Hydroxychloroquine overcomes tamoxifen resistance in breast cancer

By Will Boggs MD

NEW YORK (Reuters Health) - The antimalarial drug hydroxychloroquine overcomes breast cancer resistance to tamoxifen, according to preclinical studies of estrogen receptor-positive (ER+) mammary tumors.

"It may be possible to delay or reverse the development of resistance to antiestrogens like tamoxifen, in some breast cancer patients with ER+ disease, by also giving the antimalarial drug chloroquine," Dr. Robert Clarke from Georgetown University Medical Center, Washington, DC told Reuters Health by email. "The combination appears safe in the animal model and is being evaluated in at least one clinical study. Since chloroquine is an 'old' drug, repurposing it to help breast cancer patients should also be very cost effective."

Hydroxychloroquine inhibits autophagy, a prosurvival process that breast cancer cells induce and that antiestrogens can stimulate. Whether interfering with this process can enhance breast cancer therapy remains unknown.

Dr. Clarke and colleagues explored the possible beneficial effect of combining antiestrogen therapies (either tamoxifen, a selective estrogen receptor modulator (SERM) or fulvestrant, a selective estrogen receptor downregulator (SERD) and ER antagonist) with hydroxychloroquine in orthotopic human breast cancer xenografts in mice.

The reported their findings June 15th online in Clinical Cancer Research.

In fulvestrant resistant / tamoxifen cross-resistant LCC9 xenografts, hydroxychloroquine alone was just as effective as the combination with tamoxifen after 3 week of treatment, and the combination of fulvestrant and hydroxychloroquine was less effective than either hydroxychloroquine alone or hydroxychloroquine in combination with tamoxifen.

In MCF7-RR cells, which are resistant to tamoxifen, the combination of hydroxychloroquine and tamoxifen significantly reduced tumor size, but neither hydroxychloroquine nor tamoxifen alone significantly reduced tumor size.

Tumors from animals treated with tamoxifen or fulvestrant had reduced p62 expression, consistent with increased autophagic flux, whereas tumors from animals treated with hydroxychloroquine had increased p62 expression, suggesting a block in the later stages of autophagy.

"An ongoing clinical trial is examining the effect of combining tamoxifen and chloroquine for the treatment of ER+ ductal carcinoma in situ (DCIS)," the authors note. The name of that trial is Preventing Invasive Breast Neoplasia with Chloroquine (PINC).

"We are hopeful that this combination may show improved benefit for some breast cancer patients taking existing endocrine therapies," Dr. Clarke said. "We may have to wait to see if what we have shown in these animal models will hold up in clinical trials, but if it does, adding chloroquine to existing endocrine therapies could be very useful for some women."

"In the broader sense, it may be that we will not have to wait for many years to get new drugs approved if we can find new uses for old drugs," Dr. Clarke said. "This can be very cost effective and also greatly reduce the time to get new treatments to patients. It does require keeping an open mind, since some effective new drug combinations may not be at all intuitive."

"For researchers, our study also suggests that the tumor microenvironment may play an important role in affecting responses to antiestrogens and other drugs," Dr. Clarke said. "We see changes in activation of some immune effector cells (macrophages) that are likely to contribute to the overall efficacy of treatment. Perhaps there are ways to further activate the immune system to gain even better responses to existing therapies for some patients."

Dr. Katri S. Selander from the University of Alabama at Birmingham has studied the effects of chloroquine in triple-negative breast cancer. She told Reuters Health, "Chloroquine may have anti-cancer activity in breast cancer. The studies are, however, at a too early phase to draw any conclusions or to change clinical practice. However, clinicians treating breast cancer patients should stay tuned to the follow-up studies."

"If the clinical trials demonstrate that chloroquine inhibits relapses during adjuvant tamoxifen therapy, then chloroquine could be added as an adjuvant in addition to tamoxifen," Dr. Selander said. "It would be helpful, if there was a biomarker to identify the patients that are likely to relapse during tamoxifen-therapy. This would help in selecting those patients that likely benefit from the tamoxifen/chloroquine combination."

Dr. Jenny C. Chang from Houston Methodist Hospital, Houston, Texas has studied the effects of chloroquine on cancer stem cells. She told Reuters Health, "Many research groups have reported that chloroquine or its derivative, hydroxychloroquine, is an effective remedy to target drug resistant breast cancer stem cells."

"Recently, we reported that the chloroquine combination therapy with paclitaxel was highly effective in managing aggressive triple negative breast cancer in pre-clinical and clinical settings," Dr. Chang said. "We found that the combination therapy significantly reduced drug resistance, recurrence, and distant metastasis of triple negative breast cancer by eliminating both bulk tumors and cancer stem cells through an autophagy-independent mechanism, DNA methylation."

"A well-planned chloroquine combination therapy may be effective in managing drug resistance, recurrence, or distant metastasis of breast cancers," Dr. Chang said.

"We are now living in the era of advent personalized therapy," Dr. Chang concluded. "Each tumor is unique but also heterogeneous. Thus, it is imperative to understand and evaluate each patient with various angles in order to provide the most effective therapy to breast cancer patients."

SOURCE: http://bit.ly/1pQxW0W

Clin Cancer Res 2014.

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