# Novel Methods of Chemo-sensitizing Low-proliferative Disseminated Tumor Cells in Triple Negative Breast Cancer

> **NIH NIH R01** · UNIVERSITY OF SOUTHERN CALIFORNIA · 2023 · $621,513

## Abstract

ABSTRACT
Patients with locally invasive triple negative breast cancer (TNBC) who have persistent minimal residual disease
(MRD) despite neoadjuvant therapy are at significant risks of developing lethal metastasis. This represents one of the
outstanding unmet needs in breast cancer therapy. A major cause of this high failure risk is the presence of rare, low-
proliferative disseminated tumor cells (lpDTCs), which are highly resistant to treatment. Many lpDTCs can persist in
distant organs for many years before reactivating to form metastasis. Attempts at eliminating lpDTCs in TNBC have
not been successful due to their rarity, making it difficult to isolate individual lpDTCs to identify therapeutic targets. To
that end, we report the identification and characterization of the IL-6, IL-6 receptor, and p38 (IL-6/R/p38) axis as a
critical signaling pathway required for the maintenance of a significant majority of lpDTCs in TNBC. In cultured human
TNBC cells and mouse models of TNBC, lpDTCs in the bone marrow (BM) can be forced out of quiescence simply by
inhibiting IL-6/R signaling. More importantly, once acutely reactivated, lpDTCs become exquisitely sensitive to
chemotherapy. Thus, the IL-6/R pathway is an attractive therapeutic target. In this proposal, we will test a novel
therapeutic strategy in a Phase I and II trial in patients with TNBC by specifically inhibiting the IL-6/R pathway to force
lpDTCs into proliferation, and then use conventional chemotherapy to eliminate these cells. First, we will determine
whether this treatment strategy is safe in patients in a standard dose finding Phase I study of sarilumab, an IL-6R
inhibiting antibody drug recently approved to treat rheumatoid arthritis, sequentially combined with capecitabine, a
standard breast cancer chemotherapy drug, in patients with metastatic breast cancer (Aim 1). The Phase I’s
objectives are to determine tolerability and safety of the combination and the recommended dose of the combination
for the Phase II. Next, we will conduct a Phase II single-arm study using this recommended dose regimen in patients
with stage I-III TNBC who have persistent MRD in breast tissue or surrounding lymph nodes after neoadjuvant
therapy (Aim 2). The Phase II objectives are to determine how effective this drug combination is at clearing BM
lpDTCs, and if so whether patients cleared of BM lpDTCs have a higher rate of progression-free survival at two years
compared to patients historically treated with capecitabine alone. In Aim 3, we will isolate individual lpDTCs from BM
aspirates collected in this trial using the conventional magnet-based enrichment method and a locally developed
microfluidic device to 1) enumerate lpDTCs before and after treatment to determine the lpDTC clearing efficacy of the
test drug combination; and 2) to perform genomics analysis of single lpDTCs, primary and metastatic tumor samples
from the same patients. We will use a novel computational platform recently developed to analyz...

## Key facts

- **NIH application ID:** 10846212
- **Project number:** 7R01CA238387-04
- **Recipient organization:** UNIVERSITY OF SOUTHERN CALIFORNIA
- **Principal Investigator:** David D Tran
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $621,513
- **Award type:** 7
- **Project period:** 2020-06-15 → 2025-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10846212

## Citation

> US National Institutes of Health, RePORTER application 10846212, Novel Methods of Chemo-sensitizing Low-proliferative Disseminated Tumor Cells in Triple Negative Breast Cancer (7R01CA238387-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10846212. Licensed CC0.

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