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Bioinformatic-Chemical Approach to Credential Molecular Targets to Combat Rapid Chemo-Radiation Resistance in SCLC

Award Number: U01CA231776
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: COOPERATIVE AGREEMENT
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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Bioinformatic-Chemical Approach to Credential Molecular Targets to Combat Rapid Chemo-Radiation Resistance in SCLC - PROJECT ABSTRACT Limited stage small cell lung cancer (LS SCLC), the only curable form of SCLC, is remarkably sensitive to etoposide plus cisplatin combined with thoracic radiotherapy with response rates > 70%; however, therapy- refractory recurrence is common. LS SCLC has less than a 25% 5-year overall survival (OS) and ultimately a strategy for improving long-term SCLC outcomes needs to successfully target tumor cell populations that survive standard therapy and give rise to recurrent disease. There is, however, a considerable gap in understanding the specific mechanisms responsible for chemoradiotherapy resistance in SCLC. Our project is unique among the current portfolio of SCLC funded programs in that we have focused on chemoradioresistance to increase cure rates in LS SCLC. Recently, our work has suggested using patient- derived xenograft (PDX) models of SCLC may be an important tool to elucidate mechanisms of therapy resistance. This approach was remarkably successful, identifying a tolerable and strongly synergistic anti- SCLC interaction that led to a CTEP-approved trial based on our preclinical data - (NCI #10070; Study Chair: Hann). In this research program, we will test key hypotheses via three specific aims that will provide more mechanistic insights into the rapidly emergent chemoradiation resistance observed in LS SCLC. One central hypothesis of this proposal is that adaptive gene expression changes mediate rapid emergence of the chemoradiation resistance phenotype in LS SCLC. We have developed a novel chemoradiation treatment regimen with SCLC PDX models to facilitate these studies. Development and characterization of this novel model involves a unique collaboration between medical oncologists, radiation oncologists, bioinformaticians, medical physicists, veterinarians and molecular/cell biologists that is extremely well suited to develop an integrated program dedicated to resolving questions of SCLC chemoradioresistance. Finally, we have already identified novel gene targets that are correlated with SCLC chemoradioresistance. Our research program is organized as follows: Aim #1: Characterize natural history of response of experimental models of SCLC to chemoradiation in vivo. We will determine response rates and recurrence patterns of a panel of SCLC PDXs and transgenic mouse models. Aim #2: Characterization of molecular underpinnings of SCLC chemoradiation resistance. We will reconstruct gene regulatory networks and gene expression profiles associated with chemoradiation resistance and develop small-scale predictive classifiers for therapy response to be validated in follow-up studies. Aim #3: Pharmacologic and genetic validation of candidate genes for SCLC chemoradiation resistance in vitro and in vivo. We will validate our novel gene candidates for conferring chemoradiation resistance using pharmacologic and genetic approach with SCLC PDX-derived organoids and SCLC transgenic mouse models.


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 = -$3 )
2025	2022	THE JOHNS HOPKINS UNIVERSITY	3400 N CHARLES ST	BALTIMORE	MD	21218	BALTIMORE CITY	USA	21st Century Cures Act - Beau Biden Cancer Moonshot	001	5	2/4/2025	SUPPLEMENT FOR EXPANSION	-$1
2025	2022	THE JOHNS HOPKINS UNIVERSITY	3400 N CHARLES ST	BALTIMORE	MD	21218	BALTIMORE CITY	USA	Cancer Treatment Research	000	5	2/4/2025	NON-COMPETING CONTINUATION	-$2
														Subtotal = -$3

Issue Date FY: 2024 ( Subtotal = $0 )
2024	2022	JOHNS HOPKINS UNIVERSITY, THE	3400 N CHARLES ST	BALTIMORE	MD	21218	BALTIMORE CITY	USA	Cancer Treatment Research	000	5	10/11/2023	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2023 ( Subtotal = $0 )
2023	2022	JOHNS HOPKINS UNIVERSITY, THE	3400 N CHARLES ST	BALTIMORE	MD	21218	BALTIMORE CITY	USA	Cancer Treatment Research	000	5	5/19/2023	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2022 ( Subtotal = $967,812 )
2022	2022	JOHNS HOPKINS UNIVERSITY, THE	3400 N CHARLES ST	BALTIMORE	MD	21218	BALTIMORE CITY	USA	Cancer Treatment Research	001	5	8/22/2022	NON-COMPETING CONTINUATION	$599,374
2022	2022	JOHNS HOPKINS UNIVERSITY, THE	3400 N CHARLES ST	BALTIMORE	MD	21218	BALTIMORE CITY	USA	21st Century Cures Act - Beau Biden Cancer Moonshot	002	5	9/23/2022	SUPPLEMENT FOR EXPANSION	$368,438
2022	2021	JOHNS HOPKINS UNIVERSITY, THE	3400 N CHARLES ST	BALTIMORE	MD	21218	BALTIMORE CITY	USA	Cancer Treatment Research	000	4	3/18/2022	NON-COMPETING CONTINUATION	$0
														Subtotal = $967,812

