Tamoxifen resistant tumors in mice + antimalarial drug

Lojo · June 2014

http://www.sciencedaily.com/releases/2014/06/140613084502.htm

From ScienceDaily

"The
inexpensive anti-malarial drug hydroxychloroquine (HCQ) reverses
resistance to tamoxifen, a widely used breast cancer drug, in mice.

In the June 15 issue of Clinical Cancer Research,
investigators from Georgetown Lombardi Comprehensive Cancer Center say
adding HCQ to tamoxifen could provide a new treatment option for some
women with advanced, postmenopausal estrogen receptor-positive (ER+)
breast cancer. The ER+ subtype accounts for an estimated 70 percent of
all breast cancers. While many of these women are treated with
tamoxifen, which blocks estrogen from fueling the tumor, 50 percent of
these cancers will either not respond or will become resistant to
tamoxifen over time.

"Tamoxifen resistance when treating breast
cancer is a big issue in the clinic, and we believe our findings provide
a very promising fix to the problem," says the study's senior
investigator, Robert Clarke, PhD, DSc, dean for research at Georgetown
University Medical center, and co-director of the breast cancer program
at Georgetown Lombardi.

Clarke adds that both drugs are inexpensive, on the market and have a well-defined safety profile.

HCQ
was developed to treat malaria, but has since been repurposed as
therapy for rheumatoid arthritis and lupus. The study is the first to
test HCQ's ability to restore breast cancer cell sensitivity to
tamoxifen or to a different anti-estrogen drug known as faslodex."

farmerlucy · June 2014

very interesting!!

wallycat · June 2014

I wonder if this would be effective for ILC sub-types that do not respond to tamoxifen. Interesting.

luv_gardening · June 2014

Wallycat, I didn't realise ILC may not respond to tamoxifen. How do we find out if it applies to us?

wallycat · June 2014

I don't know how we find out. "They" said there is a subtype of ILC, so not all ILC....

http://www.medicalnewstoday.com/articles/127571.ph...

They don't know what they don't know but makes me mad I was on it for 3 years.

luv_gardening · June 2014

Thanks Wallycat.

The article says ILC is one subtype and IDC is another subtype, so it seems this applies to all ILC types. I've been on Tam for 4 years now as I have osteoporosis and can't take an AI. It frustrates me that ILC often makes up only 10 or 12% of participants in studies yet the results are generalised to both types of cancer. 100 cases is not statistically significant.

Quote...

"Riggins said because it was not clear whether tamoxifen was effective for invasive lobular carcinoma (compared to another subtype like invasive ductal carcinoma for instance), it has been a debating point among clinicians."

wallycat · June 2014

It also states it "does not work as well" ...not that it does not work at all.

And there are subtypes of ILC (luminal A and B and a bunch of others)...some are more aggressive than others, even under the ILC umbrella.

luv_gardening · June 2014

Thank for pointing that out Wallycat. I must read more carefully. So we're left in the dark as usual. I have my hopes on a drug like the melanoma one that activates our immune system to kill the cancer. They say it should work on solid tumours and I hope they test ductal and lobular separately instead of lumping us in together and assuming we'll all get the same results.

wallycat · June 2014

Joy, you're welcome. I tend to read some of this quickly too and I swear sometimes it is all a moving target.

I hope the vaccines are effective too. Would be great; my onco said she did her fellowship at one of the labs that started trials on the vaccine. I see her this year (when I muster up the courage to go) and will ask her then if she knows more (inside scoop, as it were)

We just hang on till it happens.

JohnSmith · October 2015

Nice thread.
Here's the original June 2014 Abstract: "Hydroxychloroquine inhibits autophagy to potentiate antiestrogen responsiveness in ER+ breast cancer."
In addition to Dr. Robert Clarke of Georgetown, another author of this research is Dr. David Soto-Pantoja (who worked on Anti-CD47 research at the NCI).

PURPOSE:
Estrogen receptor-α (ERα)-targeted therapies including tamoxifen (TAM) or Faslodex (ICI) are used to treat ER(+) breast cancers. Up to 50% of tumors will acquire resistance to these interventions. Autophagy has been implicated as a major driver of antiestrogen resistance. We have explored the ability of hydroxychloroquine (HCQ), which inhibits autophagy, to affect antiestrogen responsiveness.

EXPERIMENTAL DESIGN:
TAM-resistant MCF7-RR and ICI-resistant/TAM cross-resistant LCC9 ER(+) breast cancer cells were injected into mammary fat pads of female athymic mice and treated with TAM and/or ICI in combination with oral low-dose HCQ.

RESULTS:
We show that HCQ can increase antiestrogen responsiveness in MCF7-RR and LCC9 cells and tumors, likely through the inhibition of autophagy. However, the combination of ICI+HCQ was less effective than HCQ alone in vivo, unlike the TAM+HCQ combination. Antiestrogen treatment stimulated angiogenesis in tumors but did not prevent HCQ effectiveness. The lower efficacy of ICI+HCQ was associated with ICI effects on cell-mediated immunity within the tumor microenvironment. The mouse chemokine KC (CXCL1) and IFNγ were differentially regulated by both TAM and ICI treatments, suggesting a possible effect on macrophage development/activity. Consistent with these observations, TAM+HCQ treatment increased tumor CD68(+) cells infiltration, whereas ICI and ICI+HCQ reduced peripheral tumor macrophage content. Moreover, macrophage elimination of breast cancer target cells in vitro was reduced following exposure to ICI.

CONCLUSION:
HCQ restores antiestrogen sensitivity to resistant tumors. Moreover, the beneficial combination of TAM+HCQ suggests a positive outcome for ongoing neoadjuvant clinical trials using this combination for the treatment of ER(+) DCIS lesions.

Tamoxifen resistant tumors in mice + antimalarial drug

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