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Posts from the ‘Technology’ category

Transformative antibody technology in cancer research

By on July 30, 2013

Recently, I came across an exciting new development in a Nature publication and couldn’t resist teasing my Twitter followers with this terse statement:

Naturally, this mischievous tweet set off a lot of folks frantically trying to guess what I was referring to and the @replies came in thick and fast.

The National Science Foundation defines transformative as:

“Transformative research involves ideas, discoveries, or tools that radically change our understanding of an important existing scientific or engineering concept or educational practice or leads to the creation of a new paradigm or field of science, engineering, or education.  Such research challenges current understanding or provides pathways to new frontiers.”

Many suggestions came hurtling in, most related to a drug or company, but actually what I was referring to was a transformative technology – the biggest clue was in the question 🙂

Bispecific antibodies, to be more precise.

I was completely inspired by an article by a group of scientists in Nature Biotechnology by Speiss et al., (2013) – the link is included in the references below and is well with reading. It’s one of those things you read and think, “Wow, wish I had thought of that!”

Genentech kindly gave me access to one of their scientists involved, Dr Justin Scheer (gRED), who explained the rationale behind their approach and what they hope to do with this technology.  More on that in a moment, but first it’s a good idea to understand where I’m coming from.

Let’s take a look at both the potential and limitations of the various types being developed as cancer therapeutics, and the basics underpinning monoclonal and bispecific antibodies in more detail.

What are monoclonal antibodies?

Essentially, a monoclonal antibody is a manufactured molecule that’s engineered to attach to specific defects in cancer cells. They mimic antibodies the body naturally produces as part of the immune system’s response to invaders.

The immune system is trained to attack foreign invaders in the body, but it doesn’t always recognize cancer cells as enemies because they are formed from massive proliferation of the body’s own cells i.e. not foreign, unlike bacteria and viruses.

Monoclonal antibodies are usually directed to attach to certain parts of a cancer cell. An easy way to think of it is that the antibody ‘marks’ the cancer cell and makes it easier for the immune system to find and destroy.

How do monoclonal antibodies work?

The majority of currently available monoclonal antibodies are monospecific, i.e. having a single specific target e.g. CD20 or CD19, for example. The classic example in oncology is rituximab. Rituximab attaches to the CD20 protein found on B cells, which is associated with some types of lymphomas. When rituximab attaches to CD20, it makes the lymphoma cells more visible to the immune system, enabling them to be attacked and destroyed.

Treatment with rituximab lowers the number of B cells, including healthy B cells. The body will produce new healthy B cells to replace them and ensures that the cancerous B cells are less likely to recur.

While results with this approach have been impressive in some cases, there are limitations because cancer is highly complex and more than one target may be need to be addressed. This means that drug combinations are needed, increasing the complexity of clinical trial design especially in dose finding and MTD studies, risk of added or overlapping toxicities, increased costs etc.

Monoclonal antibodies such as rituximab have some other limiting factors though, as Speiss et al., (2013) observed:

“They lack natural Fc regions, they cannot bind to the neonatal FcRn receptor; binding to FcRn delays antibody clearance and improves pharmacokinetic (PK) properties.”

The lack of an Fc region also means that monoclonal antibodies typically cannot activate T-lymphocytes – because this type of cell does not possess Fc receptors – so the Fc region cannot bind to them.

A new potential solution exists

Antibodies that target two antigens are known as bispecific antibodies. Only one is currently available commercially (catumaxomab, Removab) and binds to CD3 and EpCam, although there are several in late stage development, including blinatumomab (Amgen) in ALL. The latter is interesting because it is part of the new generation of antibodies known as bi-specific T-cell engagers (BiTEs).

A bispecific monoclonal antibody (BsAb) is a manufactured protein that is composed of fragments of two different monoclonal antibodies and consequently binds to two different types of antigen.

Manufacturing a monoclonal antibody, while more complex than an oral tyrosine kinase inhibitor (TKI), is easier than a bispecific antibody. Much of the limitations seen so far with bispecific antibodies have been technological rather than clinical. What the Genentech scientists set out to do is succinctly described by Dr Scheer in the short Soundcloud below:

What are the advantages of bispecific antibodies?

The main advantage of bispecific antibodies is the ability to combine a cytotoxic cell (e.g. CD3) or ADC with a tumour specific protein target (e.g. CD19 or CD20) although a number of different combinations could be considered. In other words, you would get the ability to home in on the specific tumour target together with enhanced cell killing.

This could be a potent combination, except that technology-wise, they are difficult to engineer as Speiss and colleagues noted:

“… bispecific-antibody design and production remain challenging, owing to the need to incorporate two distinct heavy and light chain pairs while maintaining natural nonimmunogenic antibody architecture.”

There are some technological difficulties in engineering bispecific antibodies, though.  Blinatumomab was mentioned as one example by Speiss et al., (2013) because:

“… some bispecific antibody fragments (e.g., the anti-CD19-CD3 single-chain fragment blinatumomab) are expressed as a single polypeptide chain they include potentially immunogenic linkers.”

What was fascinating about the Nature Biotech paper was that they reported on a new process they had developed to manufacture bispecific antibodies:

“We present a bispecific-antibody production strategy that relies on co-culture of two bacterial strains, each expressing a half-antibody.  Using this approach, we produce 28 unique bispecific antibodies.”

One thing I thought was particularly cool about this novel approach is that bacteria are easier to manipulate and having a foreign component in the antibody will potentially mean that the human body’s immune system will hopefully pick it up more easily. Essentially, these new chemical structures could act as a powerful cancer homing device against specifically chosen targets.

The example used in the paper was a new bispecific antibody they engineered from co-cultures of EGFR and MET. Remember that Genentech/Roche already has a TKI against EGFR (erlotinib) on the market and a MET antibody (onartuzumab) in development. Neither of these drugs hit both targets and yet as Speiss and colleagues noted:

“MET and EGFR drive the growth of a marked proportion of non-small cell lung cancer tumors. MET and EGFR are often co-expressed and co-activated, and MET signaling can compensate for loss of EGFR signaling and vice versa.”

Image Courtesy of Roche's gRED unit: Bispecific antibody with two distinct binding arms that inhibits both MET (orange) and EGFR (green). The bispecific antibody, shown here in red and blue, has a natural antibody architecture

Image Courtesy of Roche’s gRED unit: Bispecific antibody with two distinct binding arms that inhibits both MET (orange) and EGFR (green). The bispecific antibody, shown here in red and blue, has a natural antibody architecture

As Dr Scheer observed, we don’t know yet is where the company will go with this exciting technology, but if the approach shows promising efficacy in future clinical trials, then it’s easy to see how multiple new bispecific antibodies could be easily developed for different tumour types, with far more potency and utility than single targeted therapies alone.

Stop and think about that possibility for a moment.

Transformative science isn’t always about finding a new target, sometimes the breakthrough is in removing the technological limitations to create a much more robust platform with enormous therapeutic potential.  At that point, the biology, targets and imagination become the limitations, not the technology itself.

I have a feeling that this platform is a much more exciting breakthrough than many realise – it’s the sort of approach where you can see, to paraphrase a famous watch company’s ad – some day all antibodies will be made this way.

References:

ResearchBlogging.orgSpiess C, Merchant M, Huang A, Zheng Z, Yang NY, Peng J, Ellerman D, Shatz W, Reilly D, Yansura DG, & Scheer JM (2013). Bispecific antibodies with natural architecture produced by co-culture of bacteria expressing two distinct half-antibodies. Nature biotechnology PMID: 23831709

Tumor Lysis Syndrome – what is it and why is it important in cancer research?

