Technology | Pharma Strategy Blog

PI3-kinase (PI3K): a hot topic in cancer research

By MaverickNY on July 19, 2010

Recently at a couple of scientific cancer meetings, American Urology Association (AUA) and American Society of Clinical Oncology (ASCO), Frank McCormick described a fascinating talk about how a wac-a-mole approach to figuring out how the phosphatidylinositol 3′-kinase (PI3-kinase or PI3K) pathway could be targeted effectively with therapeutics. The reason for research in this area is PI3K has been shown to play a major role in proliferation and survival in a wide variety of human cancers, thus making is a potential target for therapeutic intervention.

I’ve been following this target for a couple of years now and data is now starting to emerge that’s worth discussing on a broader scale, given the implications. Here’s a quick snapshot of the PI3K pathway and related pathways:

Source: Workman et al., Nature

As many of us well know, however, simply targeting one element of an aberrant pathway can lead to cross-talk and feedback loops as the cancer tries to maintain the signals important for it’s survival, so a more cunning approach is needed whereby the escape routes are closed off one by one by targeting different kinases as well as PI3K.

McCormick’s talk was a fascinating lecture that basically went through multiple pathways explaining, ‘well we tried X and this happened, so we tried blocking Y as well and this happened…’ kind of approach in a very logical and systematic fashion. Eventually, all options will be explored and a new paradigm might emerge.

It was therefore with great interest that I read a series of new papers in AACR’s journal, Clinical Cancer Research (see references below) over the weekend on both the pathway itself, and also new data with targeted PI3K agents in both breast and renal cancers.

The Data so far:

Miron et al., looked at PI3K mutations in in situ and invasive breast carcinomas and reported:

“This is the first study to show that PIK3CA mutation is a relatively early event in breast tumorigenesis preceding invasion because the frequency of PIK3CA mutations was the same in pure DCIS as in DCIS adjacent to IDC and in IDC.”

Given the frequency of mutations was the same for the 3 groups they studied (pure ductal carcinoma in situ (DCIS), DCIS adjacent to invasive carcinoma, and invasive ductal breast carcinomas), the data suggest that the PI3K mutation may play a greater role in breast tumor initiation than in invasive progression.

If this is the case, targeting PI3K early, for example in neoadjuvant therapy, may have a positive beneficial effect.

In the O’Brien paper, the researchers looked for predictive biomarkers of sensitivity to Roche/Genentech’s PI3Ki, GDC-0941 in preclinical models of breast cancer:

“We found that models harboring mutations in PIK3CA, amplification of human epidermal growth factor receptor 2, or dual alterations in two pathway components were exquisitely sensitive to the antitumor effects of GDC-0941. We found that several models that do not harbor these alterations also showed sensitivity, suggesting a need for additional diagnostic markers.”

Identifying suitable biomarkers in preclinical studies, such as the HER2 amplification and the PIK3CA mutation (but not PTEN deficiency) previously identified in other studies and now validated in O’Brien et al’s GDC-0941 study, will hopefully help in better design of future clinical studies. They also noted that decreased ERBB3 expression in PIK3CA mutant cell lines, and ERBB3 expression was increased in response to treatment with a PI3K inhibitor, suggesting that ERBB3 expression levels might be used as a biomarker for high activation of PI3K signaling and increased sensitivity to PI3K inhibitors. This kind of rigourous approach would potentially enable selecting which people are most likely to respond up front to the agent, rather than exposing those who are unlikely to get a response to additional toxicities and side effects.

In a well written editorial, Turke and Engelman, also emphasised that:

“A novel expression profile was developed to identify other breast cancers sensitive to PI3K inhibitors. These expression studies highlighted feedback networks connecting TORC1, PI3K, and mitogen-activated protein kinase (MAPK) pathways, and underscored the potential for combination therapies.”

They also went on to observe:

“It will be interesting to determine if PI3K inhibitors induce substantial apoptosis in vitro and tumor regressions in vivo in these cancer models (without HER2 amplification or PIK3CA mutation). Of course, it will be crucial to assess biomarkers identified in laboratory studies in clinical samples from patients who respond to PI3K inhibitors. Neo-adjuvant trials in breast cancer patients can be leveraged to address these translational goals, because they correlate clinical efficacy and pathologic signs of response (e.g., changes in Ki67 levels and induction of caspase cleavage) with the presence of potential biomarkers.”

In another study, Cho et al., looked at the effects of a dual PI3-Kinase/mTOR Inhibitor
NVP-BEZ235 compared with rapamycin in renal cancer (RCC) with BEZ235 (Novartis). The proof of concept for mTOR has already been shown clinically with the approval of two drugs in this indication, temsirolimus (Pfizer) and everolimus (Novartis):

“These agents induce only modest tumor regression and extend progression-free survival only a few months in most patients.”

