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Posts from the ‘Strategy’ category

PTEN is an important tumor suppressor gene in breast cancer

By on August 5, 2011

An interesting new paper has just appeared in the latest online first edition of Cancer Discovery, and discusses a functional classification for evaluating the alterations in breast cancer to ultimately determine which are drivers and passengers.

Functional Variability in Breast Cancer

The researchers are essentially using an integrated approach of combining genomics and gene expression profiles overlaid with functional data to create a systematic map.

The goal was to determine if it will help identify key vulnerabilities in genetic mutations and the breast cancer genome as part of a joint Stand Up To Cancer (SU2C) and American Association for Cancer Research (AACR) initiative.

“We have carried out a functional genetic screen in >30 commonly used models of breast cancer to identify genes critical to the growth of specific breast cancer subtypes. In particular, we describe potential new therapeutic targets for PTEN-mutated cancers and for estrogen receptor–positive breast cancers.

We also show that large-scale functional profiling allows the classification of breast cancers into subgroups distinct from established subtypes.”

Should such an approach be successful, it is easy to see how it could be replicated in other tumour types.

The beauty of this methodology, while complex, is we know that not all mutations and aberrations that appear are critical to the tumour’s survival, so creating a road map will enable clinicians to better design trials in a more personalised medicine approach to treatment.  Once we know a patients particular molecular make up and which aberrations are important, then treatment can be more selective and appropriate based on the profile and biomarkers.

Although conceptually, this article was about the idea of figuring out the critical driver oncogenes, they also focus on PTEN mutations and PIK3CA mutations as potential targets, since loss of PTEN is associated with many cancers, including breast cancer. Unravelling the heterogeneity and key targets amy well lead to new therapeutic approaches.

I first heard of PTEN inhibitors a while back in relation to a small private start-up biotech called Pintex, although they were subsequently sold to a UK company, Vernalis.  Vernalis is developing several interesting compounds including Heat-shock proteins (Hsp) and has partnerships with several large pharma companies.  I don’t think any of the PTEN inhibitors survived though and it appears to be a transfer of assets that was more valuable than the compounds they had in development.

Since then, the lead PTEN inhibitor appears to be Semafore’s SF1670, which had a recent preclinical publication in Blood magazine (see references below) and may be hitting clinical trials in the next year or two.  One interesting approach that might evolve is a ‘set-up-knock-down’ approach in tumours that have loss of PTEN and follow this with, say, a PI3K inhibitor.  Semafore also have one of those too, in SF1126, making such a dual strategy in sequencing potentially feasible:

Dual PTEN/PI3K inhibition

As Michel Becker, Semafore’s acting CEO succinctly described it to me:

“The PTEN inhibitor’s role would be to stimulate quiescent cells into a treatable/PI3K addicted state.”

Check out Wicha et al., (2006) for more details on this concept.  Given that PI3K inhibitors have, at best, resulted in stable disease in the tumour types tested to date (including breast cancer), it would be interesting to see if this would lead to better response rates and ultimately, outcomes.

Brough et al’s., (2011) research into loss of PTEN and PIK3CA mutations (mutant not wild type or point mutations) in breast cancer is most interesting, but there is still a long way to go. We need to know more of the underlying biology and the impact of inhibition of targets and the consequences. We should then be able to figure out the optimal targets and logical combination strategies that will lead to responses that are both superior and more durable than currently seen in patients with breast cancer and other tumour types.

The good news is that the basic research is looking fairly promising to date.  I can say without hesitation that combination strategies are more likely to lead to better results than targeting either PTEN or PI3K alone.

 

References:

ResearchBlogging.orgBrough, R, Frankum, JR, Sims, D, Mackay, A, Mendes-Pereira, AM, Bajrami, I, Costa-Cabral, S, Rafiq, R, Ahmad, AS, Cerone, MA, Natrajan, R, Sharpe, R, Shiu, K-K, Wetterskog, D, Dedes, KJ, Lambros, MB, Rawjee, T, Linardopoulos, S, Reis-Filho, JS, Turner, NC, Lord, CJ, & Ashworth, A (2011). Functional Viability Profiles of Breast Cancer. Cancer Discovery : 10.1158/2159-8290.CD-11-0107

Li, Y., Prasad, A., Jia, Y., Roy, S., Loison, F., Mondal, S., Kocjan, P., Silberstein, L., Ding, S., & Luo, H. (2011). Pretreatment with phosphatase and tensin homolog deleted on chromosome 10 (PTEN) inhibitor SF1670 augments the efficacy of granulocyte transfusion in a clinically relevant mouse model. Blood, 117 (24), 6702-6713 DOI: 10.1182/blood-2010-09-309864

Wicha, M. (2006). Cancer Stem Cells: An Old Idea–A Paradigm Shift Cancer Research, 66 (4), 1883-1890 DOI: 10.1158/0008-5472.CAN-05-3153

The role of PTEN in non-melanoma skin cancer

By on August 1, 2011

While reading the latest Cancer Research journal, I was surprised to learn that:

“Nonmelanoma skin cancer is the most common cancer in the United States, where DNA-damaging ultraviolet B (UVB) radiation from the sun remains the major environmental risk factor.”

