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Posts tagged ‘AKT’

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

Michael Jordan, Chicago Bulls

Michael Jordan, Chicago Bulls

Source: wikipedia

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

Domain Expertise + Work Ethic + Time = Success

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

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

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

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

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

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

 

 

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One of the hallmarks of cancer is that even within different tumour types, there is an enormous degree of heterogeneity. Ultimately, in simple terms this means that individual patients will respond to different therapies depending upon their underlying biology.   The challenge, therefore, is defining and categorising the subtypes and working out which are the passenger and driver oncogenes, since the latter will cause aberrant tumour growth and survival, while the former may result as a consequence of changing pathway activity.

This morning I was researching gliomas and came across this old paper (March 2006) that looks at molecular subtypes of gliomas i.e. glioblastomas and astrocytomas.  The article concluded:

“Recent evidence suggests that gliomas may arise from a cell type with neural stem cell-like properties. The current work demonstrates that prognostic subtypes of glioma resemble key stages in neurogenesis and implicates signaling pathways that play critical roles in regulation of forebrain neurogenesis in control of tumor aggressiveness. Longitudinal analysis of glioma cases reveals a frequent pattern of disease progression into the mesenchymal phenotype, a state associated with robust angiogenesis.

This work suggests that molecular classification of glioblastoma may predict response to targeted therapies and suggests that greater understanding of neurogenesis in the adult forebrain may yield novel therapeutic insights for glial malignancies.”

The reason I was curious about this particular paper was because following the AACR Special Conference on PI3K and mTOR that I attended last week, it made sense to look at the literature on mTOR, PI3K and AKT in more detail.

In the glioma research, it was interesting to see what predicted poor prognosis:

“A robust two-gene prognostic model utilizing PTEN and DLL3 expression suggests that Akt and Notch signaling are hallmarks of poor prognosis versus better prognosis gliomas, respectively.”

Now, while Akt and Notch signalling may be important, it doesn’t mean that they make idea targets for drug therapy.  PTEN loss of function is also a difficult target at present and it isn’t clear if it is a driver per se.  What was very clear at AACR last week was that for every action there is an equal and opposite reaction, meaning that targeting one part of a pathway may lead to switching of aberrant activity to another part of the pathway as it adapts to the changing environment.

Neal Rosen from MSKCC gave perhaps one of the best talks of the AACR meeting. He succinctly and simply put out a few constructs based on what we know so far. I will summarise some of the talks in a conference report (sign up on the top right column), but what was relevant to the paper on gliomas is that while at first sight it might make sense to target Akt, that strategy will have consequences.

According to Rosen, in general, inhibiting PI3K also stimulates HER3 expression and phosphorylation, as well as other receptor tyrosine kinases in many cell lines.  In other words, we may need a multi-targeting approach based on the original aberrant driver, the adaptive pathway and the ligand driving activity.

Double and triple combinations make sense from a scientific perspective, but they will also incur far higher costs and more complex clinical trial designs. Who knows whether other adaptive mechanisms will also evolve as a result of pursuing that strategy?  It brings vividly to mind Frank McCormick’s wac-a-mole approach that he described last year at AACR on the challenges of targeting the PI3K pathway in general, irrespective of upstream or downstream targets.

Progress is slowly being made, but we have a long way to go yet with the PI3K-mTOR pathway, although I’m hopeful of some positive progress soon. Certainly there will be some new data emerging on the biology at AACR in April and clinical data at ASCO in June.

References:

ResearchBlogging.orgPhillips, H., Kharbanda, S., Chen, R., Forrest, W., Soriano, R., Wu, T., Misra, A., Nigro, J., Colman, H., & Soroceanu, L. (2006). Molecular subclasses of high-grade glioma predict prognosis, delineate a pattern of disease progression, and resemble stages in neurogenesis Cancer Cell, 9 (3), 157-173 DOI: 10.1016/j.ccr.2006.02.019

Some of the most frequently searched words on this blog or those that arrive via organic Google searches centre around:

  • Melanoma
  • Ipilimumab
  • PLX4032

Interestingly, few are searching for RG7204, the Roche code for their compound being developed in partnership with Plexxikon or BRAF, the actual kinase target involved.