The big question here is whether targeting PI3K as well as mTOR would have any extra beneficial effects? The results demonstrated that dual inhibition of PI3K/mTOR with BEZ235 induced growth arrest in RCC cell lines both in vitro and in vivo more effectively than inhibition of TORC1 alone. If reproduced in the clinic, this may offer a new and more effective approach to treatment of the disease.

The Future:

The PI3-kinase field is particularly interesting, with several companies snapping up PI3K inhibitors including sanofi-aventis (from Exelixis) and more recently, Infinity (from Intellikine). Other oncology companies already have some in their pipeline, such as Novartis (BEZ235) and Roche/Genentech (from Piramed). Meanwhile, smaller biotechs such as Semafore and Calistoga also have some promising early phase compounds in development. Some of these compounds target PI3-kinase alone, while others target PI3K and mTOR.

This is not going to be a straightforward approach to targeting cancer and identifying biomarkers along the way will be key, as well working out the best combinations that might make a more effective therapeutic approach than single agent activity. Figuring out when best to test these agents (early or late) will also be critical. The I-SPY breast cancer trials have already led the way in creating protocols for testing novel agents in the neoadjuvant setting in breast cancer, and it may well be that PI3K inhibitors would be a good class to test in this setting based on the new evidence from Miron et al’s study.

What is particularly interesting to me is that PI3K signalling may also have a role to play in asthma and COPD (the area I did my doctoral research in) rather than just cancer. Now that would be really fascinating as the biochemical and molecular biology overlap have long been suspected, but very little research has really evolved this way. Part of that is due to drug manufacturer silos and the inability to effectively spearhead cross-therapeutic research.

It will be fascinating to watch how the PI3K data shakes out in practice over the next few years.

What do you think?

O’Brien, C., Wallin, J., Sampath, D., GuhaThakurta, D., Savage, H., Punnoose, E., Guan, J., Berry, L., Prior, W., Amler, L., Belvin, M., Friedman, L., & Lackner, M. (2010). Predictive Biomarkers of Sensitivity to the Phosphatidylinositol 3′ Kinase Inhibitor GDC-0941 in Breast Cancer Preclinical Models Clinical Cancer Research, 16 (14), 3670-3683 DOI: 10.1158/1078-0432.CCR-09-2828

Turke, A., & Engelman, J. (2010). PIKing the Right Patient Clinical Cancer Research, 16 (14), 3523-3525 DOI: 10.1158/1078-0432.CCR-10-1201

Miron, A., Varadi, M., Carrasco, D., Li, H., Luongo, L., Kim, H., Park, S., Cho, E., Lewis, G., Kehoe, S., Iglehart, J., Dillon, D., Allred, D., Macconaill, L., Gelman, R., & Polyak, K. (2010). PIK3CA Mutations in In situ and Invasive Breast Carcinomas Cancer Research, 70 (14), 5674-5678 DOI: 10.1158/0008-5472.CAN-08-2660

Cho, D., Cohen, M., Panka, D., Collins, M., Ghebremichael, M., Atkins, M., Signoretti, S., & Mier, J. (2010). The Efficacy of the Novel Dual PI3-Kinase/mTOR Inhibitor NVP-BEZ235 Compared with Rapamycin in Renal Cell Carcinoma Clinical Cancer Research, 16 (14), 3628-3638 DOI: 10.1158/1078-0432.CCR-09-3022

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Evidence for role of microRNA in Melanoma

By MaverickNY on July 16, 2010

Twitter is great for highlighting interesting journal articles, as I found when Edward Winstead from the NIH shared this paper from PLOSone on the importance of microRNA in melanoma in his Twitter stream (thanks, Ted!).

There has been a lot of interest in melanoma lately, with the rise of a couple of interesting new compounds targeting different mutations or kinases including CTLA4 by ipilimumab (BMS) and B-RAF by PLX-4032 (Plexxikon/Roche).

You can see some of the recent data I've blogged about here, here and here.

At the moment, we're waiting for the new data from PLX-4032 at a melanoma conference later this year and BMS may be filing their phase III data in ipilimumab by the end of this year after some promising reactions to the data presented last month in the plenary session at ASCO. In addition, GSK also have some compounds in earlier development that are generating interest.

How does the new data in PLOSone connect with melanoma?

Well, it's an aggressive and highly malignant cancer and scientists have long wondered how melanoma cells travel from primary tumours on the surface of the skin to the brain, liver and lungs, where they become more aggressive, resistant to therapy, and deadly. This ultimately makes treatment and control of the disease very challenging.

