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New Strategies for Treatment of NRAS Mutant Melanoma after Progression on Immune Checkpoint Inhibitors

Award Number: R01CA116021
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 08/19/2005
PERIOD OF PERFORMANCE END DATE: 09/30/2025

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New Strategies for Treatment of NRAS Mutant Melanoma after Progression on Immune Checkpoint Inhibitors - Treatment of metastatic melanoma with immune checkpoint inhibitors (ICI) has extended the life of many melanoma patients, but the vast majority of patient experience disease progression, prompting the need for alternate therapies. For ~50% of patients with BRAFmut tumors, treatment with BRAF and MEK inhibitors provide a good second-line treatment option. Unfortunately, there are few second-line options for the 25-30% of patients whose tumors harbor NRAS mutations. Since nearly 40% of all melanoma patients exhibit loss, mutation, or epigenetic silencing of the CDK4/6 regulator CDKN2A, we postulate that inhibition of CDK4/6 may induce response in NRASmut RBWT tumors with loss of CDKN2A. Because loss of CDKN2A also disrupts ARF, a suppressor of MDM2-mediated degradation of p53, it will be essential to also inhibit MDM2 to restore cell cycle control in p53WT melanoma. We have shown that NRASmut melanoma tumors with acquired resistance to ICI respond to co-treatment with a CDK4/6 inhibitor plus an MDM2, demonstrating both with reduced tumor growth and enhanced CD8+T cell recruitment into the tumor. These tumors contain a significant number of CXCR1,2 expressing myeloid-derived suppressor cells (MDSCs) that create an immune suppressive tumor microenvironment. Our preliminary data show that when CXCR2 is deleted in myeloid cells, MDSC recruitment to tumor is reduced and tumor growth is inhibited. Moreover, systemic delivery of a CXCR1,2 inhibitor reduced the growth of NRASmut melanoma in mice (p<0.02), and inducible deletion of CXCR2 in melanocytes blocks melanoma formation in the inducible BRAFV600E/PTEN-/- melanoma mouse model. These intriguing findings support prior studies indicating a role for CXCR2 inhibitors for treatment of melanoma. However, the mechanisms and generality of response to CXCR1,2 antagonism require further elucidation. Premise and Hypothesis: CXCR2 plays critical and pleotropic role in melanoma by promoting tumorigenesis and inducing an immunosuppressive tumor environment. Moreover, combined CDK4/6 and MDM2 inhibition significantly inhibits the growth of mouse and human NRASmut melanoma tumors. We hypothesize that co-inhibition of CXCR1,2, CDK4/6, and MDM2 in NRASmut melanoma with acquired resistance to ICI will inhibit tumor cell proliferation, induce tumor cell death, stimulate anti- tumor immunity, and potentially overcome the acquired resistance to ICI. We propose 3 specific aims. 1)To examine the ability of CDK4/6i plus MDM2i, combined with a CXCR1,2 antagonist treatment, or CXCR1,2 agonist alone, to enhance or restore ICI sensitivity for NRASmut melanoma tumors. 2) To determine the role of melanocyte-expressed CXCR2 in melanoma initiation. CXCR2 will be deleted coincident with induction of melanoma formation in mice and effects of this deletion on melanocyte apoptosis, senescence, differentiation and proliferation will be characterized. 3) To determine whether findings in mouse translate to human melanoma, changes in the tumor immune microenvironment (TIME) will be characterized over time in response to a CXCR1,2 antagonist (CXCR1,2i) with or without CDK4/6i+MDM2i followed by ICI therapy in humanized NRASmut patient-derived xenograft (PDX) models and human NRAS mut melanoma organoid co-cultures. These data will inform future clinical trials.


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 = $0 )
2026	2024	VANDERBILT UNIVERSITY	110 21ST AVE S	NASHVILLE	TN	37203	DAVIDSON	USA	Cancer Treatment Research	000	20	11/24/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2024 ( Subtotal = $361,357 )
2024	2024	VANDERBILT UNIVERSITY	110 21ST AVE S	NASHVILLE	TN	37203	DAVIDSON	USA	Cancer Treatment Research	001	20	4/17/2024	NON-COMPETING CONTINUATION	$19,019
2024	2024	VANDERBILT UNIVERSITY	110 21ST AVE S	NASHVILLE	TN	37203	DAVIDSON	USA	Cancer Treatment Research	000	20	2/26/2024	NON-COMPETING CONTINUATION	$342,338
														Subtotal = $361,357

Issue Date FY: 2023 ( Subtotal = $380,325 )
2023	2023	VANDERBILT UNIVERSITY	110 21ST AVE S	NASHVILLE	TN	37203	DAVIDSON	USA	Cancer Treatment Research	001	19	9/15/2023	NON-COMPETING CONTINUATION	$7,607
2023	2023	VANDERBILT UNIVERSITY	110 21ST AVE S	NASHVILLE	TN	37203	DAVIDSON	USA	Cancer Treatment Research	000	19	4/10/2023	NON-COMPETING CONTINUATION	$372,718
														Subtotal = $380,325

