High hopes for denosumab-- anti bc metastasis as well as anti bone met properties?
her2+ breast cancer particularly sensitive, it seems!
High hopes for RANKL: will the mouse model live up to its promise? Tamara Tanos and Cathrin Brisken Ecole polytechnique fédérale de Lausanne (EPFL), ISREC - Swiss Institute for Experimental Cancer Research, NCCR Molecular Oncology, SV2.832 Station 19, CH-1015 Lausanne, Switzerland author email corresponding author email Breast Cancer Research 2011, 13:302doi:10.1186/bcr2805 The electronic version of this article is the complete one and can be found online at: http://breast-cancer-research.com.la...ntent/13/1/302 Published: 28 January 2011 Abstract The steroid hormones, estrogens and progesterone are key drivers of postnatal breast development and are linked to breast carcinogenesis. Experiments in the mouse mammary gland have revealed that they rely on paracrine factors to relegate their signal locally and to amplify it. In particular, RANKL is a key mediator of progesterone action. Systemic inhibition of RANKL blocked proliferation in the mammary epithelium with potential clinical implications: a RANKL-inhibiting antibody, Denosumab (Amgen), has been approved by the US Food and Drug Administration for osteoporosis treatment. Two publications now provide evidence that progestin-driven mouse mammary tumorigenesis can be blocked by ablating RANK signaling. Can the osteoporosis drug help breast cancer patients? The burning question now is whether the role of this pathway is conserved in the human breast and whether RANKL signaling has a role in the pathogenesis of one or more subtypes of breast cancer. Viewpoint A role for progesterone in breast carcinogenesis is increasingly recognized. Breast cancer risk increases with the number of menstrual cycles a women experiences [1] and proliferation occurs in the breast epithelium during the luteal phase, when serum progesterone levels are high [2]. Moreover, postmenopausal women on hormone replacement therapy have increased breast cancer risk when taking combined estrogens and progestins but not with estrogens only [3]. Receptor activator of NF-κB ligand (RANKL) is a tumor necrosis factor (TNF) family member originally identified as a dendritic cell survival factor involved in the regulation of T-cell-dependent immune response and subsequently shown to control bone remodeling by inducing osteoclast differentiation [4]. Analysis of RANK- and RANKL-deficient mice pointed to a role for this pathway in the mammary gland during pregnancy [5] and in mammary carcinoma metastasis to the bone [6]. RANKL expression in the mammary epithelium is controlled by progesterone [7,8]. Recent work identified RANKL as a key paracrine mediator of progesterone-induced mouse mammary epithelial cell proliferation [9,10] and implicated the cytokine in stem cell control [11,12]. Systemic inhibition of RANKL signaling by intravenous injection of recombinant osteoprotegerin, its decoy receptor, blocked progesterone-induced proliferation in the mammary epithelium, suggesting RANKL may be used as a therapeutic target in the mammary gland [9]. Schramek and colleagues [13] and Gonzalez-Suarez and colleagues [14] now induced mammary carcinomas in mice using the progestin medroxyprogesterone acetate (MPA) and the mutagenic agent 7,12-dimethylbenz(a) anthracene (DMBA) and demonstrate that RANKL is a key factor in this process. Over-expression of RANK by means of a mouse mammary tumor virus (MMTV)-driven transgene accelerated hyperplasia and tumor formation [14] whereas pharmacological inhibition of RANKL [13,14] and genetic inactivation of RANK in the mammary epithelium [14] decreased incidence and delayed onset of tumorigenesis in this system. To investigate whether RANKL is similarly important in the pathogenesis of other tumor types that arise independently of exogenous hormones, Gonzalez-Suarez and colleagues used the MMTV-neu transgenic mouse model. Interestingly, in ErbB2-driven carcinogenesis, pharmacological inhibition of RANKL also reduces tumor growth and lung metastasis, suggesting that the RANK signaling pathway may be of functional relevance in a wider tumor spectrum. This is of great clinical interest given the heterogeneity of human breast cancer. Schramek and colleagues observe that RANK deletion does not alter the incidence of mammary cancer in MMTV-neuT transgenic mice. It is conceivable that the apparent discrepancy results from Keratin5-cre RANK deleted cells being outgrown by MMTV-neuT cells that have kept the wild-type RANK allele. Importantly, Gonzalez-Suarez and colleagues demonstrate that Fc-RANK inhibits proliferation of normal mammary epithelium and hyperplasias, but not in carcinomas, suggesting RANKL inhibition would be useful in early stages of tumorigenesis and/or as a preventive drug. Can these findings be extrapolated to humans? Dissociation of hormone receptor expression and proliferation in the adult mammary gland is a phenomenon that is conserved between human and rodents (reviewed in [15]), suggesting that paracrine signals are also of relevance to the human breast. Caution is required as it is unclear whether the paracrine circuitry is shared between the two species or whether the human breast may rely on distinct factors. Immunostainings of human breast carcinomas reveal that RANKL is expressed in 11% of human tumors. There is no evidence for colocalization within the epithelium for receptor and ligand but expression is found in some stromal cells [14]. This raises the possibility that the scenario is more complex in human breast cancer than in the present mouse tumor models with infiltrating immune cells providing the ligand. In any case, this drug seems too palatable not to try! The challenge lies in designing clinical trials with short endpoints and identifying adequate preclinical models to identify swiftly which particular patients may benefit from the drug. |
Re: High hopes for denosumab-- anti bc metastasis as well as anti bone met properties
Nothing understood, sorry Lani, could you explain it with your own words?
