Aging Mammary Stem Cells and Breast Cancer Prevention

NCT02642094 | Terminated Phase 2 Results FDA Drug

• 2 other identifiers: CTMS 15-20961R01CA192564-01A1
• Study Type: interventional
• Target: 58
• Locations: 1 country
• Sites: 1

Brief Summary

To examine whether rapamycin can reduce malignant markers and aberrant mammary stem/progenitor cells (MaSCs) number in surgical specimens

Conditions

Cancer of Breast

Outcome Measures

Primary Outcomes (5)

• The Effect of Short-term Rapamycin Treatment on Biomarker Ki67 Associated With Progression to Invasive Breast Cancer

  Comparing biopsy tissues before the treatment with surgical samples after rapamycin treatment in the same individuals to determine percentage nuclei with positive staining for Ki67 in the CCIS lesions.

  Baseline to 5-7 day rapamycin plus 3-7 day washout

• The Effect of Short-term Rapamycin Treatment on the Frequency of Luminal Progenitor Epithelial Cells

  Assessment will be used to measure changes in luminal progenitor cell population between controls and treated patients.

  5-7 day rapamycin treatment plus 3-7 day washout for the treatment group.

• The Effect of Short-term Rapamycin Treatment on Sphere Formation Efficiency of Mammary Stem Cells

  Measurement of difference in sphere formation efficiency (SFE) by mammary stem cells (MaSCs) in the basal myoepithelial cell population between the control and treatment groups. SFE is an in vitro method by quantifying the number of spheres formed divided by the number of cells seeded. Higher SFE indicates higher frequency of MaSCs.

  5-7 day rapamycin treatment plus 3-7 day washout for the treatment group.

• The Effect of Short-term Rapamycin Treatment on the Frequency of Mature Luminal Epithelial Cells

  Measurement of Mature luminal cell populations in the treatment group compared to the control group.

  5-7 day rapamycin treatment plus 3-7 day washout for the treatment group.

• The Effect of Short-term Rapamycin Treatment on Sphere Formation Efficiency of Luminal Progenitor Cells

  The measurement of sphere formation efficiency (SFE) between luminal progenitor (LP) cells from the control group and those from the treatment group. SFE is an in vitro method by quantifying the number of spheres formed divided by the number of cells seeded. Higher SFE indicates higher frequency of LP cells.

  5-7 day rapamycin treatment plus 3-7 day washout for the treatment group.

Study Arms (1)

The effect of short-term rapamycin treatment

EXPERIMENTAL

Subjects will be given a low dose of rapamycin at 2 mg/day for 5-7 days of treatment. A surgical specimen will be taken 3-7 days after the last dose of rapamycin. The specimens will be evaluated for lesion size, nuclear grade, presence of necrosis in each patient's core biopsy and surgical specimens, as well as IHC (ImmunoHistoChemistry) for biomarkers including p16, COX2 (cyclooxygenase-2), and Ki-67. Specimens will also be tested for rapamycin treatment on the properties of mammary stem/progenitor cells as another biomarker for gauging the efficacy of rapamycin treatment.

Drug: Rapamycin

Interventions

Rapamycin DRUG

Low dose of rapamycin at 2 mg/day for -5-7 days of treatment

Also known as: Sirolimus

The effect of short-term rapamycin treatment

Eligibility Criteria

• Age: 18 Years - 80 Years
• Sex: female
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Women with confirmed menopausal status. All patients who have NOT had a prior bilateral oophorectomy and/or are younger than age 60, will require menopausal status verified by FSH and estradiol local labs.
• Women diagnosed with DCIS/LCIS, Atypical lobular hyperplasia (ALH) or ADH lesions detected by pathology
• Women scheduled for mastectomy or lumpectomy after DCIS/LCIS, ALH or ADH diagnosis
• Women consented to the UT Health Cancer Center MD Anderson Cancer Center tissue biorepository (HSC20070684H)
• Women of child-bearing potential willing to practice 2 forms of contraception, one of which must be a barrier method until at least 30 days after the last dose of rapamycin.
• Women of child-bearing potential must have a negative serum pregnancy test at time of enrollment.
• Patients must be able to swallow and retain oral medication.
• All patients must have given signed informed consent prior to registration on study.
• Patients must have normal organ and marrow function as defined below:
• Leukocytes ≥ 3,000/uL
• Absolute neutrophil count ≥ 1,500/uL
• Platelets ≥ 100,000/uL
• AST ≤ 2.5 X ULN
• ALT ≤ 2.5 X ULN
• Total bili ≤ 1.5 X ULN or Direct bili ≤ 1 X ULN

