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Posts from the ‘Science’ category

Video preview of San Antonio Breast Cancer Symposium 2011

By on December 7, 2011

What’s hot at the 2011 San Antonio Breast Cancer Symposium?

There is a lot of exciting data coming out at SABCS 2011 over the next three days, including the BOLERO2, CLEOPATRA and NEOSPHERE clinical trial data.

I previously wrote about the exciting BOLERO2 results that were presented at the European Multidisciplinary Cancer Conference (ECCO/ESMO 2011) in Stockholm in September. More data is expected at SABCS to coincide with a publication in the New England Journal of Medicine (NEJM).

The following video outlines some of the data that I think is hot at SABCS and why it’s worth watching out for. I will be writing more about it as it’s presented.

http://www.youtube.com/watch?v=t7bnqslE6mc

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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

Gone to dog drug heaven…

By on November 29, 2011

That was the quaint phrase used by one of the presenters at the recent AACR-EORTC-NCI Molecular Targets meeting in San Francisco.

Apparently, some drug or two was considered, too toxic (fair enough) or lacking in efficacy, hence the requisite binning of a multi-million dollar program to the scrapheap.

Yesterday’s post, however, reminded me that maybe sometimes, it’s not that the efficacy was lacking but the clinical trial design or tumor type or even line of therapy was the best one.  Let’s consider a couple of recent ideas here:

  1. The aurora kinase inhibitor PHA-739358 didn’t show any efficacy in adenoncarcinoma of the prostate, but the target, aurora kinase A may be a key one in some neuroendocrine tumours of the prostate.  These are very different subsets requiring a different approach to patient selection criteria and screening, which might potentially lead to a higher response rate in a small subset.
  2. At the above AACR meeting, I was discussing mTOR inhibitors in breast cancer with a few people.  Everyone noted how interesting it was that Wyeth’s temsirolimus failed to show any efficacy in a large phase III trial in women with ER/PR+ newly diagnosed breast cancer when given an aromatase inhibitor and the mTOR.  In contrast, Novartis took a different approach and used the AI and mTOR combination in second line therapy using everolimus and exemestane and saw dramatic responses. Why the difference?  Well, mTOR is known to cause resistance to AI over time, so it would make more sense to add it in later, rather than upfront.

There are many many other examples like this.  Sometimes, the key is in better understanding of the underlying processes from basic research.

For me then, dog drug heaven might not always be due to a poor molecule, but a failure to figure out where and how the drug might have worked effectively.  Dr Len Saltz (MSKCC) summed this up nicely at the NY Chemotherapy Symposium earlier this month:

Now, while Dr Saltz was specifically discussing the potential role (or lack of) for PI3K inhibitors in colorectal cancer, I do think his maxims hold very true for any targeted agent being evaluated in the clinic and something that cannot be emphasized enough.

The first point is obvious, but many sadly seem to miss it!  More preclinical and translational research is key to determining what the targets are and which ones matter in which tumor types.  Without that rational approach, you might as well throw mud at a wall and see what happens.  The second point speaks to the therapeutic index of the drug and whether we are shutting down the pathway enough to stop aberrant activity.  The final point is absolutely crucial – is the target a driver or a passenger?  If it’s the latter, the first two will not matter a jot no matter what we throw at it, in fact all that happens there is more toxicities are introduced and that’s not a good thing for the patient on the receiving end.

These issues become even more pertinent when we consider how regimens and increasingly, clinical trials, are moving more towards double and perhaps even triple combination therapies in an effort to shut down a pathway more completely.

In the meantime, the dog drug heaven days will likely continue.

 

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Exciting new approach to targeted therapy in prostate cancer

By on November 28, 2011

Last week a very interesting article appeared in Cancer Discovery that reported a new target in neuroendocrine tumours (NET) of the prostate, a particularly aggressive subtype. Now, these tumours are “rare” and “uncommon” based on a spot check with a couple of oncology specialists I asked this morning.  In fact, according to this latest research, fewer than 2% of men with prostate cancer actually present with neuroendocrine disease and adenocarcinoma of prostate can also (rarely) evolve into neuroendocrine disease, but overall, the prognosis for NET of the prostate is generally poor.

What did they find?

Rubin and et al., (2011) used next-generation RNA sequencing to profile samples of neuroendocrine prostate cancers or NEPC (n=7), prostate adenocarcinomas or PCA (n=30) and benign (BEN) samples of prostate tissue (n=5) to try and characterise the molecular imprint. Previously, it has been shown by Tomlins et al., (2005) that TMPRSS2-ERG occurs in 50% of prostate NET, which is approximately the same rate as adenocarcinoma of the prostate. The big question is whether other molecular subtypes can be identified?

