Scientists unravel structure of key breast cancer target enzyme aromatase

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Today's blog post is much later than usual due to ongoing consulting commitments, but when an alert flashed up on my email with the above header, I couldn't resist taking a break and reading it:

"Scientists at the Ghosh lab at the Hauptman-Woodward Medical Research Institute (HWI) in Buffalo, New York have uncovered the molecular details of Aromatase, the key enzyme required for the body to make estrogen."

Wow, that got my attention.  Here's a link to the letter published in Nature.

Scientists unravel structure of key breast cancer target enzyme aromatase What does this mean in practise?  Well, put simply once we know the precise structure of the target enzyme, new generation aromatase inhibitors can be developed to improve on the effectiveness and tolerability of existing inhibitors such as Femara, Arimidex and Aromasin.

Or as the lead researcher Dr Ghosh more enthusiastically put it:

"Scientists worldwide have been trying for 35 years to crystallize this membrane-bound enzyme and we are the first to succeed. Now that we know the structures of all three key enzymes implicated in estrogen-dependant breast cancers, our goal is to have a personalized cocktail of inhibitors customized to the specific treatment needs of each patient. Our knowledge about these three enzymes will enable us to develop three mutually exclusive inhibitors customized to each patient's needs which will work in harmony together with minimal side effects."

It is important to note that 70-80% of breast cancers are fed by the female hormones estrogen (ER+) or progesterone (PR+), so inhibiting the hormones can slow down cancer growth.  Current methods of doing so include treatment with tamoxifen or the first-generation aromatase inhibitors, but knowing the structure of both is crucial to designing better drugs in the future in order to minimise drug resistance and relapse.

 

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Scientists unravel structure of key breast cancer target enzyme aromatase
  • Sarah Arrow

    Hi Sally
    This makes great reading and is very promising. What would be the next step from this?
    Thanks
    Sarah

  • http://profile.typepad.com/maverickny Sally Church

    Hi Sarah,
    As far as I can make out, they will be working to test their hypothesis that the chemical mechanism is involved in the conversion of androgens to estrogens.
    I would also imagine that they will be working with collaborators to develop medicinal complexes for testing.

  • http://www.BowenRacing.com Colin Bowen

    A friend of my wife’s is soon to undergo a mastectomy. Is this breakthrough likely to be of any benefit to her please? I wouldn’t want to send this to her raising her hopes without it being relevant.

  • http://profile.typepad.com/maverickny Sally Church

    Hi Colin,
    Thank you for your comment.
    I would say that since this breakthrough has yet to be tested and validated in humans or new second generation therapies developed, it would make sense not to raise your wife’s friends’ hope.
    New treatments may evolve in the next 8-10 years so they would be highly unlikely to help in the short term.
    The good news though, is that if her doctor deems hormone inhibition appropriate after mastectomy, then there are therapies on the market that can help.

  • http://optimism.thorscave.com/ Thor

    As a biochemist and a crystallographer, I attest to the importance of this structure and the molecular details it provides.
    From a therapeutic perspective, structure-based drug design has not been as successful as was hoped in the 80′s and 90′s. While there are success stories, majority of drugs are still developed through high-throughput screens against a target.
    Additionally, while many breast cancers are induced by estrogen and progesterone, inhibiting this enzyme may not be the ideal solution since a variety of fundamental processes require estrogen for proper function. The prevailing philosophy of cancer therapeutics has been to destroy cancer cells at the expense of healthy cells, I thing new strategies need to move towards reduced side-effects. I don’t think targeting aromatase would be a step in this direction.
    Considering the high survival rates for breast cancer, we are not so desperate for drugs that we need to continue to develop toxic therapeutics, and we can afford the extra time and effort for more effective therapeutics that with reduced general toxicity.

  • http://dovdox.com Alan Dove

    I have to agree with Thor: the finding is scientifically fascinating, but not likely to yield drugs soon, if ever. Solving the crystal structure of any membrane-bound protein is a huge accomplishment, and many crystallographers have bashed their heads against aromatase without success over the years. This was definitely worth a Nature paper.
    As for using a structure as the basis for rationally-designed inhibitors, well, that approach has pretty much failed. Everyone in basic research still mentions it in their grants, but the reality in the pharma industry is that rationally-designed compounds are no more likely to succeed than randomly generated ones from HTS libraries (which aren’t exactly stuffing the pipeline themselves). We just don’t know enough yet.

  • http://profile.typepad.com/maverickny Sally Church

    Thor, you’re absolutely right that historically cancer therapy has been about destroying any cell but that is gradually changing with new targeted therapies such as Herceptin, Gleevec, Terceva and Avastin, for example. These drugs all target a particular mechanism associated with the cancer abnormality and have generally fewer side effects than toxic chemotherapies.
    With regards to unmet medical need, breast cancer has the 3rd most deaths in the USA after lung and colorectal cancers, so while there are many therapies, a cure clearly remains elusive unless it is caught early enough for surgery.

  • http://profile.typepad.com/maverickny Sally Church

    With regards to Alan and Thor’s comment about the crystal structure, I’m not so pessimistic. Yes, the approach has not necessarily yielded as much success as we would have liked but things may change as our knowledge about the science and biology improves.
    Let me give one example of how things may be a-changing. In CML, our knowledge of the crystal structure of ATP and its binding sites has led to the development of potent tyrosine kinase inhibitors such as Gleevec, Sprycel and Tasigna. The subtleties of how each binds with BCR-ABL to prevent phosphorylation is crucial to the slowing of the disease progression and also to overcoming the development of resistance. Yes they were developed from screening, but they also related to the relevant structures, otherwise it would be a lot more hit and miss and 80%+ response rates would not be possible.
    It’s a small step in the right direction and hopefully other research such as the aromatase structure may continue to yield results in the future.

  • http://www.BowenRacing.com Colin Bowen

    Hi Sally,
    Thank you for your comment. I expected that the treatment would be too new to help my wife’s friend, but I couldn’t read this and then not ask the question.
    As for the comments by Thor and Alan Dove, they make sense to me as a novice, although I do think Thor’s comment is insensitive; “Considering the high survival rates for breast cancer, we are not so desperate for drugs that we need to continue to develop toxic therapeutics, and we can afford the extra time and effort for more effective therapeutics that with reduced general toxicity.”
    Yes, there is a high survival rate, but people are dying. They cannot “afford the extra time”, and they are desperate for any drug, toxic or not, that might improve their chances. This is a publicly accessible site, and people with breast cancer will probably read it.
    If the money was not being spent on this research, I don’t know whether it would be helping to fund other, ‘non-toxic’ treatments research. Clearly I don’t know what I’m talking about medically, but is this research really so pointless? Surely there must be some potential benefit, otherwise why would they be spending the money?

  • http://optimism.thorscave.com/ Thor

    Because this discussion is about estrogen sensitive breast cancers, people need to start focusing on exposure to xenoestrogens and lifestyle-related factors that modulate blood chemistry.
    Its sad that with so much cancer awareness, so little is done to empower people’s lifestyles in cancer prevention and treatment. I’m talking about things that the media wont cover. They stop at ‘chocolate may do this’ ‘red wine may do that’, and other stories that are too “watered-down” to help. I’m getting off topic…that’s the basis for my blog anyway.