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Posts tagged ‘mTOR’

What’s hot at ECCO 2013 – Preview of late breakers and PI3K abstracts

By on September 17, 2013

Next I’ll be off to the European Cancer Congress (ECC) in Amsterdam. This meeting alternates each year between ECCO and ESMO hosting the event at a different European city.

The last couple of years have seen some nice data that missed the ASCO deadline, other years can bring an update of the already familiar ASCO data. I suspect that this year will be one of those events, with updated PD-1 and PD-L1 data.

If you missed my colleague Pieter Droppert’s ECCO highlights yesterday, you can catch them here, including details of the iPad app and abstracts.

In addition, there were other abstracts of interest that caught my eye, including some solid late breakers:

1. T-DM1 for HER2-positive metastatic breast cancer (MBC): Primary results from TH3RESA, a phase 3 study of T-DM1 vs treatment of physician’s choice. H. Wildiers (Belgium) et al.

The study looks at advanced disease in patients who had received at least two prior regimens. This analysis looks like an interim one, given the full study timeframe is over 3.5 years. I’m particularly curious what the physician choices were to compete with Kadcyla and what the 1 year survival curves look like. It’s a wee bit early to hope that they might separate already, certainly I hope they do!

2. Evaluation of everolimus (EVE) in HER2+ advanced breast cancer (BC) with activated PI3K/mTOR pathway: Exploratory biomarker observations from the BOLERO-3 trial. G. Jerusalem (Belgium) et al.

Originally, I thought this had been presented at ASCO, but the biomarker abstract I found actually referred to BOLERO-2, where they noted that “efficacy was greater in patients with low PI3K expression”, which is an odd finding. The BOLERO-3 data from ASCO presented the initial phase III data for the combination of trastuzumab, vinorelbine and everolimus vs trastuzumab and vinorelbine alone in trastuzumab resistant HER2+ advanced breast cancer. This should be an interesting presentation worth attending.

3. FLT1 gene variation as a major determinant of recurrence in stage I-III non-small cell lung cancer. F. Innocenti (USA) et al.

Many of us familiar with FLT3 in leukemia, but FLT1 is an interesting concept with very little data (or drugs) out there. I will be curious to see if this is a druggable target and where this approach might lead.

4. Pooled analysis of long-term survival data from phase II and phase III trials of ipilimumab in metastatic or locally advanced, unresectable melanoma. F. Hodi (USA) et al.

If you look at five year survival curves for advanced melanoma in the literature, it’s historically around 20% or so when patients have received IL-2, which is where I would expect ipilimumab to be. Trials with DTIC have shown a much lower rate, at around 8-9%. Not every patient is suitable for IL-2 though, so we may be seeing similar survival rates irrespective of the immunotherapy given, but with very different safety profiles.

One of my favourite cancer pathways is PI3K-AKT-mTOR. It’s dysregulated in some 80% of cancers yet we haven’t really seen a major breakthrough with these agents in solid tumours outside of the stunning Afinitor data in relapsed ER+ metastatic breast cancer from the BOLERO-2 study presented at ECCO in Stockholm two years ago.

There are many different permutations out there from single to dual inhibitors and also specific isoforms of alpha, beta, delta and gamma.

One of the challenges with targeting PI3K is that it activates feedback loops. Thus inhibiting PI3K in advanced prostate cancer activates the androgen receptor, while single agent use in advanced breast cancer can lead to activation of HER3. In addition, there have been mixed results with biomarkers and specific mutations/tumour suppressors to date such as PIK3CA and PTEN. This increases the complexity tremendously and therefore speaks to more careful trial selection based on inclusion criteria and also logical combinations to try and shut down the compensatory pathway.

I was therefore pleased to see a few trials reporting early phase I/II data in this vein:

P017: Evaluation of tolerability and anti-tumor activity of GDC-0032, a PI3K inhibitor with enhanced activity against PIK3CA mutant tumors, administered to patients with advanced solid tumors.

