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Investigating Mechanisms of Hyperprogression on Anti-PD-1 Immunotherapy

Award Number: R21CA256360
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 01/01/2021
PERIOD OF PERFORMANCE END DATE: 12/31/2022

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Investigating Mechanisms of Hyperprogression on Anti-PD-1 Immunotherapy - Abstract The number of cancer patients being treated with checkpoint blockade immunotherapy (CBI) targeting the PD- 1/PD-L1 pathway is increasing dramatically. Recently a novel and unfavorable response pattern termed hyperprogression (HPD) has been identified which is characterized by a rapid worsening and acceleration of tumor growth after starting CBI. Our group was the first to report the genetic alterations associated with HPD, namely MDM2 amplifications and EGFR alterations. However, mechanisms of action or strategies to circumvent HPD have not been reported. Using novel tumor models, our preliminary data has identified that MDM2 amplified cells are hypersensitive to TNFα induced proliferation compared to non-MDM2 amplified tumor lines. Mechanistically we have identified that MDM2 amplification dramatically alters TNF-alpha signaling pathways, blocking apoptotic signals while simultaneously promoting NFκβ mediated cell growth and proliferation. In this study we will elucidate mechanisms of HPD and determine whether MDM2 amplification alone is sufficient to cause HPD and whether HPD can occur with other checkpoint blockade agents. We will then test whether novel MDM2/4 or TNFα inhibitors can block or prevent HPD in our unique tumor models. Our hypothesis that MDM2 amplified tumors are resistant to TNF-alpha induced apoptosis and hypersensitive to TNFα induced cell cycling which results in uncontrolled proliferation and HPD after treatment with CBI. Together these studies will significantly improve our mechanistic understanding of HPD and identify targeted drug strategies that can be rapidly translated into clinical trials to improve outcomes in cancer patients treated with CBI.


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 = $0 )
2024	2022	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Cancer Treatment Research	000	2	10/13/2023	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2022 ( Subtotal = $217,163 )
2022	2022	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Cancer Treatment Research	000	2	1/21/2022	NON-COMPETING CONTINUATION	$199,435
2022	2022	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Cancer Treatment Research	001	2	5/20/2022	NON-COMPETING CONTINUATION	$17,728
														Subtotal = $217,163

Issue Date FY: 2021 ( Subtotal = $184,371 )
2021	2021	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Cancer Treatment Research	000	1	12/17/2020	NEW	$184,371
														Subtotal = $184,371

Grand Total All Awards = $401,534

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Investigating Mechanisms of Hyperprogression on Anti-PD-1 Immunotherapy

Award Number: R21CA256360

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 01/01/2021

PERIOD OF PERFORMANCE END DATE: 12/31/2022

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