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Mechanisms of STING in malignant progression and therapy of CLL.

Award Number: R01CA269835
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 02/01/2023
PERIOD OF PERFORMANCE END DATE: 01/31/2028

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Mechanisms of STING in malignant progression and therapy of CLL. - Project Summary/Abstract Chronic lymphocytic leukemia (CLL) represents 30% of adult leukemia and is still incurable. According to the National Cancer Institute, approximately 21,250 new cases of CLL and 4,320 deaths from CLL are projected in the United States alone in 2021. Although the Bruton's tyrosine kinase inhibitor (BTKi) is an effective targeted therapy for CLL, approximately 50% of BTKi-treated CLL patients have dropped out of the therapy due to chronic adverse effects. Additionally, significantly increased numbers of CLL patients treated with BTKi or other kinase inhibitors have developed the more medically challenging diffuse large B cell lymphoma. Novel therapy that can directly target CLL or be rationally combined with BTKi is highly desirable. The stimulator of interferon genes (STING) is an endoplasmic reticulum (ER)-resident protein critical for sensing cytoplasmic DNA and promoting production of type I interferons, thereby boosting immune responses. STING agonists, such as ADU-S100, have been used as combination immunotherapy with Pembrolizumab in clinical trials to treat advanced solid tumors and lymphomas, and these therapeutic applications of STING agonists are based on the main known function of STING in eliciting anti-tumor immunity. We were the first to show that STING agonists directly induce potent mitochondria-mediated apoptosis in B cell-derived malignancies including CLL, while these agonists induce production of interferons in melanoma, hepatoma and lung cancer cells without suppressing their growth. Apoptosis of CLL, B cell lymphoma and multiple myeloma requires STING, because genetic deletion of STING results in resistance of all these cells to STING agonist-mediated apoptosis. Apoptosis of these cells is not due to the production of inflammatory cytokines but may involve the prolonged presence of agonist-bound STING. Together with our new preliminary results showing that mutation-mediated activation of STING causes rapid degradation of the B cell receptor (BCR) and significantly reduced BCR signaling (disadvantageous for CLL survival), and that novel serine residues on STING are phosphorylated in agonist-stimulated malignant B cells, we propose to identify and characterize differential phosphorylation and interacting partners of activated STING to further understand the mechanisms by which activated STING causes BCR degradation and apoptosis in CLL. Since our preliminary data show that STING deficiency can lead to increased levels of the BCR and BCR signaling in mouse CLL, and that mouse and human malignant CLL cells significantly downregulate their expression levels of STING, we will test whether STING- downregulated or STING-deficient CLL cells are less sensitive to BTKi. We will also examine how such altered STING expression and phosphorylation can regulate the survival, progression and chemoresistance of CLL. Based on our hypothesis that activation of STING can lead to the degradation of the BCR and render CLL cells more sensitive to BTKi, we propose to combine STING agonists with BTKi to treat CLL.


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: 2026 ( Subtotal = $442,928 )
2026	2026	THE METHODIST HOSPITAL RESEARCH INSTITUTE	6565 FANNIN ST STE D200	HOUSTON	TX	77030	HARRIS	USA	Cancer Biology Research	000	4	2/11/2026	NON-COMPETING CONTINUATION	$442,928
														Subtotal = $442,928

Issue Date FY: 2025 ( Subtotal = $492,142 )
2025	2025	METHODIST HOSPITAL, THE	6670 BERTNER AVE	HOUSTON	TX	77030	HARRIS	USA	Cancer Biology Research	000	3	1/24/2025	NON-COMPETING CONTINUATION	$442,928
2025	2025	METHODIST HOSPITAL, THE	6670 BERTNER AVE	HOUSTON	TX	77030	HARRIS	USA	Cancer Biology Research	001	3	8/22/2025	NON-COMPETING CONTINUATION	$49,214
														Subtotal = $492,142

Issue Date FY: 2024 ( Subtotal = $467,536 )
2024	2024	METHODIST HOSPITAL, THE	6670 BERTNER AVE	HOUSTON	TX	77030	HARRIS	USA	Cancer Biology Research	000	2	2/6/2024	NON-COMPETING CONTINUATION	$442,928
2024	2024	METHODIST HOSPITAL, THE	6670 BERTNER AVE	HOUSTON	TX	77030	HARRIS	USA	Cancer Biology Research	001	2	4/22/2024	NON-COMPETING CONTINUATION	$24,608
														Subtotal = $467,536

Issue Date FY: 2023 ( Subtotal = $492,142 )
2023	2023	METHODIST HOSPITAL, THE	6670 BERTNER AVE	HOUSTON	TX	77030	HARRIS	USA	Cancer Biology Research	000	1	2/1/2023	NEW	$492,142
														Subtotal = $492,142

Grand Total All Awards = $1,894,748

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Mechanisms of STING in malignant progression and therapy of CLL.

Award Number: R01CA269835

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 02/01/2023

PERIOD OF PERFORMANCE END DATE: 01/31/2028

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