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Functional Targeting of the Tyrosine Kinase EphA5 in Radiation-resistant Lung Cancer

Award Number: R01CA218853
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 06/04/2018
PERIOD OF PERFORMANCE END DATE: 05/31/2024

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Functional Targeting of the Tyrosine Kinase EphA5 in Radiation-resistant Lung Cancer - 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.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2024 ( Subtotal = $0 )
2024	2022	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	195 LITTLE ALBANY ST	NEW BRUNSWICK	NJ	08901	MIDDLESEX	USA	Cancer Treatment Research	000	5	9/5/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2022 ( Subtotal = $356,438 )
2022	2022	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	195 LITTLE ALBANY ST	NEW BRUNSWICK	NJ	08903	MIDDLESEX	USA	Cancer Treatment Research	000	5	5/3/2022	NON-COMPETING CONTINUATION	$356,438
														Subtotal = $356,438

Issue Date FY: 2021 ( Subtotal = $363,713 )
2021	2021	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	195 LITTLE ALBANY ST	NEW BRUNSWICK	NJ	08903	MIDDLESEX	USA	Cancer Treatment Research	000	4	5/19/2021	NON-COMPETING CONTINUATION	$363,713
														Subtotal = $363,713

Issue Date FY: 2020 ( Subtotal = $363,713 )
2020	2020	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	195 LITTLE ALBANY ST	NEW BRUNSWICK	NJ	08903	MIDDLESEX	USA	Cancer Treatment Research	001	3	8/31/2020	NON-COMPETING CONTINUATION	$0
2020	2020	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	195 LITTLE ALBANY ST	NEW BRUNSWICK	NJ	08903	MIDDLESEX	USA	Cancer Treatment Research	000	3	4/15/2020	NON-COMPETING CONTINUATION	$363,713
														Subtotal = $363,713

Issue Date FY: 2019 ( Subtotal = $352,801 )
2019	2019	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	195 LITTLE ALBANY ST	NEW BRUNSWICK	NJ	08903	MIDDLESEX	USA	Cancer Treatment Research	000	2	5/22/2019	NON-COMPETING CONTINUATION	$352,801
														Subtotal = $352,801

Issue Date FY: 2018 ( Subtotal = $363,713 )
2018	2018	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	195 LITTLE ALBANY ST	NEW BRUNSWICK	NJ	08903	MIDDLESEX	USA	Cancer Treatment Research	000	1	6/4/2018	NEW	$363,713
														Subtotal = $363,713

Grand Total All Awards = $1,800,378

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Functional Targeting of the Tyrosine Kinase EphA5 in Radiation-resistant Lung Cancer

Award Number: R01CA218853

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 06/04/2018

PERIOD OF PERFORMANCE END DATE: 05/31/2024

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