In Feb 2009, an article in PNAS (see reference below) suggested that the culprit might be a short strand of RNA called microRNA (miRNA) that is over-expressed in metastatic melanoma cell lines and tissues. It is also known that the Microphthalmia associated transcription factor (Mitf) is an important regulator in melanocyte development and has been shown to be involved in melanoma progression.
The new data reported in PLOSone this month takes our understanding a little further and shows that microRNAs are also involved in regulating Mitf in melanoma cells.

The authors concluded that:

"miR-148 and miR-137 present an additional level of regulating Mitf expression in melanocytes and melanoma cells. Loss of this regulation, either by mutations or by shortening of the 3′UTR sequence, is therefore a likely factor in melanoma formation and/or progression."

What this means is that the microRNA's involved may offer new therapeutic targets in order to either reduce the development of resistance or aggressive progression and metastasis (ie spread of melanoma) to other organs. In order words, future research may involve the addition of microRNA therapy to optimise outcomes.

For now, microRNA is very much a research on the rise but it won't be long before we start seeing the first RNA based therapies in the clinic based on a solid scientific research rationale. As our understanding of the complex biology improves, so does the chances of developing a multi-factorial strategy to combat the devastating disease.

For those of you interested in this exciting field, I'll cover a more basic primer on microRNA and RNA therapeutics in development in a future blog post.

Photo Credit: Wikipedia

Haflidadóttir, B., Bergsteinsdóttir, K., Praetorius, C., & Steingrímsson, E. (2010). miR-148 Regulates Mitf in Melanoma Cells PLoS ONE, 5 (7) DOI: 10.1371/journal.pone.0011574

Segura, M., Hanniford, D., Menendez, S., Reavie, L., Zou, X., Alvarez-Diaz, S., Zakrzewski, J., Blochin, E., Rose, A., Bogunovic, D., Polsky, D., Wei, J., Lee, P., Belitskaya-Levy, I., Bhardwaj, N., Osman, I., & Hernando, E. (2009). Aberrant miR-182 expression promotes melanoma metastasis by repressing FOXO3 and microphthalmia-associated transcription factor Proceedings of the National Academy of Sciences, 106 (6), 1814-1819 DOI: 10.1073/pnas.0808263106

Simplifying data capture and blog post workflow

By MaverickNY on July 15, 2010

Recently, I’ve had a lot of enquiries as to how I manage to write so many blog posts, either in terms of finding the time or staying current.

The answer is simple – I use tools to help simplify and minimise the effort involved. You could also use this kind of web 2.0 approach for creating a database and tracking data, intelligence, keeping current if you work in the Pharma or Biotech industry, whether a scientist, a marketer or a PR professional. Of course, you could spend hours Googling stuff or reading a few health sites online, but there are other ways to stay ahead of the pack.

The key parameters at play here can be summarised:

Gather data
Process and understand information
Perform analysis
Generate Insights

Far too many people often only do the first two tasks, but without analysis and insights, the data means very little. So what are the tools of my trade?

1. Evernote

I’ve talked about Evernote in the past, which is a nifty data capture tool we use daily here at Icarus Consultants. They have both free and premium versions to suit everyone’s pocket.

When starting projects, we clip relevant information from the internet into a new Evernote Notebook and gather it all in one place. You can use a desktop or a smart phone for this task and dump as much information as you like into it for later searching. This makes it easier to digest when looking at the big picture and gathering ideas and seeing trends. You can also search your own database for existing information, which is very useful for blog posts or writing reports around a topic.

I often create and write blog posts in Evernote too. The research information is already there and it’s straightforward to use the editor as well, as backing up and synchronising the information across multiple platforms. We’ve all written something in Word or a Blog Editor and lost the content >.< but l have found Evernote more reliable for saving information, which can then be cut/paste with minimal editing into the Blog platform or Office for reports. I also have a bunch of articles, reports and blog posts that get part drafted and finished later, acting as a useful repository for gathering ideas.

Other good uses? Need some information on the road while talking to someone? A quick search in the app my iPhone will usually bring it up.

The other side of the coin is generating and gathering data. I’ve mentioned that you can clip research to an app such as Evernote on the go, but I also have a LOT of information in RSS, whether it be news items, feeds for the latest articles in tens of cancer and science journals, blogs from a variety of sources, rss alerts by topic or keyword etc. Keeping track of this huge volume of information used to be unwieldy.

2. My 6 Sense

One tool I really love and have been using for a while is My 6 Sense. This cool app takes all the rss feeds from my Google Reader, which is clumsy and awkward to read, and processes them into a more manageable fashion.

