Pharma Strategy Blog

Commentary on Pharma & Biotech Oncology / Hematology New Product Development

Posts from the ‘Science’ category

Understanding cancer metastasis – possible new therapeutic targets

By on November 1, 2011

.

“Scientists at Dalhousie University in Nova Scotia have identified a key mechanism of metastasis that could lead to blocking tumor growth if their findings are confirmed.”

AACR press release

Loved this opening to an AACR press release about a key paper (freely available for anyone to download – see the reference session below) that was just published in Cancer Research by David Waisman’s group.

Now, before getting into the technical details, I was reflecting recently on both my recent awesome trip to the MD Anderson basic research campus at Smithville, Austin where a lot of research into tumorigenesis is conducted and pointed questions from patients about why their hasn’t been enough progress in treating and curing metastatic breast cancer.

There are several obvious reasons for this:

  1. We need to understand more about the basic mechanisms underpining function, never mind work out what role various proteins have and how they interact in health and disease before we can even think about clinical progress.
  2. As we learn more about the basic process of tumorigenesis, so we can start to apply those findings to clinical research and translational medicine in developing better predictive biomarkers that are clinically meaningful.
  3. If we have excellent biomarkers, an understanding of the processes and the targets involved, thus we should have clearer targets that suggest more logical combinations to treat disease and essentially slow or even undo the process of metastasis.

Quite frankly, based on the little we really know about the underlying biology of advanced disease, I’m sometimes surprised the results are as good as they are. That’s not to say we’re doing great, becasue clearly there is a lot of improvement that can be made, but sometimes we should stop and look at how far we’ve come and ask serious questions about what we really need to know now that can help progress things?

With all that context in mind, the current published research from Phipps et al., (2011) is worth looking at because it advances our thinking a little more. In the past, people have focused on cancer cells, thinking they were the main thing that mattered. What’s interesting about this research is that it shows how important other cells, such as macrophages, are in the tumorigenesis process:

“There is an increasingly large body of evidence correlating tumor-associated macrophage (TAM) density with poor prognosis in a varied number of solid tumors.”

 

Source: wikipedia

We also know from basic research that macrophages are critical in driving tumour growth, invasion, and metastasis.  Macrophages are like the Pacmen of cells – think of them moving around the blood stream chomping things in their wake.  The thing is, there are always macrophages in tumours – so how do they get from the bloodstream to the tumour?

The current paper details the key role that the macrophage cell surface protein, S100A10, plays in mediating macrophages, thereby allowing them to move to the site of tumour growth. This process is obviously essential to tumour development and angiogenesis.

What also struck me though, was the research also detailed what happened in animals without the S100A10 protein:

“Growth of murine Lewis lung carcinomas or T241 fibrosarcomas was dramatically reduced in S100A10- deficient mice compared with wild-type mice.

Emphasis mine.

What does all this data mean?

In order to either slow or stop metastasis in its tracks, we need to understand the whole process better, thereby finding the weaknesses and chinks in the tumour.

These results clearly show the important role that S100A10 has in facilitating macrophage activity.

Now, S100A10 is a protein and proteins often (but not always, since some of them are currently thought to be undruggable) make very good targets for therapeutic intervention.

Of course, these results clearly need to be reproduced and confirmed by other groups, but if confirmed, they potentially give us some targets to aim at. For example, we could either look at blocking the macrophages in some clever way or target the S100A10 protein directly with a rationally designed targeted therapy. These apparoaches might potentially slow, or even stop, tumour growth.

What if we found some strategies that were effective?  Maybe we could take the approach further and actually use it as a prevention strategy in high risk patients to actually prevent the development of metastasis occurring?

Time will tell, but personally, I was rather heartened by the this wonderful piece of research this morning.