By on February 18, 2013

After the hullabaloo on Friday regarding AbbVie’s suspension of the ABT-199 trials following not one, but two, unexpected deaths from tumor lysis syndrome (TLS), a few people asked what is this condition and what causes it?

In simple terms, lysis is a medical word used to describe the break up or breakdown of cells – whether through decomposition, destruction, or dissolving. Thus, we have hemolysis, which is the destruction of red blood cells with the release of hemoglobin.

Tumor lysis, however, is a medical emergency whereby the sudden production of massive amounts of potassium, phosphate, and nucleic acids into the systemic circulation overwhelms the body’s garbage disposal units, the liver and kidneys. Urgent hospital treatment is usually required, often diuretics can be helpful to flush out and dilute the excess potassium (too much can slow or stop the heart beating), but sometimes kidney dialysis is also needed to speedily remove the excess production of the potassium. Death can unfortunately (but not always) result.

TLS is most common in aggressive, fast growing (high grade) lymphomas and acute leukemias (e.g. ALL), but is less common in indolent disease such as chronic lymphocytic leukemia (CLL).

Given that AbbVie were testing their Bcl2 inhibitor in CLL, where TLS is rarer, some might think two deaths from TLS a surprise, especially given the positive results reported at the recent American Society of Hematology (ASH) meeting in December (more about the ABT-199 data).

This is not the first time TLS has been reported in leukemias though. Carl June (U Penn) presented the data on their chimeric antigen receptor therapy (CART), a collaboration with Novartis, in CLL and also childhood acute lymphoblastic leukemia (ALL) at ASH. Their lead therapy, CTL019 (formerly CART19), also leads to TLS in both ALL, where it is more common, and CLL patients, although he did state in the Ernest Beutler lecture that the patients received urgent renal dialysis and recovered.

Interestingly, Dr June described the TLS as occurring not immediately, but delayed until 20-50 days post infusion. Given what we know about autologous cellular immunotherapy, a delayed response is not a surprise, but in line with our scientific knowledge to date, since it takes a while post apheresis to activate the T-cells.

You can see from Dr June’s slide that the serum levels of creatinine and uric acid spiked around day 20, but the patient was hospitalized for TLS a few days later:

Tumor Lysis Syndrome in CLL CTL019

It is possible that the TLS occurs in CLL as a result of rapid efficacy and on target effects – in other words, the treatment is doing it’s job of killing the cancer cells, perhaps a little too well.

Final thoughts…

We will have to wait and see what happens with the larger randomized phase 3 trials for both ABT-199 and CTL019:

  • We don’t yet know whether the effect in ABT-199 is a dose-schedule issue or a compound structure issue (especially given the reformulation from the original navitoclax molecule).
  • If TLS is a persistent toxicity issue and efficacy is durable, then it may well limit both potential treatments to Academic centers with experience and resources to quickly monitor and treat such sudden events in future.
  • These are exciting molecules but care is clearly needed in managing the toxicities.

Contrast these approaches with ibrutinib, a tyrosine kinase inhibitor that targets Bruton Kinase, where the effects appear to be slow but steady inhibition of a key target driving CLL proliferation. TKI therapies are very Community oncology friendly in comparison, particularly for indolent diseases. Although the Bcl2 and CART therapies look very promising, they may need a more careful and judicious approach to reduce the risk of sudden deaths from TLS.

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Highlights of AACR 2012 – Part 2

By on April 18, 2012

Yesterday, I mentioned that some of the best bits of this year’s American Association for Cancer Research (AACR) meeting were the numerous gems in the poster sessions.

Reuben Sierra, Ming Tsao's Lab (with permission)

One of the coolest such posters I came across was from Ming Tsao’s group.

Specifically, Rafael Sierra (see photo right) was hosting an excellent piece of research entitled: “Overcoming resistance to EGFR-tyrosine kinase inhibitor therapy in non-small cell lung cancer.”

This is an area of much needed research and breakthroughs.

Why?

Well, at the ECCO meeting in Stockholm last September, Tom Lynch was discussing the role of one such EGFR therapy, cetuximab (Erbitux), in lung cancer and wearily declared prior to presenting a negative study,

“If ever there was a drug desperately needing a biomarker, it’s cetuximab”

because while some of the patients responded beautifully to the drug, many others didn’t and at that time, there was no way to determine upfront who might respond before treating.

This is clearly a waste of valuable resources and time because catch-all studies mean that the number of negative responses can balance out the positive responses in too heterogeneous a population.  That said, if you know what the potential target(s) or biomarker of response are, then you can select patients more precisely for a study and improve the subsequent overall response rates and OS advantage dramatically.

As Sierra et al., pointed out in their poster at AACR, we do know that:

“Patients that present amplification or activating mutations (L878R or exon 19 deletions) of EGFR, have higher response rates. Selection improved response rates from less than 10% to over 60–80%.”

This is very good progress, but how did their research take this concept further?

In this study, the group reported the preliminary findings from a complex study of genome-wide screenings on EGFR resistant cells to try and identify new genes that might mediate resistance and, importantly, be potentially druggable, unlike say, MYC. This would then offer new logical targets for combination therapies to be tested in the clinic in patients to determine if outcomes could be improved.

At the time of the poster presentation, the group had indeed identified a short list of potential candidates (not named as this would be available in a later publication). Conceptually though, this was an elegant study and I really liked the concept.

This morning, I was delighted to see a news snippet from the 3rd European Lung Cancer Conference in Geneva, Switzerland where the ESMO press release noted that Dr Tsao’s group performed:

“An exploratory analysis on the TORCH patient tumor samples that were available for analysis, looking for molecular biomarkers known to be potential predictors of benefit from EGFR inhibitors.”

Despite the biomarker analysis being pre-planned, however, only a third (36%) of samples were available for analysis. It is always harder to do retrospective mutation analysis on small sample sizes unless rigorously collected as per the BATTLE trials.

I’m looking forward to hearing what targets were identified in Drs Sierra and Ming’s research once published or presented in more detail at a future conference, as this may help us move the field forward in terms of rational combinations to either overcome resistance to EGFR therapy (other than the well known T790M mutation) or prevent resistance from developing early.

Now, that would be very cool and I do hope they alert us to the publication in due course – watch this space!

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On adaptive mechanisms of crizotinib resistance in ALK-positive lung cancer

By on March 23, 2012

One of the biggest challenges facing cancer research was aptly summarised by Levi Garraway and Pasi Jänne in this month’s Cancer Discovery journal:

“All successful cancer therapies are limited by the development of drug resistance. The increase in the understanding of the molecular and biochemical bases of drug efficacy has also facilitated studies elucidating the mechanism(s) of drug resistance.”

It will therefore come as no surprise to PSB readers that resistance occurs with two drugs approved by the FDA only last year; vemurafenib (BRAFV600E melanoma) and crizotinib (ALK+ lung cancer). We’ve discussed the development of resistance in melanoma here via several potential mechanisms in the past and potential strategies for overcoming them (eg MEK inhibitors), but what about lung cancer?

Two recently published papers have shed some new light on this topic. Doebele et al., (2012) and Katayama et al., (2012) both looked at mechanisms of resistance associated with ALK-rearranged lung cancers.

What did the research show?

Both of these papers were published in March, but in separate journals.