Several times a day I can check the app on my iPhone and see what’s new or relevant. Over time the app algorithms learn what your particular interests are and creates a page of what it considers to be useful items of interest in your RSS feeds via the Relevance tab or as they come in (the Time tab) as shown below (left photo).

Data is social, though; it cries out to be shared with others. The M6S app allows you to add social media sites such as Twitter, Facebook etc and share any interesting items with your friends or colleagues too. Here, you can also see the items from my shared stream as an example of what I found interesting and streamed to others to read:

Over time, as you use the app more, it gets much better at predicting what you like or may find interesting. One thing I miss from the M6S app is a Search button – what happens if I want to find a bunch of interesting articles in my RSS database on a given topic, eg PI3K or something similar? At the moment, there’s no obvious way to do that as far as I can tell, but it would certainly be really useful to me.

3. SimpleNote

I confess that after years of losing data unexpectedly, I’ve become a bot of a plain text geek. On my Macs, TextEdit was something I use daily, especially when taking notes from market research interviews on the fly. Then one day, someone mentioned SimpleNote, which is a beautifully simple yet flexible tool for gathering text notes.

For some months now, I’ve been using the App on my iPhone, which allows me to jot down ideas, tasks, notes to self etc on the fly… essentially simple notes.

Then recently, I realised that the free iPhone app also gave me access to the desktop app, which opens up a whole new world of utility and practicality. Here was something that could help me do multiple things efficiently:

Research and find interesting journal articles or news about say, PI3-kinase in My 6 Sense
Email article links to self via iPhone
On desktop, cut/paste multiple snippets of information to SimpleNote
Search SimpleNote for older articles
Write blog post in SimpleNote
Cut/paste blog post to TypePad for posting
Sync selected information with DropBox and read from any computer later

Take a look at the snapshot below for the basic SimpleNote concept:

You can see how neat and intuitive this is at first glance and how easy it is to find information, whether it be data or contact information or even the reference link months after clipping it by scrolling down in an individual note:

The DOI is really useful because when I blog about journal articles, I only have to cut/paste the DOI into the Research Blogging site and it generates a nifty bit of code that provides easy access to the article via a link for anyone interested in it.

Over time, I diligently put in tonnes of stuff into these tools, whether Evernote or SimpleNote and they come in very handy for research for blog posts and consulting reports. Essentially, I find that I tend to use Evernote for web clipping and SimpleNote for text processing.

Of course, the short answer to the blogging question is you either get more efficient and smarter at gathering, processing, analysing and generating insights or you work longer hours. Being a good European, I’d rather work smarter and hope that people appreciate the insights generated either in the blog posts here or in client report :-).

What are your favourite tools and apps that make a difference to your daily workflow?

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The Long Tail of Cancer Research

By MaverickNY on July 14, 2010

"What's really amazing about the Long Tail is the sheer size of it. Combine enough nonhits on the Long Tail and you've got a market bigger than the hits."

Source: Chris Anderson, Wired

The other other day, while barely lucid in the early hours of the morning, I was thinking about the herd instinct, the tendency to follow the masses and the counterpoint to that, i.e. the long tail.

If you're wondering what the long tail is, think of those statistical distribution plots where everything is bunched around the median, creating 50% on one side and 50% on the other. At either end the plots tail off into infinity. That's the long tail.

The long tail looks small at first, but creative marketers realise that added up (as Chris Anderson's quote above shows), you can in effect still have quite a large niche market while every one else focuses on minute shares in the middle.

I first realised the long tail effect as a sales rep in the tough anti-cholesterol market. You can spend fruitless hours chasing the majority of the primary care doctors who see reps but don't remember you when the relevant patient appears, or you can carefully invest time in the ones who don't see reps but are busy with appropriate patients and eventually crack if you try enough times. Once convinced, they often switch wholesale and your job is done with a smaller group of physicians who others can't see :-).

If we apply the principle of the long tail to cancer research, we can see things more clearly. In the old days, the majority of patients got treated pretty much the same with various chemo doublets, irrespective of whether they might work or not. In fact, in many cases, there wasn't even biomarkers such as ERCC1 to determine which patient should get platinum or not, but things are changing and now it's much easier to make these decisions and start segmenting patients according to their biochemical profile and make decisions based on the profile.

Today, we can take this niche idea to treatment a lot further.

In colon cancer, for example, we now know that patients with wild type KRAS are more likely to respond to an EGFR therapy than those with mutant KRAS. However, in lung cancer, the old adage was that erlotinib (Tarceva) was best suited for patients who were female, asian, non-smokers with adenocarcinoma is giving way to a more precise definition, i.e. do they have the EGFR mutation or not? If they do, they're more likely to respond, irrespective of smoking status. Offering these patients maintenance treatment may also be an effective treatment strategy that impacts outcomes.