In this research, it was discovered that the genes AURKA and MYCN were overexpressed and amplified in neuroendocrine prostate cancers (40%) and in prostate adenocarcinomas (5%). The findings were then validated in tumours from a larger cohort of patients (n=37 with NEPC, n=169 with PCA, and n=22 with BEN) using immunohistochemistry and FISH:

“We discovered significant overexpression and gene amplification of AURKA and MYCN in 40% of NEPC and 5% of PCA tumors, respectively, and evidence that they cooperate to induce a neuroendocrine phenotype in prostate cells.”

For those of you interested in the Aurora kinase, here’s what AurA looks like from a broad perspective as part of the cell cycle pathway:

Source: Cell Signal

In order to determine if AURKA was a valid (driver rather than passenger) target, treatment with an aurora kinase (AURKA) inhibitor (PHA-739358, Nerviano Medical Sciences) was evaluated in cell lines and xenografts to determine if the agent inhibited the growth of the neuroendocrine tumours:

“There was dramatic and enhanced sensitivity of NEPC (and MYCN overexpressing PCA) to Aurora kinase inhibitor therapy both in vitro and in vivo, with complete suppression of neuroendocrine marker expression following treatment.”

What do these results mean?

This study has identified new potential targets in neuroendocrine tumours of the prostate in AURKA and N-myc that are well worth evaluating in clinical trials with patients who have this condition:

“We propose that alterations in Aurora kinase A and N-myc are involved in the development of NEPC and that future clinical trials will help determine the efficacy of Aurora kinase inhibitor therapy.”

Interestingly, PHA-739358 (danusertib) has been studied in prostate cancer before without success, but this may be due to the fact that the trial was in patients with adenocarcinomas and not neuroendocrine tumours.

What we learn from this is that the oft heralded argument about targeted therapy – ie first find a valid driver target still holds true – some subsets may respond to therapy while others will not, so identifying the right subset for therapeutic intervention is critical if we wish to increase the chances of success in clinical testing.  While a number of aurora kinase inhibitors have gone by the wayside due to lack of efficacy or excessive toxicities, the good news is that there are still several other aurora kinase A inhibitors in active R&D in addition to PHA-739358, including:

  • MLN8237 (Millennium)
  • AT9283 (Astex)
  • AZD1152 (AstraZeneca)
  • AMG 900, a pan aurora kinase inhibitor (Amgen)

There are probably a few others, but these are the ones I can remember off the top of my head.

Overall, I think these results are very promising indeed, albeit for a small subset of patients with prostate cancer.  That said, it does suggest that another ‘slice of the pie’ has potentially been identified and I look forward to seeing a more precise and well defined clinical trial emerge in the near future in NET prostate cancer to validate the new research findings.

References:

ResearchBlogging.orgBeltran, H., Rickman, D., Park, K., Chae, S., Sboner, A., MacDonald, T., Wang, Y., Sheikh, K., Terry, S., Tagawa, S., Dhir, R., Nelson, J., de la Taille, A., Allory, Y., Gerstein, M., Perner, S., Pienta, K., Chinnaiyan, A., Wang, Y., Collins, C., Gleave, M., Demichelis, F., Nanus, D., & Rubin, M. (2011). Molecular Characterization of Neuroendocrine Prostate Cancer and Identification of New Drug Targets Cancer Discovery, 1 (6), 487-495 DOI: 10.1158/2159-8290.CD-11-0130

Tomlins, S. (2005). Recurrent Fusion of TMPRSS2 and ETS Transcription Factor Genes in Prostate Cancer Science, 310 (5748), 644-648 DOI: 10.1126/science.1117679

Update from AACR Molecular Targets 2011 #2 – Angiogenesis

By on November 22, 2011

Angiogenesis inhibitors have seen a long and rather chequered history since Judah Folkman first propounded the concept that tumours grow by adding new blood vessels. Many of these inhibitors have ended up in the dog heaven scrap heap, so to speak, while others (some monoclonals, some small molecule inhibitors) have made it to market in some indications, but failed miserably in others.  All in all, it’s been a bit of a crapshoot at best for manufacturers trying to crack this particularly difficult nut.

Perhaps the most famous (some would say infamous) drug is bevacizumab (Avastin), a monoclonal antibody to VEGF-A, which has been approved for colon, lung, glioblastoma, renal cancers but just had its approval revoked in advanced breast cancer by the FDA due to a poor risk-benefit and efficacy profile.

