# TRAIL-Induced Necroptosis as a Therapeutic Option for MAP3K7-null Prostate Cancer

> **NIH NIH F32** · UNIVERSITY OF COLORADO DENVER · 2020 · $44,790

## Abstract

Proposal Abstract
Prostate cancer (PCa) is the most commonly diagnosed solid tumor and the second leading cause of cancer-
related deaths in U.S. males. Recently the Cramer lab discovered that a specific subtype of PCa, MAP3K7-null
PCa, occurs in 30-40% of patients. MAP3K7 is a known tumor suppressor and loss of this protein is associated
with an aggressive form of the disease with a poor rate of disease-free survival. Interestingly, co-suppression
of tumor suppressor CHD1, a protein vital for transcriptional regulation and genomic stability, often occurs with
loss of MAP3K7 leading to an even more aggressive cancer phenotype. Therefore, identifying novel
therapeutic strategies for this lethal subtype of PCa can have a high impact on PCa patient survival.
Cancer cells often develop apoptosis-resistance leading to the hypothesis that cancer therapy can be improved
by activating an alternative mechanism of cell death such as necroptosis. Necroptosis is a kinase-driven,
caspase-independent form of cell death. Necroptosis is immunogenic while apoptosis suppresses anti-tumor
immune responses. Importantly, autophagy has a vital role in promoting cell death. When MAP3K7-null cells
are treated with TRAIL, they undergo necroptotic cell death. Autophagosome protein p62 is crucial for
switching cell death from apoptosis to necroptosis by recruitment of RIPK1 to the necrosome. However, the
underlying mechanisms of autophagy-mediated cell death are poorly understood. It is unknown if autophagy
only controls whether or not cells die or also promotes other aspects of programmed cell death. Our working
hypothesis is that manipulation of autophagy machinery can enhance TRAIL-induced necroptosis and be an
effective therapeutic option for MAP3K7-null PCa.
First, we will determine the role of autophagy in TRAIL-induced necroptosis. This aim will determine interacting
proteins between the autophagosome and necrosome by BioID, proximity ligation, assay, immuno electron and
super-resolution microscopy, and co-immunoprecipitation. Further, we will examine degradation of pro-
apoptotic and pro-survival proteins by the autophagosome upon treatment with TRAIL. Lastly, we will examine
the functional roles of interacting proteins by targeted knockdown and analysis of cell viability and cell death.
To determine the immunogenic effects of necroptosis, we will analyze in vivo anti-tumor effects of TRAIL.
Immune compromised and immune competent mice will be treated with TRAIL for 12 weeks after tumor
implantation through our novel prostate tissue recombination method. Tumor size and necroptotic, apoptotic
and immune markers will be analyzed in addition to immune activation. We will then repeat this experiment
with targeting of interacting proteins found in Aim 1 to enhance the anti-tumor adaptive immune response.
Significantly, this research will reveal a novel therapeutic strategy for treatment of a lethal form of PCa,
MAP3K7-null, which has no effective therapeutic strategies ...

## Key facts

- **NIH application ID:** 9988034
- **Project number:** 1F32CA250129-01
- **Recipient organization:** UNIVERSITY OF COLORADO DENVER
- **Principal Investigator:** Dannah R Miller
- **Activity code:** F32 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $44,790
- **Award type:** 1
- **Project period:** 2020-07-01 → 2021-02-14

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9988034

## Citation

> US National Institutes of Health, RePORTER application 9988034, TRAIL-Induced Necroptosis as a Therapeutic Option for MAP3K7-null Prostate Cancer (1F32CA250129-01). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9988034. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*