Losartan for Radiation-Induced Fibrosis in Breast Cancer

Recruiting at1 trial location

Overseen by Patricia H. Hardenbergh

Age: 18+

Sex: Female

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 2

Recruiting

Sponsor: Shaw Cancer Center

Must not be taking: Losartan, RAS agents, Lithium, others

Disqualifiers: Recurrent breast cancer, Connective tissue disorder, Uncontrolled illness, Pregnancy, others

Prior Safety Data

Trial Summary

What is the purpose of this trial?

This study will evaluate the efficacy of losartan (LOS), an FDA-approved transforming growth factor beta-1 (TGF-β1) blocker, to decrease radiation induced fibrosis (RIF) in the breast and the lung of breast cancer patients, testing the hypothesis that Losartan will decrease RIF, TGF- β1 and cellular senescence/inflammation in the breast and the lung of irradiated breast cancer patients relative to placebo treatment and consequently improve clinical outcomes in breast cancer patients.

Do I have to stop taking my current medications for this trial?

The trial does not specify if you must stop all current medications, but you cannot take Losartan, other renin-angiotensin system agents, agents to increase serum potassium, lithium, or aliskiren for diabetes.

What data supports the idea that Losartan for Radiation-Induced Fibrosis in Breast Cancer is an effective drug?

The available research does not provide direct evidence that Losartan is effective for treating radiation-induced fibrosis in breast cancer. However, studies show that Losartan can help in other conditions. For example, in a rat model of radiation-induced heart disease, Losartan reduced heart damage and fibrosis. In prostate cancer, Losartan enhanced the effects of radiation therapy. In breast cancer models, Losartan improved tumor control and reduced metastases when combined with radiotherapy. These findings suggest that Losartan might have potential benefits in similar conditions, but specific data for breast cancer fibrosis is not available. ^{1 2 3 4 5}

What safety data exists for Losartan in treating radiation-induced fibrosis in breast cancer?

The provided research does not directly address the safety of Losartan for radiation-induced fibrosis in breast cancer. However, Losartan is a well-known angiotensin II receptor blocker commonly used for blood pressure regulation, suggesting a known safety profile in humans. The studies mention its use in various models, including prostate cancer, heart disease, and breast cancer, without reporting specific safety concerns. Further clinical trials would be needed to establish its safety specifically for radiation-induced fibrosis in breast cancer. ^{1 2 3 6 7}

Is the drug Losartan a promising treatment for radiation-induced fibrosis in breast cancer?

Yes, Losartan is a promising treatment because it can improve the effectiveness of radiation therapy by increasing oxygen levels in tumors, which helps control tumor growth and prevent cancer spread. It also reduces fibrosis, which is the thickening and scarring of tissue, making it potentially beneficial for patients with radiation-induced fibrosis. ^{1 2 3 6 8}

Research Team

Patricia H. Hardenbergh

Principal Investigator

Vail Health Shaw Cancer Center

Eligibility Criteria

This trial is for women over 18 with stage 0-IV breast cancer who've had surgery and are set for radiation therapy. They must have normal kidney and liver function, not be pregnant or breastfeeding, and can't have autoimmune diseases, a history of certain conditions, or be on conflicting medications.

Inclusion Criteria

I am a woman eligible for this trial.

Your kidney function, measured by eGFR, is normal or higher than 60.

I have been diagnosed with breast cancer at any stage.

Exclusion Criteria

I have specific genetic mutations related to cancer.

My breast cancer has come back or I've had radiation therapy for it before.

I do not have any uncontrolled illnesses like heart failure, unstable angina, kidney disease, uncontrolled diabetes, cystic fibrosis, or fibromyalgia.

