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Commentary on Pharma & Biotech Oncology / Hematology New Product Development

Posts tagged ‘EGFR’

Transformative antibody technology in cancer research

By on July 30, 2013

Recently, I came across an exciting new development in a Nature publication and couldn’t resist teasing my Twitter followers with this terse statement:

Naturally, this mischievous tweet set off a lot of folks frantically trying to guess what I was referring to and the @replies came in thick and fast.

The National Science Foundation defines transformative as:

“Transformative research involves ideas, discoveries, or tools that radically change our understanding of an important existing scientific or engineering concept or educational practice or leads to the creation of a new paradigm or field of science, engineering, or education.  Such research challenges current understanding or provides pathways to new frontiers.”

Many suggestions came hurtling in, most related to a drug or company, but actually what I was referring to was a transformative technology – the biggest clue was in the question 🙂

Bispecific antibodies, to be more precise.

I was completely inspired by an article by a group of scientists in Nature Biotechnology by Speiss et al., (2013) – the link is included in the references below and is well with reading. It’s one of those things you read and think, “Wow, wish I had thought of that!”

Genentech kindly gave me access to one of their scientists involved, Dr Justin Scheer (gRED), who explained the rationale behind their approach and what they hope to do with this technology.  More on that in a moment, but first it’s a good idea to understand where I’m coming from.

Let’s take a look at both the potential and limitations of the various types being developed as cancer therapeutics, and the basics underpinning monoclonal and bispecific antibodies in more detail.

What are monoclonal antibodies?

Essentially, a monoclonal antibody is a manufactured molecule that’s engineered to attach to specific defects in cancer cells. They mimic antibodies the body naturally produces as part of the immune system’s response to invaders.

The immune system is trained to attack foreign invaders in the body, but it doesn’t always recognize cancer cells as enemies because they are formed from massive proliferation of the body’s own cells i.e. not foreign, unlike bacteria and viruses.

Monoclonal antibodies are usually directed to attach to certain parts of a cancer cell. An easy way to think of it is that the antibody ‘marks’ the cancer cell and makes it easier for the immune system to find and destroy.

How do monoclonal antibodies work?

The majority of currently available monoclonal antibodies are monospecific, i.e. having a single specific target e.g. CD20 or CD19, for example. The classic example in oncology is rituximab. Rituximab attaches to the CD20 protein found on B cells, which is associated with some types of lymphomas. When rituximab attaches to CD20, it makes the lymphoma cells more visible to the immune system, enabling them to be attacked and destroyed.

Treatment with rituximab lowers the number of B cells, including healthy B cells. The body will produce new healthy B cells to replace them and ensures that the cancerous B cells are less likely to recur.

While results with this approach have been impressive in some cases, there are limitations because cancer is highly complex and more than one target may be need to be addressed. This means that drug combinations are needed, increasing the complexity of clinical trial design especially in dose finding and MTD studies, risk of added or overlapping toxicities, increased costs etc.

Monoclonal antibodies such as rituximab have some other limiting factors though, as Speiss et al., (2013) observed:

“They lack natural Fc regions, they cannot bind to the neonatal FcRn receptor; binding to FcRn delays antibody clearance and improves pharmacokinetic (PK) properties.”

The lack of an Fc region also means that monoclonal antibodies typically cannot activate T-lymphocytes – because this type of cell does not possess Fc receptors – so the Fc region cannot bind to them.

A new potential solution exists

Antibodies that target two antigens are known as bispecific antibodies. Only one is currently available commercially (catumaxomab, Removab) and binds to CD3 and EpCam, although there are several in late stage development, including blinatumomab (Amgen) in ALL. The latter is interesting because it is part of the new generation of antibodies known as bi-specific T-cell engagers (BiTEs).

A bispecific monoclonal antibody (BsAb) is a manufactured protein that is composed of fragments of two different monoclonal antibodies and consequently binds to two different types of antigen.

Manufacturing a monoclonal antibody, while more complex than an oral tyrosine kinase inhibitor (TKI), is easier than a bispecific antibody. Much of the limitations seen so far with bispecific antibodies have been technological rather than clinical. What the Genentech scientists set out to do is succinctly described by Dr Scheer in the short Soundcloud below:

What are the advantages of bispecific antibodies?