We can see this effect in other cancer types too. Trastuzumab (Herceptin) is approved for women with Her-2 breast cancer, imatinib (Gleevec) and other TKIs such as dasatinib (Sprycel) and nilotinib (Tasigna) for Philadelphia-chromosome positive chromic myeloid leukemia (CML).

Histology is a very crude way to select patients, but looking at the aberrant mutations essentially creates niche long tail opportunities to treatment for pharma and biotech companies. Patients who are more likely to respond to a given therapeutic get appropriate treatment, without having to expose others who would not to unnecessary systemic effects. This is a win-win solution all around.

Why?

Well, it's good news for patients as you increase the chances of successful outcomes rather than relying on hope alone. It's also good news for manufacturers because smaller patient populations ultimately involve fewer patients in clinical trials, thereby making clinical development more cost effective and as cancer therapy moves from an acute to chronic disease, so longer term revenues are generated despite a small patient base.

As more oncology companies start looking at their pipelines, we can see many asking the critical questions – which patients are more likely to respond to a given treatment and why? As we learn more about the underlying biology of the disease, so companion diagnostics are also evolving in sophistication and sensitivity.

The other marketing advantage of developing niche targeted therapies and diagnostics is that often, you see less competition for smaller subsets of disease because it creates a high barrier to entry. Diagnostics also create barriers to entry because of the extra costs involved in their development. For smaller biotechs this can be prohibitive, and many are more actively seeking Pharma and Biotech partners to fund late stage research and clinical trials. Overall, the long tail opportunities offer big and small hurdles, depending on the circumstances.

Roche's VEGF monoclonal antibody bevacizumab (Avastin) has a very high barrier to entry in colon cancer, for example, as other VEGF inhibitors have fallen by the wayside, unable to beat the results already obtained by the first to market drug.

At the other end of the scale, the barrier to entry is much lower in renal cell cancer with numerous targeted therapies now approved for a relatively small niche indication, including sorafenib (Nexavar), sunitinib (Sutent), temsirolimus (Torisel), everolimus (Afinitor), pazopanib (Votrient) and bevacizumab (Avastin), probably reflecting the improvement over IL2, without completely reducing unwanted side effects or dramatically improving efficacy.

Some of the marketed therapies mentioned in this post are now billion dollar blockbusters despite cancer being a relatively niche market opportunity compared to the much bigger primary care markets such as metabolic or cardiovascular disease, proving that there are valuable nuggets to be found, even in the long tail.

The future in cancer research is not in broad acting systemic chemotherapies that target normal cells as well as cancer cells, but in the niche development of better and less toxic targeted therapies based on the underlying biological abnormalities with easy to use diagnostic technology based on fluid-based biomarkers. To achieve this though, will take a lot of bright smart people with expertise in oncology who dare to think differently and boldly, whether they be scientists, marketers or clinical research professionals.

Watch this space!

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Fluid-based early detection biomarkers in cancer

By MaverickNY on July 13, 2010

A really interesting idea that seems to be growing in popularity is the concept of fluid-based biomarkers from blood, urine, saliva etc, as opposed to invasive tumour biopsies. A recent paper in Cancer Research took a look at this novel and much needed concept (reference below).

One of the biggest challenges in oncology at the moment is finding easier and more convenient ways of identifying appropriate patients who might be best suited for a given therapy. In clinical trials, often tests are developed as useful biomarkers based on tumour biopsies. However, once a drug is approved, Community Oncologists often find their patients older, frailer and with a poorer performance status or more advanced disease and thus unresectable. Earlier detection of asymptomatic patients would also be useful, since in general, the earlier the patient is diagnosed, the better their long term chances are.

There is a lot of potential value, therefore, in developing fluid-based biomarkers and tests since the majority of cancer patients are treated in the Community, rather than Academic, setting.

In leukemias, FISH and QT-PCR testing have become standard, largely because it is easy to compare a blood sample with that of a bone marrow sample to validate test results. In solid tumours though, that has generally been less easy. Even the FISH test for HER-2 positive women with breast cancer has not been without it's controversies over the years.

At recent cancer meetings such as ASCO and AACR, I have noticed an increasing number of early surrogate markers being explored in solid tumours such as circulating tumour cells (CTCs) in prostate cancer as a more viable marker than PSA, as the authors also discussed:

"Fluid sampling has advantages over imaging as it is widely accepted, readily repeated, convenient, noninvasive, and low cost. Biomarkers in body fluids have the potential to detect a wide variety of primary tumors and metastases located throughout the body. Fluid biomarkers include a variety of components in blood, urine, or other fluids that reflect the presence of a tumor in the body. These include circulating tumor cells (CTC) and macromolecules such as lipids, proteins, RNA, microRNA, and DNA that originate from tumor cells."

