Pharma Strategy Blog

Commentary on Pharma & Biotech Oncology / Hematology New Product Development

Posts by MaverickNY

Immune cells and lupus pathogenesis

By on March 17, 2011

We discuss the pathogenesis of cancer quite a bit on this blog, but today I wanted to take a look at immune disorders, specifically, systemic lupus erythematosus (SLE) or lupus for short.

Lupus is an autoimmune disease characterised by often widespread multi-organ inflammation, although the skin, kidney, and joints are often affected.  The main reason behind this phenomenon is the inability of the immune system to discriminate between self-antigens and foreign ones.

Historically, the immune component of the disease has resulted in use of immunosuppressants to try and tamp down the inflammatory cascade, but these can have severe side effects in what is essentially a chronic condition.  Three papers have appeared in Science Translational Medicine this month suggesting the possibility of new combination strategies that target specific aspects of SLE pathogenesis (see references).

In his commentary on the papers, Craft noted that two of the papers address one of the key questions that has been baffling sciences for decades:

“What are the steps that lead to neutrophil activation in SLE, what are the consequences of this activation, and how do these physiological consequences further inform us about self-antigen–driven autoreactivity in SLE?”

Lande et al., (2011) and Garcia-Romo et al., (2011) both found that:

“Neutrophils from patients with SLE are activated by IFN-α, with release of neutrophil extracellular traps (NETs) that contain unwound DNA, and antimicrobial peptides.”

Taken together, the two groups make a compelling case for an important role of neutrophils in triggering interferon-alpha (IFN-a) production in lupus pathogenesis and inflammation.  Garcia-Romo and colleagues research went further, finding that lupus generated neutrophils died upon exposure to anti-ribonucleoprotein antibodies, suggesting a potential clinical intervention strategy.

Duffau et al., (2011) took a different approach to the underlying biology of the disease. They looked at CD154, which has also been shown to critical given the modest success with some patients treated with a CD154 antibody, leading to a reduction in disease activity.  They found that in vitro, activated platelets enhanced IFN-a secretion by immune complex–stimulated plasmacytoid dendritic cells through a CD154-CD40 interaction.

The researchers concluded that:

“These data identify platelet activation as an important contributor to SLE pathogenesis and suggest that this process and its sequelae may provide a new therapeutic target.”

 

Clinical Progress

Recently, the FDA approved Human Genome Sciences monoclonal antibody, belimumab (Benlysta), for the treatment of lupus.  Belimumab is interesting because it blocks the binding of soluble BLyS, a B-cell survival factor, to its receptors on B cells.  The drug does not bind B cells directly, but by binding BLyS, it inhibits the survival of B cells, including autoreactive B cells, and reduces the differentiation of B cells into immunoglobulin-producing plasma cells.

This new therapy is given as a intravenous infusion over one hour.  The recommended dosage regimen is 10 mg/kg at 2-week intervals for the first 3 doses and at 4-week intervals thereafter for maintenance treatment.

In the controlled clinical trials, the overall incidence of infections was 71% in patients treated with belimumab compared with 67% in patients who received placebo. The most frequent infections (>5% of patients receiving belimumab) were upper respiratory tract infection, urinary tract infection, nasopharyngitis, sinusitis, bronchitis, and influenza. However, when looking at serious infections, they occurred in 6.0% of patients treated with belimumab and in 5.2% of patients who received placebo, which is quite comparable.

Benlysta is being co-marketed with GSK in the US and it will be interesting to see how well the therapy does, given that is immunosuppressive and not recommended for patients with chronic infections.

In the long run, however, it will also be interesting to see whether the field advances with new developments in the pipeline as a result of the three papers discussed in this post. Clinical trials have mostly yielded disappointing results so far, but it is possible that with a better understanding of the precise immune cascade and sequelae, we may be able to devise better combination and sequencing strategies that benefit lupus patients in the near future.

