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By Anneela Saleem 30 Sep, 2016

WHAT ARE BISPHOSPONATES ?

Bisphosphonates are a class of drug that are already widely available and are commonly used to treat osteoporosis (thinning of the bones). Examples are  Alendronate (F osamax), Risedronate (Actonel) and Zoledronic acid ( Actlasa).   

Our bones are not static but are in a state of flux since they are constantly being remodelled; this involves bone cells being renewed and destroyed in a balanced way. This remodelling is controlled by cells called osteoclasts and osteoblasts

  • Osteoblasts produce new bone cells.    
  • Osteoclasts break down bone.   The activity of osteoclasts is increased in osteoporosis and cancer-related bone destruction ( bone metastases).      
 Bisphosphonates reduce osteoclast function and so protect bones from thinning and are used to treat bony metastases to reduce their growth and possible complications. T he initial Primary Breast Cancer can sometimes recur years later and this is then called  Secondary Breast Cancer . Secondary deposits tend to occur in the bones, brain, lungs or liver.   The most common site for breast cancers to spread to is bones.

It has been hypothesised that bisphosphonates   may change the micro-environment in bones   by reducing osteoclast activity    . This in turn would reduce the production of growth factors to make it less favourable for any small clusters of dormant breast cancer cells (
micrometastases) to start proliferating.    Tumour cells released from a primary breast cancer may sometimes remain dormant in the bone for years before they start proliferating and spreading to other parts of the body.    It is not exactly clear what triggers this change.



RECENT MEDIA COVERAGE SEPT 2016

These drugs have made the headlines recently (22nd  September 2016)since they have been highlighted by the cancer charity 'Breast Cancer Now' as being a valuable and inexpensive drug that reduces the risk of breast cancer recurring in post menopausal women.  This was also then reported widely in the national media with the price tag of as little as 43p a day for this drug widely headlined.  The evidence behind this was actually published in the Lancet by The Early Breast Cancer Trialists Group ( EBCTCG) in July 2015. This collaborative group has existed for over 30 years and is made up of researchers from around the world. Their research findings have forged the path for major improvements in breast cancer survival for e.g in 1984 they published  evidence to back the widespread introduction of Tamoxifen.



BISPHOSPHONATES, BONE and BREAST CANCER RECURRENCE. Lancet   The Early Breast Cancer Trialists Group ( EBCTCG) First Published Online : 23rd July 2015 Adam Brufsky, Aju Mathew.

Over the past 20 years there have been mixed results from randomised trials on bisphosphonates in breast cancer patients. To help make sense of mixed findings scientists often carry out a meta-analysis. A meta-analaysis combines  the results of all the good quality studies to increase the total number of patient participants and so makes the results more reliable and meaningful. The EBCTCG collected data from 26 different trials over the past 20 years, this gave a total number of 18,766 women;  most of them were followed up for 5-6 years. 

By carrying out this analysis they were able to establish that post-menopausal women taking bisphosphonates had significant reductions in bone recurrence and breast cancer deaths at 10 years. 

  • Bone recurrence at 10 years reduced from an absolute risk of  8.8 % to just 6.6%.
  • Breast cancer mortality at 10 years reduced from an absolute risk from 18.0% to 14.7 %

These benefits existed regardless of the type of bisphosphonate given,  how long the patients received the drug, the size of the tumour, the hormone receptor status and whether axillary nodes were involved . The women were also found to have a lowered risk of bone fractures. 


BREAST CANCER NOW CHARITY Backs Bisphophonates

The delay in these findings coming to our attention is unclear but has certainly been bolstered by 'Breast Cancer Now'. They reported the findings of a survey amongst oncologists (that form part of the UKBCG) about the use of these drugs for post-menopausal women with early breast cancer.  

(UK Breast Cancer Group (UKBCG) is a forum for clinical and medical oncologists. The focus of the UKBCG is to run an Annual Meeting to discuss and debate practical and topical management issues in breast cancer.  )

From the results of this survey Breast Cancer Now reported that

'Three in four UK breast cancer oncologists are still unable to prescribe cheap drugs that reduce the risk of the disease spreading to the bone, a new survey has found – amid a continued lack of guidance from the NHS on how to commission their use.'


CHIEF EXECUTIVE COMMENT

Baroness Delyth Morgan, Chief Executive at  Breast Cancer Now , said “While bisphosphonates are not routinely available to all eligible breast cancer patients, women’s lives are needlessly being put at risk. These are cheap and widely-available drugs and the overwhelming evidence of their ability to save lives should have changed practice by now. But they are still sitting on the shelf, blocked by bureaucratic inertia. We’re fortunate to have so many of the world’s leading oncologists working within the NHS, and we must ensure they have all the tools they need to offer the best possible breast cancer treatment. These barriers could be swiftly resolved and we’re calling on national NHS bodies to take the lead and finally give clarity on funding for these drugs through new national guidance.”