As background, you can read up on the past developments with BRAF V600 mutated melanoma herehere and here, including the phase II NEJM data, mechanisms of resistance (MEK or AKT) and how targeting CRAF as well as BRAF can lead to the development of squamous cell lesions in some patients.

This morning, Roche and Plexxikon announced the long awaited results of the phase III study (BRIM3) in newly diagnosed patients with metastatic melanoma:

“RG7204 (PLX4032) met its co-primary endpoints showing a significant survival benefit in people with previously untreated BRAF V600 mutation-positive metastatic melanoma.

Study participants who received RG7204 lived longer (overall survival) and also lived longer without their disease getting worse (progression-free survival) compared to participants who received dacarbazine, the current standard of care.”

The good news is that the survival benefit observed in the Phase II trials appears to be confirmed although the press release was rather short on specifics, presumably because the actual data will be presented at a cancer meeting later this year. However, given the current timing, I’m thinking this may augur well for an ASCO data submission. If so, ASCO is going to be interesting in metastatic melanoma this year with data anticipated from PLX4032 and ipilimumab (BMS).

Clearly, Roche intend filing the positive data with the Health Authorities, and in the meantime, they have announced plans to expand the access to PLX4032:

“Roche is now working closely with global health authorities to expand the recently announced RG7204 Early Access Program (EAP). The global EAP will be extended to include people with previously untreated, BRAF V600 mutation-positive metastatic melanoma.”

Now that we know more about the mechanisms of BRAF V600 resistance in metastatic melanoma, I’m also wondering when we might see some logical new trials evolve with PLX4032 in combination with a MEK or AKT inhibitor or perhaps sequenced, but to me it would make more sense to combine them.  It will be very interesting to see:

  • What the final survival advantage for PLX4032 is over dacarbazine
  • If a BRAF-MEK combination would further improve the OS

Fortunately, Genentech actually have two MEK inhibitors in development, GDC-0623 and GDC-0973 in solid tumours, so this approach is certainly feasible for them.

We’ll have to wait and see, but to put things in context, the phase II trial reported by Flaherty et al., (2010) in the NEJM demonstrated an approx. 6 month survival advantage in favour of PLX4032 before resistance set in.

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Metastatic melanoma is quite a hot topic right now with a rich pipeline of products in development after a decade of little or no progress.  Of course, it is a bit like three London buses coming along at once after an hour long wait in the winter weather, but better late than never.

Many of you will remember the recent data from ipilimumab (BMS), an immunotherapy that showed increased survival, albeit with some severe adverse events, from the phase III trial in newly diagnosed metastatic melanoma presented at ASCO in the plenary session earlier this year, followed by a publication in the NEJM.  The FDA filing was subsequently submitted on the basis of the positive data.

Yesterday, BMS announced that the FDA have moved the PDUFA date back 3 months from Dec 25th to March 26th, 2011.  A precise reason for the delay wasn’t given , but the company did say:

“In response to an FDA request, Bristol-Myers Squibb submitted further analysis of data pertaining to the current application for pre-treated advanced melanoma and the agency considers this to be a major amendment to the drug’s BLA.”

I’m not going to speculate on the reasons for the extra review time or what the new data was, but it is an interesting and unexpected development.

Meanwhile, there’s also been a lot of buzz around targeted BRAF inhibition in melanoma lately, specifically around the initial stunning results seen with PLX4032 (Plexxikon & Roche).  So far, it seems that responses of around 6-12 months, with a median of around 8 months are possible with an kinase inhibitor that specifically targets the V600E mutation associated with BRAF, although there two problems:

  1. The responses are not durable as resistance (eg associated with MEK or AKT amplification) sets in.
  2. Inhibiting CRAF as well as BRAF appears to lead to an unwanted excess proliferation of squamous cells, which is reversible on withdrawal of treatment.

In the first case, a couple of recent papers have looked at mechanisms of resistance around BRAF inhibition that give us some clues of where to go next.