References:

ResearchBlogging.orgPhipps, K., Surette, A., O’Connell, P., & Waisman, D. (2011). Plasminogen Receptor S100A10 Is Essential for the Migration of Tumor-Promoting Macrophages into Tumor Sites Cancer Research, 71 (21), 6676-6683 DOI: 10.1158/0008-5472.CAN-11-1748

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

3 Comments

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  ↩

Ovarian cancer patients with BRCA2 mutated tumors live longer

By on October 12, 2011

“Women with high-grade ovarian cancer live longer and respond better to platinum-based chemotherapy when their tumors have BRCA2 genetic mutations.”

MD Anderson Cancer Center press release

That statement got my attention last night while browsing the cancer news on Twitter! Many thanks to the Provost, Ray DuBois, for sharing it.

Recently, much of the focus has been on finding biomarkers associated with prognosis or response to tyrosine kinase inhibitors and other targeted agents, including PARP in breast and ovarian cancers. It is therefore fascinating that a marker of better prognosis should emerge with chemotherapy.

Given the recent controversy over the whole BRCA1/2 issue and whether there is any clinical significance, with Yang et al., (2011) noting that:

“It has been hypothesized that BRCA-deficient patients will likely have higher survival rates because of an improved response to platinum-based chemotherapy.”

Tan et al., (2008) did indeed observe that epithelial ovarian patients had better response rates than controls if BRCA-ness was present:

“BRCA-positive patients had higher overall (95.5% v 59.1%) and complete response rates (81.8% v 43.2%) to first line treatment, higher responses to second and third line platinum-based chemotherapy (second line, 91.7% v 40.9%; third line, 100% v 14.3%).”

These values were all highly significant.  The researchers therefore set out to see whether this would result in improved outcomes and:

“Determine the relationships between BRCA1/2 deficiency (ie, mutation and promoter hypermethylation) and overall survival (OS), progression-free survival (PFS), chemotherapy response, and whole-exome mutation rate in ovarian cancer.”

Taking a look at the Kaplan-Meier overall survival curves in Yang et al’s (2011) JAMA article (link below), the women who had either the BRCA1 or BRCA2 mutation clearly did better than those who were BRCA wild-type (WT) ie no mutation was present. This is a very important finding and it certainly does help to explain why mixing a heterogeneous population in a clinical trial is never a good idea. Imagine if the BRCA mutation status of the women is unknown – you could end up with unbalanced groups that can affect your outcomes based on the therapies randomised. By this, I mean a control group with chemotherapy alone could theoretically do better than one with a targeted therapy included if the groups were unbalanced for BRCA status.

Now, the current data are limited to high-grade serous ovarian cancer cases, but it would obviously be most interesting to see if a similar (or different) pattern might emerge in BRCA2 breast cancer. Obviously I’m thinking of the recent failed iniparib phase III trial here, as I never understood why BRCA status wasn’t tested and taken into account when balancing the baseline characteristics. We don’t know whether the results reported in ovarian cancer would also be seen in breast cancer, but it would be a critical question to address.

Significance of the results

Ultimately, these kind of findings can help us define and refine specific subsets of women with ovarian cancer who might respond better to certain types of therapies than others. This kind of information is crucial in helping to improve clinical trial design.

What I would really love to see is more logical combinations of targeted therapies or chemotherapy given to patients who have the best chance of responding rather than randomly expose people willy nilly to systemic agents where there is no idea or clue about how they might work. Patients deserve much better than this!

Tak Mak (U Toronto) summed this up beautifully at the recent ECCO meeting, with a most apt quote we could all do well to learn from:

“Doctors pour drugs of which they know little,
to cure diseases of which they know less,
into patients of which they know nothing.”

Moliere, 1622-1673

It is research such as Yang et al., (2011) that may actually help avoid this sorry state and begin to improve the outcomes associated with cancer therapy in the 21st century.