WHAT NEXT ?

WE all need to push for a change. Personally I will be asking my oncologist to commence me on a bisphosphonate. I was pre-menopausal at diagnosis but now aged 46 years and no periods since I had chemotherapy (along with all the menopausal symptoms) I presume I have crossed over to being post-menopausal. This can be a grey area and sometimes a blood test is warranted to confirm this. If I am told that the specialists cannot authorise  this beneficial and low-cost drug then I will raise it with the hospital trust and my local MP. 


JOIN UP TO BE A CAMPAIGNER with Breast Cancer Now- I HAVE...Follow this link

http://breastcancernow.org/get-involved/campaign-with-us/help-us-unlock-drugs-now/unlocking-off-pate...


Bibliography

1.   Full article Lancet

http://www.thelancet.com/pdfs/journals/lancet/PIIS0140-6736(15)60908-4.pdf

2.   BBC News

Breast cancer patients 'should be offered cheap bone drug'

http://www.bbc.co.uk/news/health-37432935

3.   Manchester Evening News, 22nd Sept 2016

Thousands of women with breast cancer missing out on 43p-a-day drug because of NHS confusion

http://www.manchestereveningnews.co.uk/news/greater-manchester-news/bisphosphonates-breast-cancer-dr...

4. Breast Cancer Now 

http://breastcancernow.org/news-and-blogs/news/27000-women-being-denied-43p-osteoporosis-drug-that-can-prevent-breast-cancer-spread











By Anneela Saleem 24 Jun, 2016

DENOSUMAB: What is it?

  • A fairly new drug, approved since 2010, ( also known as Prolia, Xgeva)
  • It is a lab produced Monoclonal Antibody (Ab)
  • Monoclonal Abs are made to target specific cells in the body and therefore should avoid damaging healthy cells.
  • They do so by binding tightly to their target proteins and this blocks the protein from exerting an effect.
  • Herceptin( trastuzumab) is a Monoclonal Ab that binds to HER2 receptors in HER2 positive breast cancer patients.
  • Denosumab is a monoclonal Ab that binds strongly to a protein called RANKL.
  • RANKL is known to affect bone cells and is used to treat bone disease.    
   

RANKL/RANK PATHWAY: What is it?

Our bones are constantly being remodelled which involves bone cells being renewed and destroyed in a balanced way.

  • Osteoclasts break down bone.
  • Osteoblasts produce new bone cells.

The activity of osteoclasts is increased in osteoporosis and cancer-related bone destruction (this may occur with bone metastases).

  • Osteoclasts have RANK receptors on their surface.
  • When the RANKL protein binds to this RANK receptor the osteoclasts are stimulated. 
  • However Denosumab can bind to the RANKL protein and therefore stop it interacting with the RANK receptor and blocks its action.  

Denosumab Current use: PREVENTS Fractures

 At risk groups

  • Osteoporosis
  • Men on hormone treatment for prostate cancer
  • Cancer-related bone disease

Denosumab and the Prevention of Genetic Breast Cancer 

BRAC1 gene mutations are known to be associated with a greater than 80% lifetime risk of developing breast cancer. These breast cancers tend to occur in women at a relatively young age.  

Sex hormones can trigger breast cells  to undergo cancerous changes.

The RANKL/RANK Pathway has been shown to be integral in linking the sex hormones to  breast cells.

This happens normally in pregnancy and menstruation. 

However if this becomes deregulated  the RANKL protein then allows over stimulation resulting in an increase number of breast cells that do not respond to normal cell signalling which results in breast cancer.  

The RANKL protein has now been found to be the main stimulus to BRAC1 breast cancer.


ANIMAL Studies

Results of a study published in the Journal Nature in 2010 showed that blocking this pathway in BRAC1 mice stopped them from developing invasive breast cancer. The control group that did NOT recieve RANKL blockage developed invasive breast cancer as expected.   

The team was led by  Joesph Peninger . Researchers collaborated   from The Institute of Molecular Biotechnology (IMBA), VIENNA and   The University of Maryland School of Medicine, Baltimore .