Gopal et al., (2010) decided to see what happened with AZD6244 or selumetinib (Array and AstraZeneca), a MEK and MAP/ERK inhibitor, and whether it would have any impact in mitigating BRAF resistance, given the potential close interaction within the RAS-RAF-MAPK pathway and downstream events that could be impacted through cross-talk and feedback loops:

“We analyzed a panel of Braf mutant human cutaneous melanoma cell lines for their sensitivity to growth and survival inhibition by AZD6244. We compared these effects with the baseline activation status of signaling pathways in the cells, and with AZD6244 treatment–induced changes in signaling networks.

These studies have identified the phosphoinositide 3-kinase (PI3K)-AKT pathway as a critical regulator of the efficacy of AZD6244 in Braf-mutant melanomas, including in cells without baseline activation of the pathway.”

In order to determine possible mechanisms of resistance in the cell lines, they compared the effects of AZD6244 treatment on their signaling pathways with effects in sensitive cell lines and found:

“Although all four of these Braf-mutant cell lines showed similar degree and duration of MAPK inhibition and several other proteins, the resistant cell lines increased their P-AKT levels following exposure to AZD6244, which was not observed in the sensitive cell lines.”

They went on to note:

“The functional significance of AKT activation is supported by the fact that inhibition of AKT activity, either by AKT knockdown or concurrent treatment with the mTORC1/2 inhibitor AZD8055, resulted in synergistic cell killing in the resistant cell lines.”

AstraZeneca and Merck have an ongoing partnership with their MEK (AZD6244) and AKT (MK-2206) kinase inhibitors, so combining them in a clinical trial to try and reduce resistance via feedback loops here would be an interesting approach worth trying.  Such a combination trial is currently recruiting in advanced solid tumours, not melanoma per se.  It is, however, a classic catch-all phase I study to see what kinds of cancers might respond and determine the MTD, but I would be very interested to see the data from patients with metastatic melanoma if they are enrolled.

Now, it has been shown in breast cancer cell lines showed that MEK inhibition resulted in cross-activation of the EGFR tyrosine growth factor receptor, but EGFR has not been shown to be relevant in melanoma, so Gopal et al., considered what other receptors might be responsible for mediating the effects.   In the discussion, an interesting snippet caught my eye:

“AZD6244 treatment induced a slight increase of IGF-I secretion by the cells, and knockdown of IGF-I also blocked P-AKT induction by AZD6244.  Supporting a specific role for the pathway in cell survival, recombinant IGF-I treatment blocked AZD6244-induced cell death, but not growth arrest, in the sensitive WM35.”

This might also suggest another useful combination approach to consider in clinical trials.

Previously, it has been shown that targeting BRAF can not only inhibit the important driver in melanoma, the V600E mutation, but it can also stimulate cellular signaling through the MEK-ERK pathway by activating the related family member C-RAF. This may explain the squamous cell proliferation seen in some patients with PLX4032. The more ideal BRAF inhibitor would therefore specifically target BRAF V600E, without activating CRAF at the same time.

Related to the subject of malignant melanoma, Kamata et al., (2010) just published a paper that looked at the relationship between BRAF and CRAF in the disease.  Previously it has been shown that D594A BRAF lacks kinase activity, but can induce the related gene product CRAF in addition to the mitogen-activated protein/extracellular signal-regulated kinase (ERK) kinase (MEK)/ERK pathway.  What they found was really interesting.  In a nutshell:

“We show that the aneuploid phenotype is dependent on Craf. Treatment with the MEK inhibitor U0126 did not attenuate the emergence of aneuploidy but prevented the growth of aneuploid cells.  These results provide a previously unidentified link between Craf and chromosomal stability, with important implications for our understanding of the development of cancers with driver mutations that hyperactivate Craf.”

Aneuploidy is an abnormal number of chromosomes and can lead to genetic instability, a key cancer hallmark. It’s an important concept here because Kamata et al., have offered a different reason for the CRAF proliferation observed with some BRAF inhibitors:

“Impaired activity BRAF mutants are frequently coincident with oncogenic RAS mutations in human cancers (26) and in these, albeit rare, cancers, we may expect the hyper-activated CRAF induced by the combination of both oncogenes to enhance the aneuploidy response compared with mutation of either oncogene alone.  Such a situation is likely to be highly detrimental to the individual and, indeed, this mechanism may well account for the highly aggressive melanomas we observed following the combined expression of D594A Braf and G12D Kras in melanocytes.”