Doebele et al., (2012) examined mechanisms of ALK resistance in EML4-ALK–positive non-small cell lung cancer (NSCLC) patients who had progressed while on crizotinib patients (n=11). The essence of their findings were as follows:

  • Four patients (36%) developed secondary mutations in the tyrosine kinase domain of ALK. Two of the patients exhibited a novel mutation in the ALK domain, encoding a G1269A amino acid substitution that confers resistance to crizotinib in vitro.
  • Two patients, including one with a resistance mutation, exhibited new onset ALK copy number gain (CNG).
  • One patient showed epidermal growth factor receptor (EGFR) mutant activity, without evidence of a persistent ALK gene rearrangement.
  • Two patients had a KRAS mutation, one of which occurred without evidence of persisting ALK gene rearrangement.
  • One patient showed the emergence of an ALK gene fusion–negative tumour with no identifiable alternate driver.
  • Two patients retained ALK positivity, with no identifiable resistance mechanism.

Meanwhile, Katayama et al., (2012) attempted to characterise acquired resistance, i.e. the adaptive resistance that occurs in response to treatment with a TKI. They also took biopsies from patients (n=18) with EML4-ALK–positive (NSCLC) patients who had progressed while on crizotinib. They found that in approximately a a quarter to a third of patients (22% to 36%) multiple mutations were found after sequencing of the ALK kinase domain exons. This resulted in amino-acid substitutions or insertions that are predicted to impair crizotinib binding. When this happens, the drug stops working and patients will relapse on therapy.

More specifically, there were:

  • Five patients (28%) had tumours with alterations in the ALK gene that were the underlying cause of the resistance.
  • There were four different somatic mutations within the ALK gene.
  • One case where the ALK gene was amplified.
  • One ALK mutation was highly resistant to all of the inhibitors examined.

In addition, they observed evidence of alternative mechanisms of resistance evolving, including activation of EGFR and KIT.

What do these results mean?

Firstly, it is striking that there are so many potential escape routes and mechanisms of adaptive resistance to crizotinib therapy.

Secondly, as Garraway and Jänne noted:

“Increased knowledge of drug resistance mechanisms will aid in the development of effective therapies for patients with cancer.”

However, while this is a true and accurate statement, I am left wondering how this might play out in clinical practice? By that, I mean how does a community medical oncologist, who sees the bulk of NSCLC patients go about incorporating this information? For now they can’t, as we are awaiting the results of numerous clinical trial readouts – hopefully there will be some at the annual ASCO meeting in June.

The sheer breadth of the heterogeneity also raises the issue of how will community doctors be able to process all this complex information and select patients for appropriate combination therapies based on numerous potential mechanisms of resistance. Biopsies aren’t always practical in these situations, but perhaps we may see the development of alternative methods of detection evolve in the future.

References:

ResearchBlogging.orgGarraway, L., & Janne, P. (2012). Circumventing Cancer Drug Resistance in the Era of Personalized Medicine Cancer Discovery, 2 (3), 214–226 DOI: 10.1158/2159–8290.CD–12–0012

Doebele, R., Pilling, A., Aisner, D., Kutateladze, T., Le, A., Weickhardt, A., Kondo, K., Linderman, D., Heasley, L., Franklin, W., Varella-Garcia, M., & Camidge, D. (2012). Mechanisms of Resistance to Crizotinib in Patients with ALK Gene Rearranged Non-Small Cell Lung Cancer Clinical Cancer Research, 18 (5), 1472–1482 DOI: 10.1158/1078–0432.CCR–11–2906

Katayama, R., Shaw, A., Khan, T., Mino-Kenudson, M., Solomon, B., Halmos, B., Jessop, N., Wain, J., Yeo, A., Benes, C., Drew, L., Saeh, J., Crosby, K., Sequist, L., Iafrate, A., & Engelman, J. (2012). Mechanisms of Acquired Crizotinib Resistance in ALK-Rearranged Lung Cancers Science Translational Medicine, 4 (120), 120–120 DOI: 10.1126/scitranslmed.3003316

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Cancer Clinical Trials: Companion Diagnostics or Gene Sequencing?

Last year saw some interesting developments from MD Anderson Cancer Center in early phase clinical trials that may have a far-reaching impact on the future of cancer research as we know it:

  1. At ASCO in June, Dr Tsimberidou presented the initial results from a phase I study run by the MD Anderson Department of Investigational Cancer Therapeutics group. Instead of testing patients with a given cancer (eg lung) for individual mutations eg ALK or EGFR and then offering patients a targted drug as we normally do, they ran a broad diagnostic panel across a multitude of patients with different cancers to determine what the tumour was telling them about the aberrations and selected appropriate targeted therapies. While the study was small in size, the results were better than random selection.
  2. In September at the ECCO meeting in Stockholm, Dr Gordon Mills (Head of Systems Biology) stated in his keynote presentation that 30,000 cancer patients at MD Anderson would be screened and tested for aberrations using gene sequencing. This has huge implications for clinical trial efficiency, since they will effectively generate a powerful database that will enable them to match patients to studies based on the precise selection criteria, rather than looking at a protocol and testing new patients that subsequently come in the door for each target individually.

The other thing that many readers have asked about is companion diagnostics and whether they are the future following the recent approvals of crizotinib (Xalkori) and vemurafenib (Zelboraf) in ALK+ lung cancer and BRAFV600E melanoma respectively?

More recently, we have seen numerous papers discussing the findings from massive parallel sequencing studies (more on that tomorrow) and developments in gene sequencing, including a dramatic announcement from Oxford Nanopore on Friday regarding its novel third generation sequencing progress.

I decided to discuss these issues with Dr Razelle Kurzrock, who heads up the Department of Investigational Cancer Therapeutics group at MD Anderson.  Here’s the transcript of the interview.  Please do check out the brief audio clip too, as this highlights a very important trend for the future with gene sequencing costs/time coming down.

PSB: Could you tell us a bit more about your phase I group and what you are doing with regards to matching therapies to targets?

Dr Kurzrock: Essentially we do phase 1 studies, which can be anything from new first in human drugs that are just going from animals to patients, or really any other phase 1. It might be in experimental drugs, or new combinations of two experimental drugs, combinations of an experimental and an FDA approved drug or combinations of FDA approved drugs. It is any new study that is just a new way of looking drugs is considered phase 1. That is really what we are doing. It is sort of a large scale, we have about 128 studies and we put over 1100 patients on study last year.

But I don’t think that has really gotten people interested or that we really are at the point that we are most excited about. The idea is to do molecular profiling on patients as they come in the door, then to try to match them with the appropriate targeted drugs. Of course people have done this for individual studies, like the ALK inhibitor crizotinib, the investigators and the company looked for ALK rearranged lung cancer patients.

The thing that we are doing differently is that we are not looking for one abnormality to match with one drug. We are looking at a panel of abnormalities as patients come in the door and then decide which drug to match them to. So it is a more generalized type of way of doing things and I am sure it is the way things will be done in the community in the future. It is a really simple concept, but nobody has done it like this before.

PSB: If you have more than one abnormality will you consider combination therapy or just target the main mutation first?

Dr Kurzrock: Well, I think it is either one. If you have more than one abnormality you can consider combinations or you can try and figure out what the main one is. The concept of looking for multiple abnormalities at once is really a diagnostic concept.

As an example if you had lung cancer, we know that there is ALK rearrangement in 4% of patients, then there might be an EGFR mutation in 5% of patients and probably when we look at al lung cancer there might be 20 different mutations, subsets of patients. There may be 50, we don’t know all of them yet.