Issue Date FY: 2022 ( Subtotal = $372,669 )
2022	2022	VANDERBILT UNIVERSITY, THE	110 21ST AVENUE S STE 800	NASHVILLE	TN	37203	DAVIDSON	USA	Cancer Treatment Research	000	18	3/16/2022	NON-COMPETING CONTINUATION	$342,247
2022	2022	VANDERBILT UNIVERSITY, THE	110 21ST AVENUE S STE 800	NASHVILLE	TN	37203	DAVIDSON	USA	Cancer Treatment Research	001	18	6/7/2022	NON-COMPETING CONTINUATION	$30,422
														Subtotal = $372,669

Issue Date FY: 2021 ( Subtotal = $379,970 )
2021	2021	VANDERBILT UNIVERSITY, THE	110 21ST AVENUE S STE 800	NASHVILLE	TN	37203	DAVIDSON	USA	Cancer Treatment Research	000	17	3/24/2021	NON-COMPETING CONTINUATION	$379,970
														Subtotal = $379,970

Issue Date FY: 2020 ( Subtotal = $392,929 )
2020	2020	VANDERBILT UNIVERSITY, THE	110 21ST AVENUE S STE 800	NASHVILLE	TN	37203	DAVIDSON	USA	Cancer Treatment Research	001	16	4/14/2020	COMPETING CONTINUATION	$392,929
2020	2020	VANDERBILT UNIVERSITY, THE	110 21ST AVENUE S STE 800	NASHVILLE	TN	37203	DAVIDSON	USA	Cancer Treatment Research	003	16	9/9/2020	COMPETING CONTINUATION	$26,435
2020	2019	VANDERBILT UNIVERSITY, THE	110 21ST AVENUE S STE 800	NASHVILLE	TN	37203	DAVIDSON	USA	Cancer Treatment Research	000	15	4/7/2020	NON-COMPETING CONTINUATION	$0
2020	2019	VANDERBILT UNIVERSITY, THE	110 21ST AVENUE S STE 800	NASHVILLE	TN	37203	DAVIDSON	USA	Cancer Treatment Research	002	15	9/9/2020	NON-COMPETING CONTINUATION	-$26,435
														Subtotal = $392,929

Issue Date FY: 2019 ( Subtotal = $361,688 )
2019	2019	VANDERBILT UNIVERSITY, THE	110 21ST AVENUE S STE 800	NASHVILLE	TN	37203	DAVIDSON	USA	Cancer Treatment Research	000	15	11/22/2018	NON-COMPETING CONTINUATION	$361,688
														Subtotal = $361,688

Issue Date FY: 2018 ( Subtotal = $372,875 )
2018	2018	VANDERBILT UNIVERSITY, THE	110 21ST AVENUE S STE 800	NASHVILLE	TN	37203	DAVIDSON	USA	Cancer Treatment Research	001	14	5/22/2018	NON-COMPETING CONTINUATION	$37,288
2018	2018	VANDERBILT UNIVERSITY, THE	110 21ST AVENUE S STE 800	NASHVILLE	TN	37203	DAVIDSON	USA	Cancer Treatment Research	000	14	11/27/2017	NON-COMPETING CONTINUATION	$335,587
														Subtotal = $372,875

Issue Date FY: 2017 ( Subtotal = $372,875 )
2017	2017	VANDERBILT UNIVERSITY, THE	110 21ST AVENUE S STE 800	NASHVILLE	TN	37203	DAVIDSON	USA	Cancer Treatment Research	001	13	6/7/2017	NON-COMPETING CONTINUATION	$37,288
2017	2017	VANDERBILT UNIVERSITY, THE	211 KIRKLAND HALL	NASHVILLE	TN	37240	DAVIDSON	USA	Cancer Treatment Research	000	13	11/16/2016	NON-COMPETING CONTINUATION	$335,587
														Subtotal = $372,875

Issue Date FY: 2016 ( Subtotal = $372,875 )
2016	2016	VANDERBILT UNIVERSITY HOSPITAL, CHILDREN'S REHAB UNIT	1161 21ST AVENUE SOUTH	NASHVILLE	TN	37232	DAVIDSON	USA	Cancer Treatment Research	001	12	3/9/2016	NON-COMPETING CONTINUATION	$37,288
2016	2016	VANDERBILT UNIVERSITY HOSPITAL, CHILDREN'S REHAB UNIT	1161 21ST AVENUE SOUTH	NASHVILLE	TN	37232	DAVIDSON	USA	Cancer Treatment Research	000	12	11/18/2015	NON-COMPETING CONTINUATION	$335,587
														Subtotal = $372,875