References:

ResearchBlogging.orgCraft, J. (2011). Dissecting the Immune Cell Mayhem That Drives Lupus Pathogenesis Science Translational Medicine, 3 (73), 73-73 DOI: 10.1126/scitranslmed.3002138

Lande, R., Ganguly, D., Facchinetti, V., Frasca, L., Conrad, C., Gregorio, J., Meller, S., Chamilos, G., Sebasigari, R., Riccieri, V., Bassett, R., Amuro, H., Fukuhara, S., Ito, T., Liu, Y., & Gilliet, M. (2011). Neutrophils Activate Plasmacytoid Dendritic Cells by Releasing Self-DNA-Peptide Complexes in Systemic Lupus Erythematosus Science Translational Medicine, 3 (73), 73-73 DOI: 10.1126/scitranslmed.3001180

Garcia-Romo, G., Caielli, S., Vega, B., Connolly, J., Allantaz, F., Xu, Z., Punaro, M., Baisch, J., Guiducci, C., Coffman, R., Barrat, F., Banchereau, J., & Pascual, V. (2011). Netting Neutrophils Are Major Inducers of Type I IFN Production in Pediatric Systemic Lupus Erythematosus Science Translational Medicine, 3 (73), 73-73 DOI: 10.1126/scitranslmed.3001201

Duffau, P., Seneschal, J., Nicco, C., Richez, C., Lazaro, E., Douchet, I., Bordes, C., Viallard, J., Goulvestre, C., Pellegrin, J., Weil, B., Moreau, J., Batteux, F., & Blanco, P. (2010). Platelet CD154 Potentiates Interferon-  Secretion by Plasmacytoid Dendritic Cells in Systemic Lupus Erythematosus Science Translational Medicine, 2 (47), 47-47 DOI: 10.1126/scitranslmed.3001001

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Word clouds – what are you tweeting about?

By on March 15, 2011

Some light hearted amusement for today is in order after the levity and gravity of the weekend.   One of my favourite Twitter buddies, Robert Scoble (@scobleizer) the tech geek, is always sharing cool stuff for people to try.  I noticed he posted a link to a new social media beta service, mirror.me, which creates a tag cloud of a user’s tweets.

Robert’s tag cloud looks like this, for example:

To create your tag cloud, simply go to mirror.me and authenticate the service using your Twitter username and password.  It then creates the graphic automatically, with the most commonly used words in a bigger font size.

Here’s my tag cloud as another example:

As other people join, it will also show your Twitter connections with their avatar (photo) and their tag clouds as they are created.  Very useful tool for seeing what people’s interests are and, presumably, something that will change organically if your tweets vary over time.

The tool will also show you some basic metrics, such as information about your followers and what their interests are based on their Twitter bio tags.  I was guessing that most of mine would come from the healthcare space:

Mirror.me metrics

Your results may vary depending upon your interests and followers.

There are other metrics you can look at as well, such as rankings within your interests, but I’m not sure how this works yet:

mirror.me rankings

This feature is a little weird – some famous biotech companies are ranked lower than me and a bot tweeting people’s resumes is at the top of the biotech category, for example! That certainly gave me a smile for the morning 🙂

The good news is that mirror.me tweeted that they will be adding more features over time, so it should be a useful feature to follow and explore.

 

 

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The relationship between radioactivity, leukemias and lymphomas

By on March 14, 2011

Ohayo gozaimasu!  Like many people this weekend, I have been following the twin earthquake and tsunami disaster in Northern Japan with a great sense of sadness after hearing that thousnads of people have died.  If you haven’t already seen it, pictures of Japan before and after the tsunami devastation are an astonishing testament to the power of nature.  Coming so soon after the harrowing pictures of the massacres in Libya, it certainly feels like a violent world at the moment.

It is interesting to follow the news on Twitter in real time, generally much more useful (bar some hype and silliness from some people) than CNN and other News outlets who struggled to get to grips with timely information.  I was, however, disheartened to see that the engineers at Fukushima had no choice but to resort to venting the gases and also pumping in borax and sea water into the reactor chamber.  They needed to do this to try and cool the reactors down, reducing pressure, thus try to prevent explosions (and noxious radioactivity escaping into the atmosphere) or even worse, a core meltdown.

One source of accurate information was the Nuclear Energy Institute, who provided regular, factual updates on their website and pictures to explain what was going on with the Fukushima Boiling Water Reactors or BWR in short (you can see where the NY Times and others got their pictures from, for example):

Source: Nuclear Energy Institute

Social Media is useful for collating information from local people in Japan, such as this brief but alarming video from Fukushima courtesy of Japanese tv of one of the explosions at the nuclear plant:

There was some great commentary on Twitter from nuclear professionals such as Arclight, who spent most of his weekend monitoring the situation and answering anxious people’s questions about what was going on.  In times like these, accurate information rather than speculation is more more helpful and reassuring.

