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Functional characterization and rational therapeutic targeting of 18q DNA copy number gains in diffuse large B-cell lymphoma

Award Number: R01CA240839
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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Project Summary Diffuse large B-cell lymphoma (DLBCL) is the most common form lymphoma and is conventionally treated with a combination of chemotherapeutics with the anti-CD20 antibody, Rituximab. Although more than half of patients can be cured with this approach, the remainder have a dire prognosis with a short survival. Despite the variability in patient outcome, there are currently no routinely utilized molecular biomarkers that can be employed for risk stratification or to direct a specific therapy. That is, precision medicine does not currently exist for DLBCL. We have identified a genetic alteration on the q-arm of chromosome 18 (18q) that is associated with an aggressive subtype of DLBCL, and defined the TCF4 and BCL2 genes as critical targets at this locus. The BCL2 gene encodes an important oncogene that prevents cell death, and can be targeted with the inhibitor Venetoclax. The TCF4 gene encodes a transcription factor protein that we have found to drive key malignant properties of lymphoma, such as promoting the expression of the MYC oncogene and the B-cell receptor. In addition, we have defined a way to eliminate TCF4 expression using a novel type of protein-degrader molecules that are directed towards BET proteins. This therefore provides an exciting rational therapeutic avenue for targeting TCF4. We hypothesize that combining this with an inhibitor of BCL2 will target both genes that are activated by 18q alterations, and provide a precision medicine approach for treating this aggressive subset of DLBCL. Here, we are proposing to investigate the function of 18q alterations in DLBCL and validate the mechanism by which we believe this genetic event leads to lymphoma. We will also perform pre-clinical investigation of combinations of BET and BCL2 inhibitors for the specific therapeutic targeting of 18q alterations. Together, this work will advance our understanding of DLBCL disease biology and may lead to advances in precision medicine for this disease.


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 = $418,885 )
2024	2024	UNIVERSITY OF TEXAS M. D. ANDERSON CANCER CENTER, THE	1515 HOLCOMBE BLVD	HOUSTON	TX	77030	HARRIS	USA	Cancer Biology Research	000	4	11/14/2023	NON-COMPETING CONTINUATION	$396,838
2024	2024	THE UNIVERISTY OF TEXAS MD ANDERSON CANCER CENTER, A COMPONENT OF THE UNIVERISTY OF TEXAS SYSTEM	1515 HOLCOMBE BLVD	HOUSTON	TX	77030	HARRIS	USA	Cancer Biology Research	001	4	4/16/2024	NON-COMPETING CONTINUATION	$22,047
														Subtotal = $418,885

Issue Date FY: 2023 ( Subtotal = $432,113 )
2023	2023	UNIVERSITY OF TEXAS M. D. ANDERSON CANCER CENTER, THE	1515 HOLCOMBE BLVD	HOUSTON	TX	77030	HARRIS	USA	Cancer Biology Research	000	3	11/28/2022	NON-COMPETING CONTINUATION	$396,838
2023	2023	UNIVERSITY OF TEXAS M. D. ANDERSON CANCER CENTER, THE	1515 HOLCOMBE BLVD	HOUSTON	TX	77030	HARRIS	USA	Cancer Biology Research	001	3	3/15/2023	NON-COMPETING CONTINUATION	$35,275
														Subtotal = $432,113

Issue Date FY: 2022 ( Subtotal = $432,113 )
2022	2022	UNIVERSITY OF TEXAS M. D. ANDERSON CANCER CENTER, THE	1515 HOLCOMBE BLVD	HOUSTON	TX	77030	HARRIS	USA	Cancer Biology Research	001	2	5/20/2022	NON-COMPETING CONTINUATION	$35,275
2022	2022	UNIVERSITY OF TEXAS M. D. ANDERSON CANCER CENTER, THE	1515 HOLCOMBE BLVD	HOUSTON	TX	77030	HARRIS	USA	Cancer Biology Research	000	2	12/1/2021	NON-COMPETING CONTINUATION	$396,838
														Subtotal = $432,113

Issue Date FY: 2021 ( Subtotal = $440,932 )
2021	2021	UNIVERSITY OF TEXAS M D ANDERSON CANCER CENTER	1515 HOLCOMBE BLVD UNIT 207	HOUSTON	TX	77030	HARRIS	USA	Cancer Biology Research	000	1	11/18/2020	NEW	$440,932
														Subtotal = $440,932

Grand Total All Awards = $1,724,043

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Functional characterization and rational therapeutic targeting of 18q DNA copy number gains in diffuse large B-cell lymphoma

Award Number: R01CA240839

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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