Although Vascular Endothelial Growth Factor (VEGF) has been the target most associated with angiogenesis, there are quite a few other pathways involved in the process, including Platelet Derived Growth Factor (PDGF), Placental Growth Factor (PIGF), Fibroblast Growth Factor, Notch, angiopoeitins (eg Ang1-3 and Tie2) and many others.

Recently, at the European Multidisciplinary Cancer Conference (formerly ECCO and ESMO) in September, new data emerged on two new angiogenesis compounds in colorectal cancer, namely aflibercept (VEGF-Trap) from Regeneron and BIBF1120 (Vargatef) from Boehringer. Both drugs showed promising efficacy and tolerability data in a phase III (VELOUR) and a phase II trial, respectively.

I’m not going to go into details of those trials here, but to expand on the idea of angiogenesis further, because it makes logical scientific sense to target several aspects of the process to see if improved outcomes result. Closely related to this is lymphangiogenesis, which is the formation of new lymphatic vessels from pre-existing lymphatic vessels, in a similar way to blood vessel development or angiogenesis.

According to Tobler and Detmar (2006), a simplified angiogenic and lymphangiogenic mechanism is thought to look something like this:

angiogenesis

It was therefore with great interest that I came across Regeneron’s latest poster at the AACR-EORTC-NCI Molecular Targets meeting last week. They looked at the idea of combining aflibercept (VEGF) and (Ang2) to determine whether there was a synergistic effect. The angiogenesis process is described below (courtesy of Regeneron):

VEGFAng2

The answer, in short, was yes.

They found that combined blockade of both VEGF (aflibercept) and Ang2 (REGN910) promoted noticeable tumour necrosis and growth inhibition in colorectal cancer xenografts over either agent alone.

Of course, we don’t know which biomarkers will be useful predictors of response, but that’s a discussion in itself for another post.

Now, while these results are encouraging, it does not mean they will automatically translate to patients in the clinic, but I do think it looks like a promising dual targeting approach that is well worth exploring further.  In the research there appeared to be no obvious signs of additional toxicities with the combination.  This is one specific multi-targeted approach that we may see more of in the clinic going forward. What this space for progress!

References:

ResearchBlogging.orgTobler, N. (2006). Tumor and lymph node lymphangiogenesis–impact on cancer metastasis Journal of Leukocyte Biology, 80 (4), 691-696 DOI: 10.1189/jlb.1105653

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Update from AACR Molecular Targets 2011 #1 – Breast Cancer

By on November 21, 2011

Last week I had an enjoyable time at the AACR-EORTC-NCI Molecular Targets meeting but gippy wifi in San Francisco followed by my blog hosting and RSS feed going haywire meant that reviews of the meeting were delayed until now. There are a couple of interesting topics that emerged during the meeting that I’m going to explore in extended posts this week.

Today’s review looks at new breast cancer data from the conference. There were two things that stood out for me:

  • The role of epigenetics in advanced ER/PR+ breast cancer
  • New potential targets for inflammatory breast cancer (IBC)

Let’s take a look at these in turn.

Entinostat in second-line ER/PR+ breast cancer

The other week we discussed the data from a second generation HDAC, entinostat in lung cancer, so it was no surprise to see new data emerge in breast cancer in San Francisco as well.

Syndax reported the initial results from their phase II trial (ENCORE301) in women with hormone-sensitive breast cancer who had relapsed on an aromatase inhibitor. This is the same population recently evaluated in the BOLERO2 trial with everolimus plus exemestane at ECCO in September. In total, 49 patients were included, randomised to receive either exemestane plus entinostat (n=27) or exemestane and placebo (n= 22).

Here’s the schematic for the trial design:

schema

We know that the benefits of hormone therapy decline over time as resistance sets in. One mechanism of resistance is mTOR, and the BOLERO2 data demonstrated nicely how a logical combination of an AI with everolimus can help overcome this, leading to an improvement in progression-free survival (PFS) of 6.5 months. Hopefully, overall survival (OS) data will be available at the San Antonio Breast Cancer Symposium (SABCS) next month. Of course, as with many tumour types, there is usually more than one mode of resistance at play.

There were several key points that emerged from the epigenetics study:

  1. The ENCORE301 study is the first trial to report positive data with epigenetic therapy in breast cancer.
  2. They used a biomarker – acetylation levels – to ascertain response to therapy.
  3. Surprisingly, the clinical response to the therapy could be determined after only one or two doses.