Ming et al., (2011)

In fact, more than one million new cases are diagnosed in the US annually, which accounts for 40% of all new cancer cases.  That’s a lot of skin cancer!

Source: s_manca: Great Barrier Reef

The bigger question, though, is what are the genetic underpinings of the disease?  These non-melanoma skin skin cancers tend to derive from the epidermal basal layer in response to DNA damage from sunlight.

From an incidence perspective, I would suspect that those with pale skin who are subject to harsh sunlight such as Australia would be particularly susceptible.

Researchers from the University of Chicago may have identified a role for PTEN, a known tumour suppressor, in removing DNA damage derived from UVB radiation, see Ming et al., (2011) in the references below.  UVB radiation is a known risk factor for non-melanoma skin cancer.

In previous research, the group discovered laboratory mice with reduced levels of PTEN were more likely to have UVB-induced skin cancers.  They therefore decided to test the idea in human cells to see if the finding could be replicated.

In the latest research, they reported what happened when they exposed skin cells to UVB radiation and examined the rates of DNA repair. Those with lower PTEN levels had slower rates of DNA repair, because of loss of the key DNA repair protein xeroderma pigmentosum C (XPC).

What was most interesting was what happened when the scientists restored the levels of XPC?  In that situation, the rates of DNA repair went up as well.

Overall, the current research in human cell lines suggests that cells without adequate levels of PTEN were not able to repair sufficiently, confirming the results seen in the mice.

Given a greater understanding of the molecular mechanisms underpining non-melanoma skin cancer potentially means that chemoprevention strategies can be developed down the road.  In other words, if we could identify those most at risk due to low PTEN levels, then supplements or therapeutics might be useful as a protection strategy.

Photo Credit: s_manca

References:

ResearchBlogging.orgMing, M., Feng, L., Shea, C., Soltani, K., Zhao, B., Han, W., Smart, R., Trempus, C., & He, Y. (2011). PTEN Positively Regulates UVB-Induced DNA Damage Repair Cancer Research, 71 (15), 5287-5295 DOI: 10.1158/0008-5472.CAN-10-4614

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New solutions for resistance to therapies in lung cancer?

By on July 29, 2011

One of the things that is both frustrating and fascinating is the development of resistance to therapies in cancer treatment.  By this, I mean clearly it’s not something we want to see from a patient or physician perspective and if possible, to delay it as long as feasible.  On the other hand, the mechanics behind the biology of drug resistance is a fertile field for curious scientists.

I never fail to feel a sense of awe when a group cracks open new mechanisms that improve our understanding of cancer.  It is, after all, a highly complex and fickle topic. I’ve often wondered why is it that some patients see resistance set in early and others do not? Why does resistance occur, period?

This morning my interest was piqued by a new paper published this month in Science Translational Medicine from William Pao’s group at Vanderbilt. They looked at the conundrum around EGFR inhibitors such as erlotinib, gefitinib and afatinib in non-small cell lung cancer (NSCLC) because patients treated with these drugs eventually develop acquired resistance to therapy and the cancer unfortunately starts growing again.  The big question are why and what?

“The most common mechanism of resistance is a second site mutation within exon 20 of EGFR (T790M), observed in ~50% of cases. This change leads to altered binding of the drug within the ATP pocket.”

In this elegant research, they looked at the behaviour in cell lines before and after the cells acquire resistance to targeted therapy:

“Because both drugs were developed to target wild-type EGFR, we hypothesized that current dosing schedules were not optimized for mutant EGFR or to prevent resistance.

To investigate this further, we developed isogenic TKI-sensitive and TKI-resistant pairs of cell lines that mimic the behavior of human tumors.”

What they found was really interesting

In simple terms, they noticed that NSCLC cells grow at different rates, which may possibly explain why some tumours become resistant to EGFR inhibitors faster than others.

What was surprising though, is that EGFR mutant (resistant) cells grew at a slower rate:

“On average, parental cells doubled ~1.22 times faster than T790M-containing resistant cells.”

It isn’t yet clear why this happens though.

In clinical practice, it has been noticed that patients with acquired resistance have re-responded to tyrosine kinase inhibitor (TKI) therapy after a drug holiday.  Chmielecki et al., found some evidence as to why this might happen, since they observed that:

“Lysates from parental cells and late-passage PC-9/BR–resistant cells treated with BIBW-2992 showed significantly reduced phosphorylation of EGFR and its downstream targets, extracellular signal–regulated kinase (ERK) and AKT, whereas lysates from resistant cells maintained in the presence of TKI and treated with the same concentrations of drug did not.”

Once the validity of the preclinical findings were established, they looked at evolutionary modelling to design optimal dosing strategies for the use of EGFR inhibitors in NSCLC. They incorporated PK data from clinical trials to ensure the drug doses proposed were feasible. The modelling appeared to be useful:

“This modeling predicted alternative therapeutic strategies that could prolong the clinical benefit of TKIs against EGFR-mutant NSCLCs by delaying the development of resistance.”

