already approved anti-rheumatoid arthritis drug reverses herceptin resistance!!

[Lani]

ANOTHER major discovery coming from the work of Max Wicha, of "breast cancer stem cell theory" fame

THIS MAY ONLY BE ONE WAY RESISTANCE DEVELOPS TO HERCEPTIN, BUT IT SEEMS LIKE A MAJOR WAY



Inflammatory pathway spurs cancer stem cells to resist HER2-targeted breast cancer treatment
[University of Michigan Health System]

ANN ARBOR, Mich. — Breast cancer treatments such as Herceptin that target a marker called HER2 have dramatically improved outcomes for women with this type of cancer. But nearly half of these cancers are resistant to Herceptin from the start and almost all of them will eventually become resistant.

Now, researchers at the University of Michigan Comprehensive Cancer Center have discovered one reason why the cancer cells become resistant: They turn on a completely different pathway, one that is involved in inflammation, fueling the cancer independently of HER2.

The pathway at work involves a protein called Interleukin-6, or IL-6. The researchers also showed in mice that a drug that blocks IL-6 can stop this effect and overcome the Herceptin resistance.

"Resistance to HER2-targeted therapies remains a major challenge in treating breast cancer. Our study suggests that an IL-6 inhibitor in combination with Herceptin may be a valuable addition for treating HER2-positive breast cancer," says senior study author Max S. Wicha, M.D., Distinguished Professor of Oncology and director of the U-M Comprehensive Cancer Center.

Results: of the study will be published in the Aug. 24 issue of Molecular Cell.

Not only are these cells resistant to Herceptin, but they develop higher proportions of cancer stem cells, the small number of cells within a tumor that fuel the growth and spread. This makes the tumor extremely aggressive and likely to spread throughout the body. The IL-6 inhibitor also was shown to prevent this increase in cancer stem cells.

"There is evidence that patients with a lot of IL-6 tend to do poorly. What we found now is that in many of the Herceptin-resistant breast cancers, the IL-6 inflammation loop is driving the cancer stem cell," says lead study author Hasan Korkaya, D.V.M., Ph.D., research assistant professor of internal medicine at the U-M Medical School.

The researchers found that blocking the IL-6 inflammatory loop almost completely blocked the cancer and the stem cells. Mice treated with the IL-6 blocker along with Herceptin immediately after the cancer developed never became resistant to Herceptin.

IL-6 is known to play a role in inflammatory diseases such as rheumatoid arthritis, as well as obesity and cancer. Tocilizumab, a drug that targets this protein, is approved by the U.S. Food and Drug Administration to treat rheumatoid arthritis.

The researchers are developing a clinical trial to test the IL-6 blocker along with Herceptin. That trial will likely open early in 2013.

Additional authors: Gwang-il Kim, April Davis, Fayaz Malik, N. Lynn Henry, Suthinee Ithimakin, Ahmed A. Quraishi, Nader Tawakkol, Rosemarie D'Angelo, Amanda Paulson, Susan Chung, Tahra Luther, Hayley S. Paholak, Suling Liu, Khaled Hassan, Qin Zen, Shawn G. Clouthier

Funding: National Institutes of Health grants CA 129765 and CA 101860, Susan G. Komen for the Cure

Disclosure: Max Wicha has financial holdings in OncoMed Pharmaceuticals and receives research support from Dompe.

^^^^^^

ABSTRACT: Activation of an IL6 Inflammatory Loop Mediates Trastuzumab Resistance in HER2+ Breast Cancer by Expanding the Cancer Stem Cell Population
[Molecular Cell]

Although inactivation of the PTEN gene has been implicated in the development of resistance to the HER2 targeting antibody trastuzumab, the mechanisms mediating this resistance remain elusive. We generated trastuzumab resistant cells by knocking down PTEN expression in HER2 overexpressing breast cancer cell lines and demonstrate that development of trastuzumab resistance in these cells is mediated by activation of an IL6 inflammatory feedback loop leading to expansion of the cancer stem cell (CSC) population. Long term trastuzumab treatment generates highly enriched CSCs which display an EMT phenotype secreting over 100-fold more IL6 than parental cells. An IL6 receptor antibody interrupted this inflammatory feedback loop reducing the cancer stem cell population resulting in decreased tumor growth and metastasis in mouse xenographs. These studies demonstrate that trastuzumab resistance may be mediated by an IL6 inflammatory loop and suggest that blocking this loop may provide alternative strategy to overcome trastuzumab resistance.

