Pharma Strategy Blog

Commentary on Pharma & Biotech Oncology / Hematology New Product Development

Posts tagged ‘cancer’

A year in the life of Pharma Strategy Blog

By on October 31, 2011

Last week brought the first anniversary of this blog since moving to WordPress as a platform, but as luck would have it, I was snowed under with more work than usual.

Several people have asked about the stats here recently, so it seems a good time as any to do an annual review. Although this blog has been up and running since 2006, it only started on WP on October 24th 2010.

In the last twelve months, PSB has seen the following activity:

  • 614K reads, with around 50-60K reads per month
  • 337K visitors, approx. 30K visitors per month

The busiest day was 6th June, with nearly 5K reads, thanks to a kind link from Matt Herper of Forbes Health.  Ironically, the interim and eagerly anticipated MDV3100 phase III data from Medivation is now due before the end of the year.  More on that when the announcement comes out!

What were the most popular posts? Here’s the Top Ten on Pharma Strategy Blog from the last year based on hits:

  1. PI3K: a hot topic in cancer research
  2. Update on PARP inhibitors
  3. PLX4032 phase III data in metastatic melanoma
  4. Improved survival with ipilimumab in metastatic melanoma
  5. Crizotinib and ALK rearrangements: Ross Camidge interview
  6. Abiraterone/Zytiga FDA approval
  7. Interview with Charles Sawyers
  8. PLX4032 in metastatic melanoma
  9. Update on PI3K from ASCO
  10. Brentuximab Vedotin (SGN-35) for Relapsed CD30-Positive Lymphomas

In some ways, the popularity of these particular posts are no surprise, since if you asked me to name the hot topics in oncology this year, I would have said:

  • ALK in lung cancer
  • BRAF and CTLA4 in melanoma
  • Abiraterone in advanced prostate cancer
  • ADCs and brentuximab

It wasn’t all positive though, as the ongoing PARP story has been notable largely for the negative data. That may change in the future as scientists and clinicians grapple with finding the right targets and sub populations to aim these therapies at.

I was particularly pleased to see that PI3K resonated with the audience as this one of my favourite pathways, although we still have a long way to go to crack the nut with this target.

A big thank you to everyone who read PSB, posted comments, shared articles or the many email exchanges that have taken place; it is much appreciated and I hope that you have enjoyed reading my thoughts and commentary.

Come December, I will post the annual review and predictions for 2012, but in the meantime, normal blog commentary on cancer related topics will resume tomorrow.

Can monoclonal antibodies target oncoproteins directly in the cancer cell?

By on September 9, 2011

This week a fascinating paper appeared in one of my favorite journals, Science Translational Medicine.  Until now, it had been assumed that antibodies only bind to proteins found on the cancer cell surface, largely because of the size of the molecules:

“Because antibodies are viewed as too large to access intracellular locations, antibody therapy has traditionally targeted extracellular or secreted proteins expressed by cancer cells.”

Not so fast!

Guo et al., (2011) have now demonstrated that proteins hidden within cells can be attacked by antibodies as well.

This paper is first to report that antibodies can actually directly target intracellular oncoproteins such PRL-3 that reside within cancer cells, thereby suppressing cancer growth:

“As proofs of concept, we selected three representative intracellular proteins as immunogens for tumor vaccine studies: PRL-3 (phosphatase of regenerating liver 3), a cancer-associated phosphatase; EGFP (enhanced green fluorescent protein), a general reporter; and mT (polyomavirus middle T), the polyomavirus middle T oncoprotein.

A variety of tumors that expressed these intracellular proteins were clearly inhibited by their respective exogenous antibodies or by antigen-induced host antibodies (vaccination).”

In plain English, the data clearly showed that the antibodies induced tumour regression in mice.

What fascinated me was that the tumour regression depended on the presence of immune B cells, which are responsible for antibody production, potentially by improving entry of the antibodies into the tumor cell. Vaccination with the intracellular proteins spurred production of specific antibodies by the host, which also led to tumour regression.

What are the potential mechanisms involved in the therapeutic antibody effect?

Guo et al., (2011) suggested several possibilities:

  1. A small fraction of intracellular antigens may be released due to necrosis or cancer cell lysis.
  2. Some intracellular antigens may be externalized and displayed on the surface of cancer cells by unconventional secretion.
  3. Binding of antibodies to surface-exposed intracellular proteins may then trigger immune responses such as ADCC to destroy the cancer cells.
  4. Antibodies could be taken up by the cancer cells in an antigen-specific manner.
  5. Complement-mediated events may also be involved.