References:

ResearchBlogging.orgYang, D., Khan, S., Sun, Y., Hess, K., Shmulevich, I., Sood, A., & Zhang, W. (2011). Association of BRCA1 and BRCA2 Mutations With Survival, Chemotherapy Sensitivity, and Gene Mutator Phenotype in Patients With Ovarian Cancer JAMA: The Journal of the American Medical Association, 306 (14), 1557-1565 DOI: 10.1001/jama.2011.1456

Tan DS, Rothermundt C, Thomas K, Bancroft E, Eeles R, Shanley S, Ardern-Jones A, Norman A, Kaye SB, & Gore ME (2008). “BRCAness” syndrome in ovarian cancer: a case-control study describing the clinical features and outcome of patients with epithelial ovarian cancer associated with BRCA1 and BRCA2 mutations. Journal of clinical oncology : official journal of the American Society of Clinical Oncology, 26 (34), 5530-6 PMID: 18955455

4 Comments

On Science, Blogging and Drug Development

By on October 10, 2011

Last week things were rather quiet on the blogging front due to slight hiatus while recovering from the recent ECCO meeting in Stockholm and taking a few days off to visit the MD Anderson Cancer Center Science Park in Smithville, Austin. It’s funny, but until I began interacting with one of the PhD students there, Angela Alexander, via Twitter last year, I had no idea the place existed, yet it has been around for 50 years or so!

Austin, Texas

I was invited by the graduate student program (thank you, Alexsandra) to give a talk on ‘alternative science careers’ since after all, not all scientists actually stay in research. My talk was entitled, “On Science, Blogging and Drug development.”

A PhD can be very useful in both the Pharma/Biotech industry and also as a consultant. Biochemistry is particularly handy in oncology new product development, for example.

It has to be said, I had an absolutely fabulous time in Austin from dinner with the students, an enjoyable ride to and from the facility from Lady Bird lake (thanks, Matt!) to a day spent surrounded by a lot of smart and clever people working in basic research on carcinogenesis. The students there, whether doing a PhD or Post Doc, were very impressive indeed.

The fun part for me also included a lovely tour of the facilities in the morning (thanks Alessandra), while in the afternoon there was a superb opportunity to hear what the students were working on as the labs cycled round in groups. Some made presentations of their work, while others talked more informally about what they were working on. Either way, I was engaged by their enthusiasm and dedication. Topics were highly varied and some examples included:

  • Cellular and molecular mechanisms of carcinogenesis
  • Arginine methylation and PRMT
  • DNA damage and repair
  • Chromatin and epigenetics
  • Cancer stem cells
  • miRNA

I also received a delightful informal tour of one of the labs, which was like the Taj Mahal compared to some of the cramped and ancient research spaces I’ve seen elsewhere in the country. It’s amazing to see the woodlands through the big windows with animals running wild outside. It would be hard not to be inspired working here, either from the perspective of the environment, or the sparkling people working there. MDACC have built a very close knit community, which is good to see, especially given that several sadly lost their homes with the recent forest fires in Bastrop. The sense of support within the group was palpable.

There is an ongoing seminar series that includes a wealth internal and external speakers on various science topics associated with basic research – I was particularly excited to see that Arul Chinnaiyan (U Michigan) is speaking next May, for example. Mind you, had I realised beforehand so many distinguished researchers were on the program I might have got cold feet!

It’s important to support not only translational, but also basic research, if we are to develop better targeted drugs in the future. Let’s not forget that the story of the Philadelphia Chromosome, CML and Gleevec took 40 years and several Lasker Awards and Nobel Prizes to go full circle and connect the dots that ultimately made a difference to the lives of patients. Who knows what will happen in the next 40 years as scientists begin to take advantage of the findings from other basic research to piece together the next big puzzle and find the next generation of targeted therapies?

Without solid basic research we won’t even have a target to aim for.

1 Comment

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:

2 Comments

Update on MEK and AKT inhibition in RAS driven cancers

By on October 3, 2011

A couple of interesting developments have emerged over the last week with AKT and MEK inhibitors, specifically Merck’s MK-2206 and AstraZeneca/Array’s AZD6244, that are well worth discussing.