This inevitably has implications of how we test and screen patients for clinical trials, as Dr Kurzrock astutely observed in the sound bite below:

PSB: I like the idea of doing the panel, and with over 100 studies, it must make it more efficient to assign patients to the appropriate clinical trials?

Dr Kurzrock: I think it is a lot more efficient. With the caveat that this was not a randomized study, what we saw in our pilot study was that we were getting response rates that were considerably higher than what we would expect in phase 1.

Our background response rates are about 5% of our patients will get a complete or partial remission if we just do things the old way, remembering that phase 1 patients are patients that have by definition failed all therapy. They are often in good shape, but have a highly resistant and lethal tumor.

But the response rates when we did the matching was 27%. Again, this isn’t a non-randomized trial so there are biases, but it could be actually biases that might lower the response rate or biases that might raise the response rates. But the bottom line is that it was much higher than what we would have anticipated. This of course needs to undergo more rigorous testing, but we were impressed that doing this was better for our patients and actually better for drug development.

PSB: So are you using next generation sequencing to drive your diagnostic panel?

Dr Kurzrock: That’s a good question. This is an area in very rapid flux. When we presented our data at ASCO 2011, we presented first generation data where we were just doing a very small panel of mutational analysis. Essentially we presented in mid 2011, data from 2010 mainly and the field has moved so quickly. The data was especially impressive because we used this primitive, first generation way of doing things. We are now expanding to using a Sequenom panel which looks at multiple different mutations, and I think the next generation panel is going to be the one that comes on line pretty soon. All exomic sequencing, while it can be done, the bioinformatics is still complicated and that is probably not quite ready yet. I think it will be ready maybe in a year or two years, but I think that is not quite ready to be used on large volumes of patients. But, Next Gen Sequencing, although you use the methodology, you only pick a set number of genes say 300, that is probably useable at this point.

PSB: I remember talking to Gordon Mills at ECCO and he said as the cost of sequencing costs come down, the analytical costs are going to go through the roof because it gets more and more complicated.

Dr Kurzrock: The analytical costs are now the problem. But, where I disagree is having seen how rapidly this field moves, what we need now is a jump in analytical capability. So if we assume there is not going to be a jump in knowledge, it is going to go through the roof.

I have a different assumption, I think there will be a leap. People are working on this. There is going to be a leap in the way we do things. We are going to be able to do the bioinformatics very quickly and the costs will come down just like the costs of sequencing.

In the early 1990s, I remember when everybody who knew anything said we would never sequence the human genome because it was too complicated. Then by the late 1990s we had sequenced the human genome, but it cost $3Billion dollars to sequence a patient. Now it costs $5000 and one company has said they will do it for $1000. This took leaps in technology that have occurred extraordinarily rapidly in 10 or 12 years. I absolutely think those leaps will occur in bioinformatics now, which is the sticking point.

PSB: Many oncology pharma companies seen to be going down the route of developing a companion diagnostic test with a targeted therapy e.g. crizotinib and vemurafenib, but I’m wondering is that really the way of the future?

Dr Kurzrock: I think that is not the way of the future, for the reason that I said. It is an interesting thing, the diagnostic panel is a great idea, but technology is moving so fast now that the diagnostic test is going to be outmoded, if it is not already outmoded.

And it is for the reason that I mentioned. A patient walks in the door, you can not see if that patient has whatever type of cancer whether it be breast cancer or lung cancer or whatever, you can not tell by look looking at that patient which diagnostic panel to do. You just can’t know. In essence you can choose to do one diagnostic test but that will probably be 4% of patients with that disease. So what you are going to have to do is multiple diagnostic tests to cover all the realms of possibility. If you license diagnostic tests one at a time and I have to do 20 or 50 or whatever tests, it is going to be hugely expensive, plus probably you will run out of tissue and you will have to rebiopsy the patient.

To me the way of the future will be a multi-assay panel whether it is Sequenom or next gen sequencing, probably it will be next gen sequencing or something like that, that will look at all the possible aberrations, rather than looking at them one at a time. Ultimately it is going to run up the cost if we do it that way [with individual diagnostic tests].

PSB: If we want to help more patients then we have to figure out what the aberrations are?

Dr Kurzrock: I think in the most simple sense, this is simply diagnosis. The reason we diagnose patients and we try to figure out whether you have breast cancer, you have lung cancer or colon cancer or some other cancer, is in order to give you the best treatment. That is the reason we give you a diagnosis, also to tell you the prognosis, but we want to tell you your best treatment.

Up till now, we the way we have diagnosed patients is with a light microscope that was invented back in 1590. In the simplest sense this is just a more sophisticated way of diagnosing patients, and it as at the molecular level. It is like using a molecular microscope except the molecular microscope is Next Gen Sequencing. So we really want to know when a patient walks in the door, what do you have, what is your disease at a molecular level? You can’t do that by using one probe at time, you have to look at all the relevant gene abnormalities and then figure out which one is abnormal.

In summary…

There is no doubt in my mind that broad molecular gene profiling (or massively parallel sequencing as it is often called in research) to find aberrations in the tumours of cancer patients will be:

  1. Faster
  2. More effective

for patient clinical trial selection than the current approach of biopsies for individual targets based on a single diagnostic test.  If we want to speed up clinical trials a broader screening approach will no doubt be a better starting point than searching for small needles in a haystack.

That said, the challenges going forward are still many.  These include greater analytical and bioinformatic costs, as well as figuring out which aberrations really matter.  After all, some will be drivers, but many will be passengers that merely add noise to the signal, so targeting every aberration that appears in a panel may not actually have any effect clinically and may even induce unwanted systemic side effects.

Until we determine which aberrations are the critical targets in each tumour type or subtype, as well as identify those that develop in response to therapy (adaptive resistance), then we still have a long way to go in terms of improving our understanding of the biology underlying the many diseases that make up ‘cancer’ and improving patient outcomes with therapeutic interventions.

 

 

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miRNA as a potential biomarker for early breast cancer

By on January 16, 2012

One way to potentially improve long term cancer statistics is earlier detection, and in high risk patients, appropriate initiation of earlier treatment, since it is well known that the survival in stage II or III breast cancer is noticeably better than that for stage IV metastatic disease.

A critical question then, is how do we improve earlier detection?

There are a number of ways to achieve this:

  1. Imaging techniques
  2. Prognostication
  3. Diagnostics
  4. Biomarkers

Historically, breast cancer has often been picked up using classic, but rather crude, imaging techniques such as mammography and ultrasound, although both have their limitations and challenges. Biopsies are also challenging and invasive, especially in early stage disease when the tumour(s) may be very small. I’m particularly interested in biomarkers because it offers a lot of untapped near-term promise. We know that as tumours begin to develop, they leave tell tall signs and signatures – how can we develop ways to detect these earlier and with greater accuracy than at present?

Source: wikipedia

I was fascinated to read a paper in PLoSONE (open access, see references below) this morning looking at circulating microRNAs (miRNA) as a potential blood based marker for early stage breast cancer detection.

miRNA were defined by Schrauder et al., (2012) as:

“MicroRNAs (miRNAs, miRs) are a class of small, non-coding RNA molecules with relevance as regulators of gene expression thereby affecting crucial processes in cancer development.”

They were first described by Lee et al., (1993) in C. elegans (open access, see references below) and have since been found to be stable in blood, making them ideal biomarker material.

