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Posts from the ‘Pancreatic Cancer’ category

Update on pancreatic Neuroendocrine Tumours (NET)

By on November 10, 2011

Today on 10th November, it’s the Second Annual Worldwide NET (Neuroendocrine Tumor) Cancer Awareness Day. Granted that’s a bit of a mouthful, but it also seems poignant given so many of my news feeds this morning were still full of Steve Jobs, who sadly passed away from the disease last month.

I’ve been meaning to post an update on this rare form of cancer all year, given that we now have targeted therapies now approved by the FDA for treatment, but things were hectic at the office and then with Jobs passing, the timing just seemed tacky and inappropriate.

The idea though, of an Awareness Day for a rare disease such as NET to improve both education and awareness seems an inherently good one to me, especially as there has been some progress clinically in 2011. According to Kulke et al., (2011) NET has an incidence of around 1 per 100,000 individuals. This excellent review covers the key essentials of both the disease and the treatments:

“Patients with pancreatic NET present with diverse symp- toms related to hormonal hypersecretion, tumor bulk, or both. Accurate diagnosis of this condition and differentiation of pancreatic NET from the more common pancreatic adenocarcinomas is a critical first step in developing an appropriate treatment plan.”

It has been quite the landmark year for NET since not one, but two, new therapies were approved by the FDA in May this year with very different mechanisms of action:

  • Everolimus (Afinitor) from Novartis targets the mammalian target of rapamycin (mTOR), a serine-threonine kinase, downstream of the PI3K/AKT pathway.
  • Sunitinib (Sutent) from Pfizer is a multikinase inhibitor of VEGF, PDGFR (α and β), KIT, FLT3, RET and CSF-1R.

Both of these drugs are also approved for the treatment of renal cell cancer, which while nearby geographically in the body, is a completely different type of GI cancer. They are now approved for pancreatic neuroendocrine tumours (pNET) that have progressed and cannot be treated with surgery.

It is important to note, that while NET is a rare form of pancreatic cancer, it is not the same thing as the more common pancreatic adenocarcinoma – a fact that the media often got wrong in the case of Steve Jobs and drove me potty at their ignorance and inability to grasp a simple concept.  NET is not an adenocarcinoma and has a much larger endocrinology/metabolism component and starts in the hormone-producing cells of the pancreas. There are two types of pancreatic NET:

  1. Functional (overproduce hormones)
  2. Nonfunctional (do not overproduce hormones) and are more common

There are some great resources for patients (and caregivers) want to know more about this disease – here are some examples I came across:

Let’s take a look at the new clinical data.  Both sunitinib and everolimus were compared to placebo in the phase III trial of refractory patients who were ineligible for surgery and had disease progression.

Here’s what the survival curves look like, based on the data from their respective prescribing information: 12

In the case of sunitinib, we can see that the median progression-free survival (PFS) 10.2 months versus 5.4 months for the placebo arm. This difference was highly significant (P 0.000146, HR 0.427):

sunitinib

Looking at the everolimus data, we also see a significant trend in favour of therapy over placebo, i.e. a median PFS of 11.04 months compared with 4.6 months for placebo (P 0.001, HR 0.35):

everolimus

These studies produced very comparable responses from a survival perspective and overall response rates of 9% and 5%, respectively.

While it is good to see some excellent progress on the efficacy front, these new therapies for NET are not without their challenges and side effects though.

In particular, in the phase III study, sunitinib, hypertension was the most common grade 3 event in 10% of patients (a classic function of the VEGF class of drugs) and was also shown to cause cardiac failure leading to death in 2/83 (2%) patients on therapy compared with no patients on placebo.

In contrast, everolimus should be avoided with concomitant use of strong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, clarithromycin, atazanavir, nefazodone, saquinavir, telithromycin, ritonavir, indinavir, nelfinavir, voriconazole). The most common grade 3/4 adverse reactions (incidence ≥ 5%) in the phase III pNET trial were stomatitis and diarrhea.

As Kulke et al., observed:

“Surgical resection remains the mainstay of treatment for patients with localized disease.”

However, for patients who are unresectable or have progressed there are at last new options:

“Recent studies have also reported that the tyrosine kinase inhibitor sunitinib and the mTOR inhibitor everolimus improved progression-free survival in patients with pancreatic NET, further expanding the therapeutic arsenal available to patients with this disease.”