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Re: High hopes for denosumab-- anti bc metastasis as well as anti bone met properties
I asked my onc about this drug and was told it's not available in the hospital I attend,(although I believe it is available in Ireland) as my last dexa showed severe osteopenia I'm now going to begin yearly iv's of zometa but it's sad I'll have to opt out of the bone trial I've been in for five years to take this drug!
Thanks for the info Lani! |
Re: High hopes for denosumab-- anti bc metastasis as well as anti bone met properties
unregistered--denosumab works differently than bisphosphonates like zoledronic acid,
Its mechanism of action may may it active in preventing all breast cancer metastases rather than just bone metastases and even breast cancer growth as well. I think you give up too easily--try these two sentences, with my translations: Two publications now provide evidence that progestin(progesterone family)-driven mouse mammary(breast) tumorigenesis(tumor formation) can be blocked by ablating(getting rid of) RANK signaling. Can the osteoporosis drug help breast cancer patients? The burning question now is whether the role of this pathway is conserved in the human breast(ie, the role is the same in human beings as in mice) and whether RANKL signaling has a role in the pathogenesis(process of causing) of one or more subtypes of breast cancer. |
Re: High hopes for denosumab-- anti bc metastasis as well as anti bone met properties
Thanks as ever Lani. I am off to see my oncologist Wed and will ask about having Denosumab instead of Zometa.
Trish |
Re: High hopes for denosumab-- anti bc metastasis as well as anti bone met properties
Quote:
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Re: High hopes for denosumab-- anti bc metastasis as well as anti bone met properties
Trish--this work was done in mice--it is certainly NOT standard of care and it may not yet be approved in Australia for use against established bone mets or osteoporosis (as it recently was in the US--former within past 4 months or some, the latter within the last year or so)
There are a few papers just being published on how to decide whether ZA or denosumab for any given patient--denosumab is much easier on the kidney for those with kidney insufficiency...but denosumab being a monoclonal antibody vs a simple nonbiologic chemical (ZA) is probably MUCH MORE EXPENSIVE Most papers have felt denosumab is at least as good if not better and of course it is safer in those with kidney problems, but this is still in evolving field. Hope this helps! |
Re: High hopes for denosumab-- anti bc metastasis as well as anti bone met properties
Dear Lani, sorry, does it work in er-/pr- cases?
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Re: High hopes for denosumab-- anti bc metastasis as well as anti bone met properties
again this work was done on mice (which I understand only have er- breast tumors) NOT HUMANS. The results cannot yet be extrapolated to humans
It seems to work particularly well in her2 tumors The next step is seeing if the effect is the same in human tumors implanted in mice and then after that in human tumors in humans They might be able to speed it up by doing neoadjuvant tests soon after it shows itself not to make things worse when human tumors are implanted in mice. Let's hope the research goes quickly as the drug is already approved for two indications. |
Re: High hopes for denosumab-- anti bc metastasis as well as anti bone met properties
Thank you Lani, now it is clear.
But one more question: Quote:
Sorry for pestering. |
Re: High hopes for denosumab-- anti bc metastasis as well as anti bone met properties
of course, if ya can't get the RX, you can try things like Boswellia and Curcumin to inhibit the pathway:
http://margaret.healthblogs.org/life...and-bone-loss/ |
Re: High hopes for denosumab-- anti bc metastasis as well as anti bone met properties
Thanks Lani it certainly does help. I will ask about Denosumab although I'm sure it will not yet be approved but I do want my oncologist thinking about it. Thankfully my kidneys are still OK so I can tolerate the Zometa.I do worry about the ?mandibular necrosis issue although I only have Zometa every 6 weeks.
Rich I haven't got my head around boswellia and curcumin but I think I should start. Trish |
Re: High hopes for denosumab-- anti bc metastasis as well as anti bone met properties
unregistered
since they believe it will prevent metastasis it would of course help to take it before the cancer became "locally advanced" (big with lots of lymph nodes involved) or Stage IV if truly with few side effects it could be taken on a preventative basis There were a few cases of Osteonecrosis of the Jaw with denosumab, but no more than with zoledronic acid That may keep it from being used on a preventative basis with respect to breast cancer , unless the person was also osteoporotic and needed to be on something for that osteoporosis anyway Hope this helps |
Re: High hopes for denosumab-- anti bc metastasis as well as anti bone met properties
But will it prevent more lesions (theoretically) if the person had lesions before?
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Re: High hopes for denosumab-- anti bc metastasis as well as anti bone met properties
Yes, that is the thinking. In mice it was all kinds of mets, not just bone mets
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Re: High hopes for denosumab-- anti bc metastasis as well as anti bone met properties
Great!!!!!!!!!!
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Re: High hopes for denosumab-- anti bc metastasis as well as anti bone met properties
just like to add, for interest maybe, that denosumab or prolia is registered in the uk passed several month ago, as with the u s, but is also being used for osteosporosis, a friend has recently had her injection of it for paget,s disease, being 82yrs with other health problems she has felt the side affects quite badly, just getting over chest infection, the most common side affect, but she,s at home and mobile and its early days to judge long term affect re side affects, but the benafits seem promising.
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Re: High hopes for denosumab-- anti bc metastasis as well as anti bone met properties
A drug that can prevent and prohibit lesions... that is the best news!
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Re: High hopes for denosumab-- anti bc metastasis as well as anti bone met properties
I want to know if it will be available in India so that I can ask Hena's onc.I may be a little slow on the uptake.can someone help with the generic name and trade name of the drug.Hema is on Zylotec a Biophosphate
Thanks |
Re: High hopes for denosumab-- anti bc metastasis as well as anti bone met properties
It is just approved in US and that's why there cannot be generics, but maybe it can be bought in US by internet shop.
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