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In vivo Drug Testing of Pediatric CNS Tumors Using Patient Derived Orthotopic Xenograft Models

Award Number: U01CA199288
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: COOPERATIVE AGREEMENT
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 07/14/2015
PERIOD OF PERFORMANCE END DATE: 06/30/2026

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In vivo Drug Testing of Pediatric CNS Tumors Using Patient Derived Orthotopic Xenograft Models - This application is prepared in response to the funding opportunity: NCI Pediatric In Vivo Testing Program (U01), RFA-CA-20-034 to renew our existing PPTC UO1 grant. Specifically, we propose to continue the in vivo testing program for central nervous system (CNS) tumors using our panel of patient derived orthotopic xenograft (PDOX) models. Brain tumor is the leading cause of cancer-related death in children. One of the challenges in clinical drug development is how to effectively prioritize drug candidates to ensure clinical success in cancer patients. However, efforts in identifying new anti-cancer agents for that are most likely to be effective in the clinic have been blocked for many years due to the lack of clinically relevant and molecularly accurate model system. Fortunately, we have established a panel of 150 PDOX models of pediatric brain tumors through direct injection of patient tumor specimens into the brains of SCID mice. These PDOX models are shown to have replicated the histopathology and major genetic abnormalities of the original patient tumors even during serial sub-transplantations in vivo in mouse brains. They not only represent different clinical stage (i.e., at diagnosis, relapse and terminal/autopsy) but also replicate a broad spectrum of the newly identified molecular subtypes of nearly all types of pediatric brain tumors. The xenograft tumor cells can also be cryopreserved for sustained and on-demand supply of tumorigenic PDOX cells. This capacity combined with our optimized surgical procedure, with which we can implant up to 260 mice per day, makes it possible for us to test multiple (e.g., 6-10) drugs per year for every tumor type. Our objective is therefore to make use of this unique panel of PDOX models to examine therapeutic efficacy of new agents and to analyze mechanisms of action and therapy resistance in high grade glioma, medulloblastoma, ependymoma, DIPG and ATRT. Our hypothesis is that these patient-specific PDOX tumors will respond to anti-cancer therapies similarly to the corresponding human primary tumors, and the effective agents identified through this system would have better chances of clinical success. To test this hypothesis, we will perform a series of in vitro and in vivo assays to achieve the following aims: 1) to identify genetically accurate candidate PDOX models that bear the therapeutic target(s) of new investigational drugs through data mining of our mouse model molecular characterization databases; 2) to select the most responsive models through functional in vitro screening to determine time- and dose-responses; 3) to demonstrate therapeutic efficacy of new investigational drugs in multiple target-bearing PDOX models; and 4) to perform detailed analysis of cellular and molecular mechanisms of cell killing as well as the causes of therapy resistance both in vitro and in vivo. Our novel panel of PDOX mouse models represents a broad spectrum of genetic abnormalities of pediatric CNS tumors. All the assays are well established and routinely performed in our laboratory; we are uniquely positioned to accomplish the proposed drug studies in vivo. Our findings should provide strong preclinical evidence to support the initiation of clinical trials.


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 = $621,208 )
2025	2025	ANN & ROBERT H LURIE CHILDRENS HOSPITAL OF CHICAGO	225 E CHICAGO AVE	CHICAGO	IL	60611	COOK	USA	Cancer Treatment Research	000	10	6/11/2025	NON-COMPETING CONTINUATION	$621,208
														Subtotal = $621,208

Issue Date FY: 2024 ( Subtotal = $803,123 )
2024	2024	ANN & ROBERT H LURIE CHILDRENS HOSPITAL OF CHICAGO	225 E CHICAGO AVE	CHICAGO	IL	60611	COOK	USA	Cancer Treatment Research	001	9	8/12/2024	SUPPLEMENT FOR EXPANSION	$248,237
2024	2024	ANN & ROBERT H LURIE CHILDRENS HOSPITAL OF CHICAGO	225 E CHICAGO AVE	CHICAGO	IL	60611	COOK	USA	Cancer Treatment Research	000	9	6/18/2024	NON-COMPETING CONTINUATION	$554,886
														Subtotal = $803,123

Issue Date FY: 2023 ( Subtotal = $536,704 )
2023	2023	ANN & ROBERT H LURIE CHILDRENS HOSPITAL OF CHICAGO	225 E CHICAGO AVE	CHICAGO	IL	60611	COOK	USA	Cancer Treatment Research	000	8	7/6/2023	NON-COMPETING CONTINUATION	$536,704
														Subtotal = $536,704

Issue Date FY: 2022 ( Subtotal = $608,784 )
2022	2022	ANN & ROBERT H LURIE CHILDRENS HOSPITAL OF CHICAGO	225 E CHICAGO AVE	CHICAGO	IL	60611	COOK	USA	Cancer Treatment Research	003	7	7/18/2022	NON-COMPETING CONTINUATION	$608,784
2022	2021	ANN & ROBERT H LURIE CHILDRENS HOSPITAL OF CHICAGO	225 E CHICAGO AVE	CHICAGO	IL	60611	COOK	USA	Cancer Treatment Research	001	6	3/31/2022	COMPETING CONTINUATION	$1
2022	2021	ANN & ROBERT H LURIE CHILDRENS HOSPITAL OF CHICAGO	225 E CHICAGO AVE	CHICAGO	IL	60611	COOK	USA	Cancer Treatment Research	002	5	3/31/2022	SUPPLEMENT FOR EXPANSION	-$1
2022	2019	ANN & ROBERT H. LURIE CHILDREN'S HOSPITAL OF CHICAGO	225 E CHICAGO AVE	CHICAGO	IL	60611	COOK	USA	Cancer Treatment Research	000	5	1/4/2022	NON-COMPETING CONTINUATION	$0
														Subtotal = $608,784