The main advantage of bispecific antibodies is the ability to combine a cytotoxic cell (e.g. CD3) or ADC with a tumour specific protein target (e.g. CD19 or CD20) although a number of different combinations could be considered. In other words, you would get the ability to home in on the specific tumour target together with enhanced cell killing.

This could be a potent combination, except that technology-wise, they are difficult to engineer as Speiss and colleagues noted:

“… bispecific-antibody design and production remain challenging, owing to the need to incorporate two distinct heavy and light chain pairs while maintaining natural nonimmunogenic antibody architecture.”

There are some technological difficulties in engineering bispecific antibodies, though.  Blinatumomab was mentioned as one example by Speiss et al., (2013) because:

“… some bispecific antibody fragments (e.g., the anti-CD19-CD3 single-chain fragment blinatumomab) are expressed as a single polypeptide chain they include potentially immunogenic linkers.”

What was fascinating about the Nature Biotech paper was that they reported on a new process they had developed to manufacture bispecific antibodies:

“We present a bispecific-antibody production strategy that relies on co-culture of two bacterial strains, each expressing a half-antibody.  Using this approach, we produce 28 unique bispecific antibodies.”

One thing I thought was particularly cool about this novel approach is that bacteria are easier to manipulate and having a foreign component in the antibody will potentially mean that the human body’s immune system will hopefully pick it up more easily. Essentially, these new chemical structures could act as a powerful cancer homing device against specifically chosen targets.

The example used in the paper was a new bispecific antibody they engineered from co-cultures of EGFR and MET. Remember that Genentech/Roche already has a TKI against EGFR (erlotinib) on the market and a MET antibody (onartuzumab) in development. Neither of these drugs hit both targets and yet as Speiss and colleagues noted:

“MET and EGFR drive the growth of a marked proportion of non-small cell lung cancer tumors. MET and EGFR are often co-expressed and co-activated, and MET signaling can compensate for loss of EGFR signaling and vice versa.”

Image Courtesy of Roche's gRED unit: Bispecific antibody with two distinct binding arms that inhibits both MET (orange) and EGFR (green). The bispecific antibody, shown here in red and blue, has a natural antibody architecture

Image Courtesy of Roche’s gRED unit: Bispecific antibody with two distinct binding arms that inhibits both MET (orange) and EGFR (green). The bispecific antibody, shown here in red and blue, has a natural antibody architecture

As Dr Scheer observed, we don’t know yet is where the company will go with this exciting technology, but if the approach shows promising efficacy in future clinical trials, then it’s easy to see how multiple new bispecific antibodies could be easily developed for different tumour types, with far more potency and utility than single targeted therapies alone.

Stop and think about that possibility for a moment.

Transformative science isn’t always about finding a new target, sometimes the breakthrough is in removing the technological limitations to create a much more robust platform with enormous therapeutic potential.  At that point, the biology, targets and imagination become the limitations, not the technology itself.

I have a feeling that this platform is a much more exciting breakthrough than many realise – it’s the sort of approach where you can see, to paraphrase a famous watch company’s ad – some day all antibodies will be made this way.

References:

ResearchBlogging.orgSpiess C, Merchant M, Huang A, Zheng Z, Yang NY, Peng J, Ellerman D, Shatz W, Reilly D, Yansura DG, & Scheer JM (2013). Bispecific antibodies with natural architecture produced by co-culture of bacteria expressing two distinct half-antibodies. Nature biotechnology PMID: 23831709

Overcoming drug resistance in lung cancer

On the final day of the annual 2013 meeting of the American Association for Cancer Research (AACR) in Washington DC, Jeffrey Engelman (MGH) hosted an excellent plenary session on “Cancer Evolution and Resistance” with a series of superb talks not only from himself, but also Neal Rosen (MSKCC), Todd Golub (Broad Institute) and René Bernards (Netherlands CI).

If this session is included in the webcast, I would highly recommend watching the whole thing several times, as it was one of the meeting highlights for me. Despite being on the very last day, the large hall was pretty packed and well worth waiting for. You can check availability of the AACR 2013 webcast talks here.

I’m going to focus on some of the specifics in NSCLC from Engelman’s talk for this update.