It is, however, decay heat that creates challenges, ie heat that has been stored in the rods and is expelled rapidly if they are not cooled sufficiently or exposed to air, thereby creating hot steam and pressure.  The NY Times has an excellent simplified graphic that explains how nuclear reactors work for those interested.

The problem is that high levels of radioactivity in the sea or air is never a good thing for life around it.  Years ago, there was a hugh debate (that’s an understatement) about the increased incidence of leukaemia and lymphomas in children around the Sellafield nuclear plant in Cumbria, UK, with different groups arguing for and against it (see references below as a snapshot).

The argument about cause and effect doesn’t seem to have been settled either way judging from various epidemiology studies and intense papers/letters to journals such as the BMJ over the past few decades.  Still, I’m sure most of us would probably agree that exposure to direct prolonged radiation from the sea or air is, intuitively, probably not a good thing in the long run.  Strontium, for example, one of the chemicals produced as a by product in nuclear reactors, tends to build up in teeth and bones, and may well be an irritant that can cause mutations over time.

What is clear, is that once sea water is pumped into a reactor, it is essentially dead and can never be used again, necessitating a massive clean up operation that may well take years to effect.  If anyone can do it efficiently and effectively, it is probably the Japanese with their superb engineering and sadly, experience from the Hiroshima clean up after the Second World War.

This morning, the availability of clean air, food and water took on an entirely different meaning.  In the meantime, my thoughts are sincerely with the Japanese people in their hour of need.

References:

ResearchBlogging.orgGardner, M., Snee, M., Hall, A., Powell, C., Downes, S., & Terrell, J. (1990). Results of case-control study of leukaemia and lymphoma among young people near Sellafield nuclear plant in West Cumbria. BMJ, 300 (6722), 423-429 DOI: 10.1136/bmj.300.6722.423

Gardner MJ, Hall AJ, Snee MP, Downes S, Powell CA, & Terrell JD (1990). Methods and basic data of case-control study of leukaemia and lymphoma among young people near Sellafield nuclear plant in West Cumbria. BMJ (Clinical research ed.), 300 (6722), 429-34 PMID: 2107893

Roman E, Watson A, Beral V, Buckle S, Bull D, Baker K, Ryder H, & Barton C (1993). Case-control study of leukaemia and non-Hodgkin’s lymphoma among children aged 0-4 years living in west Berkshire and north Hampshire health districts. BMJ (Clinical research ed.), 306 (6878), 615-21 PMID: 8461811

Watson GM (1991). Leukaemia and paternal radiation exposure. The Medical journal of Australia, 154 (7), 483-7 PMID: 2005848

Draper GJ, Little MP, Sorahan T, Kinlen LJ, Bunch KJ, Conquest AJ, Kendall GM, Kneale GW, Lancashire RJ, Muirhead CR, O’Connor CM, & Vincent TJ (1997). Cancer in the offspring of radiation workers: a record linkage study. BMJ (Clinical research ed.), 315 (7117), 1181-8 PMID: 9393219

Elements of success in cancer research

By on March 10, 2011

“I’ve missed more than 9000 shots in my career.  I’ve lost almost 300 games.  26 times, I’ve been trusted to take the game winning shot and missed.  I’ve failed over and over and over again in my life.  And that is why I succeed.”

Michael Jordan, Chicago Bulls

Michael Jordan, Chicago Bulls

Source: wikipedia

Continuing the sporting metaphors this week, I was catching up on blog reading last night and noticed that Jim Lefevere put up a nice post on Digital Strategist about how:

Domain Expertise + Work Ethic + Time = Success

He used Michael Jordan as an example to illustrate the competitiveness that is required for the top level.

While talking to scientists and researchers at the recent AACR PI3K-mTOR meeting about their myriad of iterative experiments with GWAS, Western Blots and such, you can imagine the parallels with scientific research.

It struck me how the scientists in this particular field of cancer research are both highly collaborative and competitive at the same time, while also being very focused and intense on the end game (implications for clinical research), perhaps more so than other sub specialty areas I’ve come across lately.

The main message I learned from the meeting can be summed up in this little forumla:

Driver Mutation + Adaptive Pathway + Ligand + Patient Selection = Possible Success

A lot of data on PI3K and mTOR can be expected at forthcoming annual meetings at AACR (April) and ASCO (June), so it will be interesting to see how the new combinations of PI3K or mTOR with AKT or MEK, for example, are panning out and in which tumour types.