In the current research, the authors set out to determine whether miRNA could discriminate early stage breast cancer (n=48) from healthy controls (n=57) using microarray analysis.

What did the research show?

The initial results appear promising:

“We found that 59 miRNAs were differentially expressed in whole blood of early stage breast cancer patients compared to healthy controls. 13 significantly up-regulated miRNAs and 46 significantly down-regulated miRNAs in our microarray panel of 1100 miRNAs.”

Two of the miRNAs (miR-202, miR-718) were subsequently validated by RT-qPCR in an independent cohort.

What do these results mean?

I thought these results were encouraging, although it should be noted that there is no doubt that blood-based miRNA-profiling is behind the improvements seen in tissue-based miRNA-profiling. The advantage though, of blood-based profiling, is that it clearly offers:

“The potential for early, non-invasive, sensitive and specific BC detection and screening.”

Of course, there is a long way to go yet, although similar early studies have been performed in other tumour types such as lung cancer (Foss et al., 2011; Boeri et al., 2011), ovarian cancer (Häuser et al., 2010) and others.

Using miRNA as a potential biomarker for early detection is not without its challenges, though. Shrauder et al., noted that Chen et al., (2008) observed that:

“Comparing serum and blood cells from the same healthy individual an almost identical miRNA profile can be found, but in cancer patients the profiles differ.”

Other studies have not shown complete congruence in the results or findings, so it may well be a while before some clarity emerges with miRNA as a potential diagnostic, most likely with improved standardisation of sample handling, protocols, detection methods and patients (stage of disease, etc).

That said, miRNA looks to be a promising but fledgling area for biomarker research in the early detection of cancer. No doubt this field will evolve further with new and more sensitive techniques.

References:

ResearchBlogging.orgSchrauder, M., Strick, R., Schulz-Wendtland, R., Strissel, P., Kahmann, L., Loehberg, C., Lux, M., Jud, S., Hartmann, A., Hein, A., Bayer, C., Bani, M., Richter, S., Adamietz, B., Wenkel, E., Rauh, C., Beckmann, M., & Fasching, P. (2012). Circulating Micro-RNAs as Potential Blood-Based Markers for Early Stage Breast Cancer Detection PLoS ONE, 7 (1) DOI: 10.1371/journal.pone.0029770

Lee, R., Feinbaum, R., & Ambros, V. (1993). The C. elegans heterochronic gene lin-4 encodes small RNAs with antisense complementarity to lin-14 Cell, 75 (5), 843-854 DOI: 10.1016/0092-8674(93)90529-Y

Foss KM, Sima C, Ugolini D, Neri M, Allen KE, & Weiss GJ (2011). miR-1254 and miR-574-5p: serum-based microRNA biomarkers for early-stage non-small cell lung cancer. Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer, 6 (3), 482-8 PMID: 21258252

Boeri M, Verri C, Conte D, Roz L, Modena P, Facchinetti F, Calabrò E, Croce CM, Pastorino U, & Sozzi G (2011). MicroRNA signatures in tissues and plasma predict development and prognosis of computed tomography detected lung cancer. Proceedings of the National Academy of Sciences of the United States of America, 108 (9), 3713-8 PMID: 21300873

Häusler, S., Keller, A., Chandran, P., Ziegler, K., Zipp, K., Heuer, S., Krockenberger, M., Engel, J., Hönig, A., Scheffler, M., Dietl, J., & Wischhusen, J. (2010). Whole blood-derived miRNA profiles as potential new tools for ovarian cancer screening British Journal of Cancer, 103 (5), 693-700 DOI: 10.1038/sj.bjc.6605833

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EGFR activates mTORC2 in glioblastoma – a potential role for new therapies

By on December 1, 2011

One of the great things about following the American Association for Cancer Research (AACR) on Twitter, is that they regularly share technical open access articles from their journals for scientists to read.  Of course, many will have access through their institution subscription, but there are also probably quite a few interested community oncologists and scientists like me that don’t. The idea of sharing some of their really important scientific research with the broader public is a great one – a little bit of goodwill goes a long way and furthers their cause too.

Yesterday, AACR kindly tweeted and shared a fascinating paper (see references below for open access to all the articles) on how EGFR signaling in glioblastoma (an aggressive form of brain cancer) activates the mTOR pathway, specifically mTORC2, and is partially suppressed by PTEN:

EGFRmTOR
Source: Tanaka et al., (2011)

We know that mTOR and it’s upstream relative, PI3K, are frequently dysregulated in cancer and may also lead to resistance to treatment with some therapies, such as aromatase inhibitors in breast and other cancers. This is also true in glioblastoma, where chemotherapies such as temozolamide are often used, as the authors noted:

“mTORC2 signaling promotes GBM growth and survival and activates NF-κB. Importantly, this mTORC2–NF-κB pathway renders GBM cells and tumors resistant to chemotherapy in a manner independent of Akt.”

One of the challenges though, is elucidating the mechanism behind mTOR activation:

“The mechanisms of mTORC2 activation are not well understood. Growth factor signaling through PI3K, potentially through enhanced association with ribosomes, and up-regulation of mTORC2 regulatory subunits have been proposed as mechanisms of mTORC2 activation.”

Recently, Clohessy et al., (2008) observed that mTORC1 inhibition was not sufficient to block GBM growth, so this new research took a different approach and focused on asking the question of whether oncogenic EGFR affects mTORC2. To test this hypothesis, they used GBM derived cell lines that represent the most common genetic events driving GBM i.e. PTEN loss with EGFR overexpression or activating mutation (EGFRvIII) present or absent. It should be noted that a good marker of mTORC2 activity is the phosphorylation of AKT S473, although SGK1 is also turning out to be a good biomarker of response.

What did they find?

The paper (open access) is well worth reading, but to summarise, here are some of the key findings from this well thought out research:

  • mTORC2 signaling promotes GBM growth and survival
  • EGFRvIII activates NF-kB through mTORC2
  • mTORC1 inhibition alone could not suppress NF-κB activation in GBM cells
  • mTORC2 mediates EGFRviii-dependent cisplatin resistance through NF-kB, independently of Akt
  • mTORC2 inhibition reverses cisplatin resistance in xenograft tumours
  • mTORC2 signaling is hyperactivated and associated with NF-kB and phospho-EGFR in the majority of clinical GBM samples

What stood out for me in their series of experiments and comprehensive analysis was that:

“Elevated phosphorylation of EGFR (Y1068) and Akt (S473) was detected in 44% and 77% of GBMs, respectively. These numbers are consistent with the independent findings of EGFR mutation and/or amplification in 45% and PI3K pathway–activating mutations in 87% of GBMs, reported in the Cancer Genome Atlas studies.”

What do these results all mean?

Looking at question regarding the mechanism underlying mTORC2 activation and its relationship with EGFR was poorly understood, this paper clearly showed that mTORC2 activation is a common event in GBM, including tumors harbouring EGFR-activating lesions. But what was particularly interesting was the finding that EGFRvIII was significantly more potent than wild-type EGFR in promoting mTORC2 activity. This is consistent with previous work from Huang et al., (2007), who found that:

“EGFRvIII preferentially activates PI3K signaling despite lower levels of receptor phosphorylation, leading to differential activation of downstream effectors.”

One outstanding question that has puzzled many researchers is what is the mechanism of rapamycin (mTOR) resistance? There are some clues in this research:

“Here we demonstrated that rapamycin (or genetic mTORC1 inhibition by raptor knockdown) promoted Akt S473 and NDRG1 T346 phosphorylation; this feedback activation could be suppressed by mTORC2 inhibition.”

