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Posts from the ‘Pathways’ category

What's hot at SABCS – Update 1

By on December 8, 2011

Yesterday evening brought a flurry of news around the New England Journal of Medicine articles for the BOLERO2 and CLEOPATRA trials, but out of respect to the presenters, I hate talking about the actual data before its being presented. Call me old fashioned if you like, but it seems odd moving up deadlines for the publication ahead of the presentations instead of releasing them on the day and is a little disrespectful of the journal towards the presenter and attendees.

I will therefore discuss the data for BOLERO2 and CLEOPATRA studies in detail after they have been presented today and tomorrow, respectively. For those of you interested in the study designs and their potential implications, you can check out my brief video highlights in the meantime.

Yesterday at the San Antonio Breast Cancer Symposium (SABCS) brought some really intriguing biology data that are well worth discussing:

  • Notch inhibition to reduce AI resistance
  • HER2 mutants
  • Targeting HER3 with an antibody and impact of ErbB3 expression on luminal cells

Notch inhibition

Perhaps one of the most intriguing presentations (to me) yesterday at SABCS looked at combining a Notch inhibitor plus an AI to reduce breast cancer resistance in preclinical models.

This is an interesting idea that is worth exploring because resistance to oral therapies, including AIs, is a common problem. Understanding the potential mechanisms of resistance should therefore lead to new trial designs and logical combinations.

In this research, the presentation focused on early data on combining MK-0752 (notch) plus hormone therapy. Interestingly, it also finally mentioned the magic word, biomarkers! I think this is a combination we will here much more about going forward.

In his award lecture, Dr Carlos Arteaga correctly observed that the medical community has not done a good job with ER+ drug-resistant disease. This situation is slowly changing as the BOLERO2 data has shown and other mechanisms of resistance will no doubt follow now that more attention is being focused on it.

HER2 mutants

Dr Boulbes from MD Anderson presented the results of some elegant research identifying three mutants to HER2, namely:

  • D808N
  • V794M
  • L726F

All three phenotypes displayed aggressive tendencies. Both the V and L phenotypes showed a dramatic lack of phosphorylation and the latter may be related to the development of HER2 resistance. Data was shown in relation to lapatinib, a HER2 small molecule TKI, which is known to develop resistance to treatment over time.

This is the first time I think HER mutant phenotypes have been reported to my knowledge and if validated clinically, they will represent a breakthrough in our understanding of how HER2 resistance develops, but more importantly, suggest directions for potential therapeutic strategies to overcome it.

Targeting HER3 with an antibody and impact of ErbB3 expression on luminal cells

HER3 has not received a lot of attention relative to its more popular HER2 cousin, largely because it is tricky to target. However, at this meeting, Dr Garner et al., showed that an anti-HER3 antibody (Novartis) nicely shrank breast cancer tumours in immunocompromised mice.

The presenter observed that the alpha-HER3 mAB recognizes and stabilizes HER3 in the inactive conformation. I was left wondering whether HER2 and 3 pairing / dimerization was shut off or something else was going on?

Dr Cook subsequently showed some clear data whereby HER3 is required for HER2 cancer growth in genetic engineering animal model. This was a very nice piece of research.

What was interesting was that Dr Garner also showed that alpha-HER3 can combine w/ trastuzumab plus a PI3K inhibitor to improve efficacy in trastuzumab-resistant settings. This caught my attention because earlier this year at the AACR PI3K special meeting, Neal Rosen (MSKCC) noted that targeting PI3K activated HER3 as one mechanism of resistance in the breast cancer model they were using and thus speculated that combined inhibition of HER3 and PI3K would lead to reduced resistance. Looks like his hypothesis was correct 🙂

And that was just the first full day of presentations with much more to come!

In the meantime, you can follow the conversations remotely using our tracking tool, accessible here on the blog.

Check back tomorrow for more updates on cancer biology and clinical trials from SABCS.

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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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Update on pancreatic Neuroendocrine Tumours (NET)

By on November 10, 2011

Today on 10th November, it’s the Second Annual Worldwide NET (Neuroendocrine Tumor) Cancer Awareness Day. Granted that’s a bit of a mouthful, but it also seems poignant given so many of my news feeds this morning were still full of Steve Jobs, who sadly passed away from the disease last month.

I’ve been meaning to post an update on this rare form of cancer all year, given that we now have targeted therapies now approved by the FDA for treatment, but things were hectic at the office and then with Jobs passing, the timing just seemed tacky and inappropriate.