 

 

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On cricket and cancer research…

By on March 9, 2011

“How the mighty have fallen so quickly.  England were national heroes after winning the Ashes.  Now they are national chumps after this shocking and embarrassing defeat.”

Geoffrey Boycott, on England’s surprise defeat by Ireland in Cricket World Cup.

England v Ireland in the Cricket World Cup

England v Ireland in the Cricket World Cup

Some of you readers will be aware that I’m a big sports fan, of cricket and football in particular, so my cheerful mood earlier this morning was somewhat muted after learning that the motherland, England, somehow managed to lose to lowly Ireland.  In cricket!

Ugh, such is life – all good Englishmen will no doubt down another pint and shake their head in sorrow.

Still, that metaphor got me thinking.  In sports, there’s always another game, another tournament, another year – life goes on regardless.  While I was growing up, the mighty West Indies were at the height of their scintillating dynasty.  Now?  Not so much. Yesterday’s champs are tomorrow’s chumps and vice versa.  In clinical R&D though, if a major trial flops or is negative, it is rare that a company will go back and reconsider another series of trials with the agent in the same tumour type, even if the trial design was flawed, unless they have others already ongoing or in very late stages of planning.

You get one shot to get right.  Maybe two, if you are lucky.

Moving forwards, the incredibly high rate and cost of failures is unsustainable.  In the oncology arena, I think we will see the smart companies get smarter about drug development.  What does this mean in practice?

  1. More exploratory, smaller, phase II trials
  2. Focus on pathways and related activities as targets
  3. Increased use of translational research in 1) to determine mechanisms of resistance, adaptive pathways, biomarkers, logical combinations
  4. Greater use of the adaptive trial design to find the best winning combinations
  5. Increased use of diagnostics and biomarkers to select more clearly defined patient populations (ie smaller subgroups)

These trends are slowly happening now, you can see it more clearly in some pathways such as PI3K-mTOR, for example.  The days of taking a targeted therapy and adding it to standard of care chemotherapy in an unselected population, as happened with iniparib in triple negative breast cancer, are unlikely to be the future of cancer research.

What the more intense integration and iteration of basic research and phase II trials will give us is perhaps, a slightly slower development process, but with a much higher chance of success. In my book, that’s a much better approach – cancer patients deserve the best shot we can give them.

Photo Credit: ICC World Cup

Aside: For those wondering, my pre tournament tip was that India would be very strong contenders for this year’s World Cup, if only their bowling manages to get organised. Their batting strength is second to none, but Pakistan have a good chance if the Indian bowling shows any chinks and cracks.  Cricket is a team game, after all.  England regrouped and recovered to beat the strong Springboks from South Africa, so all is not lost yet!  Anybody but the Aussies, that’s all that matters 😉

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Personalised therapy for prostate cancer – is it possible?

By on March 7, 2011

AACR PI3K-mTOR special conference

Recently, while in San Francisco for the AACR special conference on the PI3K-mTOR pathway in cancer, I was particularly struck by several important learnings that have since make me think more deeply about oncology drug development going forward:

  1. With targeted therapies, we need to more carefully select the patients, based on a clearly defined patient population
  2. We need to identify both the driving mutations and the adaptive pathway
  3. Aberrant activity is often also ligand driven

This means that in the future, targeted treatment may evolve in smaller subsets of disease with more logical double or even triple combinations.  It also means that there will be more, smaller phase II trials with translational research incorporated, across multiple combinations to tease out the critical, defining protocol.  Think more adaptive trial designs similar to the BATTLE and I-Spy series in lung and breast cancer, respectively.

Of course, Pharma’s immediate reaction is going to be “oh my, that’s going to be very expensive and difficult to do with novel-novels in clinical trials!”

The reality, however, is that it may not actually be sustainable to keep charging exhorbitant prices and smart companies with deep pockets and strong commitment will build portfolios with a wide range of different targets either in house, through licensing or acquisitions.  The trend in this direction is slowly, but surely, happening as knowledge of the biology of different cancers and subsets improves.