It is worth noting the strategy predicted by the model:

“We propose the use of high-dose pulsed once-weekly BIBW-2992 with daily low-dose erlotinib to delay the emergence of T790M-mediated resistance. PC-9 cells treated with this regimen required twice as long to develop resistance and did not show selection for T790M mutations.

 

In patients, the combination of two EGFR TKIs could lead to overlapping toxicities involving rash and diarrhea. Thus, in a phase IB dose-safety trial, we would recommend a more tolerable strategy, with lower doses of erlotinib still known to be effective against EGFR-mutant tumors (25 or 50 mg daily, orally).”

What’s also fascinating to me is that the overall study findings make sense for consideration when using other TKIs as well, since we know that GIST patients treated with imatinib can re-respond after a period of drug holiday (see Fumagalli et al., (2009).  Could different dosing strategies be adopted in some patients at a high risk of developing resistance based on the model approach?

It will be most interesting to see whether clinical trials in lung cancer with EGFR inhibitors evolve along the lines of those suggested by the researchers – that will be the ultimate proof of the pudding that resistance can be influenced in patients with NSCLC – until then, it’s a valuable hypothesis.

References:

ResearchBlogging.orgChmielecki, J., Foo, J., Oxnard, G., Hutchinson, K., Ohashi, K., Somwar, R., Wang, L., Amato, K., Arcila, M., Sos, M., Socci, N., Viale, A., de Stanchina, E., Ginsberg, M., Thomas, R., Kris, M., Inoue, A., Ladanyi, M., Miller, V., Michor, F., & Pao, W. (2011). Optimization of Dosing for EGFR-Mutant Non-Small Cell Lung Cancer with Evolutionary Cancer Modeling. Science Translational Medicine, 3 (90), 90-90 DOI: 10.1126/scitranslmed.3002356

E. Fumagalli, P. Coco, C. Morosi, P. Dileo, R. Bertulli, A. Gronchi, & P. G. Casali (2009). Rechallenge with imatinib in GIST patients resistant to second or third line therapy 15th Connective Tissue Oncology Society Meeting, Miami Beach, FL

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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

BRAF mutations in hairy cell leukemia

By on July 18, 2011

Last month an interesting article was published in The New England Journal of Medicine describing how BRAFV600E mutations may have a key role to play in hairy cell leukemia (HCL), which came out around the same time as the European Hematology Association (EHA) meeting that I attended in London.  The news certainly caused a buzz at the conference!

Source: Wikipedia

Hair cell leukemia is a fairly rare type of leukemia that affects B cells (lymphocytes), which are distinguished by their hairy like appearance under the microscope because they have fine projections coming from their surface.

Over the past year, we have heard much about how the BRAFV600E mutation plays a critical role in melanoma and the progress with the testing of a specific inhibitor, vemurafenib (PLX4032), in the clinic, leading to some initial clinical success in this indication.  What’s particularly interesting about the NEJM article is that it describes, for the first time, how the BRAFV600E mutation may be a key genetic alteration in HCL.

The researchers used Sanger sequencing to undertake an extensive analysis of the genome in normal and HCL peripheral blood samples. The findings were also validated in additional patients with HCL (n=47).  The results were a little surprising:

“Whole-exome sequencing identified five missense somatic clonal mutations that were confirmed on Sanger sequencing, including a heterozygous mutation in BRAF that results in the BRAF V600E variant protein.”

The mutation was only found in patient samples who had HCL, not other types of leukemia or lymphomas:

“None of the 195 patients with other peripheral B-cell lymphomas or leukemias who were evaluated carried the BRAF V600E variant, including 38 patients with splenic marginal-zone lymphomas or unclassifiable splenic lymphomas or leukemias.”

Some immunohistologic and Western blot studies, were performed.  They found that:

“HCL cells expressed phosphorylated MEK and ERK (the downstream targets of the BRAF kinase), indicating a constitutive activation of the RAF–MEK–ERK mitogen-activated protein kinase pathway in HCL.

In vitro incubation of BRAF-mutated primary leukemic hairy cells from 5 patients with PLX-4720, a specific inhibitor of active BRAF, led to a marked decrease in phosphorylated ERK and MEK.”

PLX-4720 is another BRAF inhibitor that Plexxikon have in development in addition to the original one, PLX-4032 that became vemurafenib.

Now, while is promising evidence that needs to be researched further, we must exercise caution.  Remember that just because a mutation exists, does not mean that it is a key driver.  We saw this with colon cancer and BRAFV600E mutations – where vemurafenib had little of no effect in patients, despite promising preclinical data – a stark contrast to the results in metastatic melanoma!  Why does the same target produce entirely different results when inhibited by an effective agent?  One reason could be that that BRAF is a passenger not a driver in colon cancer.

In the meantime, I will be keenly following any progress with testing of specific BRAF inhibitors for patients with hairy cell leukemia to see whether it will be a useful clinical approach in managing the disease or not.

