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Targeting the RNA modifying enzyme ALKBH5 in Medulloblastoma

Award Number: R21CA277164
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 06/01/2023
PERIOD OF PERFORMANCE END DATE: 05/31/2026

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Targeting the RNA modifying enzyme ALKBH5 in Medulloblastoma - Abstract Medulloblastoma is the most common malignant childhood brain tumor, which accounts for large number of all childhood cancer deaths. MB are very fast-growing tumors, which spreads to central nervous system (CNS) through cerebrospinal fluid, which leads to leptomeningeal metastases that occurs up to 66% in brain cancer patients. Despite the progress in treating MB, the 5-year survival rate for high-risk MB remains poor with high recurrence. Moreover, the quality of life for those kids who do survive is substantially reduced due to the high toxicity associated with the high radiation exposure and multiple drug chemotherapy they must endure at such an early age. Therefore, it is critical to identify novel factors and understand previously undefined mechanisms that drive MB growth and progression, so that safe and viable therapeutics can be developed for treating MB. In this proposal, we provide compelling evidence that RNA demethylase ALKBH5 may play an important role in MB growth and progression by supporting MB cancer (tumor initiating) stem cells (MB-CSC) and thus serve as a novel therapeutic target. Our preliminary results revealed that MB cells are highly dependent on ALKBH5 for its survival. Using multiple MB cell lines with or without ALKBH5 depletion, we discovered that depletion of ALKBH5 inhibited both short and long-term growth of MB cells. In addition, depletion of ALKBH5 inhibited the migration of MB cells. Importantly, we show that ALKBH5 silencing suppressed the self-renewal/proliferation of MB stem cell. Supporting that, ALKBH5-depletion led to significantly decreased levels of cancer stem cell markers. These are significant findings as MB stem cells are considered to be the major source of MB initiation, maintenance, relapse and render MB cells resistant to radiation. These observations led us to hypothesize that RNA demethylase ALKBH5 supports MB growth and progression by promoting cancer stem cell self-renewal; and those approaches aimed at targeting ALKBH5 level/activity will sensitize radiation response in MB patients. To test these hypotheses, we propose following two Specific Aims: In aim#1, To establish the role of ALKBH5 as a promoter of MB growth and progression. In aim#2, To determine the mechanism by which ALKBH5 regulates MB stemness and growth by identifying and characterizing ALKBH5 target genes and their m6A status in MB cells. Successful completion of this proposal will indicate RNA epigenetics as an important regulator of medulloblastoma stem cell viability and self-renewal. Given that ALKBH5 knockout mice is reported to be viable and our preliminary studies showing high dependency of MB cell survival on ALKBH5 suggest that ALKBH5 may serve as a novel and safe therapeutic target for treating MB patients.


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: 2027 ( Subtotal = -$1,435 )
2027	2024	THE UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER AT SAN ANTONIO	7703 FLOYD CURL DR	SAN ANTONIO	TX	78229	BEXAR	USA	Cancer Biology Research	000	2	10/13/2026	NON-COMPETING CONTINUATION	-$1,435
														Subtotal = -$1,435

Issue Date FY: 2024 ( Subtotal = $172,098 )
2024	2024	THE UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER AT SAN ANTONIO	7703 FLOYD CURL DR	SAN ANTONIO	TX	78229	BEXAR	USA	Cancer Biology Research	000	2	4/23/2024	NON-COMPETING CONTINUATION	$172,098
														Subtotal = $172,098

Issue Date FY: 2023 ( Subtotal = $181,156 )
2023	2023	UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER OF SAN ANTONIO	7703 FLOYD CURL DR	SAN ANTONIO	TX	78229	BEXAR	USA	Cancer Biology Research	000	1	6/1/2023	NEW	$181,156
														Subtotal = $181,156

Grand Total All Awards = $351,819

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Targeting the RNA modifying enzyme ALKBH5 in Medulloblastoma

Award Number: R21CA277164

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 06/01/2023

PERIOD OF PERFORMANCE END DATE: 05/31/2026

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