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Posts tagged ‘biomarkers’

AACR 2013 – some initial thoughts on the emerging trends

This year’s American Association for Cancer Research (AACR) annual meeting grew by 8% to approximately 18,000 attendees with 25% from 75 foreign countries, it is truly becoming a more global event for cancer researchers.

Over the next few days I plan to cover some of my highlights (basic, translational and clinical) in depth here on the blog and also with additional notes for email subscribers.  If you haven’t signed up for the PSB email alerts, there’s still time before the AACR notes go out.

Cherry Blossom in Washington DC by the Monument during AACR 2013With around 6,000 posters and many oral presentations from leading researchers, there is usually some interesting early data coming out from AACR.  This year was no exception.  My pile of poster handouts is over 6” thick with more already coming in my email!  My fervent wish for next year is that more scientists take to the QR code method of sharing their posters – aside from being green and saving trees, it’s also considerably easier on the back!  Another welcome development would be putting the posters online for later download as many of the European meetings already do.

I’m a little tired today as the event only just finished yesterday with a very good plenary session involving Jeff Engelman (MGH), Neal Rosen (MSKCC), Todd Golub (Broad Institute) and René Bernards (Netherlands Cancer Institute).  More on this later, but what a way to end the meeting with a fairly packed hall despite it being the last day.

One of my favourite activities at AACR is talking with young researchers in the poster hall, and a few of these will be highlighted in separate posts.  Many took the time to explain some complex biology and answer my many questions on a variety of topics.  Some of this information was really helpful in improving my own understanding of why I don’t like some therapeutic approaches (e.g. targeting hypoxia) others reinforced my enthusiasm for some immunotherapies such as PD-1 and PD-L1 inhibition.

What about the emergent themes from this year’s AACR meeting?

Every year brings new developments in some shape or form, but here are some of the trends I observed based on the posters and oral sessions I attended:

  • Identifying and developing strategies for overcoming resistance was MUCH more noticeable this year
  • New combination strategies (including more novel-novel approaches) was also very much to the fore
  • Increased pace of research into biomarker identification for clinical trial design
  • Continuing rise of epigenetics as a viable approach for cancer therapeutics
  • New targets emerging (more about these later)
  • Second generation agents to CDK 4/6 and 7, chimeric antigen receptor technology (CART), Polo-like Kinase (PLK1) and many others.

Over the next few days I’ll be writing more about these topics after wading through my many pages of chicken scratch notes from the oral sessions (largely driven by ones I know likely won’t be on the webcast, which goes live for the majority of sessions on May 1st) and that huge poster pile – watch this space!

 

 

ASH 2012 update on ARRY-520 in multiple myeloma

By on March 1, 2013

After highlighting the interesting biomarker program associated with AVEO’s tivozanib in renal cell and triple negative breast cancers in the last post, several people wrote in asking about other biomarker programs that have piqued my interest. Regular PSB readers will know that I’m not a fan of catch-all trials at all because the population being studied is too heterogeneous – use of biomarkers can help select which patients are more likely to respond to a particular drug and thus produce greater efficacy.

Another small biotech doing some interesting and compelling biomarker work is Array BioPharma, based in Boulder, Colorado.

What’s exciting about the ARRAY pipeline?

They have a nice pipeline of interesting targeted agents that are being developed with several big Pharma partners including AstraZeneca (selumetinib) and Novartis MEK162), both MEK inhibitors. Dennis Slamon’s lab has published some initial data on their work on predictive biomarkers with selumetinib for those interested (see References below).

MEK inhibitors are thought to target KRAS, which causes resistance in lung cancer and melanoma.  Combining MEK with a PI3K inhibitor may reduce the adaptive resistance and prolong survival. I’m expecting to see more on these at the forthcoming AACR and ASCO meetings in April and May. The approach is most likely to be incremental rather than a home run, though.

The ARRAY biomarker program that has intrigued me was presented in multiple myeloma (MM) at ASH in December. They have a novel kinase that targets Kinesin Spindle Protein (KSP) codenamed ARRY-520, which has a novel mechanism of action. For those of you interested in learning more about the basic biology of the KSP concept, I highly recommend checking out the papers in the Reference section below as they explain the targeting of the microtubilin concept well and how KSP inhibition differs from what we know of the taxanes as well as some useful background on the compound itself.