The acetylation biomarker really intrigued me. Essentially, high levels of actylation predicted for better response with entinostat and AI therapy. The concept behind this is that HDAC inhibitors induce hyperactylation of lysines on histones as part of the mechanism of action (MOA). Thus in theory, high acetylation would potentially indicate the level of response.

What did the results actually show?

The good news is that we can see that adding entinostat to exemestane nearly doubled the PFS from 2.3 to 4.3 months, but those women with high acetlyation levels saw another doubling in the response to 8.5 months:

entinostat

Of course, this is a small exploratory study, but… the concept I think, is an excellent one, and well worth testing in a larger phase III trial.

The most obvious question that jumped to my mind after seeing the initail data was what would happen if we used a triple combination of exemestane, everolimus and entinostat or another HDAC in this relapsed population?

I don’t know the answer, but would love to see a phase II study emerge to get a quick readout on the possibilities. Many of you will recall that:

a) The Wyeth mTOR trial with temsirolimus in several thousand women with breast cancer produced a resoundingly negative result, but that that was in the front-line setting and mTOR is activated over time, causing resistance.

b) Merck’s HDAC inhibitor (vorinostat, SAHA) was evaluated in several breast cancer trials and none of those produced a positive result as far as I recall. That begs the question – was it the trial design or the drug – not all HDACs may be equal.

The good news here is that there is both a positive result and also a biomarker of response. Those suggest that it would be worth testing further in the relapsed setting both as a doublet in a large phase III study and in triple combination with everolimus in a smaller phase II trial.

Overall, I was very impressed with these results and Syndax should be congratulated for an excellent study design and also developing a useful biomarker. Neither are easy to do well.

Is ALK a new target in inflammatory breast cancer (IBC)?

This one caught me completely by surprise. IBC is a rare, but rather nasty, form of breast cancer that is often diagnosed late (in stage IIIb/IV). It presents with red, inflamed and thickened skin, rather than with a tumour, like this:

IBC

Sadly, we still have a lot of progress to make in understanding the aetiology of this disease, which often shows an accelerated path to metastasis, although we don’t know why. There aren’t that many new therapies or clinical trials in this area either as a rsult of the paucity of knowledge around the biology.

Dr Fredika Robertson (MD Anderson Cancer Center) presented the initial results of some translational research in a small number (n=12) of women with IBC.

She suggested that the early evidence is that the ALK translocation may be a transforming oncogene in breast cancer.

What did they find?

As a result of earlier work from Perez-Pinera et al., (2007) showing ALK gene expression in several types of breast cancer, they decided to look at this more closely in both pre-clinical animal models and also IBC patients.

These are the initial findings in women with IBC:

ALK

Note that they found an incidence of 75% for the ALK translocation in the dozen patients tested. I personally would be leery of extrapolating the results from such a small sample size to the broader population, but it certainly would be worth investigating further.

There are several questions that come to mind:

  1. Is the effect real or not? See Krishnan et al’s (2009) paper on intravascular ALK-Positive Anaplastic Large-Cell Lymphoma mimicking inflammatory breast carcinoma (reference below).
  2. Is the ALK translocation a key driver of aberrant activity?
  3. If yes, would an ALK inhibitor be effective or not?

In order to answer the last question, there is a multi-centre phase I trial with LDK378 (Novartis) now enrolling patients with ALK+ positive advanced cancer to find out the answer. In addition, Dr Robertson mentioned a single centre trial with crizotinib in ALK+ breast cancer, although I couldn’t find it in the clinical trials database.

Conclusions:

Overall, it was good to see some new progress being made in both translational research and also in the clinic, albeit the results are still early, but rather encouraging I think.

These two concepts, ie epigenetic therapy in ER/PR+ breast cancer and ALK translocations in IBC, will be worth following over the next couple of years to see whether they progress our knowledge and eventually more effective and targeted treatments of different subsets.

In the meantime, a further update of exciting new developments in breast cancer will be posted on this blog next month from the San Antonio Breast Cancer Symposium (SABCS).

References:

ResearchBlogging.org Perez-Pinera, P., Garcia-Suarez, O., Menendez-Rodriguez, P., Mortimer, J., Chang, Y., Astudillo, A., & Deuel, T. (2007). The receptor protein tyrosine phosphatase (RPTP)β/ζ is expressed in different subtypes of human breast cancer Biochemical and Biophysical Research Communications, 362 (1), 5-10 DOI: 10.1016/j.bbrc.2007.06.050

Krishnan, C., Moline, S., Anders, K., & Warnke, R. (2009). Intravascular ALK-Positive Anaplastic Large-Cell Lymphoma Mimicking Inflammatory Breast Carcinoma Journal of Clinical Oncology, 27 (15), 2563-2565 DOI: 10.1200/JCO.2008.20.3984

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AACR Molecular Targets Meeting

By on November 12, 2011

For those of you interested in this year’s AACR-EORTC-NCI meeting on Molecular Targets being held in San Francisco this year, you can follow the tweets from the hashtag #aacr in the widget below.