Source: Martin et al.,

It was interesting to see the development of Pfizer's crizotinib in non-small cell lung cancer (NSCLC) with ALK mutations emerge recently. While Pfizer should be applauded for the speed with which they have developed the drug after the mutation was discovered, the development of the mutation test has clearly not been without its challenges.

A number of patient blogs complained about the time taken to produce the results from the tumour biopsies (several weeks to a month compared to say, 48 hrs for blood tests) and also in some cases, that their own physician ordered tests were not accepted, requiring another test validated by a central laboratory, sometimes with differing results. This does not augur well for an easy to use commercial diagnostic test for ALK if there are variations in the results.

Patients with advanced lung cancer often don't have a lot of time so this will be an issue to them and their physicians. Part of the reason for the delay is that tumour biopsy tests often require DNA sequencing to be performed, which inevitably takes time. A validated blood test would have a huge advantage in terms of time and convenience, but whether it is practically possible in an example like this, I don't know.

Whether a validated blood test is being developed in parallel isn't yet clear, but lung biopsies in the community setting are not routine in the way they are for breast cancer, for example. Finding suitable patients will therefore be akin to looking for needles in a haystack as the data so far suggests that the number of patients who were ALK positive in the NSCLC trials that looked for the mutation was around 5%. I'm not sure if this will extrapolate to the broader lung cancer universe though, as patients in a clinical trial are typically different from those in the general cancer population.

Meanwhile, another other interesting trend that is emerging is microRNA:

"In addition to proteins, mRNAs are promising biomarkers, and microarrays represent a powerful approach for their discovery in blood. A study using custom spotted arrays published in 2001 identified a signature of 12 genes whose mRNA expression was elevated in peripheral blood mononuclear cells (PBMC) of breast cancer patients."

Source: Martin et al.,

The number of articles, papers, abstracts and presentations on microRNA has increased at a tremendous rate over the last 2 years. At the AACR Molecular Targets meeting last November, it seemed as though 1 in 3 abstracts mentioned the subject in a variety of different ways from prognosis to early resistance. This is one area I'll be following to see what interesting new concepts emerge. I've had a few requests for more information on microRNA, so this will be the topic of a forthcoming blog post.

The ultimate question as always, though, is what does this all mean?

Clearly, earlier detection of disease is useful for prognosis, but predicting the impact of therapeutic intervention is also important. If we can develop biomarkers for determining which drug might work optimally for a given patient or subset, that would alleviate a lot of the pressure on healthcare systems and reducing patient exposure to drugs that would not work. At present, there are probably more tests developed than actually used in practice, but incorporating them into large scale clinical trials as part of a battery of tests may well provide more useful information in the near future across a variety of different cancer types.

Time will tell, but it makes a lot of sense to incorporate a vast battery of surrogate biomarker tests upfront and then track what happens over time, as the Medivation trial with MDV3100 has shown with PSA and CTC's in prostate cancer, to offer a practical example. You never know which of the biomarkers tested will emerge as useful in any given tumour type, so testing more rather than fewer may have a higher chance of hitting the bullseye.

Martin, K., Fournier, M., Reddy, G., & Pardee, A. (2010). A Need for Basic Research on Fluid-Based Early Detection Biomarkers Cancer Research, 70 (13), 5203-5206 DOI: 10.1158/0008-5472.CAN-10-0987

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Advancing the Use of Biomarkers in Cancer Drug Development

By MaverickNY on July 1, 2010

This was the title of a fascinating article I saw on Twitter a few minutes ago, courtesy of the American Association of Cancer Research (AACR). They are providing access to the paper free of charge to the public using this link. If you are on Twitter and interested in cancer related research, do follow them and keep track of the hot news items as they share quite a few important articles on translational research. Of all the medical associations I've come across in social media, they are also very helpful and responsive to enquiries.

So, what of the Consensus Report? Well, it's a collaborative effort from the AACR, FDA and NCI to create a position statement of the state of play so far:

"There is a growing imperative to modernize the drug development process by incorporating new techniques that can predict the safety and effectiveness of new drugs faster, with more certainty, and at lower cost."

As always, though, things are never as easy or simple as one might like.

Developing novel and useful biomarkers is an expensive and time consuming process driven largely by translational research and bioinformatics, often with a lot of diverse stakeholders involved in the process.