 

References:

ResearchBlogging.orgTiacci, E., Trifonov, V., Schiavoni, G., Holmes, A., Kern, W., Martelli, M., Pucciarini, A., Bigerna, B., Pacini, R., Wells, V., Sportoletti, P., Pettirossi, V., Mannucci, R., Elliott, O., Liso, A., Ambrosetti, A., Pulsoni, A., Forconi, F., Trentin, L., Semenzato, G., Inghirami, G., Capponi, M., Di Raimondo, F., Patti, C., Arcaini, L., Musto, P., Pileri, S., Haferlach, C., Schnittger, S., Pizzolo, G., Foà, R., Farinelli, L., Haferlach, T., Pasqualucci, L., Rabadan, R., & Falini, B. (2011). Mutations in Hairy-Cell Leukemia New England Journal of Medicine, 364 (24), 2305-2315 DOI: 10.1056/NEJMoa1014209

Biotechnology, Genomics and Personalized Medicine

By on June 29, 2011

Ruby (@divabiotech) talking at Singularity U

My friend Ruby Gadelrab is the very dynamic and vivacious Head of Marketing and Clinical Development for International Markets at Affymetrix.

She was recently invited to give a talk at the prestigious Singularity University meeting.

I was thrilled to see that Ruby has generously posted her talk online on her blog, Diva Biotech, which I’m a big fan of, and check out regularly in my RSS feeds.   The excellent presentation well worth reading if you want to come up to speed on the basics, as well as see her personal view on where the field is going in the near future.

I learned a lot from her synopsis and thought it was a nice thing to share here with PSB readers who may be interested in the topic, as this is a subject that will be very much to the fore in the next 5-10 years.

You can read all about it and download Ruby’s slides on Biotechnology, Genomics and Personalized Medicine.

Check it out!

Some thoughts on cancer research and the pipeline cliff…

By on June 28, 2011

This morning I was pondering a triangulation of several random thoughts that appeared in my Twitter stream, many from BIO, about various topics:

  1. Discussing the patent cliffs and lack of revenue generation some companies such as Lilly will no doubt be facing with John Carroll (Fierce Biotech) and Matt Herper (Forbes Health)
  2. Christiane True (PharmaLive) at the annual BIO meeting quoted a speaker as saying “doing more with less” which seems pretty much de rigeur these days
  3. Ron Leuty tweeted a quote from Chris Viehbacher’s (Sanofi) presentation at BIO, “Not doing more with less, but doing different things.”
  4. Christiane also quoted Viehbacher, “Still not enough of bright science making its way to patient benefit.”

The last point particularly made me wonder, because quite a few oncology companies have broad and deep pipelines, often with more compounds than they can possibly advance at once.  Even big Pharma or Biotech has to rationalise resources, budgets and people or nothing would get done.

How do those decisions get made?

Some are smart at life cycle management (GSK and Roche spring to mind), some think strategically about their portfolios, others get mired down in politics or – even worse – distracted by numerous committees focusing on what I call ‘fluffy puffy’ abstract things instead of moving the compounds rapidly through the pipeline to become safe and effective drugs that make a difference to patients lives.

The future of successful cancer drug development is likely going rest heavily on investment in basic science, molecular biomarkers and diagnostics, and novel-novel clinical trials that target multiple aberrations driving the disease.

Investors aren’t interested in any of these things, though; most just want a rapid or high return on their investment.  Spending less on R&D is much more in tune with their short term thinking:

Viebacher: If you sit down with investors, they clamor to stop spending on R&D, just do a buyback. #BIO2011

Tweet from Christiane True (PharmaLive) at BIO

The thing is, if pharma companies are going to rely on buying or licensing late stage compounds from Biotech, there is only so much small to medium Biotechs will be able to do going forward, because the future will mean more diagnostics and biomarkers, which are very expensive in cancer research, and in some cases, prohibitively so.  This will require closer, earlier collaboration with Academia and even different types of trials thanwe have been used to in the old chemotherapy world.

There are sometimes more challenges with clinical trial designs in small biotechs going from phase II to III, as Sanofi discovered with BiPar and iniparib and Novartis with Antisoma and ASA-404.  If we want to reduce the number of phase III failures, we have to get smarter about more iterative studies in phase II, better patient selection, incorporation of biomarkers, more logical combinations and yes, all of these will cost more dollars that will likely give investors insomnia.

Finding out more about the compound earlier will be the new name of the game – it is obviously better to abandon a weak agent on phase I or II than expensive phase III trials.

In the end, the companies who will win out in the long run are often those who think strategically, drive innovation, focus on science-based research, license earlier rather than later, invest in biomarker/diagnostic research, work in close knit cross-functional collaborative groups, avoid the twin pitfalls of bad karma and politics and ultimately ‘see’ things more clearly than the pack allows them to translate that into meaningful action.

It occurred to me that if you have to ask who the KOLs and experts are, then you have a long way to go and that doesn’t inspire confidence in the agent you’re developing.  If you have too much greed in the boardroom C-level that’s clearly going to hamper things as well, especially if they want to implement cuts down the line.  All of these myriad of factors surprisingly do matter when it comes to riding out patent cliffs and maintaining R&D momentum.