In the future, we may well see sequencing studies emerge as well as other targeted therapies to prolong outcomes for patients with this rare disease.

References:

ResearchBlogging.orgKulke MH, Bendell J, Kvols L, Picus J, Pommier R, & Yao J (2011). Evolving diagnostic and treatment strategies for pancreatic neuroendocrine tumors. Journal of hematology & oncology, 4 PMID: 21672194

  1. Sunitinib PI accessed  ↩
  2. Everolimus PI accessed  ↩

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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Update on PARP inhibitors including iniparib, olaparib and veliparib

By on May 10, 2011

A PSB reader wrote in asking whether an update on the PARP inhibitors and the clinical trials would be possible.   Following on from the last update in January that covered Sanofi’s negative iniparib phase III data in triple negative breast cancer and AstraZeneca’s decision in February not to pursue olaparib in hereditary BRCA1 and 2 positive breast cancers, it would be a good idea to see what’s left of this once highly promising class of compounds.

I first wrote about PARP inhibitors way back in 2006 and like many, I’m rather disappointed with the results we’ve seen so far.  However, all is not lost.  Abbott’s veliparib is going strong, while Pfizer (PF-01367338) and Cephalon (CEP-9722) are just getting started with their programs.

Iniparib was probably the weakest inhibitor of the class and perhaps not potent enough, since there was no increase in toxicities in the TNBC study (that can be a good and a bad thing), while olaparib has proven to be potent but challenging to combine with chemotherapy.  It doesn’t mean that a different compound or clinical approach will be unsuccessful.

The saddest thing about the iniparib trial is the lack of BRCA1 and 2 testing, given the heterogeneous nature of triple negative breast cancer. We will likely never know which different subsets responded and why from that trial, it probably could have been better designed and included more rigorous biopsies for biomarker analysis, but once done it is too late.  This is one of the dangers of applying old-style chemotherapy trial designs to targeted therapies – first know your molecular targets – or potential targets – and evaluate the biomarkers over time in response to therapy.  Otherwise, it’s a bit like blindfolding an archer and asking him to hit a target s/he can’t even see.

I don’t think all is lost with AstraZeneca’s olaparib yet, but we will have to wait and see what the current ongoing studies bring in terms of answers.  Certainly, both AstraZeneca and Abbott have a broad range of clinical trials that may yield some interesting results. We shall see.

I took a quick look at the clinical trials database and sifted through the available data for PARP inhibitors. This is what we have so far:

Parp Inhibitors

One trial I’m eagerly awaiting the results of is the ISPY2 trial in neoadjuvant breast cancer, which included veliparib as one of the treatment options in a molecular based approac,h much in the same way the BATTLE trial worked in lung cancer.  For those interested in the background to this approach in breast cancer, you can find the details in an interview with Sue Desmond-Hellmann (UCSF), when the trial was first announced.  It will be a while before we know the results, but one that is very eagerly awaited in the breast cancer community.

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GWAS and Pancreatic cancer

By on February 28, 2011

Recently, I was browsing an edition of  Science magazine I missed with a hectic travel and conference schedule this quarter.   There was an article from Ting et al., (2011) at Mass General entitled,

“Aberrant overexpression of satellite repeats in Pancreatic and other epithelial cancers.”

What caught my eye was a footnote at the end that stated:

“Massachusetts General Hospital and the authors (D.A.H., D.L., S.M., D.T.T.) have filed a patent application relating to detection of satellite and LINE sequences in human cancers.”

It seems that patent applications, or rather the declaration of them, are very much a trend on the rise lately.  Certainly, researchers and institutions appear to be more aggressively pursuing them than in the past.

So what did they find?

In this research, massive expression of major satellites in mouse pancreatic tumours in primary tumour cell lines compared with normal tissues was found.  The researchers represented these findings graphically in a pie chart, which makes it easier to see the patterns at a glance:

Massive expression of major satellites in mouse pancreatic tumours

What at the implications of this research?

The researchers suggested that the data may have important findings:

“The overexpression of satellite transcripts in cancer may reflect global alterations in heterochromatin silencing and could potentially be useful as a biomarker for cancer detection.”

