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A multi-scale analysis of the mutagenicity of cisplatin and its modulation of acquired chemoresistance in high-grade serous ovarian cancer

Award Number: F31CA243349
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

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PROJECT SUMMARY. High-grade serous ovarian cancer (HGSOC) accounts for up to 80% of ovarian cancer deaths, due to recurrence in over half of patients associated with platinum-based chemoresistance. Intratumor heterogeneity (ITH) is thought to be the main contributor in resistance. ITH permits diverse phenotypic landscapes among cells that may provide certain clones advantages in resisting or tolerating chemotherapy. Cisplatin, routinely used in HGSOC treatment, forms platinum-DNA (Pt-DNA) adducts as its main cytotoxic mechanism. However, Pt-DNA adducts are mutagenic, particularly due to the misincorporation of incorrect nucleotides by DNA polymerases β (polβ) and η (polη) opposite these adducts. Despite evidence that polβ, polη, and the bypass of Pt-DNA adducts play roles in cisplatin resistance, the molecular mechanisms that govern this mutagenic bypass are unclear. In addition, HGSOC is characterized by vast genome instability that causes intratumor genetic diversity and augments the possibilities for the acquisition of resistance. As one of the most mutagenic drugs, cisplatin further increases this genetic diversity and induces unwanted mutations that may elicit the emergence of de novo resistant clones. I hypothesize that polβ and polη execute the mutagenic events of cisplatin, and the mutagenicity of cisplatin modulates the de novo origination of resistant clones that propagate resistance in HGSOC. This proposal seeks to define the molecular mechanisms that enable the mutagenic bypass of Pt-DNA adducts, and in conjunction, determine how the mutagenicity of cisplatin modulates the acquisition of HGSOC resistance during cisplatin treatment. Recent lineage tracing through DNA barcoding technologies have enabled exciting quantitative analyses of subclonal architecture throughout treatment of cancer populations. However, subsequent analyses destroy barcoded cellular samples, limiting further studies. COLBERT enables both lineage tracing and isolation through lineage-specific gene expression of a fluorescent reporter. I will employ COLBERT in an unprecedented longitudinal study of de novo resistance that emerges throughout cisplatin treatment of HGSOC cell line populations. This proposal will perform gene expression and whole genome sequencing analyses of individual de novo resistant lineages throughout treatment to determine key de novo mutations that confer resistance, and understand how resistant lineages came to acquire resistance over time. The 2015 Ovarian Cancer Action meeting described the need for studies that aim to better understand clonal diversity and genome instability contributing to acquired HGSOC resistance. This work will address this by uniquely uniting molecular and systems level approaches to provide characterizations of cisplatin’s mutagenicity. This study will provide a holistic understanding of how cisplatin fails to act solely as a cytotoxic drug and induces undesirable mutagenic events, and how these de novo mutations may originate resistance. This work will provide insights into improving personalized therapies and platinum drug design.


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: 2024 ( Subtotal = -$2,774 )
2024	2022	UNIVERSITY OF TEXAS AT AUSTIN	110 INNER CAMPUS DR	AUSTIN	TX	78712	TRAVIS	USA	Cancer Research Manpower	000	3	10/31/2023	NON-COMPETING CONTINUATION	-$2,774
														Subtotal = -$2,774

Issue Date FY: 2022 ( Subtotal = $37,327 )
2022	2022	UNIVERSITY OF TEXAS AT AUSTIN	110 INNER CAMPUS DR MN 13	AUSTIN	TX	78712	TRAVIS	USA	Cancer Research Manpower	000	3	12/14/2021	NON-COMPETING CONTINUATION	$36,611
2022	2022	UNIVERSITY OF TEXAS AT AUSTIN	110 INNER CAMPUS DR	AUSTIN	TX	78712	TRAVIS	USA	Cancer Research Manpower	001	3	8/4/2022	NON-COMPETING CONTINUATION	$716
														Subtotal = $37,327

Issue Date FY: 2021 ( Subtotal = $36,611 )
2021	2021	UNIVERSITY OF TEXAS AT AUSTIN	110 INNER CAMPUS DR MN 13	AUSTIN	TX	78712	TRAVIS	USA	Cancer Research Manpower	001	2	2/2/2021	NON-COMPETING CONTINUATION	$516
2021	2021	UNIVERSITY OF TEXAS AT AUSTIN	110 INNER CAMPUS DR MN 13	AUSTIN	TX	78712	TRAVIS	USA	Cancer Research Manpower	000	2	12/31/2020	NON-COMPETING CONTINUATION	$36,095
														Subtotal = $36,611

Issue Date FY: 2019 ( Subtotal = $35,591 )
2019	2019	UNIVERSITY OF TEXAS AT AUSTIN	110 INNER CAMPUS DR MN 13	AUSTIN	TX	78712	TRAVIS	USA	Cancer Research Manpower	000	1	8/28/2019	NEW	$35,591
2019	2019	UNIVERSITY OF TEXAS AT AUSTIN	110 INNER CAMPUS DR MN 13	AUSTIN	TX	78712	TRAVIS	USA	Cancer Research Manpower	001	1	8/28/2019	NEW	$0
														Subtotal = $35,591

Grand Total All Awards = $106,755

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A multi-scale analysis of the mutagenicity of cisplatin and its modulation of acquired chemoresistance in high-grade serous ovarian cancer

Award Number: F31CA243349

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

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