# MUC16 in Pancreatic Cancer Progression and Metastasis

> **NIH NIH R01** · UNIVERSITY OF NEBRASKA MEDICAL CENTER · 2020 · $338,280

## Abstract

Pancreatic cancer (PC) is highly lethal disease. At the time of diagnosis more than 80%
of PC patients have either locally advanced or highly metastatic disease. Fatality of PC patients is associated
with early metastasis (spreading to distant organs), induction of multiple organ failure, cachexia (loss of weight
and muscle atrophy), and poor patient response to standard chemotherapy. PCs often overexpress and
release into the blood unusual glycoproteins that include CA19-9 and CA125 (also known as MUC16). We
have recently discovered that, in addition to serving as a biomarker, aberrantly glycosylated forms of the large
mucin type glycoproteins that comprise the material recognized in the CA19-9 and CA125 assays have
biological activity as growth factors or cytokines. Thus, we aim to define the way in which this newly discovered
activity affects the tumor progression, early metastasis and systemic effects of cancer progression. Our
preliminary data demonstrate that overexpression of tumor associated truncated carbohydrate antigens (Tn
and STn) on the MUC16 (Tn/STn-MUC16) membrane mucin glycoprotein creates a ligand for growth factor
receptors, which results in an activation of oncogenic signaling cascades through Akt and FAK that increases
the malignant potential of PC cells. Treatment of cancer cells with monoclonal antibody (mAb) AR9.6 that binds
to MUC16, blocks stimulation of the above described oncogenic signaling cascades. In addition, treatment of
PC cells and tumor bearing animals with AR9.6 mAb inhibits in vitro cancer cell growth, and in vivo tumor
growth and metastasis. Genetic deletion of aberrant glycoforms MUC16 in PC cells reduced tumor metastasis,
reduced the phosphorylation of ErbB2, ErbB3, Akt and GSK3β, and increased the median survival of the
animals. We hypothesize that aberrant glycoforms of MUC16 play a major role in PC growth, metastasis and
survival. Therefore, we propose to determine the circulating levels of abnormally glycosylated MUC16, and
correlate this to the status of altered receptor-ligand interactions and oncogenic signaling in clinical specimens,
and to clinical outcomes such as the incidence of metastasis, organ failure, cachexia, and overall survival
using a unique set of samples obtained from rapid autopsies of patients that died of PC (Aim 1). We will
validate our hypothesis that abnormal glycosylation of mucin glycoproteins contributes to pancreatic tumor
progression and metastasis using genetic engineered mouse models of PC that are further engineered to
express aberrantly glycosylated mucins (Aim 2). We will elucidate the mechanism by which aberrant
glycoforms of MUC16 mediate PC tumorigenesis, and determine the in vivo therapeutic efficacy of AR9.6 mAb
alone and in combination with Gemcitabine treatment against PC (Aim 3).These studies will lead to a new
understanding of factors that contribute to tumor progression, metastasis, and the effects of secreted tumor
products on distant organ sites, includin...

## Key facts

- **NIH application ID:** 9896780
- **Project number:** 5R01CA208108-04
- **Recipient organization:** UNIVERSITY OF NEBRASKA MEDICAL CENTER
- **Principal Investigator:** Prakash Radhakrishnan
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $338,280
- **Award type:** 5
- **Project period:** 2017-04-01 → 2022-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9896780

## Citation

> US National Institutes of Health, RePORTER application 9896780, MUC16 in Pancreatic Cancer Progression and Metastasis (5R01CA208108-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9896780. Licensed CC0.

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