D. Juric, J.R. Infante, I.E. Krop, C. Kurkjian, M.R. Patel, R.A. Graham, T.R. Wilson, J.Y. Hsu, J. Baselga, D.D. Von Hoff

According to the abstract:

“GDC-0032 is an orally bioavailable, potent, and selective inhibitor of Class I PI3K alpha, delta, and gamma isoforms, with 30-fold less inhibition of the PI3K beta isoform relative to the PI3K alpha isoform.”

Several confirmed partial responses have been reported and further trials will continue:

“GDC-0032 is a next-generation PI3K inhibitor with promising anti-tumor activity observed in patients with PIK3CA mutant tumors. GDC-0032 is being investigated in combination with endocrine therapies such as letrozole and fulvestrant for patients with hormone receptor-positive breast cancer.”

P079: Hyperglycemia in patients treated with the pan-PI3K inhibitor buparlisib (BKM120): characterization, management, and assessment for pharmacodynamics

A. Azaro, J. Rodon, J.F. Vansteenkiste, Y. Ando, T. Doi, D. Mills, C. Sarr, E. Di Tomaso, C. Massacesi, R.W. Naumann

Source: Novartis

Source: Novartis

BKM120 is also an oral pan PI3K inhibitor that does not target mTOR. Aside from the activation feedback loop effects mentioned earlier, PI3K plays a key role in glucose homeostasis. A number of earlier trials with different PI3K and mTOR inhibitors have reported hyperglycemia as a class effect although they have varied in the degree to which the event occurred.

This study highlights the importance of a potential pharmacodynamic marker (C-peptide) in assessing the insulin response and I’m looking forward to seeing more detail in the poster.

P061: Factors predisposing to development of hyperglycaemia in phase 1 studies involving PI3K, mTOR, AKT and mTORC1 and mTORC2 inhibitors

M. Wong, K.H. Khan, K. Rihawi, S. Bodla, B. Amin, K. Shah, D. Morganstein, S.B. Kaye, U. Banerji, L.R. Molife

Related to the topic of hyperglycemia, the Royal Marsden mined their database for PI3K-mTOR trials and looked at factors that might influence the presence of the glucose spike in order to essentially try and predict which patients were more at risk and improve management. While most patients did not require intervention, but in those that did, metformin and insulin were usually preferred. Interestingly, the main factor emerging in this retrospective study was a prior history of diabetes, which is not totally unsurprising. It will be useful to see if these results can be validated in prospective future trials.

P227: Anti-tumour efficacy of the PI3K inhibitor GDC0941, the dual PI3K/mTOR inhibitor GDC0980 and the MEK inhibitor GDC0973 as single agents and in combination in endometrial carcinomas

O. Aslan, A.M. Farrelly, B. Stordal, B.T. Hennessy

Much has be written about the potential for a PI3K and MEK combination in different tumour types, but so far they haven’t proven to be the home run many of us hoped for.

This preclinical paper looks at cell lines to explore potential targets and synergies in endometrial cancer (EC). They concluded,

“Our data suggest that the mutational status of PIK3CA, PTEN and KRAS can be used as biomarkers to select patients for PI3K and RAS/RAF-targeted therapies. Further, the combinations of the PI3K inhibitors GDC0941 and GDC0980 with the MEK inhibitor GDC0973 are promising approaches for the treatment of patients with PIK3CA, PTEN and KRAS-mutated EC.”

Translating data from simple cell lines to complex human bodies does not always predict response given the variable responses seen from patients with mutations and tumour suppressors in clinical trials. I think it will take a while to tease out what defines and predicts a response in each tumour type much in the same way we saw different effects in advanced melanoma when targeting BRAF with sorafenib versus BRAF V600E with vemurafenib or dabrafenib. The devil is in the details.