All in all, this is a very complex yet fascinating area of research and for those of you interested in this field, I would highly recommend reading the latest papers.

Photo Credit: Wikipedia

References:

ResearchBlogging.org Boni, A., Cogdill, A., Dang, P., Udayakumar, D., Njauw, C., Sloss, C., Ferrone, C., Flaherty, K., Lawrence, D., Fisher, D., Tsao, H., & Wargo, J. (2010). Selective BRAFV600E Inhibition Enhances T-Cell Recognition of Melanoma without Affecting Lymphocyte Function Cancer Research, 70 (13), 5213-5219 DOI: 10.1158/0008-5472.CAN-10-0118

 

Garnett MJ, Rana S, Paterson H, Barford D, & Marais R (2005). Wild-type and mutant B-RAF activate C-RAF through distinct mechanisms involving heterodimerization. Molecular cell, 20 (6), 963-9 PMID: 16364920

Gopal, Y., Deng, W., Woodman, S., Komurov, K., Ram, P., Smith, P., & Davies, M. (2010). Basal and Treatment-Induced Activation of AKT Mediates Resistance to Cell Death by AZD6244 (ARRY-142886) in Braf-Mutant Human Cutaneous Melanoma Cells Cancer Research, 70 (21), 8736-8747 DOI: 10.1158/0008-5472.CAN-10-0902

Kamata, T., Hussain, J., Giblett, S., Hayward, R., Marais, R., & Pritchard, C. (2010). BRAF Inactivation Drives Aneuploidy by Deregulating CRAF Cancer Research, 70 (21), 8475-8486 DOI: 10.1158/0008-5472.CAN-10-0603

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Last week there was lot of excitement and interest surrounding the blog post on Roche/Plexxikon's data on PLX4032 in metastatic melanoma published in the New England Journal of Medicine. A number of the discussions on Twitter and email centred around what is causing resistance to the BRAF inhibitor?

If we take a look at the BRAF pathway alone, we would get a sense of the flow from the PDGF ligand through RAS, RAF and MAPK, which essentially drives angiogenesis and proliferation, like this 2004 review article:

Picture 5
Source: Nature Reviews Cancer

However, what this sort of simple diagrammatic picture doesn't tell us though, is where cross-talk or feedback loops might interfere with the inhibition to enable cell signalling to continue, thereby guaranteeing the tumour's continued survival despite our efforts to shut it down.

Another way of looking at the problem is to consider how pathways related to RAS signalling might possibly interact with the process, like this:

RASSource: Reaction Biology

When we look at the cell signalling processes this way, we can see that inhibiting PI3-kinase or AKT at the same time as RAF might turn out to be a useful approach.

It was therefore with great interest while browsing my RSS cancer feeds that I spotted a paper by Shao and Aplin in the current Cancer Research journal entitled: "Akt3-Mediated Resistance to Apoptosis in B-RAF–Targeted Melanoma Cells" (see journal link below).

If we use a BRAF inhibitor such as PLX4032 in advanced melanoma, we are effectively trying to kill the cancer cells by inducing apoptosis, or programmed cell death, thereby reducing the tumour growth and proliferation.  However, as the researchers put it very succinctly:

"Melanoma cells are highly resistant to anoikis, a form of apoptosis induced in nonadherent/inappropriate adhesion conditions.  Depleting B-RAF or the prosurvival Bcl-2 family protein Mcl-1 renders mutant B-RAF melanoma cells susceptible to anoikis."

They therefore began looking at different approaches to dealing with anoikis using both inhibitors and RNA interference.

These concepts may help us better understand how mutant B-RAF protects melanoma cells from apoptosis, thereby providing insight into possible resistance mechanisms to B-RAF inhibitors by developing new mutations in AKT. It also paves the way for future therapeutic strategies, either in combination, or in sequence, with a V600E BRAF inhibitor such as PLX4032 and an Akt inhibitor. I'm also wondering what effect a PI3-kinase inhibitor might have, but clearly adding an Akt inhibitor to the mix may well be worth a try in the first instance.

