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Jul 26, 2013 01:42PM wardells wrote:
BZA would go under the trade name "Conbriza" in Europe. And the only real footprint the drug has made is in Spain so far...
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Posted on: Jun 15, 2013 07:02PM - edited Jun 15, 2013 08:18PM by Moderators
sincitydealer wrote:
I just saw an interview with somebody from Duke University on Fox news. He made it sound like this is the Holy Grail for estrogen positive women who've failed on Tamoxifin and Aromatase Inhibitors. I sure hope he's right! This has been approved in Europe and will most likely be approved here. He said it was right under their noses all along, and it's expected to work well on late stage breast cancer. This would be the next step after failure of the anti-hormonals instead of going on to chemo. It completely shuts down the estrogen receptors. Some of you may qualify for the trial.
Osteoporosis Drug Stops Growth of Breast Cancer Cells, Even in Resistant Tumors
About This Article
Article Details
Published: June 15, 2013
Updated: June 15, 2013
By Duke Medicine News and Communications
DURHAM, N.C. -- A drug approved in Europe to treat osteoporosis has now been shown to stop the growth of breast cancer cells, even in cancers that have become resistant to current targeted therapies, according to a Duke Cancer Institute study.
The findings, presented June 15, 2013, at the annual Endocrine Society meeting in San Francisco, indicate that the drug bazedoxifene packs a powerful one-two punch that not only prevents estrogen from fueling breast cancer cell growth, but also flags the estrogen receptor for destruction.
"We found bazedoxifene binds to the estrogen receptor and interferes with its activity, but the surprising thing we then found was that it also degrades the receptor; it gets rid of it," said senior author Donald McDonnell, PhD, chair of Duke's Department of Pharmacology and Cancer Biology.
In animal and cell culture studies, the drug inhibited growth both in estrogen-dependent breast cancer cells and in cells that had developed resistance to the anti-estrogen tamoxifen and/or to the aromatase inhibitors, two of the most widely used types of drugs to prevent and treat estrogen-dependent breast cancer. Currently, if breast cancer cells develop resistance to these therapies, patients are usually treated with toxic chemotherapy agents that have significant side effects.
Bazedoxifene is a pill that, like tamoxifen, belongs to a class of drugs known as specific estrogen receptor modulators (SERMs). These drugs are distinguished by their ability to behave like estrogen in some tissues, while significantly blocking estrogen action in other tissues. But unlike tamoxifen, bazedoxifene has some of the properties of a newer group of drugs, known as selective estrogen receptor degraders, or SERDs, which can target the estrogen receptor for destruction.
"Because the drug is removing the estrogen receptor as a target by degradation, it is less likely the cancer cell can develop a resistance mechanism because you are removing the target," said lead author Suzanne Wardell, PhD, a research scientist working in McDonnell's lab.
Many investigators had assumed that once breast cancer cells developed resistance to tamoxifen, they would be resistant to all drugs that target the estrogen receptor, McDonnell explained.
"We discovered that the estrogen receptor is still a good target, even after it resistance to tamoxifen has developed," he said.
The investigators tested a variety of breast cancer cell types, including tamoxifen-sensitive cells that are resistant to the drug lapatinib, another targeted therapy that is used to treat patients with advanced breast cancer whose tumors contain the mutant HER2 gene. These cells had previously been shown to reactivate estrogen signaling in order to acquire drug resistance. In this cell type, bazedoxifene also potently inhibited cell growth.
Paradoxically, in bone tissue, bazedoxifene mimics the action of estrogen, helping protect it from destruction. Because bazedoxifene has already undergone safety and efficacy studies as a treatment for osteoporosis, it may be a viable near-term option for patients with advanced breast cancer whose tumors have become resistant to other treatment options, Wardell reported. In clinical trials, the most often reported side effect was hot flashes in the bazedoxifene treatment groups.
The study was funded by a research grant from Pfizer Pharmaceuticals, maker of bazedoxifene.
In addition to Wardell and McDonnell, Erik Nelson and Christina Chao of the Department of Pharmacology and Cancer Biology, Duke University School of Medicine, contributed to the research.
Edited by Mods to tidy up imported formatting
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Jul 26, 2013 01:42PM wardells wrote:
BZA would go under the trade name "Conbriza" in Europe. And the only real footprint the drug has made is in Spain so far...
Jul 26, 2013 11:37PM - edited Jul 26, 2013 11:37PM by BaseballFan
Dr. Wardells,
I have been taken off zometa due to ONJ. Would that prevent me from using BZA?
Jul 27, 2013 12:03AM MaryLW wrote:
Bobbi, do you have ONJ or is the doctor taking you off Zometa so that you don't get it?
Jul 27, 2013 09:50AM BaseballFan wrote:
I have it. Small spot of exposed bone on the inside of my gum line.
Jul 27, 2013 12:24PM MaryLW wrote:
Bobbi, how long were you on Zometa? Did you have dental work done or did the ONJ happen spontaneously?
