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Posts from the ‘Pathways’ category

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  ↩

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

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

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

Update on triple negative breast cancer

By on July 12, 2011

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

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

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

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

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

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

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

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

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

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

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

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

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

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

References:

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

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On the future of cancer treatment and research

By on June 27, 2011

This week I’m preparing an in depth mini series on the molecular target landscape associated with prostate cancer, which will be scheduled for next week, so do check back if that is a topic of interest to you.

In the meantime, I came across this video from MD Anderson, where the new President-elect Dr Ronald DePinho talks about the near term future of cancer research and where he thinks we will be going.

It’s less than four minutes long, easily understandable and well worth watching:

For those of you interested in my perspectives on some of the early clinical trial approaches, there’s a guest blog post on PharmaLive’s R&D Directions entitled “ASCO followup: Patients, pathways, progress in practice” today – check it out!

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