# Investigating Mechanisms of Hyperprogression on Anti-PD-1 Immunotherapy

> **NIH NIH R21** · UNIVERSITY OF CALIFORNIA, SAN DIEGO · 2022 · $217,163

## Abstract

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.

## Key facts

- **NIH application ID:** 10320045
- **Project number:** 5R21CA256360-02
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN DIEGO
- **Principal Investigator:** Andrew B. Sharabi
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $217,163
- **Award type:** 5
- **Project period:** 2021-01-01 → 2022-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10320045

## Citation

> US National Institutes of Health, RePORTER application 10320045, Investigating Mechanisms of Hyperprogression on Anti-PD-1 Immunotherapy (5R21CA256360-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10320045. Licensed CC0.

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