Trial Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Radiation

Participants undergo radiation therapy as per local clinic procedures

Varies based on individual treatment plans

Treatment

Participants receive 25mg of Losartan or placebo daily starting from the first day of radiation therapy until one year after completion of radiation therapy

1 year

Follow-up

Participants are monitored for fibrosis, cosmetic outcomes, and incidence of reoperation

18 months

Follow-up visits at 3, 6, 12, and 18 months

Treatment Details

Interventions

• Losartan (Angiotensin II Receptor Blocker)
• Placebo (Chemotherapy)

Trial Overview The study tests if Losartan, a drug that blocks TGF-β1 involved in fibrosis, can reduce scarring in the lung and breast from radiation treatment in breast cancer patients compared to a placebo.

Participant Groups

Group I: Mastectomy with Losartan Experimental Treatment 1 Intervention

Participants who underwent a mastectomy will take losartan in a 25 milligram oral capsule once daily starting day one of radiation therapy until one year following the completion of radiation therapy.

Group II: Breast Conservation Surgery with Losartan Experimental Treatment 1 Intervention

Participants who underwent breast conservation surgery will take losartan in a 25 milligram oral capsule once daily starting day one of radiation therapy until one year following the completion of radiation therapy.

Group III: Mastectomy with Placebo Placebo Group 1 Intervention

Participants who underwent a mastectomy will take placebo in a 25 milligram oral capsule once daily starting day one of radiation therapy until one year following the completion of radiation therapy.

Group IV: Breast Conservation Surgery with Placebo Placebo Group 1 Intervention

Participants who underwent breast conservation surgery will take placebo in a 25 milligram oral capsule once daily starting day one of radiation therapy until one year following the completion of radiation therapy.

Who Is Running the Clinical Trial?

Shaw Cancer Center

Lead Sponsor

Trials

1

Recruited

40+

Steadman Philippon Research Institute

Collaborator

Trials

11

Recruited

700+

Findings from Research

In a rat model of radiation-induced heart disease (RIHD), treatment with losartan significantly reduced left ventricular hypertrophy (LVH) and fibrosis after 15 weeks, indicating its potential efficacy in managing heart damage caused by thoracic radiotherapy.

The beneficial effects of losartan were linked to the suppression of specific proteins and signaling pathways associated with heart remodeling, suggesting a mechanism of action that involves the repression of chymase and components of the TGF-β/SMAD pathway.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Investigation of the Antihypertrophic and Antifibrotic Effects of Losartan in a Rat Model of Radiation-Induced Heart Disease. Kovács, MG., Kovács, ZZA., Varga, Z., et al.[2021]

Losartan, an angiotensin II receptor blocker, effectively reduces the survival of prostate cancer cells, showing a significant antitumor effect at a concentration of 1 µM.

When combined with ionizing radiation, losartan enhances the treatment's effectiveness, further reducing prostate cancer cell proliferation without causing toxicity to non-malignant fibroblast cells.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Losartan sensitizes selectively prostate cancer cell to ionizing radiation. Yazdannejat, H., Hosseinimehr, SJ., Ghasemi, A., et al.[2016]

In a study using a murine model of metastatic HER2/neu-positive breast cancer, combining losartan with radiation therapy significantly increased tumor growth delay by an additional 5 to 8 days compared to radiation alone, indicating enhanced treatment efficacy.

Losartan treatment also reduced lung metastasis and improved animal survival, likely by increasing tumor vascularity and decreasing hypoxia, suggesting it could be a promising strategy for improving outcomes in HER2-positive breast cancer patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Combining losartan with radiotherapy increases tumor control and inhibits lung metastases from a HER2/neu-positive orthotopic breast cancer model. Li, W., Li, S., Chen, IX., et al.[2021]

Telmisartan, an angiotensin II type 1 receptor blocker, significantly improved blood flow and stabilized perfusion in solid tumours, leading to reduced transient hypoxia, which is known to make tumour cells resistant to radiation.

Tumours treated with telmisartan showed enhanced responsiveness to radiation therapy, suggesting that it can effectively modify the tumour microenvironment to improve treatment outcomes by targeting hypoxic tumour cells.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Angiotensin II type 1 receptor blocker telmisartan inhibits the development of transient hypoxia and improves tumour response to radiation. Wadsworth, BJ., Cederberg, RA., Lee, CM., et al.[2021]

Losartan, an angiotensin system inhibitor, enhances the effectiveness of the chemotherapy drug paclitaxel in ovarian cancer by normalizing the tumor microenvironment, which improves drug delivery and blood vessel perfusion.