The emphasis is mine, but what if the findings could be repeated in other cancers?  That would be quite interesting indeed.   So far, they have looked at a couple of other solid tumour cells lines:

“Similar patterns were observed in cancers of the lung, kidney, ovary, colon, and prostate.”

This research may well be worth following to see how it develops going forward.

One should note, however, that what we often see in cell lines isn’t always repeated in humans… this is a worthwhile start, but it has a long way to go yet before we possibly see solid validation in large scale clinical trials and some significant meaningful clinical benefit emerge.

References:

ResearchBlogging.orgTing, D., Lipson, D., Paul, S., Brannigan, B., Akhavanfard, S., Coffman, E., Contino, G., Deshpande, V., Iafrate, A., Letovsky, S., Rivera, M., Bardeesy, N., Maheswaran, S., & Haber, D. (2011). Aberrant Overexpression of Satellite Repeats in Pancreatic and Other Epithelial Cancers Science DOI: 10.1126/science.1200801

DNA methylation and microRNA expression in pancreatic cancer

By on November 22, 2010

Pancreatic cancer is particularly nasty, mainly because there is no easy way to detect it by screening or biomarkers in the general population, symptoms are often insidious and thus the cancer is sadly not picked up until the advanced stages.  Less than 20% of people present with early stage disease, meaning they are small, resectable and therefore treatable.

It is clear that more progress beyond incremental improvements will come as we learn more about the biology of the disease and develop accurate tests for early diagnosis.  The big question, though, is what subtle, and not so subtle, changes are happening with tumorigenesis and pathogenesis?  If we can understand the process we might be able to figure out some appropriate markers and develop a diagnostic test, since many people will not have the classic risk factors, making screening in the general population difficult.

With all this background in mind, I noticed an interesting paper recently from Cancer Research:

“… there is a need for sensitive, specific, and accurate tests that would facilitate the rapid diagnosis of pancreatic cancer and its precursors.  New candidate markers have been described in recent years that have been evaluated in serum and in pancreatic secretions and ductal brushings to detect local pancreatic neoplasia, but more accurate markers are needed.”

What’s also interesting is that following some recent posts on microRNA (see lung cancer and general information on miRNA for examples), it seems that almost every other article is about miRNA in some shape or form when I check out journals.  Maybe it was there before but I’m only just seeing it after writing about it.

As Li et al., pointed out in their paper, we know that DNA methylation and miRNA expression are important in pancreatic cancer pathogenesis, but what precisely is happening?  In their experiments, they found that:

“We identified two members of miR-200 family, miR-200a and miR-200b, that were hypomethylated and overexpressed in pancreatic cancer.”

Downstream, other changes were also taking place:

“We also identified prevalent hypermethylation and silencing of one of their downstream targets, SIP1 (ZFHX1B, ZEB2), whose protein product suppresses E-cadherin expression and contributes to epithelial mesenchymal transition.”

What does this mean in short?

“The elevated serum levels of miR-200a and miR-200b in most patients with pancreatic cancer could have diagnostic utility.”

It will be interesting to see where these ideas go, particularly in high risk populations.

ResearchBlogging.org Li, A., Omura, N., Hong, S., Vincent, A., Walter, K., Griffith, M., Borges, M., & Goggins, M. (2010). Pancreatic Cancers Epigenetically Silence SIP1 and Hypomethylate and Overexpress miR-200a/200b in Association with Elevated Circulating miR-200a and miR-200b Levels Cancer Research, 70 (13), 5226-5237 DOI: 10.1158/0008-5472.CAN-09-4227

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Amgen receives approval for denosumab (Xgeva) in SRE for cancer

By on November 19, 2010

After hearing Amgen’s denosumab (Dmab) was approved late yesterday for skeletal related events (SRE) in the oncology solid tumour indications (but not multiple myeloma) and is now named Xgeva, I was tempted to write a Fun Friday post on how Pharma brand names make the mind boggle lately as you can see a few weird looking names have emerged this year alone.  Seriously, some of them look as though they’ve been hastily put together from Scrabble tiles sometimes, or represent words more usually associated with the old Soviet Eastern bloc countries, never mind figuring out how they ought to be pronounced!  {Update: this one is pronounced x-GEE-va not x-JAY-va as a European might think ;)}

