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Mechanisms of resistance to MEK Inhibition in RAS-pathway activated chronic myelomonocytic leukemia

Award Number: K08CA252883
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP
PERIOD OF PERFORMANCE START DATE: 07/01/2022
PERIOD OF PERFORMANCE END DATE: 04/30/2027

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Mechanisms of resistance to MEK Inhibition in RAS-pathway activated chronic myelomonocytic leukemia - PROJECT SUMMARY/ABSTRACT Overview: The goal of this award is to provide Dr. Ami Patel with the training and mentored research experience to ensure success in her transition to an independent investigator with expertise in the biology and treatment of myeloid malignancies. Dr. Patel’s long term goal is to create and support an independent laboratory-based translational research program dedicated to the investigation of targeted drug resistance in myeloid neoplasms. Research: Chronic myelomonocytic leukemia (CMML) is an aggressive hematologic malignancy associated with dismal survival outcomes and low curative potential. Treatment options are extremely limited, poorly tolerated and fail to address many disease-related symptoms. Targeted agents represent a promising therapeutic opportunity for CMML patients with mutations that lead to aberrant signal transduction through the RAS/mitogen activated kinase (MAPK) pathway. The proposed research aims to understand whether this subset of CMML patients could benefit from treatment with cobimetinib, a specific inhibitor of RAS/MAPK signaling. The proposal includes a clinical trial to test the efficacy of cobimetinib in CMML patients with RAS/MAPK activation. Unfortunately, clinical experience with targeted inhibitors support the eventual emergence of drug resistance. The proposed research aims to understand, prevent and overcome anticipated MEK inhibitor resistance. Longitudinal samples from patients treated on the cobimetinib trial will be analyzed using whole exome and RNA sequencing to identify biomarkers of drug resistance. Laboratory-based preclinical studies will utilize advanced high throughput sequencing and target validation methodologies in cell lines, primary CMML cells and patient derived xenograft models of CMML to help identify mechanisms of resistance that can be cross-referenced with clinical trial findings. Pathways implicated in MEK inhibitor resistance may be candidates for targeted inhibition, leading to the development of novel combinatorial treatment strategies in RAS-activated CMML. Career Development: Dr. Patel is an accomplished hematologist-oncologist with a strong background in translational research in myeloid malignancies. However, prior to starting an independent research program, Dr. Patel requires further training in advanced sequencing and bioinformatics analysis, genome editing and techniques and clinical trial implementation and oversight. The structured protected time,didactics and mentoring provided by the K08 will allow Dr. Patel to complete this essential training. Dr. Patel has assembled a highly experienced, diverse and internationally-recognized mentoring team committed to her future success. The Huntsman Cancer Institute, an NCI-designated Comprehensive Cancer Center, and the University of Utah provide a rich and supportive institutional environment for Dr. Patel to advance her 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: 2026 ( Subtotal = $289,908 )
2026	2026	UNIVERSITY OF UTAH	201 PRESIDENTS CIR	SALT LAKE CITY	UT	84112	SALT LAKE	USA	Cancer Research Manpower	000	5	4/21/2026	NON-COMPETING CONTINUATION	$289,908
														Subtotal = $289,908

Issue Date FY: 2025 ( Subtotal = $289,908 )
2025	2025	UNIVERSITY OF UTAH	201 PRESIDENTS CIR	SALT LAKE CITY	UT	84112	SALT LAKE	USA	Cancer Research Manpower	000	4	3/13/2025	NON-COMPETING CONTINUATION	$289,908
														Subtotal = $289,908

Issue Date FY: 2024 ( Subtotal = $289,908 )
2024	2024	UNIVERSITY OF UTAH	201 PRESIDENTS CIR	SALT LAKE CITY	UT	84112	SALT LAKE	USA	Cancer Research Manpower	000	3	5/3/2024	NON-COMPETING CONTINUATION	$289,908
														Subtotal = $289,908

Issue Date FY: 2023 ( Subtotal = $289,908 )
2023	2023	UNIVERSITY OF UTAH	201 PRESIDENTS CIR	SALT LAKE CITY	UT	84112	SALT LAKE	USA	Cancer Research Manpower	000	2	4/25/2023	NON-COMPETING CONTINUATION	$289,908
														Subtotal = $289,908

Issue Date FY: 2022 ( Subtotal = $289,908 )
2022	2022	UNIVERSITY OF UTAH, THE	201 PRESIDENTS CIR	SALT LAKE CITY	UT	84112	SALT LAKE	USA	Cancer Research Manpower	000	1	6/23/2022	NEW	$289,908
														Subtotal = $289,908

Grand Total All Awards = $1,449,540

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Mechanisms of resistance to MEK Inhibition in RAS-pathway activated chronic myelomonocytic leukemia

Award Number: K08CA252883

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP

PERIOD OF PERFORMANCE START DATE: 07/01/2022

PERIOD OF PERFORMANCE END DATE: 04/30/2027

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