Issue Date FY: 2021 ( Subtotal = $1,022,242 )
2021	2021	ANN & ROBERT H. LURIE CHILDREN'S HOSPITAL OF CHICAGO	225 E CHICAGO AVE	CHICAGO	IL	60611	COOK	USA	Cancer Treatment Research	003	6	6/23/2021	COMPETING CONTINUATION	$634,384
2021	2021	ANN & ROBERT H. LURIE CHILDREN'S HOSPITAL OF CHICAGO	225 E CHICAGO AVE	CHICAGO	IL	60611	COOK	USA	Cancer Treatment Research	000	5	12/16/2020	SUPPLEMENT FOR EXPANSION	$387,858
2021	2021	ANN & ROBERT H. LURIE CHILDREN'S HOSPITAL OF CHICAGO	225 E CHICAGO AVE	CHICAGO	IL	60611	COOK	USA	Cancer Treatment Research	001	5	12/30/2020	SUPPLEMENT FOR EXPANSION	$0
2021	2019	ANN & ROBERT H. LURIE CHILDREN'S HOSPITAL OF CHICAGO	225 E CHICAGO AVE	CHICAGO	IL	60611	COOK	USA	Cancer Treatment Research	002	5	12/31/2020	NON-COMPETING CONTINUATION	$0
														Subtotal = $1,022,242

Issue Date FY: 2020 ( Subtotal = $330,984 )
2020	2020	ANN & ROBERT H. LURIE CHILDREN'S HOSPITAL OF CHICAGO	225 E CHICAGO AVE	CHICAGO	IL	60611	COOK	USA	Cancer Treatment Research	001	5	7/21/2020	SUPPLEMENT FOR EXPANSION	$330,984
2020	2019	ANN & ROBERT H. LURIE CHILDREN'S HOSPITAL OF CHICAGO	225 E CHICAGO AVE	CHICAGO	IL	60611	COOK	USA	Cancer Treatment Research	000	5	7/21/2020	NON-COMPETING CONTINUATION	$0
														Subtotal = $330,984

Issue Date FY: 2019 ( Subtotal = $6,645 )
2019	2019	ANN & ROBERT H. LURIE CHILDREN'S HOSPITAL OF CHICAGO	225 E CHICAGO AVE	CHICAGO	IL	60611	COOK	USA	Cancer Treatment Research	003	5	8/23/2019	NON-COMPETING CONTINUATION	$6,645
2019	2018	ANN & ROBERT H. LURIE CHILDREN'S HOSPITAL OF CHICAGO	225 E CHICAGO AVE	CHICAGO	IL	60611	COOK	USA	Cancer Treatment Research	002	4	11/8/2018	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$0
2019	2018	ANN & ROBERT H. LURIE CHILDREN'S HOSPITAL OF CHICAGO	225 E CHICAGO AVE	CHICAGO	IL	60611	COOK	USA	Cancer Treatment Research	001	4	10/23/2018	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$535,386
2019	2017	BAYLOR COLLEGE OF MEDICINE	ONE BAYLOR PLAZA	HOUSTON	TX	77030	HARRIS	USA	Cancer Treatment Research	000	3	10/23/2018	NON-COMPETING CONTINUATION	-$535,386
														Subtotal = $6,645

Issue Date FY: 2018 ( Subtotal = $563,912 )
2018	2018	ANN & ROBERT H. LURIE CHILDREN'S HOSPITAL OF CHICAGO	225 E CHICAGO AVE	CHICAGO	IL	60611	COOK	USA	Cancer Treatment Research	001	4	9/18/2018	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$563,912
2018	2017	BAYLOR COLLEGE OF MEDICINE	ONE BAYLOR PLAZA	HOUSTON	TX	77030	HARRIS	USA	Cancer Treatment Research	000	3	9/18/2018	NON-COMPETING CONTINUATION	$0
														Subtotal = $563,912

Issue Date FY: 2017 ( Subtotal = $578,693 )
2017	2017	BAYLOR COLLEGE OF MEDICINE	ONE BAYLOR PLAZA	HOUSTON	TX	77030	HARRIS	USA	Cancer Treatment Research	000	3	8/28/2017	NON-COMPETING CONTINUATION	$578,693
														Subtotal = $578,693

Issue Date FY: 2016 ( Subtotal = $578,693 )
2016	2016	BAYLOR COLLEGE OF MEDICINE	ONE BAYLOR PLAZA	HOUSTON	TX	77030	HARRIS	USA	Cancer Treatment Research	000	2	7/4/2016	NON-COMPETING CONTINUATION	$578,693
														Subtotal = $578,693

Issue Date FY: 2015 ( Subtotal = $604,258 )
2015	2015	BAYLOR COLLEGE OF MEDICINE	ONE BAYLOR PLAZA	HOUSTON	TX	77030	HARRIS	USA	Cancer Treatment Research	000	1	7/14/2015	NEW	$604,258
														Subtotal = $604,258

Grand Total All Awards = $6,255,246

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In vivo Drug Testing of Pediatric CNS Tumors Using Patient Derived Orthotopic Xenograft Models

Award Number: U01CA199288

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: COOPERATIVE AGREEMENT

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

PERIOD OF PERFORMANCE START DATE: 07/14/2015

PERIOD OF PERFORMANCE END DATE: 06/30/2026

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