# Heparanase in Tumor Progression, Metastasis and Chemoresistance

> **NIH NIH R01** · UNIVERSITY OF ALABAMA AT BIRMINGHAM · 2020 · $342,011

## Abstract

The long-term goal of our work is to understand how heparanase promotes the
aggressive behavior of tumors and to use that knowledge to develop curative cancer therapies. We have
identified multiple mechanisms through which heparanase drives cancer progression, metastasis and
chemoresistance and established heparanase as a viable target for cancer therapy. Moreover, we catalyzed
collaborative efforts aimed at developing and testing novel anti-heparanase drugs and demonstrated their
efficacy in pre-clinical models of cancer leading to a currently ongoing clinical trial. The challenge now is to
maximize anti-heparanase therapy to enhance its anti-tumor effects; a goal that will be attained through a
thorough understanding of heparanase mechanisms of action. The overarching hypothesis guiding our work is
that heparanase is a master regulator of the aggressive phenotype of cancer, an important contributor
to the poor outcome of many cancer patients and a prime target for therapy. This hypothesis is supported
by studies focused predominantly on the impact of heparanase expressed by tumor cells. Our latest
discoveries have revealed two novel, previously unexplored mechanisms related to heparanase regulation of
cancer. We found that: (i) heparanase expressed by non-tumor (host) cells within the microenvironment can
substantially contribute to tumor progression, and (ii) tumor secreted exosomes can shuttle heparanase to
recipient cells and enhance their chemoresistance. Our working hypothesis for Aim 1 is that heparanase
produced by host cells acts within the tumor microenvironment to support and accelerate tumor growth,
metastasis and chemoresistance. This will be studied in pancreatic carcinoma and myeloma tumors growing in
mice that express different levels of host heparanase (transgenic and knockout mice). We will investigate the
type of host cells involved (e.g., macrophages, stromal cells), their impact on tumor progression and
chemoresistance and the ability of heparanase inhibitors to block those effects of host heparanase. Our
working hypothesis for Aim 2 is that heparanase present as cargo in exosomes is delivered to recipient tumor
cells and enhances their chemoresistance. We will determine mechanistically how exosomes drive
chemoresistance and investigate the potential of anti-heparanase therapy for inhibiting exosome-mediated
chemoresistance. In addition, work in Aim 3 will develop new, highly specific anti-heparanase monoclonal
antibodies as anti-cancer therapeutics. The proposed work is significant and innovative because it couples the
discovery of new heparanase mechanisms of action with the objective of maximizing anti-heparanase therapy
and improving patient outcome.

## Key facts

- **NIH application ID:** 9934163
- **Project number:** 5R01CA211752-04
- **Recipient organization:** UNIVERSITY OF ALABAMA AT BIRMINGHAM
- **Principal Investigator:** Ralph D Sanderson
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $342,011
- **Award type:** 5
- **Project period:** 2017-06-15 → 2022-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9934163

## Citation

> US National Institutes of Health, RePORTER application 9934163, Heparanase in Tumor Progression, Metastasis and Chemoresistance (5R01CA211752-04). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/9934163. Licensed CC0.

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