According to the NY Times, the Wholesale price for Dmab in the oncology setting will be $1650 per month, making it around double the price of Zometa (Novartis).  Still, the good news for patients is that Amgen do have a patient assistance program for it and I understand from several sources that Amgen has a co-pay program that offers Xgeva to the patient with no co-pay the first month and only $25 afterwards.  There are apparently no income limits to participate, which if true, would be most unusual.  {Update: here is the link to actual details of the coupon program.}

At the NY Chemotherapy Foundation Symposium last week, several oncologists I spoke to said that a high price would be a significant barrier to use, so it would be reserved for those who do not respond or tolerate Zometa, or have poor renal function.  Urologists would probably be more interested in Xgeva, since Zometa is an infusion product and they tend to refer patients to the oncologist for this.  Xgeva, as a subcutaneous therapy, would therefore potentially be a more convenient option for urologists who have patients that progress to symptomatic metastatic prostate cancer.

The other interesting thing I noticed from the data presented on Dmab at the NY Chemotherapy Meeting, was that while time to SRE was significantly improved with Xgeva compared to Zometa, there was no difference in survival between either therapy, as measured by both progression-free survival (PFS) and overall survival (OS).  There is a risk that oncologists will look at that data and see no meaningful benefit in survival at twice the price for their cancer patients.  We’ll see what unfolds over the next few months, although the slow uptake of Prolia in the non-oncology setting does not portend well for Amgen.

Meanwhile, this week  I’m in the office working on client reports instead of having fun at cancer conferences such as the EORTC-AACR-NCI Molecular Targets meeting that is currently ongoing in Berlin 🙂

A couple of interesting stories in preclinical or early phase development have caught my eye from the meeting so far.

The BBC wrote about nanocarriers and brain cancers, based on some research in mice, for example.  We’ve previously covered nanotechnology at other AACR meetings (in pancreatic cancer), and this is probably one of my favourite disruptive technology concepts to emerge over the last twelve months.  It may be a while before something is actually approved for use in human cancer though.

Another interesting item was data on a new PARP inhibitor, MK-4827, from Merck.  I first posted on the science behind PARP inhibition way back in 2006, with quite a few subsequent posts on the clinical data since (you can find them all by using the Search widget on the right and typing PARP.   Three main compounds have already emerged with a growing body of clinical data, mainly in breast and ovarian cancers:

  1. Olaparib (KuDos/AstraZeneca)
  2. Iniparib (BiPar/Sanofi Aventis)
  3. Veliparib (Abbott)

We can now add the Merck compound to the growing list of PARP inhibitors with data in human trials from phase I and beyond.  According to the ECCO press release, the new data extends beyond breast and ovarian cancers:

“In a Phase I trial conducted at the H Lee Moffitt Cancer Center (Tampa Florida, USA), University of Wisconsin-Madison (Madison, USA) and the Royal Marsden Hospital (London, UK), MK-4827 was given to 59 patients (46 women, 13 men) with a range of solid tumours such as non-small cell lung cancer (NSCLC), prostate cancer, sarcoma, melanoma and breast and ovarian cancers.  Some patients had cancers caused by mutations in the BRCA1/2 genes, such as breast and ovarian cancer, but others had cancers that had arisen sporadically.”

These patients had metastatic, advanced disease, typically already received treatment with several other therapies and had experienced recurrence.  In this setting, response rates are expected to be low given the high tumour burden:

“The researchers saw anti-tumour responses in both sporadic and BRCA1/2 mutation-associated cancers.  Ten patients with breast and ovarian cancers had partial responses, with progression-free survival between 51-445 days, and seven of these patients are still responding to treatment.  Four patients (two with ovarian cancer and two with NSCLC) had stable disease for between 130-353 days.”

Of course, it’s still early days yet in a phase I trial, but it will be interesting to see how this new class of cancer agents evolves over the next couple of years.

Photo Credit: Amgen

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International Society of GastroIntestinal Oncology (ISGIO) meeting

By on September 22, 2010

IMG_0130It’s been quite a busy week with new projects, proposals and contracts on the go plus we’re heading off to the International Society of GastroIntestinal Oncology (ISGIO) meeting in Philadelphia tomorrow.