And finally, an oral presentation with a very different focus in the PI3K related field that I’m really looking forward to hearing:

#1859 PI3KCA mutations and correlation with pCR in the NeoALTTO trial (BIG 01-06)

J. Baselga, I. Majewski, P.G. Nuciforo, H. Eidtmann, E. Holmes, C. Sotiriou, D. Fumagalli, M.C. Diaz Delgado, M. Piccart-Gebhart, R. Bernards

The authors evaluated:

“The influence of PI3K pathway mutations (PIK3CA, KRAS, BRAF, AKT1) on sensitivity to trastuzumab (T), lapatinib (L), or both agents (L+T) in combination in early-stage HER2-positive breast cancer patients enrolled the neoALTTO trial.”

The goal here is to see the presence of any of the mutations were more likely to lead to resistance and enable better selection of therapy for patients. I will update on this study after the presentation.

More detailed posts and synopses will continue from the meeting itself on Biotech Strategy Blog, where we’ll be sharing our insights and analysis daily.

ASCO 2012 Preview – Highlights of key data emerging from Chicago

By on May 15, 2012

It’s that time of the year again where we cogitate and contemplate on what might be hot at the annual meeting of the American Society of Clinical Oncology (ASCO) before the abstracts are available (they’re released online tomorrow at 6pm ET).

This year, while interesting early data from up and coming small biotechs is likely to be eagerly presented in poster sessions, the focus is more likely going to be on big Pharma with various phase III and also late phase II trials that are due to report data.  Unfortunately, not all of these will produce overwhelmingly positive results though!

What I’m most interested is things that shift the needle meaningfully  in terms of survival by six months or more, as we saw from the recent BOLERO2 and CLEOPATRA trials in ER+ and HER2+ breast cancer.  There are plenty of agents that offer minor or incremental improvements (colon cancer has long suffered from that syndrome, sadly), but let’s be honest – most of us get excited by the possibility of major shifts in survival.

Please note that I’ve mostly selected some promising agents in development that might achieve that effect, explained why they are different and focused on new data/drugs rather than rehash what I call the ‘middlings’ i.e. minor upgrades to the standard of care.

Without much further ado, here are my ASCO preview highlights for 2012:

Please do check back during the convention both here on PSB, and also on Biotech Strategy, for reports and analysis as the interesting data emerges at ASCO.

If you have any comments or thoughts, please do share them below…

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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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Making a Difference: an interview with Dr Gordon Mills

Earlier this year, I announced that there were two people I was hoping to interview next as part of the ongoing Making a Difference series, where thought leaders share their ideas and vision on emerging and important topics in cancer research. Previous discussants have included the following:

Today, I am delighted to announce that one of those identified thought leaders, Gordon Mills (MD Anderson), kindly agreed to be filmed while at last week’s ECCO (European Multidisciplinary Cancer Conference). Dr Mills is Chairman of the Department of Systems Biology, Chief of the Section of Molecular Therapeutics, Professor of Medicine and Immunology, and Anne Rife Cox Chair in Gynecology. He is also one of the best strategic thinkers I’ve come across in cancer research who not only understands the big picture, but also the detailed subtleties.

Originally, we collected audio-visual to ensure an accurate recording for the usual transcript that gets posted here on the blog, but it came out well and the subject was so compelling that we deemed it well worth watching as the first thought leader video interview here on Pharma Strategy Blog.

Dr Mills gave one of the three keynotes in the first Presidential Symposium at the Stockholm meeting, along with Drs José Baselga (MGH) and Tak Mak (U. Toronto) in a fascinating session on Personalized Medicine. This session covered the whole gamut from therapeutics, biomarkers, assays and to metabolism. I took the liberty to include a couple of Dr Mill’s slides to illustrate the points we were discussing in the video below.

We’ve come a long way over the last decade in terms of progress, but hopefully, as technology and our knowledge improve further, the best is yet to come.