I should probably add ‘corporately ignore the short term investors for long term solid gains,’ but that would be a bit cheeky, perhaps 😉

Ultimately, what I would really like to see is less talk and more effective action:

A lot of talk about benefits and challenges with personalised healthcare but no mention of solutions #BIO2011

Tweet from Pieter Droppert in the Personalised Medicine session at BIO

I guess that’s why the American Association for Cancer Research (AACR) remains my favourite meeting in the annual conference calendar – at least Academic attendees are presenting data and discussing solutions in informal chats in corridors or poster sessions on how to address the practical issues of improving cancer research.  Inevitably, the smart companies are tapping into this resource and working alongside each other to unravel the complex mysteries.


Update on new targets in squamous cell carcinoma of the lung

By on June 22, 2011

Over the last couple of days we have looked at targeted therapies designed to inhibit some of the molecular peculiarities associated with non-squamous lung cancer, and adenocarcinomas in particular.

Squamous Cell Lung Cancer

As far as I know, there are no approved targeted therapies specifically for squamous cell carcinoma (SCC) of the lung, so chemotherapy is very much the standard of care still, although response rates tend to be disappointing.  Unlike adenocarcinomas, this subset is more often associated with smoking.  It also represents a large group of approximately 25% of NSCLC.

Previously, we have discussed FGFR1 mutations in SCC as a potential target, but although there a several FGFR inhibitors in the clinic, I couldn’t find any specifically being tested in SCC lung cancer.

Recently though, Peter Hammerman and Matthew Myerson (Dana Farber) published interesting data at the annual AACR meeting identifying a potential new therapeutic target, discodin domain receptor 2 (DDR2), in squamous cell carcinoma of the lung.

What does this new research on DDR2 tell us?

Cancer Discovery from AACR

I’ve been meaning to write about this exciting development since the AACR meeting, but the data was published in the new journal Cancer Discovery.

Somewhat perversely, the DOI references are not yet showing up in PubMed or Research Blogging, so I finally resorted to adding the reference manually.

If the link in the Reference section at the end of the blog post doesn’t work, you can download the article (open access PDF) below:

Mutations in the DDR2 Kinase Gene identify a Novel therapeutic target in squamous cell lung cancer

Essentially, Sanger sequencing was employed to look at the tyrosine kinome and determine whether any relevant mutations existed in 290 SCC samples.  The schema for the Hammerman et al’s (2011) research is described below:

Sequencing of squamous cell lung cancer samples

DDR2 is a receptor kinase that binds collagen as its exogenous ligand and has previously been shown to promote cell migration, proliferation and survival when activated.

Ultimately, DDR2 mutations were observed in 11 of the 290 samples in the validation screen.  The researchers observed that these DDR2 mutations occurred in 3.8% of lung squamous cell carcinomas, and in xenograft models these appeared to show a sensitivity to dasatinib (Sprycel), a multi-kinase inhibitor approved for the treatment of Ph+ chronic myeloid leukemia (CML).

Several kinase inhibitors were evaluated, including imatinib, but dasatinib was found to be particularly sensitive.  The reason is that has a much lower fluorescent resonance energy transfer (FRET) measurement (5.4 nM) than imatinib (71.6 nM) for recombinant DDR2.  Interestingly, both nilotinib (35.4 nM) and ponatinib (5.4 nM) also showed activity in SCC cell lines harbouring DDR2, although ponatinib appeared to be the more potent of the two, with activity in line with dasatinib in this setting.

Subsequently, it was observed that a SCC lung patient with a DDR2 mutation responded well to a combination of dasatinib and erlotinib therapy, suggesting a clinical trial might be in order to determine efficacy and also safety on a broader scale, since dasatinib is associated with adverse events such as pleural and pericardial effusions in CML, possibly from off-kinase Src activity.

For those interested, you can listen to a short podcast via Cancer Discovery with Matthew Myerson on the DDR2 mutation.

Conclusions

Overall, the landscape in lung cancer is rapidly changing as more molecular targets are being identified, along with therapies that specifically inhibit the driving cancerous activity.

EGFR mutations were the first major breakthrough in targeted therapies, but with the discovery of ALK translocations, T790M mutations (all adenocarcinomas) and now with FGFR1 and DDR2 (squamous), we have exciting opportunities to potentially match therapies to patients in non-small cell lung cancer in a new era of molecularly targeted and personalised therapy, assuming clinical trials corroborate the promise of the targets, that is.

I can see a time in the not too distant future that we will start diagnosing, testing and treating people with lung cancer based on their molecular abnormalities on a more routine basis with targeted therapies, rather than merely test for histology, which is a rather crude and heterogeneous way of looking at the conundrum.  Of course, we would still need to research and tackle the adaptive resistance pathways that emerge, but it would certainly be a huge improvement on toxic chemotherapies we have now… and that would be a major step forward for this devastating disease.

Check back tomorrow for the next article in the series on lung cancer targets!