Issue Date FY: 2015 ( Subtotal = $372,875 )
2015	2015	VANDERBILT UNIVERSITY HOSPITAL, CHILDREN'S REHAB UNIT	1161 21ST AVENUE SOUTH	NASHVILLE	TN	37232	DAVIDSON	USA	Cancer Treatment Research	002	11	3/6/2015	COMPETING CONTINUATION	$19,625
2015	2015	VANDERBILT UNIVERSITY HOSPITAL, CHILDREN'S REHAB UNIT	1161 21ST AVENUE SOUTH	NASHVILLE	TN	37232	DAVIDSON	USA	Cancer Treatment Research	001	11	12/9/2014	COMPETING CONTINUATION	$353,250
2015	2014	VANDERBILT UNIVERSITY HOSPITAL, CHILDREN'S REHAB UNIT	1161 21ST AVENUE SOUTH	NASHVILLE	TN	37232	DAVIDSON	USA	Cancer Treatment Research	000	10	12/4/2014	NON-COMPETING CONTINUATION	$0
														Subtotal = $372,875

Issue Date FY: 2014 ( Subtotal = $318,507 )
2014	2014	VANDERBILT UNIVERSITY HOSPITAL, CHILDREN'S REHAB UNIT	1161 21ST AVENUE SOUTH	NASHVILLE	TN	37232	DAVIDSON	USA	Cancer Treatment Research	001	10	5/7/2014	NON-COMPETING CONTINUATION	$22,985
2014	2014	VANDERBILT UNIVERSITY HOSPITAL, CHILDREN'S REHAB UNIT	1161 21ST AVENUE SOUTH	NASHVILLE	TN	37232	DAVIDSON	USA	Cancer Treatment Research	000	10	12/17/2013	NON-COMPETING CONTINUATION	$295,522
														Subtotal = $318,507

Issue Date FY: 2013 ( Subtotal = $308,657 )
2013	2013	VANDERBILT UNIVERSITY HOSPITAL, CHILDREN'S REHAB UNIT	1161 21ST AVENUE SOUTH	NASHVILLE	TN	37232	DAVIDSON	USA	Cancer Treatment Research	001	9	5/24/2013	NON-COMPETING CONTINUATION	$144,478
2013	2013	VANDERBILT UNIVERSITY HOSPITAL, CHILDREN'S REHAB UNIT	1161 21ST AVENUE SOUTH	NASHVILLE	TN	37232	DAVIDSON	USA	Cancer Treatment Research	000	9	12/14/2012	NON-COMPETING CONTINUATION	$164,179
														Subtotal = $308,657

Issue Date FY: 2012 ( Subtotal = $328,358 )
2012	2012	VANDERBILT UNIVERSITY HOSPITAL, CHILDREN'S REHAB UNIT	1161 21ST AVENUE SOUTH	NASHVILLE	TN	37232	DAVIDSON	USA	Cancer Treatment Research	001	8	4/20/2012	NON-COMPETING CONTINUATION	$32,836
2012	2012	VANDERBILT UNIVERSITY HOSPITAL, CHILDREN'S REHAB UNIT	1161 21ST AVENUE SOUTH	NASHVILLE	TN	37232	DAVIDSON	USA	Cancer Treatment Research	000	8	12/30/2011	NON-COMPETING CONTINUATION	$295,522
														Subtotal = $328,358

Issue Date FY: 2011 ( Subtotal = $378,198 )
2011	2011	VANDERBILT UNIVERSITY HOSPITAL, CHILDREN'S REHAB UNIT	1161 21ST AVENUE SOUTH	NASHVILLE	TN	37232	DAVIDSON	USA	Cancer Treatment Research	002	7	8/31/2011	SUPPLEMENT FOR EXPANSION	$49,840
2011	2011	VANDERBILT UNIVERSITY HOSPITAL, CHILDREN'S REHAB UNIT	1161 21ST AVENUE SOUTH	NASHVILLE	TN	37232	DAVIDSON	USA	Cancer Treatment Research	001	7	5/13/2011	NON-COMPETING CONTINUATION	$23,696
2011	2011	VANDERBILT UNIVERSITY HOSPITAL, CHILDREN'S REHAB UNIT	1161 21ST AVENUE SOUTH	NASHVILLE	TN	37232	DAVIDSON	USA	Cancer Treatment Research	000	7	1/26/2011	NON-COMPETING CONTINUATION	$304,662
														Subtotal = $378,198

Issue Date FY: 2010 ( Subtotal = $149,486 )
2010	2010	VANDERBILT UNIVERSITY HOSPITAL, CHILDREN'S REHAB UNIT	1161 21ST AVENUE SOUTH	NASHVILLE	TN	37232	DAVIDSON	USA	Cancer Treatment Research	000	6	6/17/2010	COMPETING CONTINUATION	$149,486
														Subtotal = $149,486

Issue Date FY: 2009 ( Subtotal = $287,454 )
2009	2009	VANDERBILT UNIVERSITY HOSPITAL, CHILDREN'S REHAB UNIT	1161 21ST AVENUE SOUTH	NASHVILLE	TN	37232	DAVIDSON	USA	Cancer Treatment Research	000	5	6/5/2009	NON-COMPETING CONTINUATION	$287,454
														Subtotal = $287,454

Grand Total All Awards = $6,681,280

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New Strategies for Treatment of NRAS Mutant Melanoma after Progression on Immune Checkpoint Inhibitors

Award Number: R01CA116021

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 08/19/2005

PERIOD OF PERFORMANCE END DATE: 09/30/2025

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