# Branched chain amino acids and pancreatic cancer

> **NIH NIH R01** · UNIVERSITY OF PENNSYLVANIA · 2020 · $463,725

## Abstract

PROJECT SUMMARY
Pancreatic ductal adenocarcinoma (PDA) remains one of the most intractable types of cancer,
with a 5-year survival rate below 9%. Alarmingly, the incidence of pancreatic cancer is on the
rise over the past 20 years, with particularly sharp increases in incidence among young adults.
Poor nutrition and obesity are likely culprits, with obesity and diabetes independently conferring
increased risk of PDA, but the mechanisms remain unclear.
Branched chain amino acids (BCAAs) have emerged as one potentially important link between
diet, systemic metabolism, and PDA. We have demonstrated in previous work and preliminary
data that BCAAs are avidly consumed by the pancreas, where they contribute prominently to
the TCA cycle and to acetyl-CoA pools. We have also recently shown that acetyl-CoA
metabolism plays a key role in facilitating pancreatic tumor initiation, leading to the hypothesis
that BCAA metabolism is required for efficient pancreatic tumorigenesis. Thus, one major goal
of this grant will be to test the role of BCAA catabolism in the pancreas in facilitating acinar cell
plasticity and tumor formation. We will use state-of-the-art in vivo isotope tracer approaches to
elucidate the fates of BCAAs in the pancreas. We will also employ nutritional, genetic (using
two novel mouse models), and pharmacological approaches to define the roles of BCAA
catabolism in pancreatic function and tumorigenesis.
In contrast to normal pancreatic cells, use of BCAAs as a fuel source is thought to be
suppressed as pancreatic cancer develops. Nevertheless, BCAAs are an important biomarker
of PDA, with circulating levels elevated years prior to PDA diagnosis, indicating a risk that likely
mechanistically differs from that of tumor initiation. BCAAs are also elevated in obesity and
diabetes, where they promote insulin secretion and insulin resistance, promoting a
hyperinsulinemic state. Insulin itself acts as a growth factor to promote anabolic signaling and
metabolism in PDA cells. Our second major goal is thus to evaluate the contribution of systemic
BCAA levels and hyperinsulinemia to PDA tumor growth. We will manipulate systemic BCAA
levels through nutritional, genetic, and pharmacological approaches to test the impact on tumor
growth. We will then query the impact of insulin directly on PDA cells and on cancer-associated
fibroblasts (CAFs), along with the impact of reducing hyperinsulinemia on tumor growth. Finally,
we will test the potential to target BCAA metabolism through mouse clinical trials.
These studies will provide deep insight into the roles of BCAAs in multi-step PDA tumorigenesis
and could lead to novel therapeutic strategies for this deadly disease.

## Key facts

- **NIH application ID:** 9944705
- **Project number:** 1R01CA248315-01
- **Recipient organization:** UNIVERSITY OF PENNSYLVANIA
- **Principal Investigator:** Zoltan P Arany
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $463,725
- **Award type:** 1
- **Project period:** 2020-07-01 → 2025-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9944705

## Citation

> US National Institutes of Health, RePORTER application 9944705, Branched chain amino acids and pancreatic cancer (1R01CA248315-01). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9944705. Licensed CC0.

---

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