The Cancer Biomarkers Collaboration covered recommendations in eight key areas:

Biospecimens
Analytical performance
Standardisation and harmonisation
Bioinformatics
Collaboration and data sharing
Regulatory issues
Stakeholder education and communication
Science policy

Ultimately, the goal of the collaboration is to:

"The AACR-FDA-NCI Cancer Biomarkers Collaborative is a stakeholder-driven effort to inform and accelerate the FDA Critical Path Initiative and the work of the broader cancer
community."

The paper is well worth reading for those interested in the area, so check it out.

Meanwhile, on a practical note, a new potential biomarker has emerged in small cell lung cancer (SCLC) – see link to the Journal of Thoracic Oncology below (subscription required). The problem here is that while the majority of people with SCLC initially respond well to chemotherapy, resistance develops leading to relapse. The big question is why?

To answer this question, the researchers hypothesised that:

"… tumor microRNAs (miRNAs) could serve as predictive biomarkers for chemoresistance and prognostic biomarkers for survival of patients with SCLC treated with systemic chemotherapy."

The initial microRNA research on tumour samples (n=34) showed that:

"Higher tumor miR-92a-2* levels are associated with chemoresistance and with decreased survival in patients with SCLC.
Tumor miR-92a-2* may have application in screening patients with SCLC at risk for de novo chemoresistance in an effort to design more tailored clinical trials for this subpopulation."

In other words, microRNA (miR-92a-2*) could potentially be used as both a predictive and prognostic marker in SCLC. These results will need to be validated in larger scale trials, but they offer a promising glimpse of what might be possible for future therapeutic interventions.

Khleif, S., Doroshow, J., Hait, W., et al., (2010). AACR-FDA-NCI Cancer Biomarkers Collaborative Consensus Report: Advancing the Use of Biomarkers in Cancer Drug Development Clinical Cancer Research, 16 (13), 3299-3318 DOI: 10.1158/1078-0432.CCR-10-0880

Ranade, A., Cherba, D., Sridhar, S., Richardson, P., Webb, C., Paripati, A., Bowles, B., & Weiss, G. (2010). MicroRNA 92a-2* Journal of Thoracic Oncology DOI: 10.1097/JTO.0b013e3181dea6be

Celgene buy Abraxis Bioscience for $2.9B

By MaverickNY on June 30, 2010

I did a double take at my inbox alerts this morning as things have been rather quiet of late in the Pharma and Biotech world. You can read the financial aspects of the deal in Celgene's press release.

While the timing might be a little bit of a surprise, the strategic acquisition is not and makes a lot of commercial sense for Celgene. There are a number of reasons for my thinking here:

It continues to build out of hematology with the beginnings of a solid tumour franchise since Abraxane is approved for breast cancer and has trials ongoing in pancreatic, lung, melanoma and bladder cancers.
The patent life for Abraxane is something like 2023, much longer than lenalidomide (Revlimid) and with few near term opportunities in the oncology pipeline, this adds extra protection.
Abraxane, while more expensive than generic paclitaxel, has probably been underfunded in clinical development and marketing efforts to date, so Celgene's thorough and aggressive approach may well kick start things, especially as they have cash to do so.
Buying Abraxis gives them access to nanotechnology, which I think will become more important in the future as an improved drug delivery system.

Late last year, while at the AACR Molecular Targets meeting in Boston, I wrote about nanoparticle technology and how it appears to offer a chance of improved outcomes in pancreatic cancer using Abraxane. The concept described by the researchers at Mass General was solid and promising, as was the early phase I data. Sometimes, it's not just about drug A being better or more potent than drug B, but the science and thinking behind solving a problem is elegant and well thought out. This was one of those cases. A couple of Phase II trials have so far yielded early but promising results in a devastating disease. The latest results, reported by the Abraxis in May this year, look encouraging so far.

Of course, most oncology specialists will know that melanoma, pancreatic and lung cancers as probably three of the four toughest cancers to get positive results in from phase III trials (the fourth is glioblastoma), but if any of them actually pan out with a significant difference in overall survival and FDA approval, then Celgene will have another winner on it's hands. I say 'if' because the road to approval and cancer drug development is littered with promising phase II studies that flopped or were sadly cancelled for futility in phase III.

Time will tell if this was a good acquisition or not, but for now, it's early but promising. That's ultimately both the lure and the heartache that is oncology.

You have to make the big plays to win.

How cognitive surplus will change the world: Clay Shirky

By MaverickNY on June 29, 2010

Here's an interesting and informative TED video I just came across, where Clay Shirky talks about cognitive surplus and how it will change the world.

The idea behind the concept of "cognitive surplus" is that we use spare brain cycles while online to build a more cooperative world. In other words, new technologies enable loose collaborations to evolve.

