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Understanding biased agonism in receptor tyrosine kinases to devise new modalities for their targeting in cancer

Award Number: R00CA256350
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 01/01/2025
PERIOD OF PERFORMANCE END DATE: 12/31/2027

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Understanding biased agonism in receptor tyrosine kinases to devise new modalities for their targeting in cancer - PROJECT SUMMARY/ABSTRACT This project takes a unique dynamic view of signaling by receptor tyrosine kinases (RTKs), testing the hypothesis that signaling specificity is kinetically defined, and that modulating dynamics might underlie a new therapeutic approach. Advancing with these questions will require new microscopy-based approaches in living cells – exploiting techniques that I have focused on throughout my career and taking advantage of the Lemmon lab’s biochemical expertise. Despite decades of study, and their importance as therapeutic targets, RTKs remain poorly understood mechanistically. Most RTKs dimerize upon ligand binding, and this is still believed to be the key step in their activation. The prevailing simple ‘on/off’ view is inconsistent, however, with the fact that RTKs can respond differentially to their multiple distinct activating ligands – displaying biased agonism or functional selectivity. Recent work in the Lemmon lab suggests that this selectivity is kinetically defined, with the life-time of the RTK’s activated state differing from ligand to ligand and defining the nature of the signaling outcome. Testing this new hypothesis requires single-molecule analysis of receptor activation kinetics in relevant cellular contexts. To date, kinetic arguments have only been inferred from structural and indirect signaling studies. My proposal focuses on directly observing the kinetics of RTK signaling in living cells. In particular, I will study the lifetime of different activated dimeric RTK states – and the resulting signaling kinetics – for the epidermal growth factor receptor (EGFR) when bound to its 7 different activating ligands. These studies will exploit advanced single-molecule fluorescence microscopy techniques in living cells that I have been developing, and will also correlate the results with structural and signaling work. My career goal is to obtain a research faculty position at a leading institute where I will continue to dissect the mechanisms of RTK dimerization and signaling. My successful transition to independence in this field would be significantly bolstered by augmenting my microscopy expertise with other biophysical and structural techniques in both in vitro and in vivo systems. It is with these acquired skills that I will be able to investigate how receptor dimerization dynamics define signaling specificity, and how they might be modulated pharmacologically. The success of this project will be greatly enhanced by the outstanding collaborators that I have assembled to advise me throughout my transition to independence. In addition, the exceptional research environment at the Cancer Biology Institute and the Yale Medical school area has all the necessary resources required for the proposed training and research studies. The K99/R00 would provide me with the protected time needed for this advanced training and allow me to continue to foster my growth under the mentorship of Dr. Mark Lemmon. I expect that the time provided by this award will allow me to elucidate the relationship between receptor dimerization dynamics and signal specificity, and will illuminate new avenues for pharmacological intervention.


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: 2026 ( Subtotal = $249,000 )
2026	2026	VANDERBILT UNIVERSITY	110 21ST AVE S	NASHVILLE	TN	37203	DAVIDSON	USA	Cancer Research Manpower	001	4	4/21/2026	NON-COMPETING CONTINUATION	$24,899
2026	2026	VANDERBILT UNIVERSITY	110 21ST AVE S	NASHVILLE	TN	37203	DAVIDSON	USA	Cancer Research Manpower	000	4	2/6/2026	NON-COMPETING CONTINUATION	$224,101
														Subtotal = $249,000

Issue Date FY: 2025 ( Subtotal = $249,000 )
2025	2025	VANDERBILT UNIVERSITY	110 21ST AVE S	NASHVILLE	TN	37203	DAVIDSON	USA	Cancer Research Manpower	001	3	12/13/2024	EXTENSION WITH OR WITHOUT FUNDS	-$24,900
2025	2025	VANDERBILT UNIVERSITY	110 21ST AVE S	NASHVILLE	TN	37203	DAVIDSON	USA	Cancer Research Manpower	000	3	12/10/2024	EXTENSION WITH OR WITHOUT FUNDS	$249,000
2025	2025	VANDERBILT UNIVERSITY	110 21ST AVE S	NASHVILLE	TN	37203	DAVIDSON	USA	Cancer Research Manpower	002	3	5/26/2025	EXTENSION WITH OR WITHOUT FUNDS	$0
2025	2025	VANDERBILT UNIVERSITY	110 21ST AVE S	NASHVILLE	TN	37203	DAVIDSON	USA	Cancer Research Manpower	003	3	5/30/2025	EXTENSION WITH OR WITHOUT FUNDS	$24,900
														Subtotal = $249,000

Grand Total All Awards = $498,000

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Understanding biased agonism in receptor tyrosine kinases to devise new modalities for their targeting in cancer

Award Number: R00CA256350

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 01/01/2025

PERIOD OF PERFORMANCE END DATE: 12/31/2027

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