It was therefore no surprise that two articles appeared last week in Science and Translational Medicine and piqued my interest.  Goldstein, Zong and Witte (2011) provided some thoughtful commentary on research by Ateeq et al., (2011) on the SPINK1 mutation in prostate cancer.  They observed:

The concept of one-size-fits-all therapeutics is becoming increasingly less relevant, because any one therapy is unlikely to be effective for all individuals with a complex disease such as cancer.  For the hundreds of thousands of men who are diagnosed with prostate cancer each year, their tumors do not all share the same molecular machinery, pathways, or targets.

Ateeq et al., describe how SPINK1 contributes to the aggressive phenotype.  Forced expression of recombinant SPINK1 increased prostate cancer cell proliferation and invasiveness, whereas knockdown of SPINK1 gene expression or treatment with a SPINK1-directed monoclonal antibody resulted in decreased cell division, invasiveness, and tumour growth.

SPINK1 is highly expressed in ~10% of prostate cancers, and expression has been correlated with aggressive disease.

Interestingly, SPINK1 mediated its neoplastic effects partly through interactions with the epidermal growth factor receptor (EGFR).  Ateeq et al’s experiments showed that antibodies to both SPINK1 and EGFR blocked the growth of SPINK1+/ETS tumours more than either antibody alone, and did not affect SPINK1- tumours.

In the graphic below (courtesy of Goldstein et al., 2011), you can see that in part (a) SPINK1 secreted from prostate cancer cells can stimulate EGFR dimerization, phosphorylation, and downstream signaling through phosphoinositide 3-kinase (PI3K)/AKT, mitogen-activated protein kinase (MAPK), or janus kinase (JAK) pathways in an autocrine loop.

In part (b), in addition to small-molecule agents that block AR, PI3K/AKT, MAPK, or JAK signaling pathways, monoclonal antibodies against EGFR or SPINK1 could inhibit signal transduction by blocking the physical interaction between EGFR and the SPINK1 ligand:

SPINK1 in Prostate Cancer

In the research, an approved monoclonal antibody to EGFR, cetuximab, was used, together with an un-named SPINK1 antibody with better results than either alone. We should remember though, as Goldstein et al., note:

However, disappointing results in trials of EGFR-targeted therapies for prostate cancer with gefitinib, lapatinib, or cetuximab raise doubts about the importance of the EGFR signaling pathway for most prostate cancers.

What do these results mean?

Although animal research doesn’t always translate to positive results in humans in the clinic, it is entirely possible that better patient selection and the right combinations may be necessary to target a driving mutation, ligand and adaptive pathway in order to yield better results than previously seen with EGFR inhibitors.

Overall, I think this latest research does provide a solid rationale for the development of humanised anti-SPINK1 monoclonal antibodies for targeting a subset of patients with SPINK1 positive and ETS-negative prostate cancer in clinical trials. There are mouse antibodies available for research, but I couldn’t find a humanised one in development. It will be interesting to see any company takes up the challenge going forward.

References:

ResearchBlogging.orgGoldstein, A., Zong, Y., & Witte, O. (2011). A Two-Step Toward Personalized Therapies for Prostate Cancer Science Translational Medicine, 3 (72), 72-72 DOI: 10.1126/scitranslmed.3002169

Ateeq, B., Tomlins, S., Laxman, B., Asangani, I., Cao, Q., Cao, X., Li, Y., Wang, X., Feng, F., Pienta, K., Varambally, S., & Chinnaiyan, A. (2011). Therapeutic Targeting of SPINK1-Positive Prostate Cancer Science Translational Medicine, 3 (72), 72-72 DOI: 10.1126/scitranslmed.3001498

On RANKL and denosumab in advanced cancer metastasis

By on March 2, 2011

In this week’s Nature, my eye was drawn to a Letter from Tan et al., (2011) discussing how inflammatory mechanisms influence tumorigenesis and metastatic progression, even in tumours that seemingly don’t involve pre-existing inflammation or infection such as breast and prostate cancers.

In advanced prostate cancer, metastasis is sadly inevitable.   So far as we know, lymphocytes infiltrate the tumour, causing upregulation of nuclear factor-KappaB (RANK) ligand (RANKL) and lymphotoxin (see Luo et al., 2007).

RANK signalling controls osteoclastogenesis and bone resorption and targeting it with denosumab has been shown to reduce the incidence of skeletal related events (SRE) but not overall survival in prostate cancer (see Fizzazi et al., 2011):

Overall Survival is similar in the denosumab and zoledronic acid arms

and other advanced cancers, including multiple myeloma (see Henry et al., 2011).  Overall survival was again not improved compared with zoledronic acid, as you can hear from this short podcast or read the accompanying editorial in the JCO from Dr Jack West of Swedish on the topic, which was both fair minded and well written, discussing additional factors that need to be considered, including costs, something that is all too often swept under the carpet.

