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CDK4/6 resistance:an alternate strategy to target Rb phosphorylation in cancer

Award Number: R15CA231372
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 07/12/2018
PERIOD OF PERFORMANCE END DATE: 06/30/2022

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CDK4/6 resistance:an alternate strategy to target Rb phosphorylation in cancer - SUMMARY Phosphorylation of the Rb tumor suppressor (Rb) plays an important role in tumorigenesis. The molecules that control Rb phosphorylation in “the Rb pathway” consisting of D-type cyclins, cyclin dependent kinases (CDKs) and CDK inhibitors (CDKIs) as well as Rb itself are consistently disrupted in most cancer types leading to excessive phosphorylation (hyper-phosphorylation) of the Rb protein. Hyperphosphorylation of Rb stimulates tumor growth by promoting proliferation, blocking apoptosis and increasing invasiveness. Recently inhibitors of kinases that phosphorylate Rb (CDK4/6) called palbociclib, ribociclib and abemaciclib have been approved by the FDA to treat a subset of breast cancer patients. These treatments are used in combination with hormonal or targeted therapies. Unfortunately resistance develops in response to CDK4/6 inhibitors that is due to the activation of the AKT/mTOR pathway. In this project we will test an alternate method of targeting Rb phosphorylation by the activation of phosphatase activity toward Rb. We predict that activation of phosphatase will result in the dephosphorylation of Rb without stimulation of the AKT/mTOR resistance pathway. These studies will include the evaluation of phosphatase activation in combination with hormonal or targeted therapies in three representative types of breast cancer cells (ER+,HER2+,or TNBC). Overall this project will elucidate the difference between inhibition of kinase activity and activation of phosphatase activity toward Rb phosphorylation with respect to key features of tumorigenesis: proliferation, apoptosis and invasion. These studies will yield useful information that could inform the development of future therapies that target Rb phosphorylation.


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: 2022 ( Subtotal = -$502 )
2022	2018	PACE UNIVERSITY	1 PACE PLZ	NEW YORK	NY	10038	NEW YORK	USA	Cancer Biology Research	001	1	9/21/2022	NEW	-$502
2022	2018	PACE UNIVERSITY	1 PACE PLZ	NEW YORK	NY	10038	NEW YORK	USA	Cancer Biology Research	000	1	12/13/2021	NEW	$0
														Subtotal = -$502

Issue Date FY: 2018 ( Subtotal = $399,135 )
2018	2018	PACE UNIVERSITY	1 PACE PLZ	NEW YORK	NY	10038	NEW YORK	USA	Cancer Biology Research	000	1	7/12/2018	NEW	$399,135
														Subtotal = $399,135

Grand Total All Awards = $398,633

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CDK4/6 resistance:an alternate strategy to target Rb phosphorylation in cancer

Award Number: R15CA231372

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 07/12/2018

PERIOD OF PERFORMANCE END DATE: 06/30/2022

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