancer is often refractory to RT and molecular mechanisms mediating treatment resistance and tumor repopulation remain poorly defined. We have determined that the receptor tyrosine kinase EphA5 is highly expressed in lung cancer and, more importantly, its expression in patients negatively correlates with RT success and survival, thus suggesting its involvement in the regulation of cellular responses to genotoxic insult. We have assembled multiple lines of evidence to support a potential mechanism underlying EphA5-mediated radioresistance: (i) EphA5-silenced lung cancer cells display a defective G1/S cell cycle checkpoint and are unable to resolve DNA damage, (ii) upon irradiation, EphA5 is found in the nucleus of cells where it interacts with activated ataxia-telangiectasia mutated (ATM) at sites of DNA repair and, (iii) we demonstrated that a new monoclonal antibody against EphA5 sensitizes lung cancer cells and human lung cancer xenografts to RT, and significantly prolongs survival of tumor-bearing mice. In order to initiate the translation of our findings, we have developed a new methodology that utilizes in vitro and in vivo screening approaches based on phage and yeast antibody display to select and characterize antibodies with radiosensitizing properties, and capable of recognizing targets in vivo.
In Aim 1, we will apply our combined hierarchical approach to generate anti-EphA5 antibodies with radiosensitizing properties and capable of targeting EphA5-expressing tumors in vivo.
Aim 2 will study functions of EphA5 in DNA damage response, and how to prevent it for therapeutic purposes.
Aim 3 will define biodistribution properties of selected antibodies. Toxicology studies, and exploratory pharmacodynamics/pharmacokinetics will also be performed.
In Aim 4, we will test whether targeted inhibition of EphA5 combined with ionizing radiation will improve treatment outcomes.

Public Health Relevance

We showed that EphA5 expression levels in patients negatively correlates with radiotherapy success and survival, thus suggesting its involvement in the regulation of cellular responses to genotoxic insult. We propose to generate human recombinant antibodies with radiosensitizing properties through antibody display selections in vivo. The success of this project would enable dramatic expansion of therapeutic leads available to treat lung cancers.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA218853-03
Application #
9933835
Study Section
Cancer Immunopathology and Immunotherapy Study Section (CII)
Program Officer
Welch, Anthony R
Project Start
2018-06-04
Project End
2023-05-31
Budget Start
2020-06-01
Budget End
2021-05-31
Support Year
3
Fiscal Year
2020
Total Cost
Indirect Cost
Name
Rbhs -Cancer Institute of New Jersey
Department
Type
Overall Medical
DUNS #
078728091
City
New Brunswick
State
NJ
Country
United States
Zip Code
08901