Where are we in the quest to improve outcomes in lung cancer?

Jeff Engelman, courtesy of MGH

Jeff Engelman, courtesy of MGH

Engelman discussed the basics of what we know about adaptive resistance to TKI therapy in solid tumours – most of them (EGFR and ELM4-ALK in lung, BRAF in melanomas, HER2 in breast, and cKIT in GIST) typically being in the range of 8-11 months, with only GIST seeing an impact for nearly 2 years (20 months).

Thus we can see that the resistance develops over time as mutations and amplifications in the tumour evolve in adaptation to the initial efforts to inhibit the target. Indeed, approx. 50% of EGFR lung cancers develop the T790M mutation, while ~33% of resistant ELM4-ALK cancers show new mutations (e.g. L1196M, G1269A and others).

The development of these changes essentially serves as a way to bypass tracks and and continue to allow downstream signalling of PI3K and MEK to occur, thereby driving growth and cell survival. What then happens is a myriad of other pathways become activated to help drive signalling, for example MET, HER2/HER3, IGF1R etc in EGFR driven cancers and EGFR and cKIT amplification in ALK lung cancers.

As an analogy, think of this process like a road traffic system – if the route into New York from New Jersey was cut off at the Holland Tunnel, so traffic would increase to the Lincoln Tunnel or Verrazano Bridge and if those were cut off, traffic would then flow onto the George Washington Bridge, as it adapts and seeks new escape routes from the original destination.

Eventually, the cancer evolves further with defects in growth arrest and apoptosis, as seen with transformation from NSCLC to SCLC in some patients with EGFR cancers, and even changes in the microenvironment through epithelial mesenchymal transition (EMT) and loss of BIM.

The key question is what can we do about overcoming or delaying resistance?

One strategy would be to evaluate more potent inhibitors e.g. LDK378 instead of crizotinib in ELM4-ALK cancers. Another might be to explore logical combinations to address shutting down the bypass tracks. A third might be to add in a new inhibitor to target the specific mutations that evolve e.g. T790M inhibitor in the case of EGFR driven cancers when it appears.

Some of these trials are already underway and we should have more data soon.

Another way, as we saw with the last post on metastatic melanoma, is to identify mechanisms of resistance using laboratory models and lab specimens. This approach can potentially lead to more rational drug development in the clinic. Traditionally, scientists have induced resistance in mice, looked for the mechanisms (a process that can take 1-2 years), validated them in lab samples of patients, and then treated with a new treatment strategy.

This process is obviously time consuming though and not every patient can wait that long for the answer. Engelman then explained how they are looking at ways to streamline the process in Boston. After the mouse resistance experiments are completed, they have added in a drug combination screen to look for logical treatment strategies i.e. what can be added to the original drug to overcome resistance?

A very elegant example was given for EGFR lung cancer where they evaluated 78 test drugs in a screen with and without gefitinib to determine those which led to cell death. Other examples were given for ELM4-ALK cancers.

The screen results suggested that most of the resistant models produced 3-6 hits. These might include adding a MET inhibitor to an EGFR inhibitor in EGFR mutant cancer, an EGFR inhibitor in MET amplified cancers and a SFK inhibitor in the case of ELM4-ALK cancers, for example.

These results are still early, but they do look very promising. Validation studies are still needed, but early studies they performed suggested that the hits are indeed showing efficacy in vivo.  A preclinical example for this concept was shown in vivo by adding ABT-263 (Bcl2 inhibitor) to gefitinib and seeing first a rise in tumour growth with the EGFRi and then a large drop in volume when either ABT-263 or AZD6244 (MEK) was added.

Based on the exciting initial concepts in animals, they are now moving to patient derived models since next generation sequencing (NGS) can help identify the mechanisms of resistance and combined with the drug combination screens, we may see more individual level treatments for patients on a case by case basis.  These might be based on large scale (over 100 cell lines) testing derived from resistant biopsies to identify effective combinations and match them to the relevant biomarkers.  It sounds easy and obvious, but few centres are doing this in practice.

This is true personalised medicine in action.

It is also pretty exciting to me as we know that cancer, even in different patient tumours, is very heterogeneous and requires a more personalised rather than a one size fits all approach. As Engelman observed,

“Heterogeneity of resistant clones within individual patients may pose additional challenges to overcome resistance.”