  1. At the ECCO/EMCC meeting in Stockholm last Tuesday, Johann De Bono discussed the combination data for MK-2206 and AZD6244 in KRAS driven colorectal cancer.
  2. Later the same week, Array Biopharma announced the initial results from a randomized phase II placebo-controlled study that compared the efficacy of selumetinib (AZD6244/ARRY-886) in combination with docetaxel compared to docetaxel alone in the second-line treatment of patients (n=87) with KRAS-mutant, locally advanced or metastatic non-small cell lung cancer (NSCLC).

Now, to be clear, I like the concept of AKT and MEK inhibitors, especially in select combinations, but the key thing here is the right combinations in the right context.

Let’s take a look at the lung cancer KRAS data first. One of the challenges I have with this approach, is that we’ve know for a while that BRAF and KRAS driven cancers behave rather differently according to Wee et al., (2009):

“Previous studies have found that whereas BRAF mutant cancers are highly sensitive to MEK inhibition, RAS mutant cancers exhibit a more variable response.”

Variable response is not an encouraging phrase when planning clinical trials!

Let’s take a look at the pathway itself:

We can immediately see that MEK is downstream of RAS, meaning that even if we target MEK, unfortunately RAS and KRAS is still largely untouched upstream. This is important to remember when considering the actual results later.

The other key factor to consider is what are the adaptive resistance pathways that might evolve as a result of treatment with a MEK inhibitor? In an ideal world, logical combinations would be tested that target both the primary driving mutation or aberration, as well as the adaptive resistance, to try and shut down the pathway more completely than targeting either alone. Another key question that needs to be addressed is what is driving the KRAS aberrant activity in the first place?

We’ve discussed MEK numerous times here on PSB, but the Wee et al., (2009) MEK paper stands out in particular. They identified a critical resistance pathway to MEK inhibition, namely PI3K. Although we discussed this originally in the context of BRAF driven tumours such as melanoma, it is well worth discussing again here in regards to KRAS driven tumours given a MEK inhibitor is being tested.

They observed that:

“Activating mutations in PIK3CA reduce the sensitivity to MEK inhibition, whereas PTEN mutations seem to cause complete resistance.”

It isn’t clear from the Array press release whether any of the patients with NSCLC exhibited PIK3CA mutations or loss of PTEN, but they definiely do occur in this disease. It will be interesting to see of more meta data is available at the forthcoming AACR Molecular Targets meeting next month.

I’m not a big fan of chemotherapy plus a single targeted agent, because as you can see from the evidence above, the pathway is not being shut down by one targeted agent and resistance is not being addressed at all. The chances of such a combination working (by that I mean increasing overall survival), I think would be fairly low.

According to the press release, the study did not see a significant improvement in overall survival (OS) but did show an encouraging response in the form of progression free survival (PFS):

“The key secondary endpoints of progression-free survival, objective response rate, and alive and progression-free at 6 months were all demonstrated with statistical significance, showing improvement in favor of selumetinib in combination with docetaxel versus docetaxel alone.”

Indeed, at the recent AACR and ASCO meetings, there was also some encouraging early signs from Genentech’s PI3K inhibitor, GDC-0941, as a single targeted agent with chemotherapy in NSCLC (a very small early trial), albeit not KRAS specific, but defined more broadly by squamous and non-squamous histology. Thus, all is not lost with the MEK agent yet – if we combined MEK and PI3K inhibitors in NSCLC patients previously treated with chemotherapy, we might have a better chance of succeeding and shutting down the pathway, based on evidence offered from Wee et al’s preclinical research:

“At the molecular level, the dual inhibition of both pathways seems to be required for complete inhibition of the downstream mammalian target of rapamycin effector pathway and results in the induction of cell death.”

As a result, they went onto to suggest a logical treatment approach:

“Our study provides molecular insights that help explain the heterogeneous response of KRAS mutant cancers to MEK pathway inhibition and presents a strong rationale for the clinical testing of combination MEK and PI3K targeted therapies.”