What is less well known, however, is the source of RANKL and it’s role in metastasis. Tan and colleagues therefore decided to take a closer look at this.

What did they do?

In their research, Tan et al., (2011) decided to evaluate whether RANKL, RANK and IKK-a (nuclear factor kinase-alpha) are involved in cancer metastasis.  IKK-a is a protein kinase needed for the self renewal of cancer progenitors.  The question is, how do all these relate?  They used various cell lines and models to explore the relationships.

The NF-kB pathway looks like this:

NF-kB signaling pathway

What did they find?

The results showed that RANK signalling in cancer cell lines overexpressing Erbb2 (HER2) was important for pulmonary metastasis.  This is also potentially relevant to breast cancer, since HER2 is frequently overexpressed in metastatic disease.

Using MT2 cells in Ragl-/- mamary glands, they looked at whether RANKL was involved in metastatic spread.  Most RANKL-producing T cells expressed forkhead box P3 (FOXP3), a transcriptional factor produced by T cells and were located next to stromal cells.

In all, the authors concluded that:

“Targeting RANKL-RANK can be used in conjunction with the therapeutic elimination of primary breast tumours to prevent recurrent metastatic disease.”

The challenge here though, is that while the preclinical models are very appealing in theory, in the clinic we must not forget that a significant reduction in SRE does not necessarily mean that patients live longer, as witnessed by the lack of OS benefit in the trials mentioned above.

References:

ResearchBlogging.orgTan, W., Zhang, W., Strasner, A., Grivennikov, S., Cheng, J., Hoffman, R., & Karin, M. (2011). Tumour-infiltrating regulatory T cells stimulate mammary cancer metastasis through RANKL–RANK signalling Nature, 470 (7335), 548-553 DOI: 10.1038/nature09707

Luo JL, Tan W, Ricono JM, Korchynskyi O, Zhang M, Gonias SL, Cheresh DA, & Karin M (2007). Nuclear cytokine-activated IKKalpha controls prostate cancer metastasis by repressing Maspin. Nature, 446 (7136), 690-4 PMID: 17377533

West, H. (2011). Denosumab for Prevention of Skeletal-Related Events in Patients With Bone Metastases From Solid Tumors: Incremental Benefit, Debatable Value Journal of Clinical Oncology DOI: 10.1200/JCO.2010.33.5596

Henry, D., Costa, L., Goldwasser, F., Hirsh, V., Hungria, V., Prausova, J., Scagliotti, G., Sleeboom, H., Spencer, A., Vadhan-Raj, S., von Moos, R., Willenbacher, W., Woll, P., Wang, J., Jiang, Q., Jun, S., Dansey, R., & Yeh, H. (2011). Randomized, Double-Blind Study of Denosumab Versus Zoledronic Acid in the Treatment of Bone Metastases in Patients With Advanced Cancer (Excluding Breast and Prostate Cancer) or Multiple Myeloma Journal of Clinical Oncology DOI: 10.1200/JCO.2010.31.3304

Fizazi K, Carducci M, Smith M, Damião R, Brown J, Karsh L, Milecki P, Shore N, Rader M, Wang H, Jiang Q, Tadros S, Dansey R, & Goessl C (2011). Denosumab versus zoledronic acid for treatment of bone metastases in men with castration-resistant prostate cancer: a randomised, double-blind study. Lancet PMID: 21353695

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Molecular subtypes in gliomas predict prognosis

By on March 1, 2011

One of the hallmarks of cancer is that even within different tumour types, there is an enormous degree of heterogeneity. Ultimately, in simple terms this means that individual patients will respond to different therapies depending upon their underlying biology.   The challenge, therefore, is defining and categorising the subtypes and working out which are the passenger and driver oncogenes, since the latter will cause aberrant tumour growth and survival, while the former may result as a consequence of changing pathway activity.