The second half of his really excellent talk focused on the use of sequential biopsies in patients to explain the heterogeneity and how it can lead to transformation from NSCLC to SCLC and back again in response to treatment with an EGFR inhibitor. That’s an in-depth discussion for another day though, but suffice to say it was a fascinating topic.

And finally…

I can see these novel and applied techniques eventually moving very fast and adopted in top level Academic centres where they have the resources and knowledge to marry basic and translational research with clinical practice in early stage trials, but for many Community or even regional Academic physicians, this will be virtually impossible without referral of patients to clinical trials in the Academic centres, at least for now.

Ultimately, we will see more improvements in treatment for lung cancer when we figure out not only the targets, but also how to overcome adaptive resistance, add logical new combinations, and select future treatment based on biopsies as the tumour evolves its response to each line of therapy. Treatment will essentially need to be chosen on an individual patient basis in the long run by evaluating adaptive resistance to each new combination over time.

The idea that we can use mouse models and drug combination screens with sequential patient biopsies to better understand the adaptive response to therapy over time is not new but few have managed to put processes and strategies in place to make this happen in real time. Patients often can’t wait 2 years or more for a new combination trial to open, but the Boston approach is very promising and I’d like to applaud all those at the Boston group (MGH, Dana-Farber, MIT/Broad etc) for their groundbreaking work in this field. Keep your eyes peeled for more updates in this exciting area of research!

A new opportunity for vemurafenib in BRAFV600E colon cancer

By on January 26, 2012

There’s been quite a flurry of commercial news on the Pharma front this morning, with Amgen buying Micromet (whose leading product is blinatumumab in ALL) and Celgene announcing their acquisition of Avila Therapeutics who have a Bruton Kinase Inhibitor (BTK) AVL-292 in phase IB development for lymphomas, which was all the rage at the recent American Society of Hematology (ASH) meeting last month.

The big news for me today, though, wasn’t the commercial acquisitions but a gem of a paper relating to science and its significance for future cancer treatment.

One of the unsolved scientific conundrums that arose in my interview with Dr Gordon Mills (MDACC) at the European Multidisciplinary Cancer Congress (EMCC) meeting in Stockholm last September centred around the RAS pathway, and the BRAFV600E mutation, in particular.

Dr Mills astutely noted that while vemurafenib (Zelboraf) has shown activity in patients with advanced melanoma with the BRAFV600E mutation, he raised the important question why did we not see similar activity in mutated colon cancer?  Of course, one obvious conclusion might be that the target isn’t critical to the tumour’s survival… or is it?  The challenge though, is that these patients do particularly poorly, and usually that is a sign that the mutation is actively driving aberrant activity. Therein lies the quandary, leaving many researchers such as Dr Mills puzzled at the discrepancy and asking why?

This week I’ve been doing a series on colorectal cancer and it is quite by coincidence that today we learn more about the science of colon cancer and BRAFV600E mutations since Pralahad et al., (2012) have just published a Letter in Nature explaining that their research actually suggests that resistance mechanisms might be one of the culprits:

“We performed an RNA-interference-based genetic screen in human cells to search for kinases whose knockdown synergizes with BRAF(V600E) inhibition. We report that blockade of the epidermal growth factor receptor (EGFR) shows strong synergy with BRAF(V600E) inhibition.”

This finding surprised me because melanoma typically has low levels of EGFR expression, unlike more epithelial cancers:

“We compared EGFR expression in a panel of BRAF(V600E) mutant melanoma, colon cancer and thyroid cancer cells. Melanoma cell lines indeed express low levels of EGFR.

So what actually happens in melanoma?

“Mechanistically, we find that BRAF(V600E) inhibition causes a rapid feedback activation of EGFR, which supports continued proliferation in the presence of BRAF(V600E) inhibition.”

Ah, our old friend, feedback loops!  These have an uncanny knack of popping up in advanced cancers, as the cancer attempts to ensure it’s survival and overcome the targeted therapy, causing adaptive resistance to treatment in their wake.

