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G0S2 in chronic myeloid leukemia disease progression and imatinib resistance

Award Number: K22CA216008
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP
PERIOD OF PERFORMANCE START DATE: 09/10/2018
PERIOD OF PERFORMANCE END DATE: 02/28/2022

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G0S2 in chronic myeloid leukemia disease progression and imatinib resistance - PROJECT SUMMARY/ABSTRACT Chronic myeloid leukemia (CML) is caused by BCR-ABL1, a constitutively active tyrosine kinase. The development of tyrosine kinase inhibitors (TKIs) targeting BCR-ABL1 has revolutionized the treatment of CML, turning it from a fatal into a manageable chronic condition. Many patients respond favorably to TKIs, but some patients do not achieve a response, and others lose their response, for an overall estimated failure rate of 20- 30% in chronic phase (CP-CML), and even higher rates in advanced CML. While TKI resistance is commonly linked to point mutations in the BCR-ABL1 kinase domain, ~50% of clinical resistance cannot be explained by BCR-ABL1 mutations, suggesting BCR-ABL1 kinase-independent resistance. Recurrence of active CML after discontinuation of TKIs in responding patients is thought to reflect persistence of quiescent leukemic stem cells (LSCs) that are innately resistant to TKIs despite BCR-ABL1 inhibition. Thus, understanding the molecular mechanisms underlying BCR-ABL1 kinase-independent resistance will be critical to identify alternative treatment strategies for patients with TKI resistance or advanced CML and to eradicate disease. Microarray data revealed downregulation of G0S2 mRNA expression in CML CD34+ cells from imatinib non-responders (without mutations) compared to responders, and in advanced disease compared to chronic phase. Preliminary data suggests that G0S2 may play a role in both primary TKI resistance and in blastic transformation of CML. Specific Aim 1: Determine whether G0S2 loss promotes TKI resistance and disease progression in CML. Data from this aim will investigate the functional consequence of G0S2 loss in TKI resistance and blastic transformation. We will assess the role of G0S2 in the growth, survival, and TKI sensitivity of CML cell lines and primary CML CD34+ cells both in vitro and in vivo. We will also utilize a BCR-ABL1 transgenic mouse model and G0S2 null mice to assess the role of G0S2 in CML leukemogenesis in vivo. Specific Aim 2: Identify the mechanism by which loss of G0S2 induces TKI resistance in CML. G0S2 has been implicated in metabolic pathway regulation, including fatty acid synthesis and oxidative phosphorylation. We have formed a collaborative research team to rigorously establish the mechanistic role of G0S2 downregulation in TKI resistance. We will address how reduced expression of G0S2 influences these metabolic pathways and, in turn, whether these pathways alter imatinib response. Specific Aim 3: Determine the mechanism(s) by which G0S2 is downregulated in TKI resistance and identify strategies to restore G0S2 expression. Data from this aim will identify how G0S2 is downregulated in TKI resistance and blastic transformation, and will identify ways of reprogramming TKI-resistant cells into a TKI-sensitive phenotype. We will investigate the potential role of promoter hypermethylation and binding of transcriptional repressors, as well as the contribution of known oncogenic signaling pathways. These studies will be crucial for developing novel treatment approaches for TKI- resistant CML patients and other drug-resistant leukemias, and will launch my independent research career.


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: 2022 ( Subtotal = -$14,724 )
2022	2021	TEXAS TECH UNIVERSITY HEALTH SCIENCES CENTER AT EL PASO	5001 EL PASO DR	EL PASO	TX	79905	EL PASO	USA	Cancer Research Manpower	000	4	5/31/2022	SUPPLEMENT FOR EXPANSION	-$14,724
														Subtotal = -$14,724