Some of you will remember previous KSPs that failed in the clinic such as ispinesib, for example, but not all compounds are equal or destined to fail. Much of cancer research is iterative – tweaking molecules to improve the conformation (shape), reducing side effects or improving potency. Sometimes a whole program can be canned because the company selected the wrong tumour type or trial design – you don’t always get multiple shots on goal in small biotechs!

What’s interesting to me is the focus of Array in multiple myeloma, a particularly difficult and foxy disease to impact clinically. The basic rationale behind this approach is that KSP is a microtubule protein required for mitosis (cell division); inhibition leads to cell death (apoptosis).

Now, remember the bedrock of therapy in MM has been proteasome inhibitors (bortezomib and now carfilzomib have been approved) and Immune Mediated inflammatory Disease agents or IMiDs (thalidomide, lenalidomide and now pomalidomide are all approved). This means that new agents with a different mechanism of action attract a lot of attention, especially if they can potentially be combined with existing drug classes to prolong survival and push patients into minimal residual disease (MRD) where the myeloma clone is drastically suppressed, much as we see in CML with the BCR-ABL inhibitors.

Inevitably, new drugs in MM are tested in a highly refractive population, either as a single agent or in combination with dexamethasone (dex) to determine if they have any efficacy.

Recall that two new agents approved by the FDA in relapsed/refractory MM had relative low single digit response rates (RR) as single agents i.e. carfilzomib (22.9%) and pomalidomide (7.4%) with improved RR in combination with low dose dex i.e. carfilzomib (34%) and pomalidomide (29.2%)

The two ARRY-520 analyses at ASH looked promising

Dr Satin Shah, ASH 2012

Dr Satin Shah, ASH 2012

The first part of the phase II study from Shah et al., (Abstract #449) looked at patients who were highly refractive to bortezomib and/or lenalidomide.

They observed that ARRY-520 had encouraging efficacy with and without dex. The first cohort (n=32) evaluated single agent therapy with ARRY-520 and saw 19% confirmed responses (CR) and 15% partial responses (PR); the subset who were both bortezomib and lenalidomide refractory had an ORR of 15%.

Meanwhile, the second cohort (n=18) looked at the combination with low-dose dex and demonstrated a PR or better of 22% in a heavily pre-treated population (more than 10 prior regimens). Adverse events included the usual myelosuppression (neutropenia, thrombocytopenia, anemia) seen in myeloma, but importantly, no treatment related neuropathy was observed.

The second element of the analysis looked at the same patients, but described the results from a biomarker, alpha-1-acidic glycoprotein (AAG). AAG is a serum protein that can have elevated levels in MM. As Dr Shah noted, AAG is not known to bind to standard of care agents in MM but is thought to bind to ARRY-520 with a negative impact by reducing the available amount of drug. In other words, they have a sub-therapeutic exposure to ARRY-520.

In the phase II study, they found that the hypothesis was supported: patients with high levels of AAG had poorer responses, while patients without elevated AAG levels had much better responses and the ORR increased to 33%, a dramatic improvement. The pre-dose AAG levels therefore correlated with response.

Obviously, the biomarker will need to be validated in larger, randomized controlled trials, but it would be very useful to be able to select patients upfront who could receive ARRY-520 either in combination with low dose dex or with a proteasome inhibitor or IMiD and see a more pronounced response. An initial trial with carfilzomib suggested an acceptable toxicity profile, while this is an encouraging start, we still need more data on the safety and efficacy of the combinations going forward.

Assuming the ongoing Phase Ib combination trials demonstrate good tolerability and efficacy, ARRY-520 could be potentially be combined with dexamethasone and either carfilzomib or pomalidomide in the relapsed/refractory setting for greater responses than the doublets alone.

Some additional thoughts…

I thought the Array KSP compound looked very encouraging indeed – multiple myeloma is crying out for:

  1. New agents with a different mechanism of action from the existing standards of care that can be combined to give solid results from triple combinations.
  2. More competition in the refractory setting to push out the MOS further and try to achieve minimal residue disease (MRD), which would impact the lives of patients with multiple myeloma significantly.