You may be wondering how common is this mutation in colon cancer then? Well, Pralahad et al., (2012) observed:

“Our data suggest that BRAF(V600E) mutant colon cancers (occur in) approximately 8–10% of all colon cancers.

Note: bracketed bold addition mine.

What does this data tell us?

In short, a combination of vemurafenib and an EGFR inhibitor, such as erlotinib, cetuximab or gefitinib, might be a useful clinical approach to try therapeutically in patients with colon cancer harbouring the BRAFV600E mutation.  Of course, Roche/Genentech have both vemurafenib and erlotinib (Tarceva) in their portfolio, so it would be interesting to see whether proof of clinical concept could be established quickly in a phase I clinical trial.  EGFR inhibitors tend to be rather quirky though, and it remains to be seen whether a small molecule (erlotinib, gefitinib, afatinib) or a monoclonal antibody (cetuximab, pantitumumab) would be the ideal partner for vemurafenib in this setting.

While there is much yet to be done in R&D to advance the scientific research, this important finding teaches us that there is hope for this subset with a generally poorer prognosis yet.

I look forward to following the future clinical progress to see if a viable new combination treatment emerges in BRAF V600E mutated colon cancer – watch this space!

References:

ResearchBlogging.orgPrahallad, A., Sun, C., Huang, S., Di Nicolantonio, F., Salazar, R., Zecchin, D., Beijersbergen, R., Bardelli, A., & Bernards, R. (2012). Unresponsiveness of colon cancer to BRAF(V600E) inhibition through feedback activation of EGFR Nature DOI: 10.1038/nature10868

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

By on November 8, 2011

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

Source, Wikipedia: Pyruvate Kinase Muscle isoenzyme

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

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

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

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

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

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

The researchers also went onto to note that:

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

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

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

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

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

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

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

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

Significance of these results

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

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

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

References:

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

Update on EGFR resistance in lung cancer: new directions

By on October 25, 2011

This morning I was reading a fascinating paper on lung cancer and one of my favourite proteins, CRKL, from the group of prolific lung researchers at Mass General, Dana Farber, MIT and the Broad Institute in Boston:

“Over-expression of CRKL in immortalized human airway epithelial cells promoted anchorage-independent growth and tumorigenicity. Oncogenic CRKL activates the SOS1-RAS-RAF-ERK and SRC-C3G-RAP1 pathways. Suppression of CRKL in NSCLC cells that harbor CRKL amplifications induced cell death.”

Cheung et al., (2011)

We also know that one of the mechanisms of resistance to gefitinib is over-expression of CRKL in EGFR-mutant cells by activating ERK and AKT signaling.

What was interesting about this research was the observation:

“We identified CRKL amplification in an EGFR inhibitor-treated lung adenocarcinoma that was not present prior to treatment.”

Emphasis mine.

We do know that:

  • Adaptive resistance to treatment is a common problem with kinase inhibitors
  • Some lung cancer tumours acquire the T790M mutation, which is known to confer resistance to EGFR therapies
  • Several groups have also reported other known resistance mechanisms may also occur with the EGFR T790M mutation, including MET amplification and CTNNB1 (β-catenin) mutations.

Cheung et al., (2011) tested to see if the PI3K-AKT pathway was specifically involved with CRKL resistance:

“We examined whether treatment with the PI3K inhibitor GDC-0941 suppressed growth of CRKL–over-expressing HCC827 cells in response to gefitinib. Cells were exposed to GDC-0941 alone or in combination with gefitinib. Combined treatment with GDC-0941 and gefitinib resulted in a substantial decrease in the relative proliferation of CRKL–over-expressing HCC827 cells compared to gefitinib treatment alone.”

The answer was yes, activation of PI3K-AKT signalling contributes to CRKL-induced EGFR inhibitor resistance.

It would therefore be very interesting to see what happens in the clinic to a subset of lung cancer patients with CRKL amplification who are treated with an EGFR and PI3K inhibitor to see if this reduces resistance to treatment and improves outcomes. Trials with the combination are indeed ongoing, although I think they are in a more general population of patients with EGFR driven lung cancer. Based on these findings, a subset analysis might prove to be rather instructive here.

What do these results mean?