References:

ResearchBlogging.org

Peter S. Hammerman, Martin L. Sos, Alex H. Ramos, Chunxiao Xu, Amit Dutt, Wenjun Zhou, Lear E. Brace, Brittany A. Woods, Wenchu Lin, Jianming Zhang, Elisabeth Brambilla, Christian Brambilla, Philippe Lorimier, Odd Terje Brustugun, Åslaug Helland, Iver Petersen, Joachim H. Clement, Harry Groen, Wim Timens, Hannie Sietsma, Erich Stoelben, Jürgen Wolf, David G. Beer, Ming Sound Tsao, Megan Hanna, Charles Hatton, Michael J. Eck, Pasi A. Janne, Bruce E. Johnson, Wendy Winckler, Heidi Greulich, Adam J. Bass, Jeonghee Cho, Daniel Rauh, Nathanael S. Gray, Kwok-Kin Wong, Eric B. Haura, Roman K. Thomas, & Matthew Meyerson (2011). Mutations in the DDR2 Kinase Gene identify a Novel therapeutic target in squamous cell lung cancer Cancer Discovery, 1 (1), 78-89 : 10.1158/2159-8274.CD-11-0005

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Update on EGFR inhibitors, KRAS and T790M mutations in lung cancer

By on June 21, 2011

Yesterday we discussed ELM4-ALK translocations associated with adenocarcinomas in non-small cell lung cancer (NSCLC).   Before ALK was identified, the main molecular target in this disease was EGFR mutations, which have been shown to be associated with improved responses when EGFR inhibitors such as erlotinib are given.

EGFR mutations

Although erlotinib is the EGFR inhibitor of choice in the US for patients with lung cancer who have EGFR mutations, unfortunately approx. 50% of them with development resistance as a new mutation evolves, known as T790M.  In addition, patients with EGFR mutant disease generally don’t respond well to erlotinib.

There are a number of EGFR inhibitors now in development for lung cancer, specially adenocarcinomas, and this market is rapidly getting fairly crowded, as the table shows:

EGFR Inhibitors

Note: *Although gefitinib was approved, there is very little use of this agent in the US since the FDA modified the PI to include mention of no overall survival benefit.

This table does not include all EGFR inhibitors in clinical development, since those focused on HER2+ breast and gastric cancers (trastuzumab, lapatinib, pertuzumab) and KRAS wt colorectal cancer (cetuximab and panitumumab) were excluded from this analysis. There are, no doubt, other EGFR inhibitors also being evaluated in lung cancer, but these are the main ones I’m following – it’s for illustrative purposes only!

What we can see here is that the EGFR market in lung cancer is getting pretty competitive in terms of clinical trials and is a much more mature market than the ALK one discussed yesterday, although only erlotinib is still currently available in the US for treatment of EGFR+ mutations.

Beyond that, there are at least three inhibitors in phase III trials alone:

  • Afatinib, which reported rather indifferent data in the LUX-LUNG1 trial at ESMO last September, with an improvement in response rate over placebo, but no advantage in overall survival, the primary endpoint of the trial.
  • Necitimumab, a monoclonal antibody being tested in squamous histology in combination with gemcitabine and cisplatin.
  • Nimotuzumab, another monoclonal antibody to EGFR, which is in phase III for oesophageal and H&N cancers, but currently enrolling in several phase II lung cancer trials at the moment.

Aside from the sheer awkwardness of trying to say either of the last two generic names and resorting, like many people to calling them Nessie and Nemo, I also have trouble remembering which one is which or my eyes glaze over!  The tongue twisters that are cropping up for a multitude of targeted therapies is more challenging than ever.  On top of that is the dreadful tendency of late to choose ugly brand names for cancer drugs that seem to have been purchased as a job lot from Eastern Europe brand agencies.

T790M confers resistance to erlotinib

We have known for a while that EGFR inhibitors do not work in all patients:

  • They are effective in wild type but not mutant EGFR
  • Some patients on EGFR therapy develop resistance due to a new mutation, T790M, appearing (see Hammerman et al., 2009).

There has been little progress in either of these two areas of late, although a multitude of clinical trials are now ongoing and we are awaiting data readouts.

Dr Jack West, Swedish

Dr Jack West, Swedish Cancer Institute

Dr Jack West from the Swedish Cancer Institute in Seattle blogged about his enthusiasm for the irreversible EGFR inhibitor, PF299804, in lung cancer last summer, based on the two small studies (one American and one Asian) that were reported at the time.  Another small Australian study on EGFR mutations and PF299804 was also presented at ASCO last year.

The Asian study looked promising enough at the time for Park et al., (2010) to conclude that the data from the Korean patients with KRAS wild-type NSCLC (adenocarcinoma histology) who were refractory to platinum-based chemotherapy and erlotinib (E) or gefitinib (G) that:

“Preliminary data consistent with Western trials show that in heavily treated Asian pts with NSCLC after E or G failure, PF299 is well tolerated and has antitumor activity without adversely impacting pts’ HRQOL. These results support the ongoing global P3 trial in pts with refractory NSCLC.”

KRAS mutations in NSCLC

I distinctly remember at ASCO in 2010 one of the three groups stated that a phase III trial (BR26) would be forthcoming in KRAS wt patients.  This trial is is now enrolling patients in the refractory setting after failure of erlotinib in both KRAS mutant and wild type patients, so we are unlikely to get a readout of this study before the end of 2012 at the earliest.

Dr Nathan Pennell, Taussig Cancer Center

Dr Nathan Pennell, Taussig Cancer Center

What was also interesting was another more recent post on GRACE by one of the faculty, Dr Nathan Pennell, discussing the combination of afatinib and cetuximab in EGFR+ lung cancer.

