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Mechanisms of paclitaxel sensitivity and resistance

Award Number: R01CA284747
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 03/04/2024
PERIOD OF PERFORMANCE END DATE: 02/28/2029

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Mechanisms of paclitaxel sensitivity and resistance - SUMMARY The microtubule poison paclitaxel (PTX) is standard-of-care for breast cancer treatment for all breast cancer subtypes in both early stage and metastatic disease. However, ~50% of breast cancer patients do not benefit from PTX. Though PTX causes mitotic arrest at high concentrations in cell culture, our data from two biomarker studies demonstrate that PTX levels in patient tumors are too low to cause mitotic arrest. Instead PTX causes abnormal multipolar mitotic spindles. Division on multipolar spindles causes unequal chromosome segregation (termed chromosomal instability, or CIN). While low rates of CIN are common in tumors, increasing the rate of CIN above a maximally tolerated threshold is lethal. Since PTX increases CIN, these data support a model in which PTX is effective when it increases CIN over the maximally tolerated threshold. Our long term goal is to use this novel mechanistic insight to convert PTX from generic chemotherapy into precision medicine by developing a) a biomarker to predict which tumors will respond to PTX, and b) method(s) to sensitize the ~50% of resistant cancers. Based on our preliminary data, we hypothesize that there are two major determinants of PTX sensitivity. First, tumors that have endogenous CIN close to the maximally tolerated CIN threshold are more sensitive to PTX. Second, some tumors can focus PTX-induced multipolar spindles into near-normal bipolar spindles by mid mitosis and dramatically reduce PTX-induced cytotoxicity—even when PTX affects spindles in early mitosis. Since PTX treatment increases the incidence of multipolar spindles in early mitosis, this implicates mid mitosis focusing of PTX-induced multipolar spindles as a second mechanism of PTX resistance. Aim 1 will test the hypothesis that pre-treatment CIN correlates with PTX response in primary breast cancer, as determined in an ongoing biomarker study of neoadjuvant single-agent PTX and a retrospective analysis of I-SPY2 samples. Additionally, Aim 1 will test whether experimentally inducing CIN enhances PTX response. Aim 2 will enable state-of-the-art quantitative measure of CIN by a) employing single-cell DNA sequencing (scDNAseq) to quantify all chromosomes; and b) accounting for dropout of highly aneuploid cells from the tumor population through a technique known as Approximate Bayesian Computation. Aim 3 will experimentally test how pole focusing controls PTX response. Additionally it will test the hypothesis that alisertib, an inhibitor of AurkA, can prevent pole focusing. Preventing pole focusing is expected to sensitize tumors that are resistant to PTX by forcing cells to undergo multipolar divisions, markedly elevating CIN. Finally, a CRISPR screen will be used to identify genes that confer this mechanism of primary resistance. A gene signature for pole focusing could improve a CIN-based predictive biomarker of PTX response. Together, this translational work based on the conceptual advance provided by our previous translational studies will provide basic knowledge of the biological mechanisms regulating cell death in response to a cornerstone of anti-cancer treatment. This will provide a sound basis for the future development of a predictive biomarker of PTX and strategies for sensitizing PTX-resistant cancers.


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 = $559,860 )
2025	2025	UNIVERSITY OF WISCONSIN SYSTEM	21 N PARK ST STE 6301	MADISON	WI	53715	DANE	USA	Cancer Treatment Research	001	2	4/23/2025	NON-COMPETING CONTINUATION	$503,874
2025	2025	UNIVERSITY OF WISCONSIN SYSTEM	21 N PARK ST STE 6301	MADISON	WI	53715	DANE	USA	Cancer Treatment Research	002	2	5/5/2025	NON-COMPETING CONTINUATION	$0
2025	2025	UNIVERSITY OF WISCONSIN SYSTEM	21 N PARK ST STE 6301	MADISON	WI	53715	DANE	USA	Cancer Treatment Research	003	2	5/22/2025	NON-COMPETING CONTINUATION	$55,986
2025	2024	UNIVERSITY OF WISCONSIN SYSTEM	21 N PARK ST STE 6301	MADISON	WI	53715	DANE	USA	Cancer Treatment Research	000	1	3/17/2025	NEW	$0
														Subtotal = $559,860

Issue Date FY: 2024 ( Subtotal = $529,300 )
2024	2024	UNIVERSITY OF WISCONSIN SYSTEM	21 N PARK ST STE 6301	MADISON	WI	53715	DANE	USA	Cancer Treatment Research	000	1	3/4/2024	NEW	$529,300
														Subtotal = $529,300

Grand Total All Awards = $1,089,160

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Mechanisms of paclitaxel sensitivity and resistance

Award Number: R01CA284747

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 03/04/2024

PERIOD OF PERFORMANCE END DATE: 02/28/2029

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