# A Novel Agent to Suppress Tumor Growth in Bone, Prevent Cachectic Muscle Loss and Preserve Skeletal Integrity

> **NIH VA I01** · RLR VA MEDICAL CENTER · 2022 · —

## Abstract

ABSTRACT: Over 85% of patients with advanced cancers of breast and prostate suffer from incurable bone
metastases. Osteoclast activation and osteoblast suppression lead to bone loss, pathologic fractures,
hypercalcemia and bone pain, often accompanied by loss of skeletal muscle (cachexia). Current therapies target
osteoclasts and have limited effects on tumor growth, while not restoring lost bone or muscle.
Tumor-secreted parathyroid hormone-related protein, PTHrP, is a major causal agent of bone destruction by
inducing expression of RANKL to increase osteoclast number and function. TGFβ, released during bone
resorption, stimulates breast cancer production of PTHrP [Yin et al, 1999], driving a vicious cycle of bone
metastases [Chirgwin & Guise, 2000; Kakonen et al, 2002]. PTHrP stimulates growth of PTH1R receptor-
expressing tumors and indirectly causes cancer cachexia via reprogramming of adipocytes [Kir & Spiegelman,
2016]. It causes hypercalcemia of malignancy, stimulates angiogenesis and cancer bone pain. We believe the
deleterious actions of tumor PTHrP can be blocked by a unique PTH1R ligand, while having beneficial anabolic
effects on bone - which cannot be achieved with PTHrP-neutralizing antibody. [D-Trp12,Tyr34]-bovine-PTH(7-
34), bPTH7-34DD, is a unique inverse agonist of G protein-coupled signaling by PTH1R, decreasing cAMP, while
activating β-arrestin signaling. It increases bone formation without causing hypercalcemia or osteolysis
[Maudsley et al, 2015]. Our data showed anti-osteolytic and anti-tumor actions of bPTH7-34DD in co-cultures of
breast cancer with mouse bone. It also countered adipocyte gene changes associated with cancer cachexia.
We hypothesize that bPTH7-34DD will: 1) Inhibit the vicious cycle of osteolytic bone metastases by suppressing
osteolysis & tumor growth; 2) Decrease cancer cachexia by blocking white-to-brown adipocyte conversion in
bone; 3) Preserve bone health by stimulating new bone formation; 4) Effectively treat osteolytic tumors due
breast cancer. 5) Be effective against other PTHrP-secreted tumor types. bPTH7-34DD will be tested in xenograft
models of breast cancer bone metastasis, in prevention and treatment settings. The mechanism of bPTH7-34DD
signaling will be tested in ex vivo co-cultures of cancer cells with mouse bones and in bone and fat cell lines and
1o cells and with bones and cells from wt & β-arrestin k/o (βarr2-/-) mice.
Specific Aim 1: a) Determine growth effects ex vivo of bPTH7-34DD on tumor cells; b) Determine the mechanism
of action of on i) Osteoblasts (Obs), osteoclasts (Ocs), & osteocytes (Ots); ii) On adipocytes; c) Test if responses
to bPTH7-34DD require β-arrestin, using bones & cells from βarr2-/- mice; d) Test if bPTH7-34DD blocks growth
in bone and osteolysis ex vivo with prostate and lung cancer and multiple myeloma cells
Specific Aim 2: Test bPTH7-34DD in vivo for significant effects on: a) Tumor burden; b) Osteolytic lesions; c)
Bone loss/formation systemically and adjace...

## Key facts

- **NIH application ID:** 10454796
- **Project number:** 5I01BX004514-04
- **Recipient organization:** RLR VA MEDICAL CENTER
- **Principal Investigator:** JOHN M CHIRGWIN
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2022
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2019-04-01 → 2023-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10454796

## Citation

> US National Institutes of Health, RePORTER application 10454796, A Novel Agent to Suppress Tumor Growth in Bone, Prevent Cachectic Muscle Loss and Preserve Skeletal Integrity (5I01BX004514-04). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10454796. Licensed CC0.

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