Like Dr Pennell, I would not have been enthusiastic about this potential combination after seeing the LUX-LUNG data presented by Dr Vincent Miller at ESMO last September, and knowing that cetuximab has shown weak activity in lung cancer at best, both alone and in combination with erlotinib.

However, as Dr Pennell described, the results with the afatinib plus cetuximab combination were much better than expected in erlotinib refractory lung cancer patients:

“The confirmed overall response rate in the first 45 evaluable NSCLC patients was 40%, with the response rate in the T790M patients being 50% unconfirmed (unconfirmed means they had not yet done a second set of scans to see if the tumor was still responding over 2 time points).”

Understandably, he was quietly excited by the outcome:

“This is the first time anyone has described activity for any targeted drug in the T790M EGFR population, and this provides the first glimmer of hope for the many patients out there who face the reality of knowing that their tumors are still dependent on EGFR mutations but for whom Tarceva simply doesn’t work anymore.”

This is most interesting, because while afatinib is a TKI that works similarly to erlotinib and gefitinib inside the cell on the EGFR ligand, cetuximab is a monoclonal antibody that works on the outside of the ligand, suggesting that targeting the ligand upstream and downstream may well be necessary to ensure complete EGFR inhibition in these patients ie EGFR, KRAS and T790M, we don’t know for sure, but now doubt a paper will be published soon explaining the scientific phenomenom.

The result is certainly a big surprise given the previous disappointing data for cetuximab combined with erlotinib (no responses out of 19 patients evaluated), so I’m not sure why afatinib is different given it is also a small molecule TKI.  Further large scale trials will needed to confirm these promising results.  A phase I trial with cetuximab and afatinib in NSCLC is currently enrolling patients.

For those interested, you can check out the simply stunning waterfall plot that Dr Pennell found for the combination of afatinib and cetuximab, with both EGFR+ and EGFR- patients responding.  I confess I nearly fell off my chair when I looked – the data is not what was expected at all!

Meanwhile, Pfizer also appear to be looking at PF299804 in HER2+ gastric cancer, which is logical given the activity previously demonstrated by trastuzumab.  There are over 20 studies with this pan-EGFR agent.  Although I’m sure I read somewhere that PF299804 specifically targets the T790M mutations that develop with erlotinib, it will be interesting to see what happens with wild-type and mutant subsets, since we know that erlotinib and gefitinib only work in wild type not mutant EGFR.  Another clinical trial is also enrolling patients with Pfizer’s pan-EGFR (PF299804) and MET inhibitor (crizotinib) in NSCLC.  More on c-MET inhibitors will follow in another post.

All that said, the rationale for targeting T790M mutations in erlotinib-refractory disease is fairly compelling in theory, but the trials will not be easy as there are several challenges that must be overcome:

  1. Design and implementation – patient and inhibitor selection will be crucial
  2. High risk, especially if the compound is a weak inhibitor
  3. Heavily pre-treated refractory patients tend to be sick with a higher tumour burden that is more resistant to therapy
  4. It is a small, difficult to treat subset
  5. Finding patients with good performance status who meet all the eligibility criteria is never easy in small refractory subset populations
  6. Would combinations be superior to single agent therapy or should sequencing be investigated?
  7. An upfront trial as a head to head with erlotinib would clearly be easier to execute, but also high risk if the agent is too similar

The more you look at the conundrum, the more one realises that addressing it is not as easy as it first looks.  Some basic research looking at sequencing versus combinations in cells lines and xenografts with different agents may be a useful starting point.

That said, the news last Friday that Ariad are advancing their dual EGFR-ALK inhibitor AP26113 into the clinic later this year is good news for patients with lung cancer, because more available options is always better than fewer.   It will be interesting to see how the drug fares in either ALK-refractory patients (refractory to crizotinib) or in EGFR mutations (refractory to erlotinib) as potential fast track to market strategies.

Conclusions

Overall, the landscape in lung cancer is rapidly changing as new molecular targets are being identified, along with new targeted therapies that specifically inhibit the driving cancerous activity.

EGFR mutations were the first major breakthrough in targeted therapies for lung cancer, but with the discovery of ALK translocations, T790M mutations, MET and FGFR1 ampliflication, and DDR2 mutations, we now have exciting opportunities to potentially match therapies to patients in across a range of different non-small cell lung cancer subsets in a new era of molecularly targeted and personalised therapy.

Beyond erlotinib, there is a clear high unmet medical need for new targeted therapies that specifically inhibit either the T790M mutation associated with resistance to initial therapy or will work in KRAS mutant EGFR lung cancers.  The afatinib + cetuximab combination in erlotinib refractory NSCLC looks very promising and I’m very much looking forward to watching all the new developments evolve in this area.

Disclosure: I am an unpaid member/volunteer of the GRACE Board.

