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ROLE OF SORD IN SUGAR-MEDIATED CANCER METASTASIS

Award Number: R01CA262437
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 03/08/2022
PERIOD OF PERFORMANCE END DATE: 02/28/2028

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ROLE OF SORD IN SUGAR-MEDIATED CANCER METASTASIS - Colorectal cancer (CRC) is the second leading cause of cancer-related deaths in the USA. An estimated 53,200 people will die from CRC in 2020. Another disturbing fact is that the rates of incidence and mortality from young adults have been increasing since the 1990s for unknown reasons. The mortality of CRC patients is mainly attributed to tumor metastasis, a complex, multistep process. This proposal aims to uncover the underlying mechanisms that control CRC metastasis and the key pathways and environmental factors that contribute to it. One possible factor is sugar-sweetened beverages (SSBs), the consumption of which has dramatically increased in the past four decades. SSBs are any liquids that are sweetened with refined sugars, such as sucrose and high-fructose corn syrup (HFCS), both of which consist of glucose and fructose in a ratio of approximately 1:1. More than half of the adults in the USA consume SSBs on a given day. Epidemiological studies have shown a positive correlation between SSBs consumption and the recurrence of and mortality from advanced-stage CRC. However, it is still unclear whether SSB consumption can directly affect metastasis on advanced-stage CRC and, therefore mortality, independently of obesity. This question is critical because certain CRC patients regularly consume SSBs. Moreover, oncologists and nutritionists in the US recommend that their CRC patients drink energy drinks and concentrated juices—which are, in fact, SSBs with high amounts of added sugar—because these SSBs also contain calories, protein, and/or micronutrients. Our preliminary data show that a medium containing both glucose and fructose (hereafter, the HFCS condition) increased the migration and invasion of CRC cell lines (hereafter, CRC motility), which was correlated with an increased level of sorbitol. The deletion of a NAD(H)-dependent sorbitol dehydrogenase (SORD) decreased CRC motility and sorbitol level in the HFCS condition. Our xenograft mice models also showed that HFCS treatment increased CRC metastasis (local invasion and liver metastasis), and SORD was necessary for the metastasis. Notably, the loss of SORD also inhibited CRC motility in the high-glucose condition, in which glucose converts to fructose via the polyol pathway. It is known that chronic consumption of SSBs causes a high concentration of glucose in the blood. Thus, we hypothesize that SORD plays a key role in accelerating CRC metastasis by interacting with sugars. We propose three aims: Aim 1: Determine how SORD accelerates CRC motility in the HFCS condition. Aim 2: Determine how SORD increases CRC motility in the high-glucose condition. Aim 3: Understand the role of SORD in CRC metastasis. Successful completion of these proposed studies will characterize SORD as a novel therapeutic target for CRC metastasis. Further, our results will identify metabolic pathways and metabolites that may serve as new biomarkers or targets for preventing CRC metastasis. Finally, our study will highlight the danger of HFCS consumption, especially in the form of SSBs, which may accelerate CRC metastasis. This will change current clinical practices and dietary guidelines for CRC patients, significantly reducing CRC mortality.


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 = $408,671 )
2026	2026	THE UNIVERISTY OF TEXAS M.D. ANDERSON CANCER CENTER	1515 HOLCOMBE BLVD	HOUSTON	TX	77030	HARRIS	USA	Cancer Biology Research	001	6	4/16/2026	NON-COMPETING CONTINUATION	$40,867
2026	2026	THE UNIVERISTY OF TEXAS M.D. ANDERSON CANCER CENTER	1515 HOLCOMBE BLVD	HOUSTON	TX	77030	HARRIS	USA	Cancer Biology Research	000	6	1/28/2026	NON-COMPETING CONTINUATION	$367,804
														Subtotal = $408,671

Issue Date FY: 2025 ( Subtotal = $360,071 )
2025	2025	THE UNIVERISTY OF TEXAS M.D. ANDERSON CANCER CENTER	1515 HOLCOMBE BLVD	HOUSTON	TX	77030	HARRIS	USA	Cancer Biology Research	001	5	5/22/2025	NON-COMPETING CONTINUATION	$36,007
2025	2025	THE UNIVERISTY OF TEXAS M.D. ANDERSON CANCER CENTER	1515 HOLCOMBE BLVD	HOUSTON	TX	77030	HARRIS	USA	Cancer Biology Research	000	5	3/3/2025	NON-COMPETING CONTINUATION	$324,064
														Subtotal = $360,071

Issue Date FY: 2024 ( Subtotal = $326,678 )
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	000	4	2/9/2024	NON-COMPETING CONTINUATION	$309,484
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	$17,194
														Subtotal = $326,678

Issue Date FY: 2023 ( Subtotal = $24,398 )
2023	2023	UNIVERSITY OF TEXAS M. D. ANDERSON CANCER CENTER, THE	1515 HOLCOMBE BLVD	HOUSTON	TX	77030	HARRIS	USA	Cancer Biology Research	000	3	4/18/2023	NON-COMPETING CONTINUATION	$24,398
2023	2022	BAYLOR COLLEGE OF MEDICINE	1 BAYLOR PLZ	HOUSTON	TX	77030	HARRIS	USA	Cancer Biology Research	001	1	5/18/2023	NEW	-$19,506
2023	2022	UNIVERSITY OF TEXAS M. D. ANDERSON CANCER CENTER, THE	1515 HOLCOMBE BLVD	HOUSTON	TX	77030	HARRIS	USA	Cancer Biology Research	002	2	5/18/2023	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$19,506
														Subtotal = $24,398

Issue Date FY: 2022 ( Subtotal = $414,665 )
2022	2022	UNIVERSITY OF TEXAS M. D. ANDERSON CANCER CENTER, THE	1515 HOLCOMBE BLVD	HOUSTON	TX	77030	HARRIS	USA	Cancer Biology Research	002	2	9/8/2022	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$376,368
2022	2022	BAYLOR COLLEGE OF MEDICINE	ONE BAYLOR PLAZA	HOUSTON	TX	77030	HARRIS	USA	Cancer Biology Research	000	1	3/8/2022	NEW	$398,243
2022	2022	BAYLOR COLLEGE OF MEDICINE	1 BAYLOR PLZ	HOUSTON	TX	77030	HARRIS	USA	Cancer Biology Research	001	1	9/8/2022	NEW	-$359,946
														Subtotal = $414,665

Grand Total All Awards = $1,534,483

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ROLE OF SORD IN SUGAR-MEDIATED CANCER METASTASIS

Award Number: R01CA262437

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 03/08/2022

PERIOD OF PERFORMANCE END DATE: 02/28/2028

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