Of course, clinical trials like this always progress incrementally, such that we test a MEK or a PI3K inhibitor alone to determine safety and efficacy activity, then perhaps in combination, which requires another phase I dose finding study to determine the ideal dosages and whether they are too toxic or not combined.

So while either single agent targeted therapy with chemotherapy in and of itself is not a win, there are signs that combining the two may be more appropriate. I would still want to know what is driving the KRAS activity though, given MEK and PI3K are downstream of it. It is entirely possible that a third agent would be needed to shut down the pathway more completely in that patient subset.

At ECCO, De Bono (Royal Marsden) discussed the combination of AstraZeneca’s MEK inhibitor (AZD6244) and Merck’s AKT inhibitor (MK-2206) in RAS mutant colorectal (CRC) and lung (NSCLC) cancers. The results here were not a big win in the former, with 8/15 patients showing no antitumour activity to date.

There are several things we can conclude from the initial data:

  • If we have the right combination for the right target in the right patient subset, then the therapeutic index of the agents is lacking and we need better drugs
  • Are the targets (AKT and MEK) critical?
  • Is something else driving the KRAS activity (see below)*?
  • Are we shutting down the adaptive resistance pathways (escape routes?)
  • Which patient subsets are most likely to respond and how do we best characterise them (ie need more biomarker data)?

And so on… there are always more questions than answers sometimes.

    * Note: This situation could well be similar to BRAF in malignant melanoma, where it is the V600E mutation that is driving the BRAF activity, thus specifically targeting ithe mutation rather than the kinase will have a greater clinical effect than targeting BRAF broadly. In this case, if we really believe KRAS is critical to the lung or colorectal tumour’s survival, then we need to figure out what is driving it before progress is made. Frank McCormick’s elegantly simple wac-a-mole concept for pathway inhibition is very apt here!

No doubt we will see more detailed data and an update soon, perhaps even at the forthcoming AACR Molecular Targets meeting next month.

References:

ResearchBlogging.orgWee, S., Jagani, Z., Xiang, K., Loo, A., Dorsch, M., Yao, Y., Sellers, W., Lengauer, C., & Stegmeier, F. (2009). PI3K Pathway Activation Mediates Resistance to MEK Inhibitors in KRAS Mutant Cancers Cancer Research, 69 (10), 4286-4293 DOI: 10.1158/0008-5472.CAN-08-4765

4 Comments

What’s hot at ECCO, ESMO, EMCC in Stockholm 2011?

By on September 21, 2011

After a wild day yesterday once we realised Continental had mysteriously and unaccountably changed our flights to Stockholm from Weds to Weds to Thurs to Tues, it seems that Cinderella will be going to the ball after all.

European Multidisciplinary Cancer Conference (EMCC) here we come, whew!

There are a couple of sessions I’m particularly looking forward to this year:

    1. Presidential Symposium on Sat 25th with talks from some of the leading lights in translational research:
      • Tak Mak (U Toronto) on metabolism and cancer
      • Jose Baselga (MGH) on the challenges of personalised medicine
      • Gordon Mills (MDACC) on the future of personalised medicine

 

    1. Various abstract highlights include:
      • Update on phase II ERIVANCE data for the Hedgehog inhibitor, vismodegib, in basal cell carcinoma (see phase I data from AACR)
      • Biomarkers, including VEGF-A in the bevacizumab trials and an update on KRAS
      • Phase II T-DM1 (trastuzumab emtansine) data in breast cancer
      • Reversing drug resistance in breast cancer (Mon 27th)
      • Updated data from the phase I and III (BRIM3) studies of vemurafenib (Zelboraf) in BRAF V600E-mutation positive metastatic melanoma (will be interesting to see how this compares to the ASCO data
      • Update on therapies in prostate cancer, including new phase III Alpharadin data (see Biotech Strategy Blog)

 

  1. Scientific symposia on PARP inhibitors and PI3K inhibitors (both on Tues 28th). I’m gutted these two important sessions clash, as they are both key events I’d love to attend 🙁

All in all, it promises to be a fun and interesting meeting. For those interested, here’s the link to the full details of the EMCC programme.