They also looked at a patient sample to determine if there were any hints for further translational research:

“In a clinical sample from a GBM patient analyzed before and 10 days after treatment with rapamycin, mTORC2 signaling was elevated concomitant with significant mTORC1 inhibition, as measured by decreased S6 phosphorylation.”

This is important because to date, based on much of the data that has emerged from mTOR and PI3K inhibitors we have seen that single agent therapy often leads to either stable disease or low response rates, so the question is how can we improve this by understanding the mechanisms of resistance better in order to direct future combination approaches (as opposed to single agent studies) logically:

“These data suggest the possibility that failure to suppress mTORC2 signaling, including NF-κB signaling, may underlie resistance to rapamycin and the poor clinical outcome associated with it in some patients with GBM.”

This is a crucial finding because some early mTOR inhibitors such as rapamycin target mTORC1 effectively, but are weak inhibitors of mTORC2. The new generation of inhibitors may address this issue better and shut down the mTOR pathway more effectively, although that may not be enough on it own.

Clearly, future research studies will be needed to better understand the potential role of mTORC2/NF-κB signaling in mediating resistance to treatment in GBM:

“The results reported here provide a potential mechanism for mutant EGFR-mediated NF-kB activation in GBM and other types of cancer. The results also suggest that EGFR tyrosine kinase inhibitor resistance could also potentially be abrogated by targeting mTORC2-mediated NF-kB activation.”

So far this is a good start, but we still have a long way to go. There are a number of mTOR and PI3K inhibitors in development for the treatment of GBM – I’m looking forward to seeing the results of those trials and learning which combinations and lines of therapy might see the best results with mTOR inhibitors. Hopefully, there might be some early readouts at ASCO next June.

References:

ResearchBlogging.orgTanaka, K., Babic, I., Nathanson, D., Akhavan, D., Guo, D., Gini, B., Dang, J., Zhu, S., Yang, H., De Jesus, J., Amzajerdi, A., Zhang, Y., Dibble, C., Dan, H., Rinkenbaugh, A., Yong, W., Vinters, H., Gera, J., Cavenee, W., Cloughesy, T., Manning, B., Baldwin, A., & Mischel, P. (2011). Oncogenic EGFR Signaling Activates an mTORC2-NF- B Pathway That Promotes Chemotherapy Resistance Cancer Discovery, 1 (6), 524-538 DOI: 10.1158/2159-8290.CD-11-0124

Cloughesy TF, Yoshimoto K, Nghiemphu P, Brown K, Dang J, Zhu S, Hsueh T, Chen Y, Wang W, Youngkin D, Liau L, Martin N, Becker D, Bergsneider M, Lai A, Green R, Oglesby T, Koleto M, Trent J, Horvath S, Mischel PS, Mellinghoff IK, & Sawyers CL (2008). Antitumor activity of rapamycin in a Phase I trial for patients with recurrent PTEN-deficient glioblastoma. PLoS medicine, 5 (1) PMID: 18215105

Huang, P., Mukasa, A., Bonavia, R., Flynn, R., Brewer, Z., Cavenee, W., Furnari, F., & White, F. (2007). Quantitative analysis of EGFRvIII cellular signaling networks reveals a combinatorial therapeutic strategy for glioblastoma Proceedings of the National Academy of Sciences, 104 (31), 12867-12872 DOI: 10.1073/pnas.0705158104

Epigenetics – an emerging new potential treatment for lung cancer?

By on November 11, 2011

A couple of articles in the latest Cancer Discovery looked at some rather promising, and perhaps a little unexpected, findings pertaining to epigenetic therapy.

What are epigenetics?

If you read up on epigenetics in the medical journals, you will come across some of the most dense and complex articles I’ve ever come across in cancer biology. That said, there are a few readable examples around such as Bird’s (2007) short insight piece in Nature.

Personally, I tend to think of epigenetics – in very simple terms – as changes in gene function that can occur without a change in the sequence of the DNA. This means that we see things such as DNA methylation (where something new is added) and gene silencing (where something important is somehow switched off or lost). A classic change in cancer that often appears in many tumour types is PTEN loss, for example.

As Rodriquez-Paredes and Esteller (2011) noted in their editorial,

“No one doubts that tumorigenesis is a consequence of not only genetic but also epigenetic alterations…

Cancer epigenomes are characterized by global changes in DNA methylation and covalent histone modification patterns.”

 

What types of epigenetic therapy are there?

While some readers might be vaguely familiar with DNA methylating agents and histone deacetylase inhibitors (HDAC), there are quite a few other types in preclinical development including:

  • histone methyltransferase inhibitors
  • histone kinase inhibitors
  • sirtuin inhibitors
  • microRNA-related compounds

and others, to name a few.

Currently, however, there are a couple of epigenetic therapies that have been approved (eg SAHA or vorinostat), which belongs to the histone deactelyase class of inhibitors (HDAC) indicated for CTCL, while another is the DNA methyltransferase inhibitors (eg azacitadine/Vidaza and decitabine/Dacogen), which are approved for the treatment of MDS and AML, respectively. There are also several other HDACi in development, including entinostat (Syndax), which has shown activity in breast and lung cancers (see Huang et al., 2009 as an example) and panobinostat (Novartis), which is being evaluated in both hematologic malignancies and solid tumours (prostate and melanoma).

Yet what really caught my attention in the paper by Jeurgens et al., (2011) and the accompanying editorial (see references below) was that these two therapy classes are being evaluated in combination for… lung cancer. You likely won’t find HDACs or DNA methyltransferase inhbitors in the top 30 of therapies used for lung cancer at present, but that may change sooner than you think.

Background to epigenetics in lung cancer

To put this story in context, the authors (see Brock et al., 2008) previously identified a potential gene signature for recurrence associated with stage I lung cancer after surgical resection:

“Analysis of DNA methylation in tumors and mediastinal lymph nodes from a series of patients with surgically resected stage I NSCLC defined several prognostic markers associated with rapid tumor recurrence.

Four gene targets of tumor-specific epigenetic silencing, CDKN2a, CDH13, APC, and RASSF1a, were identified as strongly associated with disease recurrence and death, both singly and in combination.

Methylation of any 2 of these 4 target genes in tumor and mediastinal lymph nodes conferred a markedly worse prognosis in patients with stage I lung cancer (P < 0.001), similar to patients with stage III disease.”

As far as I’m aware, to date the clinical data with epigenetic therapies has been reported in hematologic malignancies such as leukemia, lymphoma and MDS. This is the first time we’ve seen some meaningful data in solid tumours.

What about the latest clinical trial in lung cancer?

Jeurgens and colleagues at Johns Hopkins conducted:

“A phase I/II trial of combined epigenetic therapy with azacitidine and entinostat, inhibitors of DNA methylation and histone deacetylation, respectively, in extensively pretreated patients with recurrent metastatic non–small cell lung cancer.
This therapy is well tolerated, and objective responses were observed, including a complete response and a partial response in a patient who remains alive and without disease progression approximately 2 years after completing protocol therapy.”

The NSCLC patients (n=45) were mainly smokers or former smokers (n=40) with primarily adenocarcinoma (n=34) who had been heavily pre-treated (median of 3 prior therapies).

Median overall survival in the entire group was 6.4 months, which compared favourably with the expected 4.0 months in historical controls.

“Four of 19 patients had major objective responses to subsequent anticancer therapies given immediately after epigenetic therapy.”