There are a number of AKT inhibitors in development in various companies pipelines. This is where the challenges and hurdles begin if a company doesn't have a relevant inhibitor because traditional R&D focuses on developing one's own pipeline with or without the current standard of care rather than cross-development with other companies with novel combination treatments unless a partnership, particularly with a small biotech, is specifically sought out.

As far as I know, Roche/Genentech or Plexxikon don't have an AKT in their pipelines, but there are some currently in early clinical development with other companies. The PI3K-mTOR-AKT pathway has been discussed in more detail in previous blog posts.

The most interesting and promising compound in this class is probably Merck's MK-2206, currently in phase II development for a number of different tumour types.

Other Akt inhibitors in R&D include:

  • Keryx: perifosine in phase II development for myeloma and colorectal cancer
  • Rexahn: Archexin in phase II trials in pancreatic cancer
  • Nerium: oleandrin in phase I development for metastatic renal and colorectal cancers
  • GSK: GSK2141795 and GSK21110183 are both in phase I trials for either hematologic malignancies or solid tumours

GSK had an earlier Akt inhibitor in phase I, GSK690693, but I believe it may have been terminated due to problems with hyperglycaemia, a common problem associated with PI3K-IGF-1R feedback. This problem has since been addressed and managed in other trials associated with these agents by the simple addition of metformin in the protocol. GSK now appear to be focusing on the follow-on compounds instead.

All in all, it's interesting to see how our knowledge of the biochemical and molecular pathways helps us better understand how cancer works and how we can use the data to devise improved strategies for tackling melanoma in the future. I'll be watching how this field develops with close interest.

 

ResearchBlogging.org Dibb, N., Dilworth, S., & Mol, C. (2004). Opinion: Switching on kinases: oncogenic activation of BRAF and the PDGFR family Nature Reviews Cancer, 4 (9), 718-727 DOI: 10.1038/nrc1434

Shao, Y., & Aplin, A. (2010). Akt3-Mediated Resistance to Apoptosis in B-RAF-Targeted Melanoma Cells Cancer Research, 70 (16), 6670-6681 DOI: 10.1158/0008-5472.CAN-09-4471

Crouthamel, M., Kahana, J., Korenchuk, S., Zhang, S., Sundaresan, G., Eberwein, D., Brown, K., & Kumar, R. (2009). Mechanism and Management of AKT Inhibitor-Induced Hyperglycemia Clinical Cancer Research, 15 (1), 217-225 DOI: 10.1158/1078-0432.CCR-08-1253

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Over the past few years it has been interesting to watch AACR organise and group it's sessions by pathways, so you end up with a higgledy piggledy collection of different inhibitors, therapeutics, chemotherapies etc as well as a mix of different tumour types.  This works well for the scientist, less so for the clinician who may specialise in only a few cancer types.  

Meanwhile, at ASCO, everything is organised by cancer track, so if you want to search for data on say, MEK, AKT or c-MET inhibitors for example, then the data is now all over the place and trying to get round and find it all is much more difficult.  The chances of missing something, or worse, having clashes in interesting sessions is much higher.  I'm already looking a potential schedule with too many clashes and periods of nothing.  That's not a very efficient way to organise the data, yet this was not something I experienced at AACR to the same extent.

image from farm4.static.flickr.comPersonally, I find myself much preferring the AACR approach because it's ultimately logical and allows you to see patterns and trends more strategically, providing you approach it sensibly. You do need to think in 3D though, much like that 3 level chess board beloved by Spock in the original Star Trek. This way allows you to see potential connections and future approaches more easily rather than being hemmed in by tumour siloes.

In the long run, I confidently predict that the future trend of personalised medicine is going to be more based on a pathways approach allied with mutational analysis based on constitutive activation, rather than simply thinking in terms of cancer type by line of therapy.  Once you start understanding which subsets exist and which inhibitors can be combined together, it is not hard to see a new world evolving out there that may lead to better outcomes and improved quality of life.