Social media comes to ECCO

 

The official Twitter hashtag of the meeting is #emcc2011, a bit long I know, and I would much rather have the shorter, more descriptive and well known #ECCO or #ESMO, but it is a three organisation event afterall, with ECCO, ESMO and ESTRO all involved. You can also follow the EMCC conference organisers on Twitter (@EuropeanCancer).

This inevitably creates branding issues given it seems everyone in the industry has been seemingly asking me over the last two weeks if I’m going to ECCO or ESMO in equal measures! None outside of Twitter have mentioned EMCC at all. Ah well.

9 Comments

Using folate receptor alpha fluorescence imaging in ovarian cancer

By on September 20, 2011

The other day an interesting paper came to my attention entitled:

“Intraoperative tumor-specific fluorescence imaging in ovarian cancer by folate receptor-α targeting: first in-human results”

Thanks to my translational research friend Angela Alexander for highlighting it!

The idea behind this concept is that fluorescence technology can be used to help guide ovarian cancer surgery more effectively, since the tumours tend to be small and hard to see for surgeons performing the excision:

“Tumor-specific intraoperative fluorescence imaging may improve staging and debulking efforts in cytoreductive surgery and thereby improve prognosis.”

Folate receptor-α as a tool for imaging originally came from an understanding of the biology of the disease:

“The overexpression of folate receptor-α (FR-α) in 90–95% of epithelial ovarian cancers prompted the investigation of intraoperative tumor-specific fluorescence imaging in ovarian cancer surgery using an FR-α–targeted fluorescent agent.”

This marker (FR-α) be easily detected either on tumour cells in ascites fluid or on tumor tissue obtained during staging laparoscopy or primary surgery.

What did the results show?

“In this limited series, we showed that the use of intraoperative tumor-specific fluorescence imaging of the systemically administered FR-α–targeted agent folate-FITC offers specific and sensitive real-time identification of tumor tissue during surgery in patients with ovarian cancer and the presence of FR-α–positive tumors.”

It was also encouraging to see further validity is also provided by negative results:

“One patient presented with a malignant tumor that did not express FR-α, and consequently, no fluorescence was detected.”

What do these results mean?

I think van Dam et al., (2011) encapsulated the significance of the imaging test nicely:

“The use of targeted fluorescent agents could provide a paradigm shift in surgical imaging as it allows an engineered approach to improving tumor staging and the technique of cytoreductive surgery and thereby improving the outcome in ovarian cancer.”

There are potential applications too associated with clinical research too, since Morphotek/Eisai are investigating farletuzumab, a humanized IgG1 antibody that targets folate receptor alpha in ovarian and other cancers. Using this imaging technique could be used to determine the drugs effectiveness in reducing the tumour in patients in a non-invasive fashion.

Of course, the initial trials are being undertaken in the metastatic setting, but if successful, I could see a role for the agent developing in neoadjuvant disease to shrink the tumour margins prior to surgery. Having an appropriate marker test, coupled with a valid imaging technique could well lead to improvements in survival down the line.

Overall, folate receptor-α could well be an interesting new development to watch out for over the next couple of years as data from the imagining and drug trials mature.

References:

ResearchBlogging.orgvan Dam, G., Themelis, G., Crane, L., Harlaar, N., Pleijhuis, R., Kelder, W., Sarantopoulos, A., de Jong, J., Arts, H., van der Zee, A., Bart, J., Low, P., & Ntziachristos, V. (2011). Intraoperative tumor-specific fluorescence imaging in ovarian cancer by folate receptor-α targeting: first in-human results Nature Medicine DOI: 10.1038/nm.2472

error: Content is protected !!