These responses in a small subset of patients were fascinating – the most dramatic response was seen in one patient who experienced a complete response (CR) that lasted for 14 months. A further 10 people had stabilisation that lasted at least 12 weeks (1 for 14 months and another for 18 months).

Moreover, the four gene signature referred to earlier turned out to be potentially useful as both a prognostic and predictive biomarker:

“Demethylation of a set of 4 epigenetically silenced genes known to be associated with lung cancer was detectable in serial blood samples in these patients and was associated with improved progression-free (P = 0.034) and overall survival (P = 0.035).”

One patient who did particularly well on the combination therapy was subsequently re-challenged with chemotherapy and had such a good response that the nodules in his lungs reduced significantly.  After being diagnosed in December 2006 with stage IV NSCLC, he was still alive and well to tell his astonishing and heartwarming story on the press conference five years later.

Overall, the authors rightly concluded that:

“This study demonstrates that combined epigenetic therapy with low-dose azacitidine and entinostat results in objective, durable responses in patients with solid tumors and defines a blood-based biomarker that correlates with clinical benefit.”

Emphasis mine.

While these results are very exciting, they are also preliminary and will need to be validated in larger scale clinical trials along with the blood biomarkers for clinical response. They do offer a very strong proof of concept for the combination of epigenetic therapy with a DNA methyltransferase inhibitor and an HDAC inhibitor with clear activity in a subset of patients.

What do these results mean in practice?

Personally, I thought these results were absolutely fascinating and offer us a glimpse into the future where we can utilise epigenetic therapies to:

  1. Effectively repair damaged DNA in tumours
  2. Offer low dose therapies with fewer side effects that give a respite from chemotherapy, while doing more good than harm
  3. Enable sensitization of subsequent therapies to improve outcomes
  4. Predict which patients are most likely to respond to epigenetic therapies, while sparing those unlikely to from any systemic side effects

To get a good clinical perspective of what these results mean, I spoke with Dr Jeff Engelman, Director, Center for Thoracic Cancers at Mass General in Boston. He described the data as ‘impressive’:

“I don’t think this is going to impact the practicing oncologist today, but from a scientific stand point, from an oncology development stand point, from a future stand point, it is I think impressive to many of us, to me.

Seeing that epigenetics could have a dramatic effect even on a subset of lung cancers, we’ve never seen epigenetic modulators have such an effect on solid tumors, so it really opens the door that this may be another type of therapy that we will be able to employ for the right patients.  A totally different type of approach.”

He also went on to put the story in a broader context, which I thought was very helpful:

“It is somewhat analogous to the first trials with EGFR inhibitors where had we treated 40 patients with those we would have seen a few great responses.”

“With EGFR, it was given to tons of patients, and there was a subset that responded, and it took a couple of years to find out why. Then all of sudden, boom everything makes sense and we go forward. This feels more like that, we have seen some great responses and now need to figure out why.”

Clearly, the gene signature identified by Brock et al., (2008) in stage I patients needs to be validated in a broader population of patients in clinical trials, but at least it offers a starting point to try and determine which patients with lung cancer might respond to epigenetic therapy. I think Engelman is correct here; once we determine the right biomarkers of response and how often they occur, then patients with lung cancer can be screened and appropriate therapy offered, whether that be EGFR therapy, ALK therapy, or something completely different such as treatment with epigenetic drugs.

The amazing thing is how much progress is being made of late in lung cancer and that’s very good news indeed. I look forward to hearing more about this story and also the other slices or targets as they are identified and the story evolves further.

References:

ResearchBlogging.orgBird, A. (2007). Perceptions of epigenetics Nature, 447 (7143), 396-398 DOI: 10.1038/nature05913

Brock, M., Hooker, C., Ota-Machida, E., Han, Y., Guo, M., Ames, S., Glöckner, S., Piantadosi, S., Gabrielson, E., Pridham, G., Pelosky, K., Belinsky, S., Yang, S., Baylin, S., & Herman, J. (2008). DNA Methylation Markers and Early Recurrence in Stage I Lung Cancer New England Journal of Medicine, 358 (11), 1118-1128 DOI: 10.1056/NEJMoa0706550

Huang, X., Gao, L., Wang, S., Lee, C., Ordentlich, P., & Liu, B. (2009). HDAC Inhibitor SNDX-275 Induces Apoptosis in erbB2-Overexpressing Breast Cancer Cells via Down-regulation of erbB3 Expression Cancer Research, 69 (21), 8403-8411 DOI: 10.1158/0008-5472.CAN-09-2146

Juergens, R., Wrangle, J., Vendetti, F., Murphy, S., Zhao, M., Coleman, B., Sebree, R., Rodgers, K., Hooker, C., Franco, N., Lee, B., Tsai, S., Delgado, I., Rudek, M., Belinsky, S., Herman, J., Baylin, S., Brock, M., & Rudin, C. (2011). Combination Epigenetic Therapy Has Efficacy in Patients with Refractory Advanced Non-Small Cell Lung Cancer Cancer Discovery DOI: 10.1158/2159-8290.CD-11-0214

Rodriguez-Paredes, M., & Esteller, M. (2011). A Combined Epigenetic Therapy Equals the Efficacy of Conventional Chemotherapy in Refractory Advanced Non-Small Cell Lung Cancer Cancer Discovery DOI: 10.1158/2159-8290.CD-11-0271

5 Comments

Redefining subsets of triple negative breast cancer

By on November 9, 2011

Heterogeneity remains one of the biggest barriers to progress in clinical research. Triple negative breast cancer is an excellent example of this conundrum as I’ve said many times here on this blog – it’s defined not what it is but what it’s not.  By that, I mean it’s a broad catch-all for all those women with breast cancer who are essentially ER/PR- HER2- but beyond that are likely other subsets yet to be identified or characterised.

That said, once we have a better sense of what those smaller groups are (from basic and translational research) then progress with targeted therapeutics is much more likely. Why? Because by reducing the inherent variability we increase the chances of success with a given target. If you don’t have a valid and well defined target to aim at then the risks of a negative result in large scale clinical trials are much much higher.

We may also see a new subgroup breast cancers emerge defined solely by their ER/PR- status irrespective of the HER gene.  This in itself would be an interesting idea as it lends itself well to the current grouping of patients.

Nature Genetics

This morning’s coffee browsing in Nature Genetics brought up something that piqued my interest greatly – Haiman and colleagues sent in a Letter reporting on a common risk variant for ER- breast cancer associated with chromosome 5P5, i.e. the TERT-CLPTM1L locus.

The essence of their research was given ER- breast cancer tends to be higher in women of African than European ancestry and confers a poorer prognosis, what common risk alleles could be identified? They collated information from genome-wide association study (GWAS) data in women of African (n=1,004 ER-, n=2,745 controls) and European (n=1,718 ER-, n=3,670 controls) ancestry. Here’s what they found:

“The (5P5) variant was also significantly associated with triple-negative (ER-negative, progesterone receptor (PR)-negative and human epidermal growth factor-2 (HER2)-negative) breast cancer, particularly in younger women (defined as less than 50 years of age).”

In addition, they also observed that:

“In combining the results across all studies (6,009 ER-negative cases and 20,708 controls with genotype data), rs10069690 was significantly associated with an increased risk of ER-negative breast cancer.”

What particularly struck me, however, was a little nugget buried deep in the discussion:

“We found no significant association with rs1006960 among ER- and PR-positive cases when stratified by HER2 status.”