This is the fifth interview in the series with thought leaders in the Making a Difference series – it covers a wide range of critical topics including BRAF, mTOR, PI3K, EGFR and RAS – please do check it out:

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On mTOR and Tuberosis Sclerosis Complex (TSC)

By on July 26, 2011

It’s that time of year in the dog days of summer when many people in the industry are either incredibly busy, heads down, rolling out new things for the third quarter or else it’s a pleasant lull between the strategic and tactical phases and a good time to catch your breath.  Here in the Icarus office, we’re busy creating and writing a new series of syndicated reports in a variety of different tumour types and pathways.  I have hundreds of snippets and notes saved electronically from various cancer meetings this year, making it a great opportunity to collate and process them into broader insights. If you have any particular needs in this area, now is a good time to let us know, so do email me and your wishes may get added to the list.

Last week I was in Boston and happened by chance to walk past the Whitehead Institute. This reminded me that I had David Sabatini’s new mTOR paper in Science queued up to blog about on Pharma Strategy Blog.

The mTOR pathway is highly complex and consists of a huge network of interwined proteins and kinases:

Source: wikipedia

Hsu et al., (2011) described what they found from defining the mTOR-regulated phosphoproteome using quantitative mass spectrometry and protein libraries to build a complete picture:

“The adaptor protein Grb10 was identified as an mTORC1 substrate that mediates the inhibition of phosphoinositide 3-kinase typical of cells lacking tuberous sclerosis complex 2 (TSC2), a tumor suppressor and negative regulator of mTORC1.

Our work clarifies how mTORC1 inhibits growth factor signaling and opens new areas of investigation in mTOR biology.”

We know, for example, that mTORC1 inhibits PI3K-Akt signaling, but the precise molecular connections involved are poorly understood.  S6K1 phophosphorylation, which destabilises the insulin receptor substrate 1 (IRS1), is one mechanism known to be involved.  Hsu et al., demonstrated that other mechanisms are also critical:

“mTORC1 inhibits and destabilizes IRS1 and simultaneously activates and stabilizes Grb10.”

They went to separate the effects of acute and chronic stimulation of mTOR:

“Whereas acute mTORC1 inhibition leads to dephosphorylation of IRS1 and Grb10, chronic mTORC1 inhibition leads to changes in the abundance of IRS and Grb10 proteins, which are likely the most important effects of mTOR inhibitors to consider in their clinical use.”

This important article is particularly relevant because not long after the publication, Novartis announced positive data with their mTOR inhibitor, everolimus (Afinitor) in patients with tuberous sclerosis complex (TSC).

TSC is a genetic disorder that affects affects approximately 1-2 million people worldwide and is associated with a variety of resulting disorders including seizures, swelling in the brain, developmental delays and skin lesions. It can also cause non-cancerous tumours to form and can affect many different parts of the body such as the brain and kidney, for example.

The rationale behind such as study was described in the Novartis press release:

“Tuberous sclerosis complex is caused by defects in the TSC1 and/or TSC2 genes. When these genes are defective, mTOR activity is increased, which can cause uncontrolled tumor cell growth and proliferation, blood vessel growth and altered cellular metabolism, leading to the formation of non-cancerous tumors throughout the body, including the brain.”

In other words, giving an mTOR inhibitor such as everolimus may help by reduce cell proliferation, blood vessel growth and glucose uptake associated with the TSC defect.

In patients with brain lesions, surgery is usually considered the only viable option, so a study showing a 35% response rate (50% reduction or more) in the SEGA lesions, is a positive step forward.  The new data was from a phase III trial (n=117) and appears to support the initial positive phase II study, so it will likely lead to a registration filing in this indication for everolimus.