This morning I was researching gliomas and came across this old paper (March 2006) that looks at molecular subtypes of gliomas i.e. glioblastomas and astrocytomas.  The article concluded:

“Recent evidence suggests that gliomas may arise from a cell type with neural stem cell-like properties. The current work demonstrates that prognostic subtypes of glioma resemble key stages in neurogenesis and implicates signaling pathways that play critical roles in regulation of forebrain neurogenesis in control of tumor aggressiveness. Longitudinal analysis of glioma cases reveals a frequent pattern of disease progression into the mesenchymal phenotype, a state associated with robust angiogenesis.

This work suggests that molecular classification of glioblastoma may predict response to targeted therapies and suggests that greater understanding of neurogenesis in the adult forebrain may yield novel therapeutic insights for glial malignancies.”

The reason I was curious about this particular paper was because following the AACR Special Conference on PI3K and mTOR that I attended last week, it made sense to look at the literature on mTOR, PI3K and AKT in more detail.

In the glioma research, it was interesting to see what predicted poor prognosis:

“A robust two-gene prognostic model utilizing PTEN and DLL3 expression suggests that Akt and Notch signaling are hallmarks of poor prognosis versus better prognosis gliomas, respectively.”

Now, while Akt and Notch signalling may be important, it doesn’t mean that they make idea targets for drug therapy.  PTEN loss of function is also a difficult target at present and it isn’t clear if it is a driver per se.  What was very clear at AACR last week was that for every action there is an equal and opposite reaction, meaning that targeting one part of a pathway may lead to switching of aberrant activity to another part of the pathway as it adapts to the changing environment.

Neal Rosen from MSKCC gave perhaps one of the best talks of the AACR meeting. He succinctly and simply put out a few constructs based on what we know so far. I will summarise some of the talks in a conference report (sign up on the top right column), but what was relevant to the paper on gliomas is that while at first sight it might make sense to target Akt, that strategy will have consequences.

According to Rosen, in general, inhibiting PI3K also stimulates HER3 expression and phosphorylation, as well as other receptor tyrosine kinases in many cell lines.  In other words, we may need a multi-targeting approach based on the original aberrant driver, the adaptive pathway and the ligand driving activity.

Double and triple combinations make sense from a scientific perspective, but they will also incur far higher costs and more complex clinical trial designs. Who knows whether other adaptive mechanisms will also evolve as a result of pursuing that strategy?  It brings vividly to mind Frank McCormick’s wac-a-mole approach that he described last year at AACR on the challenges of targeting the PI3K pathway in general, irrespective of upstream or downstream targets.

Progress is slowly being made, but we have a long way to go yet with the PI3K-mTOR pathway, although I’m hopeful of some positive progress soon. Certainly there will be some new data emerging on the biology at AACR in April and clinical data at ASCO in June.

References:

ResearchBlogging.orgPhillips, H., Kharbanda, S., Chen, R., Forrest, W., Soriano, R., Wu, T., Misra, A., Nigro, J., Colman, H., & Soroceanu, L. (2006). Molecular subclasses of high-grade glioma predict prognosis, delineate a pattern of disease progression, and resemble stages in neurogenesis Cancer Cell, 9 (3), 157-173 DOI: 10.1016/j.ccr.2006.02.019

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

Targeting PI3-kinase and mTOR in cancer

By on February 24, 2011

Today, I’m heading off to San Francisco for the AACR Special Conference on Targeting PI3-Kinase and mTOR in cancer.  For those of you needing a brief primer on the pathway, you can find more about it in this 2010 post, which vies with one about ipilimumab in melanoma as the top two posts on Pharma Strategy since the end of October.

You can view the PI3K-mTOR program here.

I’m really excited to be attending this event – a lot of the ‘big guns’ in the PI3-kinase field are speaking at this event, including Lewis Cantley, Jeffrey Engelman, David Sabatini, Carlos Arteaga, Neal Rosen, Gordon Mills and many others.

There are also presentations from scientists at various Pharma and Biotech companies with PI3-kinase inhibitors in development, so it won’t just be about the basic translational research per se, but also about how the R&D is progressing to date with new therapeutics.

If anyone is at the meeting, please do stop and say hello – it’s always nice to meet readers in person – I bumped into a few at last weeks ASCO/ASTRO/SUO GU cancers symposium, for example.

I’ll be tweeting a few snippets from the conference, including tonight’s keynote by Jose Baselga (Mass General Hospital), but excluding unpublished data, under the hashtag #PI3K.  The aggregated tweets from that hashtag will be captured between now and Saturday in the widget below for easy following for those remote and interested in this sub-specialty:

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