"Our finding is so exciting because there is already an approved drug against RANKL called "Denosumab". It is an antibody with very few side effects, which binds tightly to RANKL, thereby inhibiting its ability to act. Based on our discovery, the already approved drug Denosumab or other future drugs that will block RANKL/RANK, could be used for breast cancer prevention in BRCA mutation carriers," explains Verena Sigl (2) 



A n EXCITING NEW STUDY WAS PUBLISHED IN NATURE ON MONDAY 20TH JUNE 2016

'RANK ligand as a potential target for breast cancer prevention in BRCA1-mutation carriers'. (3)

Summary

  • Prophylactically removed healthy breast tissue cells were used for lab research .
  • 33 samples of breast tissue had  NO BRCA1 mutations
  • 24 samples of breast tissue HAD BRAC1  mutations

  • Analysis showed that the molecule RANK was prevalent in some of the cells in BRAC1 breast tissue. 
  • These cells were the most likley to become cancerous

  • I nhibiting RANKL protein  in these cell cultures greatly reduced the  growth and spread of breast cancer cells.


WHAT THE FUTURE HOLDS 

Animal and lab studies have provided sufficient data to move on to the next step. This is to conduct clinical trials in women with BRAC1 mutations. Research teams intend to begin trials in the next two years but it could take up to ten years to obtain the outcome results. If  Denosumab  proves successful t his could provide a very valuable treatment option for women genetically predisposed to breast cancer.    For women that are considering  future preventative surgery this could provide an interim measure.  For others that do not wish to have surgery this offers them an additional reassurance alongside regular imaging and surveillance.  

"We're very hopeful that this new approach using Denosumab as an inhibitor could offer hope for women who are at very high risk for breast cancer," Professor Lindeman said.  (3, 4)


1. Osteoclast differentiation factor RANKL controls development of progestin-driven mammary cancer.

Daniel Schramek, Andreas  Leibbrandt, Verana Sigl, Joesph Peninger et al  , Nature Medicine 

Nature  468,  98–102  (04 November 2010)  

2010  cell research  studies led by a team from The Institute of Molecular Biotechnology (IMBA), VIENNA and

The University of Maryland School of Medicine, Baltimore , 

http://www.nature.com/news/2010/100929/full/news.2010.504.html

http://www.nature.com/nature/journal/v468/n7320/full/nature09387.html


2. Prevention of genetic breast cancer within reach

https://www.sciencedaily.com/releases/2016/05/160531082159.htm


3. RANK ligand as a potential target for breast cancer prevention in BRCA1-mutation carriers.

Jane E Visvader & Professor Geoffrey J Lindeman et al.   

Nature Medicine  June 20th 2016  

doi:10.1038/nm.4118

(Walter and Eliza Hall Institute of Medical Research)

http://www.ncbi.nlm.nih.gov/pubmed/27322743


4. Unlikely drug may block breast cancer in high-risk women

By Jacqueline Howard, CNN

Updated 1920 GMT (0320 HKT) June 21, 2016

http://edition.cnn.com/2016/06/21/health/brca1-breast-cancer-drug/




 


 


By Anneela Saleem 02 Jun, 2016

The results of a clinical trial looking at the affects of dual therapy for HER2 Breast Cancer patients was presented by Professor Nigel Bundred ( Manchester, UK) and Professor Judith Bliss ( London, UK) at the 10th European Breast Cancer Conference in March 2016 .


BACKGROUND


HER2 positive breast cancer is breast cancer that has a high number of human epidermal growth factor receptors on its surface as shown below. Excess HER2 receptors stimulate the cancer cells to divide and grow quickly. HER2 positive breast cancers can be treated with targeted therapies such as Trastuzumab and Lapatinib.

By Anneela Saleem 02 Jun, 2016

A study has been published this month by Scientists at The Edinburgh Cancer Discovery Unit, Edinburgh University, in the Journal of Medicinal Chemistry.

The researchers led by Professor Neil Carragher and Dr Asier Unciti-Broceta have identified a chemical compound, eCF506.

eCF506 blocks the growth of breast cancer cells in lab studies.

It does so by targeting a molecule called src tyrosine kinase that is required for the cancer cells to grow and spread.

Src Inhibitors

These are a class of drugs that are already being developed to target src tyrosine kinase; they are currently being tested in clinical trials. However, eCF506 is different because it doesn’t affect other molecules in the cell, meaning it is more selective and therefore more effective at blocking src tyrosine kinase. This also means that it should have fewer side effects than the other drugs already being developed.

Pioneering Approach

The approach to discovering this chemical compound was itself pioneering and should pave the way for a powerful and more cost-effective way of discovering new drugs to treat other cancers and other diseases. The team used imaging techniques at a cellular level that enabled them to visualise how drugs affect cells.

What Next?

This discovery is at a lab stage and further pre-clinical trials need to take place before any clinical trials are established for eCF506. However, this is a very promising discovery and it will be exciting to see how this unfolds.

 

For Further Information- link to abstract , full article can also be obtained from this link. 

http://pubs.acs.org/doi/abs/10.1021/acs.jmedchem.6b00065

Follow this link to learn more about the complexity of cells and cell signalling

https://medivizor.com/blog/2016/05/23/oncology-basics-2016-understanding-cell/


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