Beyond Kyprolis and Pomalyst, here are other agents in phase III studies being tested in refractory MM such as the HDACs e.g. panobinostat and vorinostat. The vorinostat data presented at ASH in 2011 was singularly disappointing, but hopefully we will hear about the phase III panobinostat results later this year.

In the meantime, Array have a nice compound in ARRY-520 and a potentially useful biomarker of response to help select patients upfront who are more likely to respond to treatment. As far as I know, they don’t yet have a partner for the program and may well need one for the large phase III trials that will be needed for FDA approval or they may well try to go it alone using the capital raised from the MEK partnerships. MM is certainly a promising avenue worth exploring for ARRY-520 and I look forward to hearing more about its development.

References:

ResearchBlogging.orgGaron, E., Finn, R., Hosmer, W., Dering, J., Ginther, C., Adhami, S., Kamranpour, N., Pitts, S., Desai, A., Elashoff, D., French, T., Smith, P., & Slamon, D. (2010). Identification of Common Predictive Markers of In vitro Response to the Mek Inhibitor Selumetinib (AZD6244; ARRY-142886) in Human Breast Cancer and Non-Small Cell Lung Cancer Cell Lines Molecular Cancer Therapeutics, 9 (7), 1985-1994 DOI: 10.1158/1535-7163.MCT-10-0037

Sarli, V., & Giannis, A. (2008). Targeting the Kinesin Spindle Protein: Basic Principles and Clinical Implications Clinical Cancer Research, 14 (23), 7583-7587 DOI: 10.1158/1078-0432.CCR-08-0120

Tunquist, B., Woessner, R., & Walker, D. (2010). Mcl-1 Stability Determines Mitotic Cell Fate of Human Multiple Myeloma Tumor Cells Treated with the Kinesin Spindle Protein Inhibitor ARRY-520 Molecular Cancer Therapeutics, 9 (7), 2046-2056 DOI: 10.1158/1535-7163.MCT-10-0033

miRNA as a potential biomarker for early breast cancer

By on January 16, 2012

One way to potentially improve long term cancer statistics is earlier detection, and in high risk patients, appropriate initiation of earlier treatment, since it is well known that the survival in stage II or III breast cancer is noticeably better than that for stage IV metastatic disease.

A critical question then, is how do we improve earlier detection?

There are a number of ways to achieve this:

  1. Imaging techniques
  2. Prognostication
  3. Diagnostics
  4. Biomarkers

Historically, breast cancer has often been picked up using classic, but rather crude, imaging techniques such as mammography and ultrasound, although both have their limitations and challenges. Biopsies are also challenging and invasive, especially in early stage disease when the tumour(s) may be very small. I’m particularly interested in biomarkers because it offers a lot of untapped near-term promise. We know that as tumours begin to develop, they leave tell tall signs and signatures – how can we develop ways to detect these earlier and with greater accuracy than at present?

Source: wikipedia

I was fascinated to read a paper in PLoSONE (open access, see references below) this morning looking at circulating microRNAs (miRNA) as a potential blood based marker for early stage breast cancer detection.

miRNA were defined by Schrauder et al., (2012) as:

“MicroRNAs (miRNAs, miRs) are a class of small, non-coding RNA molecules with relevance as regulators of gene expression thereby affecting crucial processes in cancer development.”

They were first described by Lee et al., (1993) in C. elegans (open access, see references below) and have since been found to be stable in blood, making them ideal biomarker material.

In the current research, the authors set out to determine whether miRNA could discriminate early stage breast cancer (n=48) from healthy controls (n=57) using microarray analysis.

What did the research show?

The initial results appear promising:

“We found that 59 miRNAs were differentially expressed in whole blood of early stage breast cancer patients compared to healthy controls. 13 significantly up-regulated miRNAs and 46 significantly down-regulated miRNAs in our microarray panel of 1100 miRNAs.”

Two of the miRNAs (miR-202, miR-718) were subsequently validated by RT-qPCR in an independent cohort.

What do these results mean?

