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Molecular analysis and therapeutic targeting of PI3K signaling in thyroid cancer

Award Number: R01CA128943
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 02/01/2009
PERIOD OF PERFORMANCE END DATE: 11/30/2025

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Molecular analysis and therapeutic targeting of PI3K signaling in thyroid cancer - Thyroid cancer is the most common endocrine malignancy and ranks as the sixth most common cancer diagnosed in women. Rising incidence of thyroid cancer is reflected by the projected 52,000 new cases in 2019. A majority of patients have differentiated thyroid cancer and are managed successfully with a combination of surgery and radioiodine (RAI) therapy. However, tumors may present or recur as RAI-refractory or metastatic, in which case they have a poorer prognosis and death is common. Among these, anaplastic thyroid cancer (ATC), although relatively rare, represents a true clinical emergency: ATC is typically unresectable at presentation, highly resistant to therapy, RAI-resistant, and associated with a median survival of less than 9 months when patients are treated with multimodal therapy, and less than 3 months with palliative care. Cytotoxic chemotherapy and radiation are generally ineffective in prolonging survival of ATC patients. Thus, ATC remains one of the most lethal tumors and needs novel, effective, and especially rational therapeutic approaches. The major obstacle to this goal is the lack of a detailed understanding of the pathways altered both in the early stages (drivers) and during progression of ATC. As the patient population is small, our mechanistic knowledge is based on the retrospective analysis of patient material and on cell lines often of dubious origin. We now know that TP53 is lost or mutated in 70% of ATCs, and that in almost 40% the PI3K cascade is constitutively activated. Additional common drivers include BRAF (40%) and RAS (27%) activating mutations. Despite this knowledge, it is increasingly clear that we are still missing a comprehensive wiring chart depicting all the interactions between different, cooperating driver pathways. Such detailed map is of paramount importance to design effective multidrug combinations that consider less known signaling conduits, mechanisms of resistance, and feedback pathway activation. The current application has two broad, long-term objectives. The first goal is to utilize a combination of in vivo, ex vivo, and in vitro approaches to test the hypothesis that activation and/or overexpression of the SGK1 protein kinase are integral and essential components of the neoplastic transformation process initiated by constitutive activation of PI3K, RAS, and SRC in thyroid epithelial cells and that SGK1 targeting is essential for effective inhibition of tumor growth. The second objective is to use genetically engineered mouse models, as well as cell culture approaches, to test the hypothesis that mutations in mTORC1-activating pathways, including loss of NF2 and activation of PI3K signaling, cooperate with oncogenic RAS by contributing crucial signals needed for RAS-mediated transformation of thyroid epithelial cells. This genetic interaction opens a window of opportunity for targeted therapeutic approaches.


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 = $401,385 )
2024	2024	ALBERT EINSTEIN COLLEGE OF MEDICINE	1300 MORRIS PARK AVE	BRONX	NY	10461	BRONX	USA	Cancer Biology Research	000	17	11/29/2023	NON-COMPETING CONTINUATION	$380,260
2024	2024	ALBERT EINSTEIN COLLEGE OF MEDICINE	1300 MORRIS PARK AVE	BRONX	NY	10461	BRONX	USA	Cancer Biology Research	001	17	4/16/2024	NON-COMPETING CONTINUATION	$21,125
														Subtotal = $401,385

Issue Date FY: 2023 ( Subtotal = $422,510 )
2023	2023	ALBERT EINSTEIN COLLEGE OF MEDICINE	1300 MORRIS PARK AVE	BRONX	NY	10461	BRONX	USA	Cancer Biology Research	002	16	9/18/2023	NON-COMPETING CONTINUATION	$8,450
2023	2023	ALBERT EINSTEIN COLLEGE OF MEDICINE	1300 MORRIS PARK AVE	BRONX	NY	10461	BRONX	USA	Cancer Biology Research	000	16	12/1/2022	NON-COMPETING CONTINUATION	$380,260
2023	2023	ALBERT EINSTEIN COLLEGE OF MEDICINE	1300 MORRIS PARK AVE	BRONX	NY	10461	BRONX	USA	Cancer Biology Research	001	16	3/15/2023	NON-COMPETING CONTINUATION	$33,800
														Subtotal = $422,510

Issue Date FY: 2022 ( Subtotal = $414,060 )
2022	2022	ALBERT EINSTEIN COLLEGE OF MEDICINE	1300 MORRIS PARK AVE	BRONX	NY	10461	BRONX	USA	Cancer Biology Research	001	15	5/23/2022	NON-COMPETING CONTINUATION	$33,799
2022	2022	ALBERT EINSTEIN COLLEGE OF MEDICINE	1300 MORRIS PARK AVE	BRONX	NY	10461	BRONX	USA	Cancer Biology Research	000	15	11/5/2021	NON-COMPETING CONTINUATION	$380,261
														Subtotal = $414,060