The idea though, of an Awareness Day for a rare disease such as NET to improve both education and awareness seems an inherently good one to me, especially as there has been some progress clinically in 2011. According to Kulke et al., (2011) NET has an incidence of around 1 per 100,000 individuals. This excellent review covers the key essentials of both the disease and the treatments:

“Patients with pancreatic NET present with diverse symp- toms related to hormonal hypersecretion, tumor bulk, or both. Accurate diagnosis of this condition and differentiation of pancreatic NET from the more common pancreatic adenocarcinomas is a critical first step in developing an appropriate treatment plan.”

It has been quite the landmark year for NET since not one, but two, new therapies were approved by the FDA in May this year with very different mechanisms of action:

  • Everolimus (Afinitor) from Novartis targets the mammalian target of rapamycin (mTOR), a serine-threonine kinase, downstream of the PI3K/AKT pathway.
  • Sunitinib (Sutent) from Pfizer is a multikinase inhibitor of VEGF, PDGFR (α and β), KIT, FLT3, RET and CSF-1R.

Both of these drugs are also approved for the treatment of renal cell cancer, which while nearby geographically in the body, is a completely different type of GI cancer. They are now approved for pancreatic neuroendocrine tumours (pNET) that have progressed and cannot be treated with surgery.

It is important to note, that while NET is a rare form of pancreatic cancer, it is not the same thing as the more common pancreatic adenocarcinoma – a fact that the media often got wrong in the case of Steve Jobs and drove me potty at their ignorance and inability to grasp a simple concept.  NET is not an adenocarcinoma and has a much larger endocrinology/metabolism component and starts in the hormone-producing cells of the pancreas. There are two types of pancreatic NET:

  1. Functional (overproduce hormones)
  2. Nonfunctional (do not overproduce hormones) and are more common

There are some great resources for patients (and caregivers) want to know more about this disease – here are some examples I came across:

Let’s take a look at the new clinical data.  Both sunitinib and everolimus were compared to placebo in the phase III trial of refractory patients who were ineligible for surgery and had disease progression.

Here’s what the survival curves look like, based on the data from their respective prescribing information: 12

In the case of sunitinib, we can see that the median progression-free survival (PFS) 10.2 months versus 5.4 months for the placebo arm. This difference was highly significant (P 0.000146, HR 0.427):

sunitinib

Looking at the everolimus data, we also see a significant trend in favour of therapy over placebo, i.e. a median PFS of 11.04 months compared with 4.6 months for placebo (P 0.001, HR 0.35):

everolimus

These studies produced very comparable responses from a survival perspective and overall response rates of 9% and 5%, respectively.

While it is good to see some excellent progress on the efficacy front, these new therapies for NET are not without their challenges and side effects though.

In particular, in the phase III study, sunitinib, hypertension was the most common grade 3 event in 10% of patients (a classic function of the VEGF class of drugs) and was also shown to cause cardiac failure leading to death in 2/83 (2%) patients on therapy compared with no patients on placebo.

In contrast, everolimus should be avoided with concomitant use of strong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, clarithromycin, atazanavir, nefazodone, saquinavir, telithromycin, ritonavir, indinavir, nelfinavir, voriconazole). The most common grade 3/4 adverse reactions (incidence ≥ 5%) in the phase III pNET trial were stomatitis and diarrhea.

As Kulke et al., observed:

“Surgical resection remains the mainstay of treatment for patients with localized disease.”

However, for patients who are unresectable or have progressed there are at last new options:

“Recent studies have also reported that the tyrosine kinase inhibitor sunitinib and the mTOR inhibitor everolimus improved progression-free survival in patients with pancreatic NET, further expanding the therapeutic arsenal available to patients with this disease.”

In the future, we may well see sequencing studies emerge as well as other targeted therapies to prolong outcomes for patients with this rare disease.

References:

ResearchBlogging.orgKulke MH, Bendell J, Kvols L, Picus J, Pommier R, & Yao J (2011). Evolving diagnostic and treatment strategies for pancreatic neuroendocrine tumors. Journal of hematology & oncology, 4 PMID: 21672194

  1. Sunitinib PI accessed  ↩
  2. Everolimus PI accessed  ↩

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

A year in the life of Pharma Strategy Blog

By on October 31, 2011

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

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

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

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

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

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

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

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

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

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

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

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

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

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