Jaffer Ajani does a really nice job of organising this educational conference. It includes the latest updates in the field from a esteemed panel of experts, as well as practical case studies, to help teach a diverse international and US audience how to manage complex or unusual cases.

There’s not a lot of science, but there is serious emphasis is on practical learning and questions from the attendees are encouraged, which I really like. They also have proffered papers on clinical issues, which encourages young up and coming clinicians or researchers to present their work and gain some feedback.

The thought leaders are generally relaxed, approachable and chatty during the breaks, so this makes networking much more fun. John Marshall from DC, for example, is nearly always guaranteed to make the audience (and sometimes his fellow panel members) sit up and pay attention by asking provocative questions or creating a controversy to challenge people’s thinking. A good debate usually follows as a result.

If anyone is going to the meeting or is in Philly and wants to meet up, do let me know and schedule permitting, I do try to accomodate requests. My email link is in the right margin and the phone link in the About page under the blog header – just click on the Google Voice widget to leave a message.

Finally, I would really like to thank all the readers who share papers, suggest topics either in person at conferences or by email or through their thoughts and observations as a result of interacting with this blog. It is much appreciated and I learn from others too. Science, cancer research, drug development and commercialisation were not meant for lonely activity by the nudist on the late shift, but as an interactive learning environment where we can all benefit. That’s what makes it all much more fun.

Please keep the correspondence and suggestions for new blog topics coming. I may not get round to them all in the week they are sent, but do try to research and schedule them at some point.

Wnt signaling and cancer

By on September 8, 2010

In April at the AACR annual meeting, Bert Vogelstein talked about 12 critically aberrant pathways in cancer and we have talked about a few of these on this blog this year. Today, I want to take a look at another one of those key pathways, Wnt (pron. wint).

Background

Wnt is well known for it's network of proteins playing key roles in both development and cancer.  In simple terms, the process begins when Wnt proteins bind to cell-surface receptors of the Frizzled family, causing the receptors to activate the Dishevelled (dvl) family proteins, leading to a change in the amount of B-catenin that reaches the nucleus.

The basic pathway is described in the schematic below:

Picture 6Source: Cell Signal

Previously, we have discussed the simplicity of Hh signalling driving medulloblastoma and KRAS mutations (WT, wild-type) being critical for deciding EGFR therapy in colorectal cancer, but in pancreatic ductal adenocarcinoma (PDAC) things are a lot more complex.  Morris et al., noted that:

"Analysis of PDAC mouse models driven by targeted pancreatic expression of oncogenic KRAS suggest that both temporal and spatial control of Hh and Wnt–B-catenin activity are involved in specifying a cell lineage that can progress to PDAC."

For those of you interested in more detailed biology associated with PDAC, I urge you to check out Hezel et al's excellent review on the topic (see reference link below).

Wnt–B-catenin signalling in PDAC

An interesting observation in the literature is that the KRAS mutation is nearly universal (>95%) in human PDAC. Furthermore, Morris et al., observed that:

"Wnt–β-catenin signalling is frequently activated in PDAC and contributes to tumour cell proliferation and biology.  Genetic models that allow Wnt–β-catenin deregulation reveal that this pathway can transform pancreatic cells but is insufficient to drive PDAC initiation."

So what else is going on?

In their review, the authors specifically look at:

  • the ability of KRAS to alter cell fate in the pancreas
  • how the timing and location of Hh and Wnt–B-catenin signalling contribute to PDAC development.

It's well worth a read with lots of helpful schematic diagrams to illustrate the underlying biology.

Clearly, we have a long way to go before we know more about the molecular basis of what is happening in this disease.  Some of the many factors that still need to be elucidated include:

  • which components of the complex pathway are activated in cancer
  • how they interact
  • whether there are differences in the tumour epithelium and the microenvironment
  • determine which Hh and B-catenin targets are ‘mission critical’ for maintaining proliferation, viability and differentiation
  • how can we block the critical signalling proteins?

Wnt in multiple Myeloma

Other research has focused on the role of Wnt in multiple myeloma (see Guiliani et al., in the references).  Their results results supported the link between the production of Wnt antagonists by multiple myeloma cells and the presence of bone lesions in multiple myeloma patients. They also demonstrated that myeloma cells do not inhibit canonical Wnt signaling in human bone microenvironment.