Issue Date FY: 2021 ( Subtotal = $422,510 )
2021	2021	ALBERT EINSTEIN COLLEGE OF MEDICINE	1300 MORRIS PARK AVE	BRONX	NY	10461	BRONX	USA	Cancer Biology Research	001	14	1/28/2021	NON-COMPETING CONTINUATION	$21,126
2021	2021	ALBERT EINSTEIN COLLEGE OF MEDICINE	1300 MORRIS PARK AVE	BRONX	NY	10461	BRONX	USA	Cancer Biology Research	000	14	11/5/2020	NON-COMPETING CONTINUATION	$401,384
														Subtotal = $422,510

Issue Date FY: 2020 ( Subtotal = $422,510 )
2020	2020	ALBERT EINSTEIN COLLEGE OF MEDICINE	1300 MORRIS PARK AVE	BRONX	NY	10461	BRONX	USA	Cancer Biology Research	002	13	5/13/2020	COMPETING CONTINUATION	$2,691
2020	2020	ALBERT EINSTEIN COLLEGE OF MEDICINE	1300 MORRIS PARK AVE	BRONX	NY	10461	BRONX	USA	Cancer Biology Research	000	13	11/26/2019	COMPETING CONTINUATION	$422,510
2020	2019	ALBERT EINSTEIN COLLEGE OF MEDICINE	1300 MORRIS PARK AVE	BRONX	NY	10461	BRONX	USA	Cancer Biology Research	001	12	5/13/2020	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	-$2,691
														Subtotal = $422,510

Issue Date FY: 2019 ( Subtotal = $384,100 )
2019	2019	ALBERT EINSTEIN COLLEGE OF MEDICINE, INC.	1300 MORRIS PARK AVE	BRONX	NY	10461	BRONX	USA	Cancer Biology Research	003	11	4/23/2019	NON-COMPETING CONTINUATION	-$34,907
2019	2019	ALBERT EINSTEIN COLLEGE OF MEDICINE, INC.	1300 MORRIS PARK AVE	BRONX	NY	10461	BRONX	USA	Cancer Biology Research	001	11	2/12/2019	NON-COMPETING CONTINUATION	-$321,896
2019	2019	ALBERT EINSTEIN COLLEGE OF MEDICINE	1300 MORRIS PARK AVE	BRONX	NY	10461	BRONX	USA	Cancer Biology Research	002	12	2/12/2019	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$321,896
2019	2019	ALBERT EINSTEIN COLLEGE OF MEDICINE	1300 MORRIS PARK AVE	BRONX	NY	10461	BRONX	USA	Cancer Biology Research	004	12	4/23/2019	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$34,907
2019	2019	ALBERT EINSTEIN COLLEGE OF MEDICINE, INC.	1300 MORRIS PARK AVE	BRONX	NY	10461	BRONX	USA	Cancer Biology Research	000	11	11/16/2018	NON-COMPETING CONTINUATION	$384,100
														Subtotal = $384,100

Issue Date FY: 2018 ( Subtotal = $396,625 )
2018	2018	ALBERT EINSTEIN COLLEGE OF MEDICINE, INC.	1300 MORRIS PARK AVE	BRONX	NY	10461	BRONX	USA	Cancer Biology Research	001	10	5/22/2018	NON-COMPETING CONTINUATION	$39,663
2018	2018	ALBERT EINSTEIN COLLEGE OF MEDICINE, INC.	1300 MORRIS PARK AVE	BRONX	NY	10461	BRONX	USA	Cancer Biology Research	000	10	11/15/2017	NON-COMPETING CONTINUATION	$356,962
														Subtotal = $396,625

Issue Date FY: 2017 ( Subtotal = $396,625 )
2017	2017	ALBERT EINSTEIN COLLEGE OF MEDICINE, INC.	1300 MORRIS PARK AVE	BRONX	NY	10461	BRONX	USA	Cancer Biology Research	001	9	6/6/2017	NON-COMPETING CONTINUATION	$39,663
2017	2017	ALBERT EINSTEIN COLLEGE OF MEDICINE, INC.	1300 MORRIS PARK AVE	BRONX	NY	10461	BRONX	USA	Cancer Biology Research	000	9	11/8/2016	NON-COMPETING CONTINUATION	$356,962
														Subtotal = $396,625