This study strongly suggests that CRKL may well be a valid therapeutic target:

“These observations show that CRKL over-expression induces cell transformation, credential CRKL as a therapeutic target for a subset of NSCLC that harbor CRKL amplifications, and implicate CRKL as an additional mechanism of resistance to EGFR-directed therapy.”

“Although CRKL amplifications occur in a relatively small fraction of NSCLC, the finding that a similar fraction of NSCLC with translocations involving ALK respond to treatment with crizotinib indicates that targeting genetic alterations present even in a subset of NSCLC may have clinical importance.”

The general idea that CRKL could act as an oncogene in other cancers with CRKL amplifications is also an intriguing idea that needs be explored further.

The paper is very well written and worth checking out for those interested in EGFR mutations, resistance to therapy and development of new therapies.

References:

ResearchBlogging.orgCheung, H., Du, J., Boehm, J., He, F., Weir, B., Wang, X., Butaney, M., Sequist, L., Luo, B., Engelman, J., Root, D., Meyerson, M., Golub, T., Janne, P., & Hahn, W. (2011). Amplification of CRKL induces transformation and EGFR inhibitor resistance in human non small cell lung cancers Cancer Discovery DOI: 10.1158/2159-8290.CD-11-0046

Engelman JA, Zejnullahu K, Mitsudomi T, Song Y, Hyland C, Park JO, Lindeman N, Gale CM, Zhao X, Christensen J, Kosaka T, Holmes AJ, Rogers AM, Cappuzzo F, Mok T, Lee C, Johnson BE, Cantley LC, & Jänne PA (2007). MET amplification leads to gefitinib resistance in lung cancer by activating ERBB3 signaling. Science (New York, N.Y.), 316 (5827), 1039-43 PMID: 17463250

Sequist, L., Waltman, B., Dias-Santagata, D., Digumarthy, S., Turke, A., Fidias, P., Bergethon, K., Shaw, A., Gettinger, S., Cosper, A., Akhavanfard, S., Heist, R., Temel, J., Christensen, J., Wain, J., Lynch, T., Vernovsky, K., Mark, E., Lanuti, M., Iafrate, A., Mino-Kenudson, M., & Engelman, J. (2011). Genotypic and Histological Evolution of Lung Cancers Acquiring Resistance to EGFR Inhibitors Science Translational Medicine, 3 (75), 75-75 DOI: 10.1126/scitranslmed.3002003

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Useful resource on new therapies for lung cancer

By on October 21, 2011

“You no longer need to sit through a chicken dinner to watch top oncology researchers run through slides on what’s new and exciting.

This non-small cell lung cancer edition of the Cancer Educators Slide Library allows you to take your iPad to the backyard, sit down in the sunset breeze and watch Drs John Heymach, Tom Lynch, Vince Miller, Tony Mok and course director Dr Roman Perez-Soler spin an amazing decade-long tale of research innovation and discovery that has fundamentally changed clinical practice.”

Amusing openings in emails always grab my attention!

Actually, the program on advances in lung cancer from Research to Practice is well worth watching if you have the time.  I haven’t attended any of their live CME meetings at conferences, but this online one is nicely put together and the slides do look very nice indeed on the iPad.

Check it out if interested in the new developments in lung cancer.

The elusive mystery of KRAS and EGFR inhibitors in colorectal cancer

By on October 20, 2011

The other week during a conversation with Dr Gordon Mills (MDACC) at the European Multidisciplinary Meeting (EMCC) in Stockholm, he mentioned the conundrum of variable responses to EGFR inhibitors in colorectal cancers and the impact of RAS.  Originally, it was thought that patients who had wild type, but not mutated, KRAS were more likely to respond (see Allegra et al., 2009 in the references below).

The reality, however, is that variable responses to therapy have actually been reported by several groups with cetuximab and panitumumab. De Roock et al., (2010) reported better outcomes with cetuximab in patients with p.G13D-mutated tumours than with other KRAS-mutated tumours, contrary to the US and EU Guidelines, so the situation is clearly more complex than first thought.

Dr Mills speculated that part of the issue may lie in the sensitivity of the assays used at different institutions, since Sanger sequencing requires that 20% of the DNA must have RAS present, whereas the next generation sequencing techniques used at MD Anderson will pick up 1% of the DNA. We don’t know whether that difference will matter or not yet, but it’s an intriquing element that may well be highly relevant going forward.