In other words, it could be highly complex with several factors involved. These will no doubt be studied further to elucidate the mechanisms more precisely.

What are the implications of this research?

Remember – tumours targeted with unrelated antibodies usually produce no beneficial response – which was also seen in this research.

Overall, I think if the concept of targeting targeting intracellular oncoproteins with antibody therapy or vaccination were to be reproducible in human research, then new, highly specific cancer targets may well emerge in clinical trials, much in the same way the HER2 protein was used as a highly specific target for a subset of breast cancer patients.

In order to have higher response rates from cancer therapeutics, we need to have better, more specific targets than we currently see in the clinic.  I’ll be following this development to see where it goes, whether new translational research and also specific monoclonal antibodies will emerge, as a result of these findings from the basic research.

It might take a little while, but that would be great news for cancer patients.

References:

ResearchBlogging.orgGuo, K., Li, J., Tang, J., Tan, C., Hong, C., Al-Aidaroos, A., Varghese, L., Huang, C., & Zeng, Q. (2011). Targeting Intracellular Oncoproteins with Antibody Therapy or Vaccination Science Translational Medicine, 3 (99), 99-99 DOI: 10.1126/scitranslmed.3002296

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The other side of cancer

By on September 7, 2011

One of the key things that drives drug development and R&D is hope.

Photo Credit: Harry Willis

Hope for better drugs, hope for new targeted therapies that make a real difference to the lives of people, hope for more gentle therapies that increase survival, hope for longer remissions… and so on.

One thing that is rarely talked about or discussed, however, is palliative care and end of life decisions.  Sometimes the best option is no further treatment.  These, sadly and inevitably, come too especially in patients with incurable or metastatic disease. Those ‘the time has come’ moments are rightly mostly private affairs for families and close friends.

And yet they matter, or should do, because it is the very essence of humanity at these times that sets Mankind apart.

Please take a just few moments to read my friend Jody Schoger’s beautiful post.

I promise you – it will change your day.

 

Photo Credit: Harry Willis via Flickr

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Continued aggregation of the ASCO 2011 tweets

By on June 4, 2011

This latest widget captures all the tweets and discussion about ASCO data including the week before the meeting – this year the tweets are going at a tremendous velocity, with a much wider variety of people joining in.

Check it out below:

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Using Flipboard to keep up with science and cancer research

By on May 24, 2011

A lot of people have asked me over the last year how I keep up with so much information in cancer research.  I thought it would be a nice idea to illustrate one way I consume information on a daily basis.

Since getting an iPad2, my life has changed for the better.  There are a number of really useful apps that let you browse information in a more user-friendly way.  Four of these include:

  1. Flipboard
  2. Zite
  3. Reeder
  4. Feedly

After trying them all over time, I found that for me, the one that resonated most for me was Flipboard.

What you get starts out like this:

Oh dear, that wasn’t welcome news this morning, bearing in mind I’m flying to ASCO in Chicago and then to London for the European Hematology Association meeting back to back in a few weeks.  The return of #ashcloud tweets on Twitter looks imminent!

Here’s how Flipboard works…

  1. Select your Twitter lists
  2. Other people’s curated Twitter lists you follow
  3. RSS feeds for blogs, journals, pubmed searches, etc

And the inside of the magazine becomes organised into recognisable categories:

You can then flip through the categories and see what’s interesting to you for further reading.  It also enables you to see broad trends much more easily.

Here’s an example from my journal and Pubmed feeds, since I have searches for all the key pathways that are associated with cancer.  Some are more active than others, but over time, you get a mix of new articles whenever you browse them.

This is much easier to browse than reading lists and lists of things in Google Reader – Flipboard brings them life:

Now you can sort the chaff from the wheat – we know that the BRAF V600E mutation is important in melanoma, but not colon cancer for example, but I sure didn’t know it might have a role to play in thyroid cancer!

Reading the abstracts this way is much more impactful and user-friendly.

Another thing that is useful is browsing one’s Twitter lists on topics such as Cancer, Medicine etc.  In the latter, I spotted an interesting tweet about how an app could be used to record your ECG on an iPhone – how cool is that?


You can see the play button for the video on the iPad (it obviously won’t work on the photo though, in case you just clicked on it ;)) – you just click and listen while travelling or sitting in the comfort of your office.

The way technology has evolved over the last couple of years is simply amazing, but best of all, it makes processing information you have selected as relevant to your personal interests much more user-friendly and digestible.