Issue Date FY: 2016 ( Subtotal = $396,625 )
2016	2016	ALBERT EINSTEIN COLLEGE OF MEDICINE INC	111 E 210TH ST	BRONX	NY	10467	BRONX	USA	Cancer Biology Research	000	8	11/25/2015	NON-COMPETING CONTINUATION	$356,962
2016	2016	ALBERT EINSTEIN COLLEGE OF MEDICINE INC	111 E 210TH ST	BRONX	NY	10467	BRONX	USA	Cancer Biology Research	001	8	2/17/2016	NON-COMPETING CONTINUATION	$39,663
2016	2015	ALBERT EINSTEIN COLLEGE OF MEDICINE INC	111 E 210TH ST	BRONX	NY	10467	BRONX	USA	Cancer Biology Research	002	7	4/21/2016	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	-$51,696
2016	2015	ALBERT EINSTEIN COLLEGE OF MEDICINE OF YESHIVA UNIV	1300 MORRIS PARK AVENUE	BRONIX	NY	10461		USA	Cancer Biology Research	003	6	4/21/2016	COMPETING CONTINUATION	$51,696
														Subtotal = $396,625

Issue Date FY: 2015 ( Subtotal = $396,625 )
2015	2015	COM AFFILIATION, INC.	111 E 210TH ST	BRONX	NY	10467	BRONX	USA	Cancer Biology Research	005	7	9/23/2015	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$0
2015	2015	ALBERT EINSTEIN COLLEGE OF MEDICINE INC	111 E 210TH ST	BRONX	NY	10467	BRONX	USA	Cancer Biology Research	004	7	9/22/2015	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$221,563
2015	2015	ALBERT EINSTEIN COLLEGE OF MEDICINE OF YESHIVA UNIV	1300 MORRIS PARK AVENUE	BRONIX	NY	10461		USA	Cancer Biology Research	003	6	9/22/2015	COMPETING CONTINUATION	-$221,563
2015	2015	ALBERT EINSTEIN COLLEGE OF MEDICINE OF YESHIVA UNIV	1300 MORRIS PARK AVENUE	BRONIX	NY	10461		USA	Cancer Biology Research	002	6	2/23/2015	COMPETING CONTINUATION	$20,875
2015	2015	ALBERT EINSTEIN COLLEGE OF MEDICINE OF YESHIVA UNIV	1300 MORRIS PARK AVENUE	BRONIX	NY	10461		USA	Cancer Biology Research	001	6	11/21/2014	COMPETING CONTINUATION	$375,750
2015	2013	ALBERT EINSTEIN COLLEGE OF MEDICINE OF YESHIVA UNIV	1300 MORRIS PARK AVENUE	BRONIX	NY	10461		USA	Cancer Biology Research	000	5	11/18/2014	NON-COMPETING CONTINUATION	$0
														Subtotal = $396,625

Issue Date FY: 2014 ( Subtotal = $102,705 )
2014	2014	ALBERT EINSTEIN COLLEGE OF MEDICINE OF YESHIVA UNIV	1300 MORRIS PARK AVENUE	BRONIX	NY	10461		USA	Cancer Cause and Prevention Research	000	5	7/3/2014	SUPPLEMENT FOR EXPANSION	$102,705
														Subtotal = $102,705

Issue Date FY: 2013 ( Subtotal = $314,070 )
2013	2013	ALBERT EINSTEIN COLLEGE OF MEDICINE OF YESHIVA UNIV	1300 MORRIS PARK AVENUE	BRONIX	NY	10461		USA	Cancer Biology Research	000	5	12/17/2012	NON-COMPETING CONTINUATION	$167,059
2013	2013	ALBERT EINSTEIN COLLEGE OF MEDICINE OF YESHIVA UNIV	1300 MORRIS PARK AVENUE	BRONIX	NY	10461		USA	Cancer Biology Research	001	5	6/6/2013	NON-COMPETING CONTINUATION	$147,011
														Subtotal = $314,070

Issue Date FY: 2012 ( Subtotal = $334,117 )
2012	2012	ALBERT EINSTEIN COLLEGE OF MEDICINE OF YESHIVA UNIV	1300 MORRIS PARK AVENUE	BRONIX	NY	10461		USA	Cancer Biology Research	001	4	4/26/2012	NON-COMPETING CONTINUATION	$33,411
2012	2012	ALBERT EINSTEIN COLLEGE OF MEDICINE OF YESHIVA UNIV	1300 MORRIS PARK AVENUE	BRONIX	NY	10461		USA	Cancer Biology Research	000	4	12/30/2011	NON-COMPETING CONTINUATION	$300,706
														Subtotal = $334,117

Issue Date FY: 2011 ( Subtotal = $334,117 ) (Continued on the next page)
Grand Total All Awards = $5,827,484

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Molecular analysis and therapeutic targeting of PI3K signaling in thyroid cancer

Award Number: R01CA128943

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 02/01/2009

PERIOD OF PERFORMANCE END DATE: 11/30/2025

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