I thought these results were encouraging, although it should be noted that there is no doubt that blood-based miRNA-profiling is behind the improvements seen in tissue-based miRNA-profiling. The advantage though, of blood-based profiling, is that it clearly offers:

“The potential for early, non-invasive, sensitive and specific BC detection and screening.”

Of course, there is a long way to go yet, although similar early studies have been performed in other tumour types such as lung cancer (Foss et al., 2011; Boeri et al., 2011), ovarian cancer (Häuser et al., 2010) and others.

Using miRNA as a potential biomarker for early detection is not without its challenges, though. Shrauder et al., noted that Chen et al., (2008) observed that:

“Comparing serum and blood cells from the same healthy individual an almost identical miRNA profile can be found, but in cancer patients the profiles differ.”

Other studies have not shown complete congruence in the results or findings, so it may well be a while before some clarity emerges with miRNA as a potential diagnostic, most likely with improved standardisation of sample handling, protocols, detection methods and patients (stage of disease, etc).

That said, miRNA looks to be a promising but fledgling area for biomarker research in the early detection of cancer. No doubt this field will evolve further with new and more sensitive techniques.

References:

ResearchBlogging.orgSchrauder, M., Strick, R., Schulz-Wendtland, R., Strissel, P., Kahmann, L., Loehberg, C., Lux, M., Jud, S., Hartmann, A., Hein, A., Bayer, C., Bani, M., Richter, S., Adamietz, B., Wenkel, E., Rauh, C., Beckmann, M., & Fasching, P. (2012). Circulating Micro-RNAs as Potential Blood-Based Markers for Early Stage Breast Cancer Detection PLoS ONE, 7 (1) DOI: 10.1371/journal.pone.0029770

Lee, R., Feinbaum, R., & Ambros, V. (1993). The C. elegans heterochronic gene lin-4 encodes small RNAs with antisense complementarity to lin-14 Cell, 75 (5), 843-854 DOI: 10.1016/0092-8674(93)90529-Y

Foss KM, Sima C, Ugolini D, Neri M, Allen KE, & Weiss GJ (2011). miR-1254 and miR-574-5p: serum-based microRNA biomarkers for early-stage non-small cell lung cancer. Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer, 6 (3), 482-8 PMID: 21258252

Boeri M, Verri C, Conte D, Roz L, Modena P, Facchinetti F, Calabrò E, Croce CM, Pastorino U, & Sozzi G (2011). MicroRNA signatures in tissues and plasma predict development and prognosis of computed tomography detected lung cancer. Proceedings of the National Academy of Sciences of the United States of America, 108 (9), 3713-8 PMID: 21300873

Häusler, S., Keller, A., Chandran, P., Ziegler, K., Zipp, K., Heuer, S., Krockenberger, M., Engel, J., Hönig, A., Scheffler, M., Dietl, J., & Wischhusen, J. (2010). Whole blood-derived miRNA profiles as potential new tools for ovarian cancer screening British Journal of Cancer, 103 (5), 693-700 DOI: 10.1038/sj.bjc.6605833

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Custirsen – a new treatment for castrate resistant prostate cancer?

By on August 8, 2011

I’ve been following the development of Oncogenex’s custirsen for a while based on various posters presented at meetings such as ASCO and AUA, but with the publication of phase II data in prostate cancer, it seems a good time to discuss the compound in more detail.

According to Oncogenex:

“OGX-011, also known as custirsen sodium, inhibits the production of clusterin, a protein that is associated with treatment resistance in a number of solid tumors, including prostate, breast, non-small cell lung, ovarian, and bladder cancers.”

Essentially, I think of it a chemo-enhancer, although more technically, it seems to help delay the onset of resistance developing by targeting clusterin (CLU).  CLU is a stress-activated cytoprotective chaperone.  It is upregulated by a several cancer drugs and confers resistance when overexpressed.

Low levels of CLU are therefore more desirable and may be useful as a predictive biomarker of response.

Previous data on custirsen from the phase II front-line trial showed an encouraging shift to the right in the survival curves, validating the hypothesis that resistance is delayed:

The current phase II clinical trial received support from both Sanofi and Oncogenex. Results were reported by Saad et al., (2011), who assessed the weekly administration of custirsen in combination with either docetaxel or mitoxantrone in second-line metastatic castrate resistant prostate cancer (CRPC).  Patients had previously been treated with a minimum of 2 cycles of a docetaxel-based chemotherapy regimen and progressed during or within 6 months of discontinuation of docetaxel treatment.