That’s a big win for busy people on the go!

What apps do you like?  Do share them in the comments below.

 

 

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Recognizing some excellent cancer bloggers and curators

By on May 6, 2011

It’s the end of a long week and today I thought it would be nice to highlight some people who write about cancer in the blogosphere since some people have emailed asking me what blogs do I read.

Here are a few cancer news sources I enjoy each week – some are writers, some survivors, some physicians, some analysts and not all have blogs, but some use other social media tools creatively to aggregate useful cancer information.

I heartily suggest you check them all out – their linked names take you to their Twitter stream and the other link to their blog or social media resource:

  1. Jody Schoger: Women with Cancer
  2. Alicia Stales: Awesome Cancer Survivor Blog
  3. Dr. Jack West: GRACE – expert mediated discussions on cancer esp. lung cancer
  4. Matthew Herper: Forbes Health
  5. Adam Feuerstein: The Street
  6. Dr. Len Lichtenfeld (ACS): Dr Len’s Blog
  7. Dr. Elaine Schattner: Medical Lessons blog
  8. Dr. Anas Younes: Curates an awesome Facebook page with regular cancer news
  9. Dr. Wafik El Diery: Has a superb cancer daily on Paper.li that I read each morning on my Flipboard
  10. Dr. Ray DuBois and Dr Naoto Ueno from MD Anderson and Dr Robert Miller from Johns Hopkins also share lots of interesting cancer news in their Twitter streams

There are many others, but I’ll stop there for this week and add a few more in the next update.

Disclosure: I am an unpaid member of the GRACE board.

Who do you enjoy reading and why?  If you have any other suggestions, please do include them in the comments below.

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Hormonal therapy and cancer – the controversy rages on

By on April 15, 2011

Hormone replacement therapy (HRT) is one of those subjects where many have a strong opinion either way and I suspect even if we have another dozen trials evaluating at the pros and cons, those opinions won’t change very much.

That said, the latest large randomised, double blind, placebo controlled study from the Women’s Health Initiative (WHI) in postmenopausal women with a prior hysterectomy (n=10,739) taking conjugated equine estrogens (CEE) such as Premarin has just reported their health outcomes analysis.

The original goal of the trial was to examine health outcomes after a mean of 10.7 years of follow-up.  The study was stopped, however, after a mean of 7.1 years of follow-up because there was an increased risk of stroke. LaCroix et al., (2011) provided some context:

“The Women’s Health Initiative Estrogen-Alone Trial was stopped early after a mean of 7.1 years of follow-up because of an increased risk of stroke and little likelihood of altering the balance of risk to benefit by the planned trial termination date. Postintervention health outcomes have not been reported.”

The baseline characteristics looked well balanced between the two arms, so I took a quick look at the hazard ratio plots to see which factors favoured placebo and noted not only stroke, but also deep vein vein thrombosis (DVT) and pulmonary embolism.  It was easy to see why the trial was stopped early based on those results, especially as there were no significant differences in statin or aspirin use between the two groups.

Interestingly, looking at the topline hazard ratios on the cancer side, invasive breast cancer was lower on the treatment side, but colorectal cancer was more favourable in the placebo arm.  Previous trials have shown an increase in treatment related breast cancers. Part of this reason may lie in the type of hormone treatments given (estrogens only versus combination therapy) and variations in the patient groups.  Of course, the news media instantly picked up on the cancer issue rather than the cardiovascular effects.

Things started to get interesting, however, as I noticed that in the abstract, LaCroix et al., (2011) clearly stated:

“Among postmenopausal women with prior hysterectomy followed up for 10.7 years, CEE use for a median of 5.9 years was not associated with an increased or decreased risk of CHD, deep vein thrombosis, stroke, hip fracture, colorectal cancer, or total mortality.  A decreased risk of breast cancer persisted.”

Eh?  That’s not what you see in the hazard ratio plots, so I went back to re-read the paper and discussion in more detail.

The differences can be explained in the long term follow-up after treatment:

“Among postmenopausal women with prior hysterectomy who stopped taking CEE after a median of 5.9 years of use, several patterns of health risks and benefits seen during the intervention period were not maintained during the postintervention period, while other trends persisted.”

In other words, you often lose an effect post treatment, which can be a good or bad thing depending upon the parameter itself.

With the stroke and cardiovascular events seen in the intervention period on treatment, for example, in the post intervention period those effects “rapidly dissipated” during the postintervention period.

