Cardiomyopathy is a major complication of doxorubicin (DOX) chemotherapy, and 10-21% of breast cancer patients receiving DOX experience compromised cardiac function. Recent advancements have increased cancer survivorship but it remains clinically challenging to mitigate the cardiotoxic side effects. Although there are several strategies used to reduce the occurrence and severity of DOX-induced cardiotoxicity, they are not particularly effective. Hence, there is an urgent need to develop new strategies that prevent the cardiotoxic effects of DOX but maintain its potency as a cancer therapy. Because the cellular events responsible for the antitumor activity of DOX and DOX-induced cardiotoxicity are distinctly different, it may be possible to develop therapies that selectively mitigate DOX-induced cardiotoxicity. Thus, the investigators propose to test an adjuvant therapy that combines the phytochemical sulforaphane (SFN) with DOX to attenuate DOX-induced cardiomyopathy. SFN activates the transcription factor Nrf2 and induces defense mechanisms in normal cells. Furthermore, SFN inhibits carcinogenesis and metastases and enhances cancer cell sensitivity to DOX, seemingly through Nrf2-independent mechanisms. SFN has also been tested in several clinical trials, although never together with DOX. Our early animal studies suggest that by activating Nrf2, SFN selectively protects the mouse and rat from DOX cardiotoxicity, enhances survival and enhances the effects of DOX on cancer growth in a rat breast cancer model. The investigators suspect that SFN affects DOX metabolism in cancer cells to enhance tumor regression, or it may synergistically activate other key antitumor mechanisms. Hence, SFN may improve the clinical outcome of cancer therapy by (1) attenuating DOX cardiotoxicity and (2) enhancing the effects of cancer treatment on the tumor. Our hypothesis is that SFN protects the heart from DOX-mediated cardiac injury without altering the antitumor efficacy of DOX. In Aim 1, the investigators will conduct an early-phase clinical trial to determine if SFN is safe to administer to breast cancer patients undergoing DOX chemotherapy. In Aim 2, the investigators will determine if SFN decreases DOX-induced inflammatory responses and enhances Nrf2- and SIRT1-target gene expression in breast cancer patients. Notably, transcript and protein signatures in peripheral blood mononuclear cells (PBMCs) can predict cardiac function in patients undergoing DOX chemotherapy for breast cancer. The investigators will also determine if SFN/DOX treatment activates Nrf2- and SIRT1-dependent gene expression, alters the levels of biomarkers for presymptomatic DOX-cardiotoxicity and mitigates the generation of cardiotoxic metabolites in PBMCs and plasma. These studies will facilitate the development of SFN co-treatment as a strategy to enhance the efficacy and safety of DOX cancer therapy.
Age 18 to 89 years
No prior diagnosis of coronary artery, carotid artery or peripheral artery disease
Not pregnant or breastfeeding (urine pregnancy test will be done if female of childbearing potential)
Breast cancer requiring treatment with DOX-containing regimen above
Currently on a research study with an investigational drug, or has been on one in the previous 30 days
Pregnant (by urine pregnancy test)
Baseline ejection fraction of less than 50%, evidence of left ventricular hypertrophy or baseline EKG reported as abnormal per cardiologist.
Inability to provide informed consent.
Parallel
sulforaphane
DrugThe participants will be dosed, based on weight, in a double-blind fashion with identical appearing placebo or sulforaphane caplets in a daily dose for 12 weeks of: two caplets for individuals \<100 lb., four caplets for individuals 100-200 lb. and eight caplets for individuals \>200 lb. Avmacol or placebo will be prescribed by Dr. Awasthi and will be dispensed by local pharmacy or study coordinators at TTUHSC/UMC Lubbock. We will be doing pill counts to make sure that volunteers have used as directed. We will measure the Sulforaphane level in plasma by well-established method.
Placebo Oral Tablet
DrugThe participants will be dosed, based on weight, in a double-blind fashion with identical appearing placebo or sulforaphane caplets in a daily dose for 12 weeks of: two caplets for individuals \<100 lb., four caplets for individuals 100-200 lb. and eight caplets for individuals \>200 lb. Avmacol or placebo will be prescribed by Dr. Awasthi and will be dispensed by local pharmacy or study coordinators at TTUHSC/UMC Lubbock. We will be doing pill counts to make sure that volunteers have used as directed. We will measure the Sulforaphane level in plasma by well-established method.
Change in cardiac function after DOX therapy with or without sulforaphane through diagnostic studies
2D Echo will be used to measure cardiac function amongst patients on DOX therapy who are exposed to sulforaphane or placebo.
Elevation of troponin levels as a surrogate evidence of DOX related cardiotoxicity will be checked at baseline, prior to each DOX therapy and then at 1 year from baseline assessment (Each cycle is 14 days).
Troponin will be used to assess for cardiotoxicity amongst patients on DOX therapy who are exposed to sulforaphane or placebo.
Tumor size in patients on DOX therapy with or without sulforaphane treatment will be assessed at baseline, at completion of DOX chemotherapy (4 cycles planned with each cycle being 14 days) and at 1 year from baseline assessment.
We will use PET imaging for comparison of change in tumor size for patients on DOX therapy with or without sulforaphane.
Click on the lead sponsor to view all of their trials.
