NCT06452394

NEODOXy: Targeting Breast Cancer Stem Cells With Doxycycline

NEODOXy: Targeting Cancer Stem Cells With NEOadjuvant DOXYcycline in Patients With Early Estrogen Receptor Positive / Human Epidermal Growth Factor Receptor 2- Negative Breast Cancer. A Prospective, Multicenter, Single Arm, Open Label Phase II Trial

• Status: Recruiting
• Phase: Phase 2
• Study type: Interventional
• Enrollment: 50 (estimated)
• Sponsor: Swiss Cancer Institute · Academic / Other
• Sex: All
• Age: 18 Years
• Healthy volunteers: Not accepted

Summary

Despite modern surgical and medical treatments, breast cancer can re-occur and lead 20% of patients to death. During the last 20 years, pre-clinical studies have shown that treatment failures may be due to the presence of a sub-type of cancer cells, the cancer stem cells, which are resistant to chemotherapy and radiotherapy. By chance, doxycycline, an old, inexpensive and safe molecule seems to target effectively these cancer stem cells. This study proposes to check for the clinical efficacy of doxycycline to target the cancer stem cells and improve the response to neoadjuvant chemotherapy in ER+/HER2- breast cancers.

Detailed description

Patients with early stage ER+/HER2- breast cancer (BC) have a low pathologic complete response (pCR) rate of less than 15%. Over the past 20 years, studies have identified a subset of cancer cells with tumorigenic and stem-like properties, known as cancer stem cells (CSCs), that are involved in tumour initiation, metastasis, relapse and resistance to treatment. Cancer cells with stem-like properties are known to possess cellular plasticity that not only enables self-renewal capacity, but also exhibits high tumourigenic potential and resistance to oncological therapies such as chemotherapy and/or radiotherapy. CSCs can arise from normal adult breast stem cells through mutations or directly from differentiated tumor cells. Tumour hypoxia has been shown to be one of the major factors promoting and maintaining the stemness phenotype. The metabolism of CSCs in hypoxia relies on a delicate balance between reduced energy requirements through reduced proliferation and an altered balance between mitochondrial oxidative phosphorylation ("OXPHOS") and cytosolic glycolysis, while maintaining mitochondrial redox homeostasis to control reactive oxygen species (ROS) levels. Any slight imbalance in mitochondrial redox homeostasis in CSCs, leading to transient effects on ROS, may promote their differentiation towards their non-stem tumour cell counterparts. Consequently, specific drugs targeting mitochondrial metabolism, leading to increased ROS levels, may destabilise CSCs. This study proposes to check for the clinical efficacy of doxycycline to target the cancer stem cells and improve the response to neoadjuvant chemotherapy in ER+/HER2- breast cancers. The change in the stemness marker, ALDH1, assessed before and after treatment and the effect of doxycycline on the pathological response will be studied. The translational work will be to better define these stem cells and to grow organoid cultures to study the effects of the different drugs in vitro. This study also aims to address a number of translational research questions using a tumor sample obtained from an additional core biopsy prior to treatment initiation and using a fresh tumor sample from the surgical specimen in the case of residual tumor after neoadjuvant treatment: * Quantify and characterise the effects of doxycycline on tumors * Identify factors that facilitate or prevent the effects of doxycycline * Estimate the effect of doxycycline compared to other CSC-targeting drugs

Conditions

• Breast Cancer

Interventions

Type	Name	Description
DRUG	Doxycyclin	Belongs to the class of tetracyclines. It has bacteriostatic activity against a broad range of gram-positive and gram-negative bacteria. Its mechanism of action lies in the binding to the 30S ribosomal subunit

Timeline

• Start date: 2025-07-16
• Primary completion: 2028-06-30
• Completion: 2028-12-31
• First posted: 2024-06-11
• Last updated: 2025-12-30

Locations

8 sites across 1 country: Switzerland