You may not qualify if:

• Women who are pregnant.
• Women who are receiving any other concomitant treatment for their DCIS/LCIS, ALH or ADH
• Women who are taking rapamycin for another diagnosis.
• Women with an allergy to rapamycin or its derivatives.
• Active infection requiring systemic therapy.
• Patients who are taking any pills containing herbal (alternative) medicines are NOT eligible for participation. Patients must be off any such medications by the time of registration.
• Immunocompromised subjects, including patients with human immunodeficiency virus
• Women currently taking strong CYP3A4 inducers or inhibitors. Drugs that cannot be coadministered with rapamycin include but are not limited to: Calcium channel blockers: nicardipine, Antifungal agents: clotrimazole, fluconazole, Antibiotics: troleandomycin, Gastrointestinal prokinetic agents: cisapride, metoclopramide, Other drugs: bromocriptine, cimetidine, danazol, HIV-protease inhibitors (e.g., ritonavir, indinavir), Anticonvulsants: carbamazepine, phenobarbital, phenytoin, Antibiotics: rifapentine. The research team can provide a full list of these medications.
• Patients with any of the following conditions or complications are NOT eligible for participation:
• GI tract disease resulting in an inability to take oral medication
• Malabsorption syndrome
• Require IV alimentation
• History of prior surgical procedures affecting absorption
• Uncontrolled inflammatory GI disease (e.g., Crohn's, ulcerative colitis)

Sponsors & Collaborators

• LuZhe Sun: lead
• National Cancer Institute (NCI): collaborator

Study Sites (1)

University of Texas Health Science Center San Antonio

San Antonio, Texas, 78229, United States

Location

Related Publications (1)

• Bouamar H, Broome LE, Lathrop KI, Jatoi I, Brenner AJ, Nazarullah A, Gorena KM, Garcia M, Chen Y, Kaklamani V, Sun LZ. mTOR inhibition abrogates human mammary stem cells and early breast cancer progression markers. Breast Cancer Res. 2023 Oct 30;25(1):131. doi: 10.1186/s13058-023-01727-z.

  PMID: 37904250 DERIVED

MeSH Terms

Conditions

Breast Neoplasms

Interventions

Sirolimus

Condition Hierarchy (Ancestors)

Neoplasms by Site; Neoplasms; Breast Diseases; Skin Diseases; Skin and Connective Tissue Diseases

Intervention Hierarchy (Ancestors)

Macrolides; Lactones; Organic Chemicals

Limitations and Caveats

Our hypothesis was that a low dose and short term treatment with rapamycin in patients with early stage breast cancer would show significantly attenuation of mammary stem and progenitor cell activity and tumor progression biomarkers in a non-randomized study.

Results Point of Contact

• Title: LUZHE SUN, Ph.D.
• Organization: University of Texas Health Science Center

sunl@uthscsa.edu

210-567-5746

Study Officials

• LuZhe Sun, PhD

  University of Texas Health Science Center San Antonio, Co-PI

  PRINCIPAL INVESTIGATOR

• Ismail Jatoi, MD

  University of Texas Health Science Center San Antonio

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: BASIC SCIENCE
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Co-Principal Investigator

Study Record Dates

• First Submitted: November 25, 2015
• First Posted: December 30, 2015
• Study Start: July 1, 2016
• Primary Completion: March 1, 2022
• Study Completion: May 1, 2022
• Last Updated: December 5, 2023
• Results First Posted: December 5, 2023

Record last verified: 2023-12

Locations

US (1)