# PTHrP and Cancer Cachexia

> **NIH NIH R21** · YALE UNIVERSITY · 2020 · $184,250

## Abstract

PROJECT SUMMARY/ABSTRACT
Cancer cachexia anorexia syndrome (CACS) is a disease of disordered energy metabolism leading to the
pronounced loss of body mass. It afflicts 80% of patients with advanced malignancies and is a direct cause of
20% of cancer deaths. Metabolic phenotypes in patients with tumor-induced cachexia are heterogeneous but
all suffer from negative energy balance associated with active catabolism of fat and muscle tissue. It is thought
that cancers secrete factors that trigger tissue catabolism to increase the availability of circulating nutrients for
tumor cells. Parathyroid hormone-related protein (PTHrP) is a growth factor that is structurally related to
parathyroid hormone (PTH) and, when secreted by tumor cells, causes a paraneoplastic syndrome known as
humoral hypercalcemia of malignancy (HHM). Some studies have suggested that PTHrP may also contribute
to CACS by inducing “browning” of white adipose tissue (WAT). We created a tetracycline-regulated
transgenic model of PTHrP overexpression in breast cancer (Tet-PTHrP;PyMT mice) and found that
overexpression of PTHrP in mammary tumors causes hypercalcemia, severe fat wasting, anorexia and
pronounced weight loss. However metabolic studies in these mice did not find evidence of WAT browning or
increased energy expenditure but suggested that PTHrP and hypercalcemia may act together to trigger
lipolysis, anorexia and progressive fat loss. Therefore, the central premise of this application is that PTHrP and
calcium synergize to disrupt energy metabolism and to contribute to CACS in patients with humoral
hypercalcemia of malignancy (HHM). In order to explore the effects of PTHrP in CACS further we propose the
following Aims. First, in Aim 1, we will study whether PTHrP activates lipolysis and muscle catabolism in vivo
and will characterize whether inflammatory cytokines and/or anorexia contribute to this response. Second, in
Aim 2, we will examine whether hypercalcemia acts on the calcium-sensing receptor (CaSR) to augment the
lipolytic effects of PTHrP using cultured adipocytes in vitro and by pharmacologically and genetically inhibiting
CaSR signaling in Tet-PTHrP;PyMT mice in vivo. Our experiments are designed to explore and extend exciting
preliminary data demonstrating that PTHrP contributes to CACS and to determine whether hypercalcemia
augments the metabolic effects of elevated levels of PTHrP. We believe these studies will pave the way for
further mechanistic studies in patients with CACS and for the development of therapeutic strategies to block
PTHrP and or CaSR signaling in cancer patients with cachexia.

## Key facts

- **NIH application ID:** 9881247
- **Project number:** 5R21AR073146-02
- **Recipient organization:** YALE UNIVERSITY
- **Principal Investigator:** John J Wysolmerski
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $184,250
- **Award type:** 5
- **Project period:** 2019-03-01 → 2021-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9881247

## Citation

> US National Institutes of Health, RePORTER application 9881247, PTHrP and Cancer Cachexia (5R21AR073146-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9881247. Licensed CC0.

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