Issue Date FY: 2021 ( Subtotal = $1,120,184 )
2021	2021	JOHNS HOPKINS UNIVERSITY, THE	3400 N CHARLES ST	BALTIMORE	MD	21218	BALTIMORE CITY	USA	21st Century Cures Act - Beau Biden Cancer Moonshot	000	3	4/5/2021	SUPPLEMENT FOR EXPANSION	$153,517
2021	2021	JOHNS HOPKINS UNIVERSITY, THE	3400 N CHARLES ST	BALTIMORE	MD	21218	BALTIMORE CITY	USA	21st Century Cures Act - Beau Biden Cancer Moonshot	005	4	8/27/2021	SUPPLEMENT FOR EXPANSION	$368,438
2021	2021	JOHNS HOPKINS UNIVERSITY, THE	3400 N CHARLES ST	BALTIMORE	MD	21218	BALTIMORE CITY	USA	21st Century Cures Act - Beau Biden Cancer Moonshot	002	3	6/23/2021	SUPPLEMENT FOR EXPANSION	$0
2021	2021	JOHNS HOPKINS UNIVERSITY, THE	3400 N CHARLES ST	BALTIMORE	MD	21218	BALTIMORE CITY	USA	Cancer Treatment Research	004	4	8/24/2021	NON-COMPETING CONTINUATION	$243,168
2021	2021	JOHNS HOPKINS UNIVERSITY, THE	3400 N CHARLES ST	BALTIMORE	MD	21218	BALTIMORE CITY	USA	Cancer Treatment Research	003	4	8/13/2021	NON-COMPETING CONTINUATION	$355,061
2021	2021	JOHNS HOPKINS UNIVERSITY, THE	3400 N CHARLES ST	BALTIMORE	MD	21218	BALTIMORE CITY	USA	21st Century Cures Act - Beau Biden Cancer Moonshot	001	3	4/29/2021	SUPPLEMENT FOR EXPANSION	$0
														Subtotal = $1,120,184

Issue Date FY: 2020 ( Subtotal = $611,606 )
2020	2020	JOHNS HOPKINS UNIVERSITY, THE	3400 N CHARLES ST	BALTIMORE	MD	21218	BALTIMORE CITY	USA	Cancer Treatment Research	002	3	9/14/2020	NON-COMPETING CONTINUATION	$0
2020	2020	JOHNS HOPKINS UNIVERSITY, THE	3400 N CHARLES ST	BALTIMORE	MD	21218	BALTIMORE CITY	USA	Cancer Treatment Research	001	3	8/5/2020	NON-COMPETING CONTINUATION	$611,606
2020	2019	JOHNS HOPKINS UNIVERSITY, THE	3400 N CHARLES ST	BALTIMORE	MD	21218	BALTIMORE CITY	USA	Cancer Treatment Research	000	2	2/6/2020	NON-COMPETING CONTINUATION	$0
														Subtotal = $611,606

Issue Date FY: 2019 ( Subtotal = $593,258 )
2019	2019	JOHNS HOPKINS UNIVERSITY, THE	3400 N CHARLES ST	BALTIMORE	MD	21218	BALTIMORE CITY	USA	Cancer Treatment Research	000	2	8/1/2019	NON-COMPETING CONTINUATION	$593,258
														Subtotal = $593,258

Issue Date FY: 2018 ( Subtotal = $611,606 )
2018	2018	JOHNS HOPKINS UNIVERSITY, THE	3400 N CHARLES ST	BALTIMORE	MD	21218	BALTIMORE CITY	USA	Cancer Treatment Research	000	1	9/3/2018	NEW	$611,606
														Subtotal = $611,606

Grand Total All Awards = $3,904,463

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Bioinformatic-Chemical Approach to Credential Molecular Targets to Combat Rapid Chemo-Radiation Resistance in SCLC

Award Number: U01CA231776

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: COOPERATIVE AGREEMENT

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

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