Jul 27, 2013 01:11PM BaseballFan wrote:
I had a root canal and that started the whole thing. I was on zometa for four years.
Jul 27, 2013 06:35PM wardells wrote:
Bobbi, I'm sorry to hear about your diagnosis! Ugh. I do not find where BZA is contra-indicated of ONJ. compassionate use! might make for a good justification...
Jul 28, 2013 10:53PM cp418 wrote:
Petition to Pfizer to assess Bazedoxifene for breast cancer has been posted in the Clinical Trials and News forum. Hopefully enough signatures will gain attention to further evaluate this drug for breast cancer patients.
Jul 29, 2013 12:19AM justjudie wrote:
cp418: Excellent idea. I will go to the petition to see if I can sign up. Bobbi, do they do anything about the ONJ or just leave it alone? Sorry to see you have developed this problem.
Jul 29, 2013 10:07AM blainejennifer wrote:
Done and linked to Facebook. Time for my weekly call and letter, too. Thanks for creating the petition.
Jul 29, 2013 12:10PM cp418 wrote:
Thank you so much!! I hope we can make a difference at least to be heard. I don't use FB so many thanks for moving it onward.
Aug 7, 2013 08:47PM Linda-n3 wrote:
Saw my MO this week and asked about getting this drug under compassionate use, but she said it has to actually be in phase III trials .... BUT she also said there are some phase III trials coming up, and I said I would consider going on one, but the problem is I might end up in the placebo group. Drats. Tumor has not shrunk, but has not gotten larger. She said my LE is probably resistant to therapy because of the local/regional tumor invasion, chemo MIGHT give me faster reduction of tumor and therefore better control of LE, but I just cannot bring myself to chemo right now as I think it is only grade 2 tumor, meaning cells just aren't multiplying all that fast, and chemo works best with rapidly dividing cells. So I am continuing on letrozole and afinitor, hoping BZA gets expedited and available before I am dead.
Thanks again to Dr. Wardells, and thanks to all who are sending emails, calls and petitions to Pfizer.
Aug 9, 2013 02:26PM wardells wrote:
Linda-n3, ask your doctor to consider petitioning Pfizer to add palbociclib (PD-0332991) to your current Letrozole. This drug is a new CDK4/6 inhibitors (targets cell division) and received a breakthrough designation from the FDA after combination with letrozole significantly improved progression free survival as compared to letrozole alone (26 months vs 7 months!). This drug combo just entered phase III trials.
Good luck!
Aug 9, 2013 03:40PM chele wrote:
How did I not see this??
Dr. Wardells Thank You so much for your input.
I see my MO this Tuesday, I'll be asking him about BZA! I'm off Xgeva due to osteomylitis of the jaw. Maybe BZA would be a great solution for me!
Now I'm off to sign the petition.
Aug 11, 2013 05:45AM jcb51 wrote:
Thank you very much for starting the petition. cp418. I signed and will post on FB.
Jan
Aug 13, 2013 03:18AM KiwiCatMom wrote:
Just giving a special thanks to Dr. Wardells for being part of the forum and for your work on our behalf. I have bone mets and my radiation oncologist has told me that he has no hope of me being alive 5 to 6 years from diagnosis. My goal is to prove him wrong and the work you're doing may well help me do so! I've asked for a referral to a medical oncologist who participates in trials and I'll definitely take your advice to him. So thank you so much!
Aug 13, 2013 09:29AM BaseballFan wrote:
Wow, KiwiCatMom....I'd run as fast as I can from that radiation onc! This thread alone gives us reason to believe your RO is wrong.
Thanks, Dr. Wardells. We appreciate your input more than you can imagine.
Aug 13, 2013 10:42AM chele wrote:
Kiwicat, I think your RO is wrong. I have bone mets throughout my core. I have no expiration date. I can't imagine what he is thinking telling you that.
Aug 15, 2013 08:48AM Moderators wrote:
Thought you all might like to see Dr. Wardell's Breastcancer.org Blog Post on this subject, How Breast Cancer Drugs Are Developed: The Bazedoxifene Story - August 13, 2013
We hope you find this helpful, and big thanks once again to Dr. Wardell!
--The Mods
Aug 15, 2013 02:15PM Linda-n3 wrote:
Many many thanks, Dr. Wardell!!!!!
And thanks, Mods, for posting this - sometimes I forget to look at the blogs....
Aug 15, 2013 05:25PM Latte wrote:
Fantastic blog post. Thanks Dr Wardell, I think it is great when people from the field come here and talk to us!
Aug 15, 2013 05:50PM CJRT wrote:
Thank you, Mods, and Dr. Wardell for helping to educate all of us and keep us current with the newest research and ways to advocate for newer, better treatments.
Aug 17, 2013 11:11AM meirav wrote:
Hi,
Does anyone know if this can replace Zomera in a protocol containing Gem-Carbo?
is it more effective?
Aug 17, 2013 12:26PM wardells wrote:
Meirav, I'm assuming that your Dr has you on Zometa because for prevention/treatment of bone mets. If it's just to increase/maintain bone density, then I would lean toward BZA.