Patients with ovarian cancer who received angiotensin system inhibitors alongside standard treatments had a significantly longer overall survival (30 months) compared to those on other antihypertensives, suggesting a potential benefit of this combination therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Losartan treatment enhances chemotherapy efficacy and reduces ascites in ovarian cancer models by normalizing the tumor stroma. Zhao, Y., Cao, J., Melamed, A., et al.[2020]

Losartan, an AT1 receptor antagonist, effectively induces apoptosis in human pancreatic stellate cells (hPSCs) in a dose- and time-dependent manner, without promoting cell proliferation.

The study suggests that Losartan may have anti-fibrotic effects by reducing the migration and type I collagen production of hPSCs, indicating its potential therapeutic role in pancreatic fibrosis associated with cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effects of angiotensin II receptor antagonist, Losartan on the apoptosis, proliferation and migration of the human pancreatic stellate cells. Liu, WB., Wang, XP., Wu, K., et al.[2022]

Topical losartan significantly reduced corneal opacity and the generation of myofibroblasts after photorefractive keratectomy (PRK) in rabbits, indicating its potential efficacy in preventing late haze scarring fibrosis.

Losartan, an angiotensin II receptor inhibitor, appears to work by inhibiting TGF-β signaling, leading to decreased production of non-basement membrane collagen type IV, which is associated with scarring.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Losartan Inhibition of Myofibroblast Generation and Late Haze (Scarring Fibrosis) After PRK in Rabbits. Sampaio, LP., Hilgert, GSL., Shiju, TM., et al.[2022]

Losartan, an approved medication, can reduce collagen production in tumor-associated fibroblasts, which may help improve the delivery of nanotherapeutics in dense tumors.

In mouse models of breast, pancreatic, and skin tumors, losartan not only decreased stromal collagen but also enhanced the effectiveness of both intratumoral oncolytic herpes simplex viruses and intravenous pegylated liposomal doxorubicin (Doxil).

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Losartan inhibits collagen I synthesis and improves the distribution and efficacy of nanotherapeutics in tumors. Diop-Frimpong, B., Chauhan, VP., Krane, S., et al.[2023]

References

1. Switzerland pubmed.ncbi.nlm.nih.gov

Investigation of the Antihypertrophic and Antifibrotic Effects of Losartan in a Rat Model of Radiation-Induced Heart Disease. [2021]

2. France pubmed.ncbi.nlm.nih.gov

Losartan sensitizes selectively prostate cancer cell to ionizing radiation. [2016]

3. England pubmed.ncbi.nlm.nih.gov

Combining losartan with radiotherapy increases tumor control and inhibits lung metastases from a HER2/neu-positive orthotopic breast cancer model. [2021]

4. Ireland pubmed.ncbi.nlm.nih.gov

Angiotensin II type 1 receptor blocker telmisartan inhibits the development of transient hypoxia and improves tumour response to radiation. [2021]

5. United States pubmed.ncbi.nlm.nih.gov

Losartan treatment enhances chemotherapy efficacy and reduces ascites in ovarian cancer models by normalizing the tumor stroma. [2020]

6. United States pubmed.ncbi.nlm.nih.gov

Effects of angiotensin II receptor antagonist, Losartan on the apoptosis, proliferation and migration of the human pancreatic stellate cells. [2022]

7. United States pubmed.ncbi.nlm.nih.gov

Losartan Inhibition of Myofibroblast Generation and Late Haze (Scarring Fibrosis) After PRK in Rabbits. [2022]

8. United States pubmed.ncbi.nlm.nih.gov

Losartan inhibits collagen I synthesis and improves the distribution and efficacy of nanotherapeutics in tumors. [2023]