Targeting different parts of the Wnt pathway has, however, produced some interesting results. Studies with an orally bioavailable GSK-3a/B dual inhibitor increased markers of cellular differentiation in vitro and bone mass in vivo, proving that we have much to learn about this complex pathway before a likely pharmacologic agent will emerge commercially.

Wnt inhibitors in the pipeline

While several inhibitors of Notch and Hedgehog pathways have reached the clinical trial stage, drugable targets for Wnt inhibitors seem to have have proven elusive so far. I haven't come across too many agents inhibiting Wnt, although I was amused to hear from a friend that one is called Soggy-1.  

The Novartis Institute of Biomedical Research (NIBR) reported on XAV939 in a Nature article.  XAV939 selectively inhibits B-catenin-mediated transcription and acts via tankyrase inhibition. Huang et al., (2009) succinctly noted:

"The development of targeted Wnt pathway inhibitors has been hampered by the limited number of pathway components that are amenable to small molecule inhibition."

Given that few first generation inhibitors hit the mark first time, we may have to test quite a few different generations of Wnt inhibitors or even inhibitors of different parts of the pathway in combination, before a successful strategy finally emerges from R&D pipelines in the future.

 

ResearchBlogging.org

Morris JP 4th, Wang SC, & Hebrok M (2010). KRAS, Hedgehog, Wnt and the twisted developmental biology of pancreatic ductal adenocarcinoma. Nature reviews. Cancer PMID: 20814421

Giuliani, N., Morandi, F., Tagliaferri, S., Lazzaretti, M., Donofrio, G., Bonomini, S., Sala, R., Mangoni, M., & Rizzoli, V. (2007). Production of Wnt Inhibitors by Myeloma Cells: Potential Effects on Canonical Wnt Pathway in the Bone Microenvironment Cancer Research, 67 (16), 7665-7674 DOI: 10.1158/0008-5472.CAN-06-4666

Hezel, A. (2006). Genetics and biology of pancreatic ductal adenocarcinoma Genes & Development, 20 (10), 1218-1249 DOI: 10.1101/gad.1415606

Huang, S., Mishina, Y., Liu, S., Cheung, A., Stegmeier, F., Michaud, G., Charlat, O., Wiellette, E., Zhang, Y., Wiessner, S., Hild, M., Shi, X., Wilson, C., Mickanin, C., Myer, V., Fazal, A., Tomlinson, R., Serluca, F., Shao, W., Cheng, H., Shultz, M., Rau, C., Schirle, M., Schlegl, J., Ghidelli, S., Fawell, S., Lu, C., Curtis, D., Kirschner, M., Lengauer, C., Finan, P., Tallarico, J., Bouwmeester, T., Porter, J., Bauer, A., & Cong, F. (2009). Tankyrase inhibition stabilizes axin and antagonizes Wnt signalling Nature, 461 (7264), 614-620 DOI: 10.1038/nature08356

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MET, HGF and EGFR inhibition in cancer

By on September 7, 2010

Hepatocellular Growth Factor (HGF) and MET receptor tyrosine kinase signalling play important roles in development as well tumorigenesis.  In a Nature review article, Comoglio noted:

"Signals generated by the tyrosine kinase receptor Met elicit a complex biological response including cell dissociation, migration, protection from apoptosis, proliferation and differentiation."

They are also involved in liver regeneration and repair (Huh et al., 2004).

Background

HGF and MET have been shown to be active in a wide range of different cancers from bladder cancer to Wilms Tumours, although it is not yet clear in which tumours the pathway is critical to survival or merely over-expressed as a consequence of events.  

The pathway is fairly complex, but here is a simple version:

Picture 2
Source: Angion Biomedica

There is a more detailed pathway schematic in Eder et al's paper (see reference below) for those interested.

Activation of HGF or MET, results in downstream signalling of the RAS-ERK and PI3K-mTOR pathways. The EGFR ligand has been excluded from this schematic for simplicity, but you can imagine how they can interact and thus dual inhibition of both will essentially reduce the risk of either cross-talk or feedback between the two, which reactivates the downstream pathways unless inhibited.