I'm not sure I like the term 'cognitive surplus' but Shirky is an eloquent, thoughtful and engaging speaker who is well worth listening to:

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New imaging technique shows promise in detection of Alzheimer's Disease

By MaverickNY on June 25, 2010

"Dr. Skovronsky thought he had a way to make scans work. He and his team had developed a dye that could get into the brain and stick to plaque. They labeled the dye with a commonly used radioactive tracer and used a PET scanner to directly see plaque in a living person’s brain. But the technology and the dye itself were so new they had to be rigorously tested.

And that is what brought Dr. Skovronsky, a thin and eager-looking 37-year-old, to his e-mail that recent day.

Five years ago, Dr. Skovronsky, who named his company Avid in part because that is what he is, had taken a big personal and professional gamble. He left academia and formed Avid Radiopharmaceuticals, based in Philadelphia, to develop his radioactive dye and designed a study with hospice patients to prove it worked.

Hospice patients were going to die soon and so, he reasoned, why not ask them to have scans and then brain autopsies afterward to see if the scans showed just what a pathologist would see. Some patients would be demented, others not.

Some predicted his study would be impossible, if not unethical. But the F.D.A. said it wanted proof that the plaque on PET scans was the same as plaque in a brain autopsy."

Source: NY Times

If you haven't already read the article in the NY Times, click on the link above and check it out. It's well worth reading. How many of us have elderly parents who have Alzheimer's, who sadly died from the devastating condition or know friends going through the trials and tribulations as caregivers?

I love this story – a scientist gets germ of an idea, is convinced it will work, leaves his employment and sets up a company (Avid Radiopharmaceuticals) to research the possibilities. That's the very entrepreneurial spirit that made America great.

Basically, the concept is that using a special dye to highlight the plaques would show up on brain scans in Alzheimer's patients. At moment, the only known way of showing proof of the disease is when a pathologist looks for the black specks of plaques in the brain during a post mortem. Finding a way to be sure that the disease exists earlier has proven elusive so far. In the NY Times article, they showed what Dr Skovronsky has found so far. You can see the plaque buildup (red) in Alzheimers on the bottom compared to someone who did not have the disease:

Source: Dr Skovronsky in the NY Times

If the results prove conclusive and the dye gets FDA approval, researchers will have the first reliable method of detecting the disease early and also a potential marker of determining whether any future therapies are having an impact in reducing the plaques.

The data is being presented next month at the Alzheimer's Association so there is bound to be a lot of excitement and anticipation surrounding the data. This is the sort of thing we scientists get excited about, even if it's not in our field. My first thoughts on reading the NY Times were, "A dye? Wow, I wish I had thought of that!" I got goosebumps just reading it.

Of course there is a long way to go, but let's hope for the future of new drugs in the pipeline that the dye will turn out to be a great marker and the tide turns on future development of better and earlier pharmaceutical intervention for a devastating disease.

Should use of CT scans be reduced?

By MaverickNY on June 24, 2010

Last night I was reading about the latest Iressa (gefinitib) data in lung cancer published in the NEJM, but unfortunately the DOI code isn't yet available for easy tagging and linking of the article in Research Blogging, so it will have to wait until it's out.

There was, however, a pair of interesting articles on computerised tomography (CT) scans (see references and links below). While the use of such scans has clearly improved diagnosis, it has come at a cost – both in terms of expenditure and also with respect to increased risk of radiation exposure:

"We found that the risk of cancer from a single CT scan could be as high as 1 in 80 — unacceptably high, given the capacity to reduce these doses."

Source: Smith-Bindham, NEJM

"Changing the culture of medical practice to encourage more thoughtful use of imaging today will help to ensure that future patients will benefit from continued imaging innovation."

Source: Hillman and Goldsmith, NEJM

Good points both, but little is likely to change unless the payers and insurers force them economically. Physicians are typically cautious and conservative by nature and would rather check to see if any cancer might be present than risk missing it or be hit with a law suit for negligence. Given that radiation has not been shown conclusively to be cancer-causing, most would probably rather be safe than sorry.

Smith-Bindman, R. (2010). Is Computed Tomography Safe? New England Journal of Medicine DOI: 10.1056/NEJMp1002530

Hillman, B., & Goldsmith, J. (2010). The Uncritical Use of High-Tech Medical Imaging New England Journal of Medicine DOI: 10.1056/NEJMp1003173

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Pharma Strategy Blog

Commentary on Pharma & Biotech Oncology / Hematology New Product Development

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New imaging technique shows promise in detection of Alzheimer's Disease

Should use of CT scans be reduced?