Bone quality is maintained by the complementary actions of osteoblasts (bone building cells) and osteoclasts (break down bone) - the skeleton is constantly being maintained by these processes, sort of like roadwork - the osteoclasts ripping up the old pavement and the osteoblasts putting down fresh pavement. Both Zometa and BZA are effective in treating osteoporosis, but by different methods. Zometa "freezes" the process - no breakdown, no building. This can result in a "strong but brittle" skeleton that doesn't hold up to an active lifestyle (ie tennis twice a week), so I would lean toward BZA if the need is to preserve bone density. BZA reverses post-menopausal bone loss by restoring the balance of bone maintanence (loss of estrogen means that there are fewer osteoblasts and more osteoclasts, and that tips the scales toward overall loss of bone).
Bone mets are known to be very "osteoclastic" in nature. Zometa would help to retain the quality of bone by stopping the breakdown, and there is clinical data to show that zometa is beneficial. We don't have the same data for BZA as yet, and so the short version of my long answer is that we don't know yet. While BZA would target the breast cancer cells within the bone mets, it may not be as effective as Zometa in freezing osteoclast activity.
Aug 17, 2013 12:44PM MaryLW wrote:
Dr. Wardell, thank you for your clear explanation of how bone density is maintained and how Zometa works. I seem to be the only person on the planet not using Zometa or a similar drug for bone mets. The truth is that I am terrified of ONJ--more afraid of that than bone mets progression. My MO is considering putting me on Evista, which apparently isn't associated with ONJ. Do you know of any other alternatives to bisphosphonates? I know Xgeva isn't one, but has the same horrific side effect possibility.
Aug 18, 2013 09:38AM wardells wrote:
Mary, there are radiation treatments for bone mets, but it looks like you may already have had some of those, and that is more a treatment than prevention. (your history says that you have put up quite the fight - good for you!) Whether Evista might be useful may depend on whether you are still on the Faslodex - because Evista and Faslodex both target the estrogen receptor, but by different ways. Evista binds to the receptor and blocks it's activity, whereas faslodex does the same, but also causes the cells to destroy the receptor - that's why it would seem to be a strange conbination to me. If you are having a good response to faslodex, then there may not be enough of the estrogen receptors around for Evista to have an effect. Evista taken alone hasn't really been studied as a treatment for bone mets, so I can't find much as far as how well it might work. I think that if you are willing to try it and your Dr can explain why he thinks it will help, then I would defer to him on that one - I don't really see how it would cause harm. And if you haven't already, keep trying for compassionate use of BZA from Pfizer - because that would take the place of both drugs, sadly.
Aug 18, 2013 11:00AM HLB wrote:
I am on XGEVA and I too am terrified of ONJ! I do understand how the bisphosfonates work, but I didn't quite understand the way you explained the way BZA would work and how it is different? I think the xgeva is really working well but would love to know about something else that worked without that onj risk, and the brittle bone risk. Thanks :-)
Aug 18, 2013 12:04PM wardells wrote:
HLB, the answer to your question lies in how estrogen itself works on bone. In the prior post, I explained how osteoclasts (break down bone) and osteoblasts (build bone) work together renew bone throughout the pre-menopausal years. How estrogen works on bone is still not completely understood, but the overall result is that estrogen encourages the maturation of the osteoblasts to increase their number, and at the same time decreases the number of osteoclasts by slowing their development - the overall result is more osteoblasts and fewer osteoclasts, and the balance swings toward increasing bone density. After menopause, the effects of estrogen are lost, and then the balance tips toward the osteoclasts and bone breakdown.
BZA is in the "selective estrogen receptor modulator" (SERM) drug class - you can think of it as a much improved tamoxifen. the 'selective' part comes from the fact that these drugs bind to the estrogen receptor and then either block or mimic estrogen receptor activity, depending on the tissue. for example, all of the SERMs increase bone density by stimulating the same effects as estrogen in the bones. Most of the SERMs block estrogen receptor activity in the breast (to different degrees). Where the SERMs differ most is in the uterus. That is why, for all of it's initial benefit in breast cancer treatment and increase in bone density, tamoxifen therapy for long periods (5+ years) can increase the patient's risk of endometrial cancer. Evista doesn't come with the same risk of endometrial cancer and does increase bone density, but it is not as effective as tamoxifen at blocking estrogen receptor activity - and that is why it is not used as a first treatment for breast cancer.
BZA is different from tamoxifen and evista in that it is strongly opposes estrogen receptor activity in both the breast and uterus, and also increases bone density. The nitty gritty science as to how a single drug can both mimic and block estrogen activity depending on the tissue has turned out to be complex, and we are still working that out.
Aug 18, 2013 01:38PM MaryLW wrote:
Dr. Wardell, thank you so much for your explanation. It's all so complex, and it helps me to have the information written so that I can keep referring to it.
Aug 19, 2013 09:57PM HLB wrote:
Thank you! I understand very well now.