No doubt we will see future subgroup analyses emerge from this trial, it would be interesting to see, for example, whether mammogram screening was higher in either group and whether that impacted the findings or not.  Certainly that has been suggested in the past as one reason for the higher incidence of breast cancer in HRT users in other studies – in other words if you got looking for it more often you may well find it.

That said, the HRT story is likely to run and run as will emotions and opinions.

For some different perspectives, I can highly recommend checking out blog posts on the subject from Medical Lessons for a physician’s take and Flash Free for a science writer’s thoughts.  There was also an insightful commentary (open access) in Cancer Prevention Research from Craig Jordan and Leslie Ford (see references), who noted:

“Administration of estrogen replacement therapy (ERT) to hysterectomized postmenopausal women decreases the incidences of breast cancer.  Though paradoxical because estrogen is recognized to stimulate breast cancer growth, laboratory data support a mechanism of estrogen-induced apoptosis under the correct environmental circumstances.”

Personally?  I wouldn’t take it and I’m too young anyway, but I would like to see more granular research on which subpopulations are most likely to benefit, something that is not really that clear even now.  I’ll leave you with a striking insight from Jordan and Ford:

“The important issue for the decision of breast cancer cells to survive or die in response to estradiol depends entirely on the cell populations present in an estrogenized environment or following estrogen deprivation.”

Maybe we need more cowbell.

References:

This post was chosen as an Editor's Selection for ResearchBlogging.orgLaCroix AZ, Chlebowski RT, Manson JE, Aragaki AK, Johnson KC, Martin L, Margolis KL, Stefanick ML, Brzyski R, Curb JD, Howard BV, Lewis CE, Wactawski-Wende J, & WHI Investigators (2011). Health outcomes after stopping conjugated equine estrogens among postmenopausal women with prior hysterectomy: a randomized controlled trial. JAMA : the journal of the American Medical Association, 305 (13), 1305-14 PMID: 21467283

Jungheim ES, & Colditz GA (2011). Short-term use of unopposed estrogen: a balance of inferred risks and benefits. JAMA : the journal of the American Medical Association, 305 (13), 1354-5 PMID: 21467291

Jordan, V., & Ford, L. (2011). Paradoxical Clinical Effect of Estrogen on Breast Cancer Risk: A “New” Biology of Estrogen-Induced Apoptosis Cancer Prevention Research DOI: 10.1158/1940-6207.CAPR-11-0185

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What can Zebrafish tell us about metastatic melanoma?

By on March 30, 2011

This week’s Nature is chock full of interesting articles on various cancer related topics so it was quite hard to pick just one to discuss in a blog post.   Nevertheless, two on Zebrafish was very striking, since the Letters discusses how models have revealed oncogenes and potential new drug targets in a particularly difficult to treat tumour type, i.e. melanoma.

Zebrafish, source: wikipedia

We now know that in melanoma, the BRAF V600E mutation drives signaling and proliferation of the MAPK pathway and that resistance also develops to treatment with targeted therapies such as PLX4032 and other inhibitors after six months or so.  The question then is what factors are driving the resistance and are other (druggable) oncogenes involved?

A multinational group of researchers from Boston, Rome and Paris used Zebrafish melanoma models to explore events in a:

“Recurrently amplified region of chromosome 1 for the ability to cooperate with BRAF(V600E) and accelerate melanoma.”

In doing so, they discovered something very interesting:

“SETDB1, an enzyme that methylates histone H3 on lysine 9 (H3K9), was found to accelerate melanoma formation significantly in Zebrafish.”

Chromatin was also found to be involved in tumorigenesis associated with SETDB1.

Histone methylation has been mooted as a promotor of cancer in other tumour types such as renal cell carcinoma and others, thus this study lends support to that theory.

In the second letter, White et al., (2011) report that DHODH inhibition with either leflunomide and NSC210627 led to a marked decrease in melanoma growth, both in vivo and in a xenograft model.  They used the Zebrafish to successfully identify:

“Small molecule suppressors of neural crest progenitors that give rise to melanoma.”

What do these findings mean?

SETDB1 is focally amplified in a number of malignancies, which means that it would be interesting to see if it also promotes histone methyltransferase activity in other cancers too.

The results from the Letters to Nature suggest that both DHODH and SETBD1 could be valid new targets for therapeutic intervention if drugs could be designed and developed to shut down the activity and prevent acceleration of the disease.  Future new logical combinations or sequencing of therapies in melanoma could therefore emerge from these important research findings.