Inhibitors in the Pipeline

This year we have discussed several MET inhibitors on this blog, namely:

  • Pfizer's crizotinib, which is a weak MET inhibitor, but potent ALK inhibitor
  • Combination of MET and EGFR inhibition previously with ARQ-197 (Arqule/Daiichi-Sankyo) in early lung cancer

I did some research on MET inhibitors in the pipeline and was surprised to find that there are over 30 of them in development, with nearly a dozen in the clinic already.  ARQ-197 is clearly leading the pack and moving into phase III soon, as I classify PF-2341066 as an ALK inhibitor, since that's where it's most active.

Here are some of the active compounds I recently came across, although not all of them may still be actively pursued:

Picture 3
Most of the others in the clinic are in more generic phase I allcomer solid tumour trials, as companies look for safety and efficacy signals before determining which tumour types to focus on for major development.

Several compounds appear to specifically target both HGF and MET, eg MetMAB (Roche) and AMG102 (Amgen), whereas others target purely c-MET eg ARQ-197 and some are multi-kinase Inhibitors, eg XL880 and MK-2461, so it remains to be seen which approach will ultimately work best with these agents, and in what combinations for different tumour types.

Single agent vs combination?

Undoubtedly, the data so far suggests that dual inhibition with an EGFR inhibitor such as erlotinib will be more effective than single agent targeting of MET alone. 

A recent paper in Cancer Research on MET, HGF and EGFR inhibition with SGX523 (SGX Pharma and Lilly) therefore piqued my interest.  I actually thought this compound had been discontinued, following unexpected toxicities two years ago (see here and here), principally compromised kidney function, but it may have been revived by the research group, as the two latest published papers are from late 2009 and last month and Lilly acquired the biotech company in 2008.

The authors looked at a SCID mouse model with the goal of predicting efficacy.  Indeed, they concluded that:

"Our findings also indicate that simultaneously targeting the MET and EGFR pathways can provide synergistic inhibitory effects for the treatment of cancers in which both pathways are activated."

Looking at the data though, most of the tumour suppression occurred when SGX523 was combined with erlotinib than either alone as a single agent, suggesting this approach may have more utility in the clinic.

References:

ResearchBlogging.org

Zhang YW, Staal B, Essenburg C, Su Y, Kang L, West R, Kaufman D, Dekoning T, Eagleson B, Buchanan SG, & Vande Woude GF (2010). MET Kinase Inhibitor SGX523 Synergizes with Epidermal Growth Factor Receptor Inhibitor Erlotinib in a Hepatocyte Growth Factor-Dependent Fashion to Suppress Carcinoma Growth. Cancer research, 70 (17), 6880-90 PMID: 20643778

Buchanan SG, Hendle J, Lee PS, Smith CR, Bounaud PY, Jessen KA, Tang CM, Huser NH, Felce JD, Froning KJ, Peterman MC, Aubol BE, Gessert SF, Sauder JM, Schwinn KD, Russell M, Rooney IA, Adams J, Leon BC, Do TH, Blaney JM, Sprengeler PA, Thompson DA, Smyth L, Pelletier LA, Atwell S, Holme K, Wasserman SR, Emtage S, Burley SK, & Reich SH (2009). SGX523 is an exquisitely selective, ATP-competitive inhibitor of the MET receptor tyrosine kinase with antitumor activity in vivo. Molecular cancer therapeutics, 8 (12), 3181-90 PMID: 19934279

Comoglio PM (2001). Pathway specificity for Met signalling. Nature cell biology, 3 (7) PMID: 11433311

Huh CG, Factor VM, Sánchez A, Uchida K, Conner EA, & Thorgeirsson SS (2004). Hepatocyte growth factor/c-met signaling pathway is required for efficient liver regeneration and repair. Proceedings of the National Academy of Sciences of the United States of America, 101 (13), 4477-82 PMID: 15070743

Comoglio PM, Giordano S, & Trusolino L (2008). Drug development of MET inhibitors: targeting oncogene addiction and expedience. Nature reviews. Drug discovery, 7 (6), 504-16 PMID: 18511928

Eder JP, Vande Woude GF, Boerner SA, & LoRusso PM (2009). Novel therapeutic inhibitors of the c-Met signaling pathway in cancer. Clinical cancer research : an official journal of the American Association for Cancer Research, 15 (7), 2207-14 PMID: 19318488

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