# The role of PGC1beta and ERRalpha as novel targets for therapy in colorectal cancer

> **NIH NIH K08** · UNIVERSITY OF NEBRASKA MEDICAL CENTER · 2020 · $237,582

## Abstract

Abstract
Significance: This proposal has the potential to impact a large number of patients since colorectal cancer
(CRC) is the 3rd leading cause of cancer deaths in both genders. K-Ras is mutated in approximately 40% of
all CRCs and this mutation makes tumors resistant to EGFR-targeted therapies. Our studies aim to develop
novel strategies for treatment of tumors with K-Ras mutations. Additionally, we propose that our treatment
strategies will have a high therapeutic index, since we are targeting proteins that are expendable for normal
growth, but required for malignancy. We also anticipate that our findings will be applicable to other tumors with
mutant Ras proteins, which constitute up to 30% of all human malignancies.
Background: We have determined that 5' AMP-activated protein kinase (AMPK), peroxisome proliferator-
activated receptor gamma coactivator 1-beta (PGC1β), and estrogen-related receptor alpha (ERRα) are novel
regulators of tumor metabolism in K-Ras mutant CRCs. PGC1β is a transcriptional co-activator and ERRα is a
transcription factor that are present in highly metabolic tissues, such as heart, skeletal muscle, brain and brown
adipose tissue, where they interact to transcribe genes involved in metabolism and mitochondrial biogenesis.
PGC1β and ERRα are dramatically over-expressed in CRC cell lines and human liver metastases compared to
non-transformed human colon epithelial cells (HCECs) and normal human colon tissue, respectively. AMPK, a
critical regulator of energy homeostasis, is a potent regulator of PGC1β, ERRα, and tumor survival.
Research Plan: In this application, we present preliminary data on the critical role of AMPK, PGC1β, and
ERRα as novel regulators of tumor metabolism and survival in K-Ras mutant CRCs and we hypothesize that
these are promising targets for the development of novel treatment strategies because they are expendable for
normal cell growth. To test this hypothesis, first, we will examine the role of PGC1β and ERRα downstream
effector Ras-related GTP-binding protein D (RagD), a positive regulator of mTORC1 signaling and tumor
growth. Second, we will characterize the critical regulatory role of AMPK on PGC1β activity. Lastly, we will
assess the role of PGC1β, ERRα, and an ERRα inhibitor in metastatic disease using the orthotopic cecal
implantation mouse model of metastasis. This proposal will advance our knowledge of these underexplored
metabolic effectors that are required for K-Ras mutant CRCs and have the potential for the development of
several types of novel therapeutics.
Career Development: I have worked closely with my mentors to create a scientific and career development
plan designed to help me transition to independence as a physician-scientist. Specifically, I will gain valuable
training in metabolic regulation of cancer growth, models of metastasis, leadership skills, grantsmanship, and
ethical research. My mentorship committee consists of outstanding faculty members with expertise in
mentor...

## Key facts

- **NIH application ID:** 9935014
- **Project number:** 5K08CA222887-03
- **Recipient organization:** UNIVERSITY OF NEBRASKA MEDICAL CENTER
- **Principal Investigator:** Kurt Fisher
- **Activity code:** K08 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $237,582
- **Award type:** 5
- **Project period:** 2018-07-02 → 2023-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9935014

## Citation

> US National Institutes of Health, RePORTER application 9935014, The role of PGC1beta and ERRalpha as novel targets for therapy in colorectal cancer (5K08CA222887-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9935014. Licensed CC0.

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