Meanwhile, at the EMCC meeting there was an update on panitumumab, a monoclonal anti-EGFR in the PICCOLO trial in EGFR mutated colorectal trial that may shed some new light on the matter. This trial, like many UK studies, was highly complex. While the primary endpoint of overall survival was not met, the biomarker analysis revealed some interesting subtleties.1

The trial involved patients (n=1198) randomised to receive either panitumumab or cyclosporin with single-agent irinotecan in advanced colorectal cancer. According to the authors:

“It opened as a 3-arm study in 2007; but from June 08 prospective KRAS testing was introduced and KRAS-wt patients were randomised to Irinotecan / Irinotecan + Panitumumab, KRAS-mut patients to Irinotecan / Irinotecan + Cyclosporin.”

 

What do the latest findings show?

Firstly, the PICCOLO results confirmed some previous findings in that improvement in PFS and response rate were seen in patients with KRAS/BRAF wild-type tumours who received panitumumab, but no benefit from panitumumab in patients with KRAS or BRAF mutated tumours.

Secondly, the biomarker subset analysis revealed some subtle hints of where we can look in further trials. In explaining the lack of overall survival benefit, the subset analysis showed that almost a third (29%) of the wild-type patients were also found to have other mutations, thereby conferring resistance to the drug. The question then is why and what was the cause?  In digging deeper, some interesting nuggets emerged…

Thirdly, it seems that the patients who tended to see a good response had a broad wild type profile for KRAS, NRAS, BRAF and PI3K, whereas those who had a mutation for any of the above kinases did not have as good a response. This suggests that the biomarker testing may need to be extended beyond wild-type and mutant KRAS to avoid resistance to EGFR therapy developing. The results also provide a clear direction in where the adaptive resistance pathways are and thereby where different/new combination strategies may need to evaluated in the clinic.

The future for advanced colorectal cancer is very bright as we learn more about the biology of the disease and how to treat it, but it is also becoming highly complex!

References:

ResearchBlogging.orgAllegra CJ, Jessup JM, Somerfield MR, Hamilton SR, Hammond EH, Hayes DF, McAllister PK, Morton RF, & Schilsky RL (2009). American Society of Clinical Oncology provisional clinical opinion: testing for KRAS gene mutations in patients with metastatic colorectal carcinoma to predict response to anti-epidermal growth factor receptor monoclonal antibody therapy. Journal of clinical oncology : official journal of the American Society of Clinical Oncology, 27 (12), 2091-6 PMID: 19188670

De Roock W, Jonker DJ, Di Nicolantonio F, Sartore-Bianchi A, Tu D, Siena S, Lamba S, Arena S, Frattini M, Piessevaux H, Van Cutsem E, O’Callaghan CJ, Khambata-Ford S, Zalcberg JR, Simes J, Karapetis CS, Bardelli A, & Tejpar S (2010). Association of KRAS p.G13D mutation with outcome in patients with chemotherapy-refractory metastatic colorectal cancer treated with cetuximab. JAMA : the journal of the American Medical Association, 304 (16), 1812-20 PMID: 20978259

  1. M.T. Seymour, S.R. Brown, S. Richman, G.W. Middleton, T.S. Maughan, N. Maisey, M. Hill, C. Olivier, V. Napp, P. Quirke Panitumumab in Combination With Irinotecan for Chemoresistant Advanced Colorectal Cancer – Results of PICCOLO, a Large Randomised Trial With Prospective Molecular Stratification. ECCO, Stockholm 2011: Abstract #6007  ↩

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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New developments in the biology pancreatic cancer

By on September 16, 2011

At the American Association for Cancer Research (AACR) Second Frontiers in Basic Cancer Research Conference this week, two interesting presentations on pancreatic cancer caught my eye. It has long been my belief that we will see no major breakthroughs for this devastating disease until our understanding of the biology advances.

Here’s a quick snapshot of each one:

EGFR Essential for the Development of Pancreatic Cancer

Barbara M. Gruener, a researcher at the Technical University in Munich, Germany stated that,1

“Originally, we wanted to characterize the known role of EGFR in pancreatic cancer to a higher extent so that EGFR targeted therapy could be more individualized.”