Issue Date FY: 2021 ( Subtotal = $119,800 )
2021	2021	TEXAS TECH UNIVERSITY HEALTH SCIENCES CENTER AT EL PASO	5001 EL PASO DR	EL PASO	TX	79905	EL PASO	USA	Cancer Research Manpower	001	4	6/7/2021	SUPPLEMENT FOR EXPANSION	$119,800
2021	2020	TEXAS TECH UNIVERSITY HEALTH SCIENCES CENTER	3601 4TH STREET	LUBBOCK	TX	79430	LUBBOCK	USA	Cancer Research Manpower	002	3	7/21/2021	NON-COMPETING CONTINUATION	$0
2021	2020	TEXAS TECH UNIVERSITY HEALTH SCIENCES CENTER AT EL PASO	5001 EL PASO DR	EL PASO	TX	79905	EL PASO	USA	Cancer Research Manpower	004	4	9/9/2021	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$25,041
2021	2020	TEXAS TECH UNIVERSITY HEALTH SCIENCES CENTER AT EL PASO	5001 EL PASO DR	EL PASO	TX	79905	EL PASO	USA	Cancer Research Manpower	000	4	6/4/2021	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$0
2021	2019	TEXAS TECH UNIVERSITY HEALTH SCIENCES CENTER	3601 4TH STREET	LUBBOCK	TX	79430	LUBBOCK	USA	Cancer Research Manpower	003	2	9/9/2021	NON-COMPETING CONTINUATION	-$25,041
														Subtotal = $119,800

Issue Date FY: 2020 ( Subtotal = $195,590 )
2020	2020	TEXAS TECH UNIVERSITY HEALTH SCIENCES CENTER	3601 4TH STREET	LUBBOCK	TX	79430	LUBBOCK	USA	Cancer Research Manpower	002	3	6/30/2020	NON-COMPETING CONTINUATION	$195,590
2020	2020	TEXAS TECH UNIVERSITY HEALTH SCIENCES CENTER	3601 4TH STREET	LUBBOCK	TX	79430	LUBBOCK	USA	Cancer Research Manpower	001	3	6/26/2020	NON-COMPETING CONTINUATION	-$195,590
2020	2020	TEXAS TECH UNIVERSITY HEALTH SCIENCES CENTER AT EL PASO	5001 EL PASO DR	EL PASO	TX	79905	EL PASO	USA	Cancer Research Manpower	004	4	7/29/2020	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$195,590
2020	2020	TEXAS TECH UNIVERSITY HEALTH SCIENCES CENTER	3601 4TH STREET	LUBBOCK	TX	79430	LUBBOCK	USA	Cancer Research Manpower	003	3	7/29/2020	NON-COMPETING CONTINUATION	-$195,590
2020	2020	TEXAS TECH UNIVERSITY HEALTH SCIENCES CENTER	3601 4TH STREET	LUBBOCK	TX	79430	LUBBOCK	USA	Cancer Research Manpower	000	3	6/17/2020	NON-COMPETING CONTINUATION	$195,590
														Subtotal = $195,590

Issue Date FY: 2019 ( Subtotal = $195,590 )
2019	2019	TEXAS TECH UNIVERSITY HEALTH SCIENCES CENTER	3601 4TH STREET	LUBBOCK	TX	79430	LUBBOCK	USA	Cancer Research Manpower	000	2	7/11/2019	NON-COMPETING CONTINUATION	$195,590
														Subtotal = $195,590

Issue Date FY: 2018 ( Subtotal = $193,030 )
2018	2018	TEXAS TECH UNIVERSITY HEALTH SCIENCES CENTER	3601 4TH ST	LUBBOCK	TX	79430	LUBBOCK	USA	Cancer Research Manpower	000	1	9/9/2018	NEW	$193,030
														Subtotal = $193,030

Grand Total All Awards = $689,286

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G0S2 in chronic myeloid leukemia disease progression and imatinib resistance

Award Number: K22CA216008

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP

PERIOD OF PERFORMANCE START DATE: 09/10/2018

PERIOD OF PERFORMANCE END DATE: 02/28/2022

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