[Bunty]

Thank you once again Lani! This is very interesting - I wonder if an oncologist would prescribe Tocilizumab to someone who has resistance to Herceptin to see if there would be an improvement?
Cheers Marie

[Ellie F]

Thanks Lani
I know you highly regard Max Wicha (so does my onc here in England). I hope they are able to get this into trials in 2013 and if successful there won't be any hassle about getting the drug. Wouldn't it be wonderful if something already approved could save lives of women with bc!
Ellie

[Mandamoo]

This is very exciting - especially for those of us with Herceptin resistance from the start! I have always wondered what else may be driving the cancer growth - maybe this is it. Time will tell I suppose.

['lizbeth]

More good news, thank you Lani

But I find it confusing that my sister, who is diabetic but hasn't had cancer has a very high level of inflammation in her body. I've had cancer, but my CRP was quite low. Is this a different type of inflammation than IL-6?

[Lani]

CRP and IL6 are two different things.

[sarah]

wow, thanks Lani

[StephN]

Good one, Lani !

I have been hearing for several years that inflammation could be a bad actor in mets. That is why I decided to do what I could at the outset of my raging liver mets in 2001 to reduce any inflammation in my body.

Without having particulars on what kind of inflammation, and knowing I am prone to all sorts of allergies, I just made a few changes such as cutting out refined sugar as much as possible, cutting out caffine, drinking detox teas, and even changed my laundry detergent and house cleaners to non toxic brands.

All that was a shot in the dark, but I did feel better, and was able to fight off my mets.

Lani - I know you don't give advice per se, but are the steps above normally good ones if a person wants to reduce the inflammation in their body?

[karen z]

Lani,
Many thanks.

[europa]

Thank you so much Lani! I was told by several biochemist friends that inflammation plays a big part in cancer. I was told to drink turmeric tea once a day and I have been. I noticed a HUGE difference with my joints. My mother also has arthritis and drinks the tea and she too has seen a dramatic improvement. I wonder if there are any other things we can do to help inflammation other than the obvious (no sugars, certain carbs, caffeine and liquor).

[europa]

Found this and thought it could be useful
http://foodforbreastcancer.com/

[Lani]

Steph

I too do my best not to give advice

Don't think caffeine, sugar perse (all gets converted to glucose including carbohydrates, fats, proteins anyway), or things covered by the loose term "toxics" are the culprits in inflammation

But, unfortunately, obesity seems to be a cause of chronic inflammation

Anti-oxidants may help it seems

Keeping a reasonable weight, eating fresh fruits and vegetables, perhaps taking anti-inflammatories and keeping vitamin D store levels adequate seem to be what the literature recommends. I would not make recommendations myself as I am not qualified to--but I really am quite unsure anyone really knows at present. This area seems to be a work in progress (no big pharma money in it)

[StephN]

Lani - Thanks for the reply. I know we are a bit off track here, but maybe there are things we can do short of taking another extremely strong drug. If it is necessary so be it.

There is no one overweight in my direct family. I am considered in the normal range for my height and weight. (Was always on the "thin" side prior to all the chemos, etc.)

My onc did prescribe Celebrex as a COX-2 inhibitor in 2002, which I did take for close to 3 years. This was on anecdotal evidence at that time. But COX-2 has now been proven as a piece of the mets puzzle. (Articles are available on these studies.)

I have been using Alpha Lipoic Acid supplement to add to the other antioxident foods in my diet.

If Big Pharma is not on board, we need to take some steps ourselves as educated patients.

['lizbeth]

Lani,

I see my knowledge of inflammation and IL6 is pretty scanty. After I complete my HHP I would like to go take basic chemistry and biology courses, as my last college classes were over 25 years ago. I'm kicking around the idea of a degree in Science.

My questions are: What field of study does IL6 fall into? and which field is the study of cell pathways?

[Lani]

My college chemistry was taken 40 years ago, but principles must have been well-taught as they have held up well.

As I recall general chemistry was a prerequisite for organic chemistry which was a prerequisite for biochemistry

Don't know if immune pathways would now be presented in the subset of biology class which lie within physiology, but would imagine so IL 6 and pathways related to stem cells as in the article above would fall within physiology (the part studying the immune system, inflammation etc)

A friend of mine got a mailing from the fundraising dept at Stanford, which described how they got rid of their departments of infectious disease, allergic disease and immunology and started a multidisciplinary institute of inflammation, immunity and transplantation-- so fields are being renamed and repurposed nowadays it seems.