Who knows, we might even be able to get rid of toxic chemotherapies altogether and prescribe a cocktail of more targeted agents based on the patients characteristics.

Now that would be a fine thing indeed.  Thoughts?

Photo Credit: GiftsforyouBiz

One of the interesting things about scientific conferences such as AACR and ASCO is that everyone looks at the same data differently as if it were through a kaleidoscope.

Brand marketers focus on their competition by tumour type or disease, scientists look at specific mechanisms or pathways, investors look at particular companies and so on. 

Someone asked me the other day how I analyse the data.  I hadn't really thought about it much until then, but on reflection what I'm interested in is trends and how research evolves from a big picture science view so that means I look at pathways like a true biochemist.  This also teaches us where the gaps are and what opportunities may arise in the future.  It's not exactly rocket science, but it is a useful approach sometimes.

Phosphoinositide 3-kinasesImage via Wikipedia

One of the clear trends emerging at AACR the other week is that dual inhibition of both the PI3K-mTOR and RAS-ERK pathways may be necessary in some cancers such as melanoma to reduce cross-talk, feedback and feedforward loops, drug resistance and loss of PTEN gain of function, just as one might also target IGF-1R and EGFR to reduce cross-talk and add in another inhibitor, eg MEK or AKT.

Given the increasingly critical role of MEK and AKT in various combinations in the future to reduce the potential for drug resistance occurring, this bodes well for a host of companies.  I wasn't, therefore, surprised to see Novartis snap up Array's MEK inhibitor (ARRY-162) given they already have an mTOR on the market (everolimus, Afinitor), two PI3-kinases in development and others including a RAS inhibitor.  Having a MEK inhibitor as well may therefore give them a lot of flexibility with different combinations in multiple cancer types if this approach pans out. 

Merck are also following a similar approach with their mTOR inhibitor, ridaforolimus, which they have finally grabbed commercial control of from their partner, Ariad.  Let's not forget they also have an AKT inhibitor, dalotuzumab and a MEKi through their partnership with AstraZeneca to play with too.

This is all good news for several biotech companies though, if some big Pharma companies start catching onto the trend and realise they need may a PI3K-mTOR inhibitor and a MEK or AKT inhibitor to stock up in their pipeline before the field gets too crowded.

Which companies might have new and interesting data in this area?

Well, Keryx and Aeterna Zentaris, Semafore, Calistoga, Intellikine and a few others all have PI3K inhibitors in development, while Exelixis have a deal in place with sanofi-aventis for XL147 and XL765 and Roche/Genentech have a pan-PI3K inhibitor, GDC-0941.  Novartis have two (BEZ235 and BKM120). Some of these compounds are single PI3K inhibitors and some are dual inhibitors of PI3K-mTOR.

Looking at the ASCO abstract titles, Exelixis appear to have the most abstracts in this area this year, so it will be interesting to see what sort of data they have across a range of different tumour models and early phase I results in solid and hematologic malignancies, with a variety of different combinations. 

One session I'm really looking forward to at this year's ASCO is a Clinical Science Symposium entitled, "Paths for Clinical Development of PI3K Inhibition" with some of the heavyweights in the field such as Neil Rosen (MSKCC), Skip Burris (Sarah Cannon), Jose Baselga (Spain) and Carlos Arteaga (Vanderbilt).  Arteaga is presenting a talk in that session entitled, "Next steps in clinical development of PI3K inhibitors?"

More later on this blog after the posters and the data become available at the meeting.

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There are a lot of clinical trials out there right with tyrosine kinase inhibitors; unfortunately many will fail because they were rushed into phase II or III trials without thinking through all the options.  There are, however, some smart companies out there who do think.

What was noticeable at AACR this year, was the surfeit of posters and presentations regarding logical combinations designed to eliminate escape routes and hence resistance.  For example, cross-talk is a common problem between ligands, eg IGF-1R and EGFR, so combining the two may reduce the problem but that isn't the whole story.

