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Transcriptional activation of LAMC1 as a resistance mechanism in recurrent PFA Ependymoma

Award Number: R21NS120075
ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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Brain and other tumors of the central-nervous system (CNS) are the most common cancers in children aged 0- 14 years in the USA. Ependymoma (EPN) is the third most common pediatric brain tumor and a leading cause of death in childhood cancer patients. The most common and aggressive subgroup, posterior fossa ependymoma group A (PFA), occurs mainly in young children and frequently leads to recurrences. Despite extensive DNA sequencing studies, the only molecular marker associated with particularly poor survival is gain of the chromosome arm 1q. The overall objective of this proposal is to identify the molecular mechanisms that cause the poor survival of 1q+ PFA EPN patients. To approach this objective, we have analyzed the 3D conformation of 1q+ PFA EPN tumor genomes using HiC. As a result, we identify complex inter-chromosomal structural variants (SVs) that result in the formation of new topologically associated domains (‘neo-TADs’) leading to transcriptional activation of LAMC1. Based on these results, we now hypothesize that the transcriptional activation of LAMC1 by the formation of SV-induced neo-TADs is a common resistance mechanism in recurrent 1q+ PFA EPN tumors. Thus, strategies that target LAMC1 may reveal new vulnerabilities and overcome resistance to therapy in the treatment of PFA EPN relapse patients. The rationale for this project is that resolving SVs in a larger cohort of available PFA EPN relapse samples using HiC and functional inhibition experiments against LAMC1 in relapse PFA EPN models are likely to provide a strong scientific framework in which basic mechanisms of epigenetically linked activation of proliferation and new therapeutic opportunities can be identified. The central hypothesis will be tested by pursuing to answer two specific aims: First, we aim to determine the frequency of SVs in a larger cohort of 1q+ PFA ependymomas and their impact on regulatory domains (Aim 1). Second, we aim to determine the therapeutic potential of targeting LAMC1 in patient-derived models of relapse PFA ependymomas (Aim 2). Ultimately, our studies have the potential to improve our understanding of the epigenetic regulation that drives the acquisition of stemness and resistance to therapy and to advance the treatment of PFA EPN patients. The research proposed in this application is innovative, in the applicant’s opinion, because it interrogates a new molecular mechanism of transcriptional LAMC1 activation in recently derived faithful models of PFA EPN. The proposed research is significant, because it is expected to provide new therapeutic opportunities for a pediatric brain tumor type that is a leading cause of death in childhood cancer patients. Ultimately, our studies have the potential to improve our understanding of the epigenetic regulation that drives the acquisition of stemness and to advance the treatment of diseases.


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 = $0 )
2024	2022	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	2	12/8/2023	NON-COMPETING CONTINUATION	-$615
2024	2022	SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE	10901 N TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	002	3	12/8/2023	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$615
2024	2022	SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE	10901 N TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	3	12/4/2023	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$0
														Subtotal = $0

Issue Date FY: 2023 ( Subtotal = $37,180 )
2023	2022	SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE	10901 N TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	3	2/17/2023	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$195,948
2023	2022	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	2	2/17/2023	NON-COMPETING CONTINUATION	-$158,768
														Subtotal = $37,180

Issue Date FY: 2022 ( Subtotal = $197,500 )
2022	2022	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	2	10/28/2021	NON-COMPETING CONTINUATION	$177,750
2022	2022	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	2	3/22/2022	NON-COMPETING CONTINUATION	$19,750
														Subtotal = $197,500

Issue Date FY: 2021 ( Subtotal = $236,563 )
2021	2021	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	11/30/2020	NEW	$236,563
														Subtotal = $236,563

Grand Total All Awards = $471,243

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Transcriptional activation of LAMC1 as a resistance mechanism in recurrent PFA Ependymoma

Award Number: R21NS120075

ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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