In other words, it is the estrogen receptor status that is the defining characteristic. This suggests that not all triple negative women will behave in the same way, so identifying the factors that are important may change our thinking in how to approach patients in the future.

What do these findings mean?

This study is important because it identifies, for the first time, an aberration ie a common variant at the TERT-CLPTM1L locus that is associated with ER- breast cancer that also tended to occur in younger women. As we begin to dig deeper into the molecular biology of ‘triple negative breast cancer’, I use parentheses loosely here as that definition may one day change with more research, we are likely to:

  • Define new subsets of patients who may respond differently
  • Identify possible new targets for clinical trials of rationally targeted agents
  • Smaller trials will be needed for well-defined subsets that have a greater chance of a good response, this in turn makes an accelerated development potentially possible as we saw recently with crizotinib for ALK-positive lung cancer.

I look forward to following the burgeoning research in this area and suspect that we will see many more groups begin to isolate and identify important aberrations that drive the disease and offer new targets for therapeutic intervention.

References:

ResearchBlogging.orgHaiman, C., Chen, G., Vachon, C., Canzian, F., Dunning, A., Millikan, R., Wang, X., Ademuyiwa, F., Ahmed, S., Ambrosone, C., Baglietto, L., Balleine, R., Bandera, E., Beckmann, M., Berg, C., Bernstein, L., Blomqvist, C., Blot, W., Brauch, H., Buring, J., Carey, L., Carpenter, J., Chang-Claude, J., Chanock, S., Chasman, D., Clarke, C., Cox, A., Cross, S., Deming, S., Diasio, R., Dimopoulos, A., Driver, W., Dünnebier, T., Durcan, L., Eccles, D., Edlund, C., Ekici, A., Fasching, P., Feigelson, H., Flesch-Janys, D., Fostira, F., Försti, A., Fountzilas, G., Gerty, S., Giles, G., Godwin, A., Goodfellow, P., Graham, N., Greco, D., Hamann, U., Hankinson, S., Hartmann, A., Hein, R., Heinz, J., Holbrook, A., Hoover, R., Hu, J., Hunter, D., Ingles, S., Irwanto, A., Ivanovich, J., John, E., Johnson, N., Jukkola-Vuorinen, A., Kaaks, R., Ko, Y., Kolonel, L., Konstantopoulou, I., Kosma, V., Kulkarni, S., Lambrechts, D., Lee, A., Marchand, L., Lesnick, T., Liu, J., Lindstrom, S., Mannermaa, A., Margolin, S., Martin, N., Miron, P., Montgomery, G., Nevanlinna, H., Nickels, S., Nyante, S., Olswold, C., Palmer, J., Pathak, H., Pectasides, D., Perou, C., Peto, J., Pharoah, P., Pooler, L., Press, M., Pylkäs, K., Rebbeck, T., Rodriguez-Gil, J., Rosenberg, L., Ross, E., Rüdiger, T., Silva, I., Sawyer, E., Schmidt, M., Schulz-Wendtland, R., Schumacher, F., Severi, G., Sheng, X., Signorello, L., Sinn, H., Stevens, K., Southey, M., Tapper, W., Tomlinson, I., Hogervorst, F., Wauters, E., Weaver, J., Wildiers, H., Winqvist, R., Berg, D., Wan, P., Xia, L., Yannoukakos, D., Zheng, W., Ziegler, R., Siddiq, A., Slager, S., Stram, D., Easton, D., Kraft, P., Henderson, B., & Couch, F. (2011). A common variant at the TERT-CLPTM1L locus is associated with estrogen receptor–negative breast cancer Nature Genetics DOI: 10.1038/ng.985

Understanding cancer metastasis – possible new therapeutic targets

By on November 1, 2011

.

“Scientists at Dalhousie University in Nova Scotia have identified a key mechanism of metastasis that could lead to blocking tumor growth if their findings are confirmed.”

AACR press release

Loved this opening to an AACR press release about a key paper (freely available for anyone to download – see the reference session below) that was just published in Cancer Research by David Waisman’s group.

Now, before getting into the technical details, I was reflecting recently on both my recent awesome trip to the MD Anderson basic research campus at Smithville, Austin where a lot of research into tumorigenesis is conducted and pointed questions from patients about why their hasn’t been enough progress in treating and curing metastatic breast cancer.

There are several obvious reasons for this:

  1. We need to understand more about the basic mechanisms underpining function, never mind work out what role various proteins have and how they interact in health and disease before we can even think about clinical progress.
  2. As we learn more about the basic process of tumorigenesis, so we can start to apply those findings to clinical research and translational medicine in developing better predictive biomarkers that are clinically meaningful.
  3. If we have excellent biomarkers, an understanding of the processes and the targets involved, thus we should have clearer targets that suggest more logical combinations to treat disease and essentially slow or even undo the process of metastasis.

Quite frankly, based on the little we really know about the underlying biology of advanced disease, I’m sometimes surprised the results are as good as they are. That’s not to say we’re doing great, becasue clearly there is a lot of improvement that can be made, but sometimes we should stop and look at how far we’ve come and ask serious questions about what we really need to know now that can help progress things?

With all that context in mind, the current published research from Phipps et al., (2011) is worth looking at because it advances our thinking a little more. In the past, people have focused on cancer cells, thinking they were the main thing that mattered. What’s interesting about this research is that it shows how important other cells, such as macrophages, are in the tumorigenesis process:

“There is an increasingly large body of evidence correlating tumor-associated macrophage (TAM) density with poor prognosis in a varied number of solid tumors.”

 

Source: wikipedia

We also know from basic research that macrophages are critical in driving tumour growth, invasion, and metastasis.  Macrophages are like the Pacmen of cells – think of them moving around the blood stream chomping things in their wake.  The thing is, there are always macrophages in tumours – so how do they get from the bloodstream to the tumour?

The current paper details the key role that the macrophage cell surface protein, S100A10, plays in mediating macrophages, thereby allowing them to move to the site of tumour growth. This process is obviously essential to tumour development and angiogenesis.

What also struck me though, was the research also detailed what happened in animals without the S100A10 protein:

“Growth of murine Lewis lung carcinomas or T241 fibrosarcomas was dramatically reduced in S100A10- deficient mice compared with wild-type mice.

Emphasis mine.

What does all this data mean?

In order to either slow or stop metastasis in its tracks, we need to understand the whole process better, thereby finding the weaknesses and chinks in the tumour.

These results clearly show the important role that S100A10 has in facilitating macrophage activity.

Now, S100A10 is a protein and proteins often (but not always, since some of them are currently thought to be undruggable) make very good targets for therapeutic intervention.

Of course, these results clearly need to be reproduced and confirmed by other groups, but if confirmed, they potentially give us some targets to aim at. For example, we could either look at blocking the macrophages in some clever way or target the S100A10 protein directly with a rationally designed targeted therapy. These apparoaches might potentially slow, or even stop, tumour growth.

What if we found some strategies that were effective?  Maybe we could take the approach further and actually use it as a prevention strategy in high risk patients to actually prevent the development of metastasis occurring?

Time will tell, but personally, I was rather heartened by the this wonderful piece of research this morning.

References:

ResearchBlogging.orgPhipps, K., Surette, A., O’Connell, P., & Waisman, D. (2011). Plasminogen Receptor S100A10 Is Essential for the Migration of Tumor-Promoting Macrophages into Tumor Sites Cancer Research, 71 (21), 6676-6683 DOI: 10.1158/0008-5472.CAN-11-1748

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