Feedback loops also exist, so targeting PI3-kinase alone is less likely to be effective than targeting both PI3-kinase and mTOR.  Neal Rosen from MSKCC showed some interesting data to this effect and argued cogently that oncogenes tend to lead to constitutive negative feedback.  He also noted that the BRAF mutation predicts for sensitivity to MEKi, for example.  Michael Korn also discussed the feedback activation loop between the RAS-ERK and PI3K pathways and how the inhibition of autophagy (where cells self digest themselves) can enhance apoptosis and the anti-tumour effect with smart combinations.

Targeting both MEK and AKT may therefore also have more effect than either alone, as you can see in the chart below: 

Picture 10Source: Array Biopharma

In a recent trial reported at the the ASCO GI meeting in January, Merck described an elegant design where IGF-1R, EGFR and AKT inhibitors were all combined to target advanced pancreatic cancer, with promising early results.  I thought this was a prescient approach at the time, since it clearly sought to eliminate both cross-talk and feedback, so it was interesting to see numerous researchers advocating similar approaches in different tumour types based on the overexpression profiles at AACR last week. The design is based on rational biochemistry, which regular PSB readers will know I'm a big fan of, rather than randomly adding a kinase inhibitor to whatever is the standard chemotherapy of the day in a haphazard blunderbuss approach.

There are a number of MEKi and AKTi inhibitors out there (I counted nearly a dozen last time I checked), as well as a plethora of PI3-kinase and mTOR inhibitors, either alone or in combination.  Merck and AstraZeneca announced an interesting deal earlier this year to jointly pursue research with their AKT (MK-2206) and MEK (AZD6244) inhibitors.  This collaboration makes a lot of sense biochemically.  Novartis (a client) have one of a broadest kinase pipelines in the industry and just added to it prior to AACR in a deal with Array BioPharma to license their MEK inhibitors, of which ARRY-162 is the lead candidate. 

The compounds that ultimately win the race may not necessarily be the ones furthest ahead in clinical trials right now, but the ones with the smartest clinical trial designs to eliminate some of the issues associated with kinase inhibition – cross-talk, feedback, feed-forward loops and additional mutations. 

MEKi and AKTi are two of my favourite kinase approaches right now because they offer the flexibility to add to existing TKI's such as erlotinib, sorafenib or everolimus, for example, potentially improving the outcomes further in a variety of different cancers, never mind the future combination possibilities.  It's going to be a very interesting and hot area to watch in the near future, that's for sure.

If you have any thoughts or questions on this fascinating topic, please do add them in the comments below.

 

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It’s been a bit of a long week on lung cancer articles and while I was planning on talking about something else today, this new article in my database caught my eye:

Picture 157
Part of the reason is nostalgia – it’s 20 years ago since I finished my doctorate on early detection of preclinical lung disease and while I was interested in the methods of detecting changes in breathing patterns associated with smoking, part of me wished I’d done research on molecular biology at the time rather than applied physiology.

The reason is that I realised while doing the literature search is that biochemical and physiological changes in the airways would ultimately tell us more about early detection.

In the article above, the researchers suggest a potential mechanism by which the tobacco-specific carcinogen NNK promotes lung tumour formation and development. Now, bearing in mind that most solid tumours take years to develop from hyperplasia to full aggressive carcinoma, finding how it actually happens and why is still an inexact science, as are methods for early detection given not all smokers get lung cancer and non-smokers are not immune from the disease.

Lin et al., suggest that NNK induces the accumulation of a protein known as DNMT1 in the nucleus and that this protein silences genes that suppress tumour formation.  They offered evidence to support their hypothesis, including the observation that DNMT1 accumulates in both lung adenomas from NNK-treated mice and tumours from lung cancer patients that were smokers.  DNMT1 overexpression in lung cancer patients who smoked continuously correlated with poor prognosis.

However, the interesting part of their abstract to me was:

“We determined that in a human lung cell line, glycogen synthase kinase 3β (GSK3β) phosphorylated DNMT1 to recruit β-transducin repeat–containing protein (βTrCP), resulting in DNMT1 degradation, and that NNK activated AKT, inhibiting GSK3β function and thereby attenuating DNMT1 degradation.”