In addition…

If you haven’t taken a look yet, this weeks Nature magazine is well worth reading for several other useful articles on cancer that are related to research including vaccines, biomarkers, liver cancer, genome sequencing in multiple myeloma, FAS and NF-kB signalling in lung cancer.  There is also a whole Outlook section (open access) on Cancer Prevention that is relatively easy to read, even for the layman that is worth checking out.

References:

ResearchBlogging.orgCeol, C., Houvras, Y., Jane-Valbuena, J., Bilodeau, S., Orlando, D., Battisti, V., Fritsch, L., Lin, W., Hollmann, T., Ferré, F., Bourque, C., Burke, C., Turner, L., Uong, A., Johnson, L., Beroukhim, R., Mermel, C., Loda, M., Ait-Si-Ali, S., Garraway, L., Young, R., & Zon, L. (2011).  The histone methyltransferase SETDB1 is recurrently amplified in melanoma and accelerates its onset.  Nature, 471 (7339), 513-517  DOI: 10.1038/nature09806

White, R., Cech, J., Ratanasirintrawoot, S., Lin, C., Rahl, P., Burke, C., Langdon, E., Tomlinson, M., Mosher, J., Kaufman, C., Chen, F., Long, H., Kramer, M., Datta, S., Neuberg, D., Granter, S., Young, R., Morrison, S., Wheeler, G., & Zon, L. (2011).  DHODH modulates transcriptional elongation in the neural crest and melanoma Nature, 471 (7339), 518-522  DOI: 10.1038/nature09882

Mindfulness and Health: Kids Kicking Cancer

By on March 25, 2011

Today is Friday and I try to post something lighthearted and fun at the end of a busy week.  With that in mind, someone sent me this great link to Kids Kicking Cancer.  As someone who experienced a childhood cancer, I can identify with this awesome concept – help the kids feel victors not victims:

Kids Kicking Cancer

They have some great use of social media tools to spread their message and provide links to inspiring stories about the Kids.  There is a Facebook Page and a YouTube channel, for example.  After watching one of their their videos, I simply couldn’t resist sharing a genuine feel-good story about what their vision is:

“Kids Kicking Cancer uses martial arts breathing, meditation and imagery techniques to ease the pain of very sick children while empowering them to heal physically, spiritually and emotionally.

Our mantra of “Power Peace Purpose” allows the children to know that they are victors not victims. In turn they teach adults, corporations and other children how to control stress, pain, fear and anger.

When they hear from the Hollywood superstars that “you boys and girls are the real heroes” it helps them to recognize that they really do have the enormous power to bring themselves to an inner healing peace.”

Check out this short inspiring video and spread a little happiness…

Many of us live busy stressful lives and forget to nurture the spirit and mindfulness to decompress from the hurly burly of life.  I was therefore really pleased to see that there is also a an iPhone app and Blackberry app that are worth checking out for breathing exercises to manage stress for everyone, not just kids, as well.  Do check them out and share them with your family and friends!

Elements of success in cancer research

By on March 10, 2011

“I’ve missed more than 9000 shots in my career.  I’ve lost almost 300 games.  26 times, I’ve been trusted to take the game winning shot and missed.  I’ve failed over and over and over again in my life.  And that is why I succeed.”

Michael Jordan, Chicago Bulls

Michael Jordan, Chicago Bulls

Source: wikipedia

Continuing the sporting metaphors this week, I was catching up on blog reading last night and noticed that Jim Lefevere put up a nice post on Digital Strategist about how:

Domain Expertise + Work Ethic + Time = Success

He used Michael Jordan as an example to illustrate the competitiveness that is required for the top level.

While talking to scientists and researchers at the recent AACR PI3K-mTOR meeting about their myriad of iterative experiments with GWAS, Western Blots and such, you can imagine the parallels with scientific research.

It struck me how the scientists in this particular field of cancer research are both highly collaborative and competitive at the same time, while also being very focused and intense on the end game (implications for clinical research), perhaps more so than other sub specialty areas I’ve come across lately.

The main message I learned from the meeting can be summed up in this little forumla:

Driver Mutation + Adaptive Pathway + Ligand + Patient Selection = Possible Success

A lot of data on PI3K and mTOR can be expected at forthcoming annual meetings at AACR (April) and ASCO (June), so it will be interesting to see how the new combinations of PI3K or mTOR with AKT or MEK, for example, are panning out and in which tumour types.

 

 

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