References:

ResearchBlogging.orgHammerman PS, Jänne PA, & Johnson BE (2009). Resistance to Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors in Non-Small Cell Lung Cancer. Clinical Cancer Research, 15 (24), 7502-7509 PMID: 20008850

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Update on emerging therapies in ALK+ lung cancer

By on June 20, 2011

Last week’s post on FGFR1 mutations in squamous cell lung cancer and the new EGFR/ALK combination agent, AP26113 (Ariad) drew a lot of attention from readers, with many writing in for more details or correctly suggesting an update in squamous cell carcinoma was long overdue.

Oddly, there wasn’t much in the way of new or exciting data in lung cancer at the recent American Society of Clinical Oncology (ASCO), but there are some recent developments that are worth looking at in EGFR, ALK+ and squamous cell carcinoma.

Let’s take a look at each in turn over a series of blog posts.

In the old days, lung cancer was first divided into Small Cell Carcinoma (SCC) and Non-Small Cell Lung Carcinoma (NSCLC), which have a broad split of about 20:80.  As we learned more about the disease, NSCLC was eventually divided further in squamous and non-squamous histology, as therapies such as pemetrexed (non-squamous) and bevacizumab (non-squamous) emerged.

Erlotinib was found to work best in adenocarcinomas, ie EGFR mutation-positive tumours.  As far as I know, there are no approved targeted therapies for the treatment of squamous histology and much of the focus has been in mutations associated with adenocarcinomas, which mostly (but not always) tend to be associated with non-smokers.

ELM4-ALK translocations

Within adenocarcinomas, we are learning that EGFR isn’t the only mutation that might be a potential target, as the recent data in crizotinib published in the NEJM by Kwak et al., (2010) on ELM4-ALK translocations has shown.

For those of you interested in the development of the ALK translocations in lung cancer, Dr Ross Camidge also provided an excellent overview when we interviewed him on Pharma Stratgy Blog last year.  It’s worth checking out if you missed it, and has become one of our most popular posts since last October.

Dr Jack West from GRACE has diligently curated a huge volume of posts, interviews and webcasts on lung cancer, including this nifty chart showing the currently identified mutations in adenocarcinomas:

Mutations in lung cancer

Source: GRACE

Of course, as luck would have it, EGFR mutations and ALK translocations tend to be mutually exclusive, so there would probably be little benefit in combining agents that target EGFR or ALK mutations, even in adenocarcinomas.

Crizotinib, the first ALK inhibitor to successfully make it past phase II trials, has already been filed by Pfizer for approval with the FDA and should provide a new option for lung cancer patients with this translocation very soon.  This is an exciting development because oncologists will be able to order a FISH test using the companion diagnostic developed by Abbott (also submitted to the FDA) to determine if their patients will be suitable for crizotinib therapy.

Although crizotinib was originally developed as a c-MET inhibitor, its activity there was very weak (the Roche and ArQule compounds, MET-Mab and ARQ197 respectively, are much more potent and continue to look promising in phase II trials), the discovery of the ALK translocation changed the clinical development plan dramatically and for the better.

Unsurprisingly, there aren’t too many ALK inhibitors in development to date, with crizotinib being the lead compound:

ALK Inhibitors

This is a small, but rapidly growing niche; already we can see that compounds are emerging into the clinic hot on crizotinib’s heels.  The Infinity compound is a little different – it’s a heat shock protein (Hsp), while both the Novartis and Astellas agents are small molecule TKIs.  As far as I know, there isn’t a monoclonal antibody or antibody drug conjugate in the clinic for this particular target yet.

Like crizotinib, AP26113 is also a small molecule TKI, but differs in that it appears to be a dual inhibitor of ALK and EGFR, including the T790M mutation that has been shown to confer resistance to EGFR inhibitors such as erlotinib in adenocarcinomas (see Hammerman et al., 2009).

Conclusions

The time between the discovery of the ELM4-ALK translocation in adenocarcinomas and moving crizotinib into clinical trials was pretty rapid, and a tribute to Pfizer’s scientists and clinicians who made that happen so expeditiously.  It will be interesting to how this niche develops once FDA approval has occurred, and whether the other inhibitors in development will be merely ‘me-too’ agents or able to raise the bar beyond crizotinib in terms of efficacy, safety or overcoming resistance due to the structure forming a different binding shape in the kinase domain.  Time will tell.

Disclosure: I am an unpaid member/volunteer of the GRACE Board.

{UPDATE: Thanks to Luke Timmerman of Xconomy tweeting about Tesaro, I noticed they now have a deal as of March with Amgen for unnamed ALK inhibitors in their pipeline.}

 

References:

ResearchBlogging.orgKwak EL, Bang YJ, Camidge DR, Shaw AT, Solomon B, Maki RG, Ou SH, Dezube BJ, Jänne PA, Costa DB, Varella-Garcia M, Kim WH, Lynch TJ, Fidias P, Stubbs H, Engelman JA, Sequist LV, Tan W, Gandhi L, Mino-Kenudson M, Wei GC, Shreeve SM, Ratain MJ, Settleman J, Christensen JG, Haber DA, Wilner K, Salgia R, Shapiro GI, Clark JW, & Iafrate AJ (2010). Anaplastic lymphoma kinase inhibition in non-small-cell lung cancer. The New England Journal of Medicine, 363 (18), 1693-703 PMID: 20979469

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