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Targeting centrosome‐mitotic kinases as a novel therapeutic approach against breast cancers in Hispanic/Latinas.

Award Number: R01CA266046
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/15/2022
PERIOD OF PERFORMANCE END DATE: 08/31/2027

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Targeting centrosome‐mitotic kinases as a novel therapeutic approach against breast cancers in Hispanic/Latinas. - Triple-negative breast cancer (ER-PR- and Her2- or TNBC) is the most aggressive breast cancer subtype. Incidence and mortality from TNBCs are higher in individuals with significant African genomic ancestry in our catchment areas (Tampa and Puerto Rico). TNBCs are more likely to be detected at higher stages and grades. Centrosome amplification (CA)-driven mitotic dysfunction leading to chromosome instability (CIN) and aneuploidy may also contribute to metastasis and poor clinical outcomes of these TNBC patients. The Co-PIs published that the centrosome/mitotic kinases TTK and NEK2 generate CA/CIN and that TTK and NEK2 drive the epithelial to mesenchymal transition (EMT). Preliminary data indicate that TTK and NEK2 are dysregulated in TNBCs and differentially expressed in patients from different ancestral genomic backgrounds. Also, by using a novel NCI-BMAP3 region breast cancer tissue microarray (TMA) containing samples from breast cancer patients from our catchment area, the Co-PIs found that TTK is overexpressed in TNBC and TTK correlates with EMT in TNBC. Inactivating TTK restored Rb in TNBC cells, suggesting it can restore Palbociclib responses. Co-inactivating TTK in TNBC cells reduced the levels of centrosome/mitotic regulators and EMT markers, and co-inactivating TTK/NEK2 significantly reduced the migration and invasion of TNBC. The study team hypothesizes that TTK and NEK2 dysregulation in breast cancer patients from our catchment areas contributes to their poor survival outcomes by driving cancer cell survival and early metastasis. To test this hypothesis, the team proposes the following Specific Aims: (1) Investigating signaling pathways linking mitotic kinases to early metastasis and poor prognosis of in patients from different ancestral genomic backgrounds with breast cancer. The team will determine if expression signatures and copy number variations correlate with the expression of mitotic kinases with EMT markers, and survival outcomes, using RNA and DNA seq done by the ORIEN consortium and a novel TMA. (2) To address how co-inactivation of mitotic kinases suppresses the mesenchymal state, metastasis, and restores Palbociclib responses in TNBC cells. This will be addressed by single and combinatorial inhibition of TTK, NEK2, and TBK1 in primary cell lines and PDX models of TNBC from patients with breast cancer. Results from the proposed experiments will identify actionable targets (TTK, NEK2, and other novel kinases found in Aim 1) against the aggressive growth and early metastatic progression in patients with TNBC.


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: 2025 ( Subtotal = $1,319,332 )
2025	2025	PONCE MEDICAL SCHOOL FOUNDATION INC	388 CALLE LUIS F SALA	PONCE	PR	00716	PONCE	USA	Cancer Biology Research	002	4	9/12/2025	SUPPLEMENT FOR EXPANSION	$239,942
2025	2025	PONCE MEDICAL SCHOOL FOUNDATION INC	388 CALLE LUIS F SALA	PONCE	PR	00716	PONCE	USA	Cancer Biology Research	001	4	9/4/2025	EXTENSION WITH OR WITHOUT FUNDS	$1,079,390
2025	2024	PONCE MEDICAL SCHOOL FOUNDATION INC	388 CALLE LUIS F SALA	PONCE	PR	00716	PONCE	USA	Cancer Biology Research	000	3	9/4/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $1,319,332

Issue Date FY: 2024 ( Subtotal = $604,083 )
2024	2024	PONCE MEDICAL SCHOOL FOUNDATION INC	388 CALLE LUIS F SALA	PONCE	PR	00716	PONCE	USA	Cancer Biology Research	000	3	8/9/2024	NON-COMPETING CONTINUATION	$486,917
2024	2024	PONCE MEDICAL SCHOOL FOUNDATION INC	388 CALLE LUIS F SALA	PONCE	PR	00716	PONCE	USA	Cancer Biology Research	001	3	9/25/2024	SUPPLEMENT FOR EXPANSION	$117,166
														Subtotal = $604,083

Issue Date FY: 2023 ( Subtotal = $487,437 )
2023	2023	PONCE MEDICAL SCHOOL FOUNDATION INC	388 CALLE LUIS F SALA	PONCE	PR	00716	PONCE	USA	Cancer Biology Research	001	2	9/1/2023	NON-COMPETING CONTINUATION	$487,437
2023	2022	PONCE MEDICAL SCHOOL FOUNDATION INC	388 CALLE LUIS F SALA	PONCE	PR	00716	PONCE	USA	Cancer Biology Research	000	1	2/17/2023	NEW	$0
														Subtotal = $487,437

Issue Date FY: 2022 ( Subtotal = $483,219 )
2022	2022	PONCE MEDICAL SCHOOL FOUNDATION INC	388 CALLE LUIS F SALA	PONCE	PR	00716	PONCE	USA	Cancer Biology Research	000	1	9/15/2022	NEW	$483,219
														Subtotal = $483,219

Grand Total All Awards = $2,894,071

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Targeting centrosome‐mitotic kinases as a novel therapeutic approach against breast cancers in Hispanic/Latinas.

Award Number: R01CA266046

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 09/15/2022

PERIOD OF PERFORMANCE END DATE: 08/31/2027

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