This is one of my favourite meetings of the year. I’m not expecting the same volume of tweets as the annual AACR meeting, mainly because a lot of the data being presented tends to be of an unpublished nature so people tweet those less – I certainly do!

If anyone has any questions, you can tweet me @maverickny. AACR also have an official Twitter and are very helpful.

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

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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

How a metabolic protein PKM2 may have a key role in tumorigenesis

By on November 8, 2011

This morning I was taking a breather from work to catch up on my Science and Nature reading.

Source, Wikipedia: Pyruvate Kinase Muscle isoenzyme

There was a most intriquing Letter to Nature from Lu and colleagues at MD Anderson, describing how PKM2 (pyruvate kinase muscle) may not just have an established role to play in metabolism (via the Warburg effect in glycolysis), but how it may also have important non-metabolic functions in tumour formation and growth:

“Here we demonstrate, in human cancer cells, that epidermal growth factor receptor (EGFR) activation induces translocation of PKM2, but not PKM1, into the nucleus, where K433 of PKM2 binds to c-Src-phosphorylated Y333 of b-catenin.”

In other words, it directly contributes to gene transcription for cancer cell proliferation.

From a scientific point of view, understanding the process of tumorigenesis, ie tumour formation and growth, is critical to figuring out how to stop it.  If we know precise elements of the process, then a more targeted and focused approach can be used in the clinic based on a solid rationale that has a better chance of success.  That’s much more sensible than literally throwing mud at walls randomly and hoping something sticks!

It is well known that EGFR activation and PKM2 expression are instrumental in tumorigenesis, but the question is how and what:

“These findings reveal that EGF induces b-catenin transactivation via a mechanism distinct from that induced by Wnt/Wingless and highlight the essential non-metabolic functions of PKM2 in EGFR-promoted b-catenin transactivation, cell proliferation and tumorigenesis.”

The researchers also went onto to note that:

“PKM2-dependent b-catenin transactivation is instrumental in EGFR promoted tumour cell proliferation and brain tumour development.  In addition, positive correlations have been identified between c-Src activity, b-catenin Y333 phosphorylation and PKM2 nuclear accumulation in human glioblastoma specimens.”

The basis for this idea came from an analysis of samples from tumours of patients with glioblastoma (n=84) who had been previously treated with radiation and chemotherapy after surgery.

They observed that patients who had low beta-catenin Y333 phosphorylation or low expression of PKM2 in the nucleus (n=28 each) had a median survival of 185 weeks and 130 weeks, respectively.

However, median survival decreased for those who had high levels of beta-catenin phosphorylation or nuclear PKM2 expression (n=56 each) to 69.4 weeks and 82.5 weeks, respectively.

Overall, there were a number of important findings, as explained in MD Anderson’s excellent press release describing the work:

“PKM2-dependent beta-catenin activation is instrumental in EGFR-promoted tumor cell proliferation and brain tumor development.

c-Src activity, beta-catenin Y333 phosphorylation, and PKM2 nuclear accumulation are positively correlated in human glioblastoma (GBM) specimens.

Levels of beta-catenin phosphorylation and nuclear PKM2 are correlated with grades of glioma malignancy and prognosis.”

Significance of these results

These results are not only unexpected, they also have some future practical implications, becuase EGFR inhibitors have not proven useful therapeutically in GBM:

  • New biomarkers: c-Src-dependent beta-catenin Y333 phosphorylation levels could potentially be used as a biomarker for selecting patients for treatment.
  • New treatment approaches: Src inhibitors (eg dasatinib, bosutinib, saracatinib) in an appropriately selected patient population most likely to respond, as opposed to allcomer trials, where the inherent tumour heterogeneity hides the positive treatment effect of responders.

This is an important article and well worth taking a few minutes out of your day to read.

References:

ResearchBlogging.orgYang, W., Xia, Y., Ji, H., Zheng, Y., Liang, J., Huang, W., Gao, X., Aldape, K., & Lu, Z. (2011). Nuclear PKM2 regulates β-catenin transactivation upon EGFR activation Nature DOI: 10.1038/nature10598

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