# Engineered adipokine receptor inhibitor for the treatment of triple negative breast cancer in obese patients

> **NIH NIH R41** · ARREVUS, INC. · 2021 · $400,000

## Abstract

PROJECT SUMMARY
 An estimated 1 million cases of breast cancer (BC) are diagnosed annually worldwide. Of these, approximately
170,000 are triple-negative (ER-/PR-/HER2-) breast cancer (TNBC). TNBCs have an aggressive clinical course,
worse prognosis, shorter disease-free interval, and worse overall survival compared to receptor positive breast
cancers. Owing to the lack of target receptors, chemotherapy remains the only systemic therapeutic option in
the adjuvant and metastatic setting of this disease. Even with combined surgery, cisplatin, and radiotherapy,
response rates remain low at 50-60%. Thus, novel therapeutics are greatly needed.
 Obesity increases the risk of BC in postmenopausal women by 30-50% and decreases the efficacy of BC
therapies in all patients. Many studies have shown the critical role of leptin, and leptin receptor (ObR/LEPR) in
TNBC recurrence and metastasis. To counteract the oncogenic activity of leptin in TNBC, several groups have
designed ObR antagonists and have shown success in TNBC studies. However, previous ObR antagonists had
intrinsic limitations in their potency, solubility, and limited activity in obese mice. To overcome this, we are
proposing to advance a novel second-generation ObR antagonist called Allo-aca, that binds ObR with a Kd of 2
pM and inhibits leptin-induced mitogenic activity at picomolar and low nanomolar concentrations. Studies have
shown Allo-aca enhanced survival by 51% compared to treatment with cisplatin (28.1 vs 18.6 days respectively)
in a MDA-MB-231 TNBC mouse model and also inhibits VEGF activity. Furthermore Allo-aca: 1) is the most
potent ObR antagonist in vitro and in vivo; 2) has a wide therapeutic index of ~ 50:1 in mice; 3) is highly soluble
in aqueous solution and crosses the blood-brain barrier; 4) inhibits proinflammatory transcription factor NFҡB
and reduces inflammatory disease; 5) and has shown efficacy in numerous disease models with obese mice.
These studies suggest that Allo-aca has the potential to overcome the limitations of previous ObR antagonists.
 In this Phase I proposal, we propose to assess whether Allo-aca exerts any off-target effects in a standard
screen against key channels and receptors in Aim 1. In parallel in Aim 2, we will assess the in vitro effects of
Allo-aca on cell proliferation and its impact on molecular markers such as epithelial-mesenchymal transition and
ObR signaling. We will follow-up with mouse studies in Aim 3 to identify the most optimal dose of Allo-aca (Aim
3A) that results in the greatest enhancement in survival against the well-defined 4T1 xenograft model and assess
inhibition of tumorigenesis and metastasis against two additional PDX models (Aim 3B). These studies will be
conducted in mice fed a high fat diet to induce weight gain. Altogether, this proposal will allow us to directly test
our hypothesis that Allo-aca can increase survival and is an effective suppressor of tumorigenesis and
metastasis through inhibition of the LEP-ObR axis ...

## Key facts

- **NIH application ID:** 10138223
- **Project number:** 1R41CA257425-01
- **Recipient organization:** ARREVUS, INC.
- **Principal Investigator:** Carl Neil Kraus
- **Activity code:** R41 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $400,000
- **Award type:** 1
- **Project period:** 2021-03-01 → 2023-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10138223

## Citation

> US National Institutes of Health, RePORTER application 10138223, Engineered adipokine receptor inhibitor for the treatment of triple negative breast cancer in obese patients (1R41CA257425-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10138223. Licensed CC0.

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