Ah, our friend AKT.  

The potential role of AKT in lung cancer came up repeatedly at last week’s AACR lung cancer meeting. The researchers there had begun to realise that blocking EGFR or IGF-1R and c-MET or AKT (either directly or indirectly via PI3K inhibition) might cut off an escape route for the cancer cell and reduce drug resistance:

Picture 159
Source:
Vivanco and Sawyers

Drs Jeffrey Engelman (MGH) and David Carbone (Vanderbilt) covered excellent quick reviews at AACR on the latest findings related to EGFR inhibition relating to c-MET and proteomics respectively.  As our knowledge of various mutations and biologic pathways improves, so does our understanding of how we can better target aberrations and treat patients with NSCLC more effectively.

Engelman’s group has just published a paper on c-MET and EGFR inhibition (see references).  They noticed that rare MET-amplified cells exist in some EGFR-mutant lung cancers before treatment. What makes the research relevant to this overview is that MET amplification activates ERBB3/PI3K/AKT signaling in EGFR mutant lung cancers and causes resistance to EGFR kinase inhibitors. They demonstrated that MET activation by its ligand, HGF, induces drug resistance through GAB1 signaling. Using high-throughput FISH analyses in both cell lines and in patients with lung cancer, they identified subpopulations of cells with MET amplification prior to drug exposure.

The concept that HGF induces resistance to tyrosine kinase inhibitors in EGFR-addicted cancers is a novel one.  They saw that HGF accelerates MET amplification by expanding preexisting MET-amplified cells. What was particularly relevant though was that analysis of pretreatment cancers identified those poised to become MET amplified, thereby offering a way to segment NSCLC patients for more personalised treatment, increasing the chances of better response rates, longer overall survival and improved patient outcomes.

Then came the killer statement:

“EGFR kinase inhibitor resistance, due to either MET amplification or autocrine HGF production, was cured in vivo by combined EGFR and MET inhibition.”

Oh my.  This leaves us seriously wondering what will happen in practice by combining erlotinib (Tarceva) or gefitinib (Iressa) with a MET inhibitor in patients with NSCLC?  Tang et al., reported some promising preclinical work in 2008 (see references) but solid data in human patients has yet to be reported.

 

I can’t wait for ASCO this year to find out!

References:

ResearchBlogging.orgLin, R., Hsieh, Y., Lin, P., Hsu, H., Chen, C., Tang, Y., Lee, C., & Wang, Y. (2010). The tobacco-specific carcinogen NNK induces DNA methyltransferase 1 accumulation and tumor suppressor gene hypermethylation in mice and lung cancer patients Journal of Clinical Investigation DOI: 10.1172/JCI40706

Vivanco, I., & Sawyers, C. (2002). The phosphatidylinositol 3-Kinase–AKT pathway in human cancer Nature Reviews Cancer, 2 (7), 489-501 DOI: 10.1038/nrc839 

Massion, P. (2004). Early Involvement of the Phosphatidylinositol 3-Kinase/Akt Pathway in Lung Cancer Progression American Journal of Respiratory and Critical Care Medicine, 170 (10), 1088-1094 DOI: 10.1164/rccm.200404-487OC

Turke, A., Zejnullahu, K., Wu, Y., Song, Y., Dias-Santagata, D., Lifshits, E., Toschi, L., Rogers, A., Mok, T., & Sequist, L. (2010). Preexistence and Clonal Selection of MET Amplification in EGFR Mutant NSCLC Cancer Cell, 17 (1), 77-88 DOI: 10.1016/j.ccr.2009.11.022

Tang, Z., Du, R., Jiang, S., Wu, C., Barkauskas, D., Richey, J., Molter, J., Lam, M., Flask, C., Gerson, S., Dowlati, A., Liu, L., Lee, Z., Halmos, B., Wang, Y., Kern, J., & Ma, P. (2008). Dual MET–EGFR combinatorial inhibition against T790M-EGFR-mediated erlotinib-resistant lung cancer British Journal of Cancer, 99 (6), 911-922 DOI: 10.1038/sj.bjc.6604559

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