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Validation of EGFR Protein Complexes as Molecular Diagnostics

Award Number: UH3CA202970
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: COOPERATIVE AGREEMENT
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/06/2016
PERIOD OF PERFORMANCE END DATE: 06/30/2024

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Validation of EGFR Protein Complexes as Molecular Diagnostics - DESCRIPTION (provided by applicant): We recently developed a new approach to characterizing activity of receptor tyrosine kinases (RTK) on tumor cells by visualizing signaling associated protein complexes using proximity ligation assay technology. This was motivated by the (i) the poor performance of many RTK expression assays, such as IHC or FISH, that measure protein or gene expression rather than signaling activity, (ii) the need to better characterize active signaling events in tumor cells driven by tumor stromal mechanisms, (iii) the realization that some patients still benefit from anti-RTK directed therapy despite their tumors lacking genomic alterations, and (iv) the need to develop assays that can better identify mechanisms of acquired resistance to kinase inhibitor therapy and thus guide clinicians about subsequent treatment. Activation of RTK through diverse mechanisms, including gene mutation, gene amplification, or overproduction of activating growth factor ligands, leads to assembly of protein complexes on RTK that facilitate downstream signal transduction. Exploiting this fact, we have developed proximity ligation assays (PLA) to annotate protein complexes reflecting an activated EGFR. PLA can be developed starting with mass spectrometry based protein-protein interaction datasets to characterize in situ EGFR complexes reflecting active signaling in cancer tissues. We have developed one such assay reflecting EGFR in complex with its adaptor protein GRB2. We show these assays reflect EGFR kinase activity both in vitro using cancer cell lines and in vivo using mouse xenograft models of lung cancer. Importantly, these assays perform well in formalin fixed paraffin embedded (FFPE) tissues enabling wide spread utility in typical hospital tumor samples. We demonstrate feasibility and utility in characterizing EGFR:GRB2 complexes in nearly 300 patient derived xenograft models of cancer. Further, our data indicate good concordance of high PLA signals across three independent cohorts of lung cancer patients numbering 350 unique cases. Our human tumor data shows high PLA signal in tumors with activating EGFR mutation as expected but we can further identify tumors with high PLA signal that lack EGFR mutation or with KRAS mutation, thus representing tumor stromal activation of EGFR. We show these assays can detect EGFR driven resistance in lung cancers driven by EML4-ALK translocations and along with other published studies indicate a role of EGFR PLA assays to detect acquired resistance to kinase inhibitors driven by EGFR signaling. Our vision is that PLA technology can be used to define signaling associated protein complexes for many RTK beyond EGFR, including MET, FGFR, and AXL, which are primary targets of emerging therapeutics and also involved in resistance. This offers the future potential to have multiple PLA assays each reflecting signaling associated protein complexes for RTK matched to therapeutics. During the UH2 aim, we will conduct analytic validation studies of our existing EGFR PLA in a CLIA-compliant environment. During the UH3 aim, we will conduct clinical validation studies by investigating the association of PLA with response to EGFR-directed therapies.


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: 2025 ( Subtotal = -$32,500 )
2025	2022	H. LEE MOFFITT CANCER CENTER AND RESEARCH INSTITUTE HOSPITAL, INC.	12902 USF MAGNOLIA DR	TAMPA	FL	33612	HILLSBOROUGH	USA	Cancer Detection and Diagnosis Research	000	5	10/21/2024	NON-COMPETING CONTINUATION	-$32,500
														Subtotal = -$32,500

Issue Date FY: 2023 ( Subtotal = $1,000 )
2023	2022	H. LEE MOFFITT CANCER CENTER AND RESEARCH INSTITUTE HOSPITAL, INC.	12902 MAGNOLIA DR	TAMPA	FL	33612	HILLSBOROUGH	USA	Cancer Detection and Diagnosis Research	002	5	9/1/2023	NON-COMPETING CONTINUATION	$0
2023	2022	H. LEE MOFFITT CANCER CENTER AND RESEARCH INSTITUTE HOSPITAL, INC.	12902 MAGNOLIA DR	TAMPA	FL	33612	HILLSBOROUGH	USA	Cancer Detection and Diagnosis Research	001	5	2/10/2023	NON-COMPETING CONTINUATION	$0
2023	2022	H. LEE MOFFITT CANCER CENTER AND RESEARCH INSTITUTE HOSPITAL, INC.	12902 MAGNOLIA DR	TAMPA	FL	33612	HILLSBOROUGH	USA	Cancer Detection and Diagnosis Research	000	5	12/15/2022	NON-COMPETING CONTINUATION	$1,000
														Subtotal = $1,000

Issue Date FY: 2022 ( Subtotal = $137,649 )
2022	2022	H. LEE MOFFITT CANCER CENTER AND RESEARCH INSTITUTE HOSPITAL, INC.	12902 MAGNOLIA DR	TAMPA	FL	33612	HILLSBOROUGH	USA	Cancer Detection and Diagnosis Research	000	5	6/30/2022	NON-COMPETING CONTINUATION	$137,649
														Subtotal = $137,649

Issue Date FY: 2021 ( Subtotal = $308,748 )
2021	2021	H. LEE MOFFITT CANCER CENTER AND RESEARCH INSTITUTE HOSPITAL, INC.	12902 MAGNOLIA DR	TAMPA	FL	33612	HILLSBOROUGH	USA	Cancer Detection and Diagnosis Research	000	4	6/23/2021	NON-COMPETING CONTINUATION	$308,748
														Subtotal = $308,748

Issue Date FY: 2020 ( Subtotal = $97,114 )
2020	2020	H. LEE MOFFITT CANCER CENTER AND RESEARCH INSTITUTE HOSPITAL, INC.	12902 MAGNOLIA DR	TAMPA	FL	33612	HILLSBOROUGH	USA	Cancer Detection and Diagnosis Research	000	3	7/22/2020	NON-COMPETING CONTINUATION	$97,114
														Subtotal = $97,114

Issue Date FY: 2019 ( Subtotal = $335,614 )
2019	2019	H. LEE MOFFITT CANCER CENTER AND RESEARCH INSTITUTE HOSPITAL, INC.	12902 MAGNOLIA DR	TAMPA	FL	33612	HILLSBOROUGH	USA	Cancer Detection and Diagnosis Research	000	2	5/23/2019	EXTENSION WITH OR WITHOUT FUNDS	$331,179
2019	2019	H. LEE MOFFITT CANCER CENTER AND RESEARCH INSTITUTE HOSPITAL, INC.	12902 MAGNOLIA DR	TAMPA	FL	33612	HILLSBOROUGH	USA	Cancer Detection and Diagnosis Research	001	2	6/12/2019	EXTENSION WITH OR WITHOUT FUNDS	$4,435
														Subtotal = $335,614

Grand Total All Awards = $847,625

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Validation of EGFR Protein Complexes as Molecular Diagnostics

Award Number: UH3CA202970

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: COOPERATIVE AGREEMENT

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

PERIOD OF PERFORMANCE START DATE: 09/06/2016

PERIOD OF PERFORMANCE END DATE: 06/30/2024

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