 

References:

ResearchBlogging.orgHsu, P., Kang, S., Rameseder, J., Zhang, Y., Ottina, K., Lim, D., Peterson, T., Choi, Y., Gray, N., Yaffe, M., Marto, J., & Sabatini, D. (2011).  The mTOR-Regulated Phosphoproteome Reveals a Mechanism of mTORC1-Mediated Inhibition of Growth Factor Signaling. Science, 332 (6035), 1317-1322 DOI: 10.1126/science.1199498

Update on triple negative breast cancer

By on July 12, 2011

One of the challenges of triple negative breast cancer is that it is defined by what it is not (ie ER/PR-, HER2-), rather than what it is.  This broad subgroup of breast cancer is therefore more heterogeneous in nature than many people actually realise.  It also means that unless we uncover the various driving mutations underlying it, we are sadly doomed to the world of repeatedly poor response rates.  We can do better than this.

The other day I saw a new paper in the Journal of Clinical Investigation (open access) that caught my eye:

“Identification of human triple-negative breast cancer subtypes and preclinical models for selection of targeted therapies”

Researchers from Vanderbilt-Ingram cancer centre identified six different subtypes relating to this disease.  Six!

They found the subtypes by looking at gene expression profiles in 21 different breast cancer sets and identified the triple negative cases (n=587).  From these cases, cluster analysis identified the six TNBC subtypes.  These subtypes included:

  • two basal-like (BL1 and BL2)
  • an immunomodulatory (IM)
  • a mesenchymal (M)
  • a mesenchymal stem–like (MSL)
  • a luminal androgen receptor (LAR)

Here’s where it gets very interesting though – these newly identified subtypes are sensitive to different therapies:

“BL1 and BL2 subtypes had higher expression of cell cycle and DNA damage response genes, and representative cell lines preferentially responded to cisplatin.

M and MSL subtypes were enriched in GE for epithelial-mesenchymal transition, and growth factor pathways and cell models responded to NVP-BEZ235 (a PI3K/mTOR inhibitor) and dasatinib (an abl/src inhibitor).

The LAR subtype includes patients with decreased relapse-free survival and was characterized by androgen receptor (AR) signaling.”

In other words, based on identifying a women with triple negative breast cancer’s precise subtype, they could be used as a potential biomarker for selection into appropriate clinical trials.  By doing this we may be able to screen those women more likely to respond to a given therapy and then determine in randomised controlled clinical trials whether the molecular hypothesis is indeed correct before treatment in a broader population.

Many of you will no doubt be wondering how this relates to PARP inhibitors such as iniparib, which until recently were the hottest thing in breast cancer.  The simple answer is, it doesn’t.  None of the subtypes identified appear to have a known sensitivity to PARP inhibitors, that I know of.  What is important is that new molecular subtypes have been identified and these appear to be sensitive to therapies either already available commercially or in clinical development for other tumour types.

Overall, this is an excellent and well designed study with the most useful and instructive findings.  It’s like finding 6 needles in a haystack at once and will hopefully guide us in a much more focused way.  I really do hope that clinical researchers respond quickly and get some new clinical trials going up and running soon with appropriate patient selection criteria in triple negative breast cancer.

We need more cowbell like this in cancer research.  This is the stuff dreams are made of.

References:

ResearchBlogging.orgLehmann, B., Bauer, J., Chen, X., Sanders, M., Chakravarthy, A., Shyr, Y., & Pietenpol, J. (2011). Identification of human triple-negative breast cancer subtypes and preclinical models for selection of targeted therapies Journal of Clinical Investigation, 121 (7), 2750-2767 DOI: 10.1172/JCI45014

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What's hot at ASCO 2011?

By on May 31, 2011

This weekend I’m heading off to Chicago for the annual meeting of the American Society of Clinical Oncology (ASCO).  I’ll be writing some in depth pieces and daily highlights from the conference, but in the meantime, many of you will be wondering what might be interesting amongst the 5,000 or so abstracts.

Here’s a quick snapshot of some data I’m looking forward to catching up on – there’s no clapperboard or guy with a teleprompter behind the camera, just a few ideas and some things to watch out for:

http://youtu.be/TNwQvV4aYl8

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Elements of success in cancer research

By on March 10, 2011

“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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Molecular subtypes in gliomas predict prognosis

By on March 1, 2011

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

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