However, sometimes serendipity intervenes and some useful, unexpected, nuggets are revealed. In this case, she presented compelling evidence that demonstrated that:

  • Despite KRAS, lack of EGFR blocks pancreatic cancer development
  • EGFR plays an “unappreciated” central role early in the carcinogenic process

Now, while we know the mutation of the KRAS gene is an important factor in the development of many cancers, including pancreatic cancer, Gruener’s results suggests that despite the presence of KRAS, the development of preneoplastic precursor lesions and pancreatic ductal adenocarcinoma is blocked without the EGF receptor:

“EGFR seems to be involved in the early transdifferentiation processes of the pancreas in vivo and in vitro.”

What does this research mean in practice?

Firstly, these results were a surprise:

“With oncogenic active KRAS, you would expect that the lack of a receptor that is upstream of the KRAS signaling pathway does not impair the carcinogenic effects of KRAS almost completely.”

To me, the data strongly suggests that EGFR therapy might be a logical approach for early pancreatic cancer treatment than is currently undertaken, i.e. for advanced metastatic disease, when the tumor burden is much higher. Obviously, some clinical data will be needed to support and validate the preclinical findings, but this at least offers some pointers where we might start.

Virus Shows Promise for Imaging and Treating Pancreatic Cancer

The second abstract that really appealed to me was from Dana Haddad (MSKCC), who talked about the potential for an oncoloytic virus in pancreatic cancer 2

I confess that my first reaction was a little sceptical, as vaccines and viruses have yet to show dramatic activity in solid tumours, never mind a difficult to treat one such as pancreatic cancer. That said, let’s take a look at Dr Haddad’s research in detail.

First of all, she specified what an oncolytic virus actually is and what it does:

“Defined as viruses that selectively replicate in cancer cells with consequent direct destruction via cell lysis.
Leaves non-cancerous tissue unharmed.”

So a targeted approach, rather than a broad non-specific effect (I’m warming up already!)

One of the challenges though, is that biopsy is currently the gold standard for monitoring viral therapy in clinical trials, but these repeated biopsies are invasive and often difficult. There is therefore a need for new and improved methods for:

  • non-invasive monitoring
  • real time assessment of response to therapy
  • monitoring of potential viral toxicity

Haddad et al., looked at the feasibility of systemic virotherapy, together with monitoring radiotherapeutic response of pancreatic cancer xenografts treated with a vaccinia virus encoding the human sodium iodide symporter (hNIS), GLV-1h153.

hNIS is a cell surface protein that mediates transport of iodine mainly in thyroid gland. The value of this approach is that it has:

  1. imaging potential by using several carrier free radionuclide probes
  2. therapeutic potential by combining radioiodine with viral therapy

GLV-1h153 was injected systemically or intratumorally into pancreatic cancer xenografts in nude mice and 124I-positron emissions tomography (PET) was used image tumors.

The results clearly showed that:

  • PET signal intensity correlated with antitumor response
  • Colonization of tumors with GLV-1h153 facilitated uptake of radioiodine at potentially therapeutic doses
  • Combining GLV-1h153 with 131I led to enhanced tumor kill compared to either treatment alone

What do these findings mean in practice?

Dr Haddad summarized this nicely:

“It has been shown, for the first time, that vaccinia virus construct GLV-1h153 facilitates:
non-invasive long-term deep tissue monitoring of viral therapy, monitoring of tumor therapeutic response,
potential for targeted radiotherapy.”

She also went on to suggest that:

“GLV-1h153 can be directly translated to human clinical trials:
parent virus already in phase I clinical trials,
radiotracers and imaging modalities FDA approved.”

I think that we will see more clinical research evolve on GLV-1h153, since it appears to be a promising oncolytic agent, based on the data thus far. That’s good news for the San Diego biotech company, Genelux Corporation, who were involved with this oncolytic research. It’s still very early days, but the data looks promising enough to pursue clinical trials in humans further.  A phase I trial has recently been completed by the Royal Marsden Cancer Centre in the UK, with preliminary data presented at ASCO earlier this year.

  1. Press release – Gruener source ↩
  2. Press release – Haddad source  ↩
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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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