Overall, patients (n=42) were randomized to receive either docetaxel + prednisone + custirsen (DPC) or mitoxantrone + prednisone + custirsen (MPC).

What did the data show?

Given that the preclinical in vitro and in vivo models have demonstrated the potential of custirsen to enhance chemotherapy and reduce docetaxel resistance, I was keen to see how the concept would pan out in humans.  We all know that preclinical evidence is no guarantee of success in clinical trials!  Although the primary goals of the trial were to measure safety and tolerability, the effects on tumour response and disease progression were interesting.

DPC (n=20):

  • Received: median of eight cycles
  • Overall survival:15.8 months
  • TTPP: 10.0 months
  • 10 of 13 (77%) evaluable patients had pain responses
  • Three of 13 (23%) evaluable patients had objective partial responses
  • PSA declines of ≥90%, ≥50%, and ≥30% occurred in 4 (20%), 8 (40%) and 11 (55%) patients, respectively.

MPC (n=22):

  • Received a median of six cycles
  • Overall survival was 11.5 months
  • TTPP was 5.2 months
  • 6 of 13 (46%) evaluable patients had pain responses
  • No objective responses were observed
  • PSA declines of ≥50% and ≥30% occurred in 6 (27%) and 7 (32%) patients, respectively.

Based on experience, we would expect the results with docetaxel chemotherapy to be better than mitoxantrone, since the latter is only palliative at best.

Additionally, custirsen treatment was shown to significantly decrease levels of the target protein, CLU, and low serum CLU levels during treatment demonstrated superior survival.

Two phase III trials in combination with docetaxel are now ongoing in both the first and second line setting in CRPC.  The trials are currently enrolling patients, so results will not be available for a while, ie 2013 at the earliest.

Many of you will remember the video discussion from the American Urological Association meeting earlier this year, where we highlighted the potential for custirsen in combination with an AR antagonist such as MDV3100 from Medivation/Astellas.  For those interested, the initial data from the custirsen/MDV3100 combination is shown in the short vlog.

In the meantime, the results look most encouraging, although there is a-ways to go yet, since phase II data is no guarantee of phase III performance.

{Update: Luke Timmerman from Xconomy posted about the slow recruitment to the phase III trials and the protocol amendment to include Sanofi’s cabazitaxel (Jevtana).

References:

ResearchBlogging.orgSaad, F., Hotte, S., North, S., Eigl, B., Chi, K., Czaykowski, P., Wood, L., Pollack, M., Berry, S., Lattouf, J., Mukherjee, S., Gleave, M., & Winquist, E. (2011). Randomized Phase 2 Trial of Custirsen (OGX-011) with Docetaxel or Mitoxantrone in Patients with Metastatic Castrate-Resistant Prostate Cancer: CUOG Trial P06c Clinical Cancer Research. DOI: 10.1158/1078-0432.CCR-11-0859

2 Comments

Some thoughts on cancer research and the pipeline cliff…

By on June 28, 2011

This morning I was pondering a triangulation of several random thoughts that appeared in my Twitter stream, many from BIO, about various topics:

  1. Discussing the patent cliffs and lack of revenue generation some companies such as Lilly will no doubt be facing with John Carroll (Fierce Biotech) and Matt Herper (Forbes Health)
  2. Christiane True (PharmaLive) at the annual BIO meeting quoted a speaker as saying “doing more with less” which seems pretty much de rigeur these days
  3. Ron Leuty tweeted a quote from Chris Viehbacher’s (Sanofi) presentation at BIO, “Not doing more with less, but doing different things.”
  4. Christiane also quoted Viehbacher, “Still not enough of bright science making its way to patient benefit.”

The last point particularly made me wonder, because quite a few oncology companies have broad and deep pipelines, often with more compounds than they can possibly advance at once.  Even big Pharma or Biotech has to rationalise resources, budgets and people or nothing would get done.

How do those decisions get made?

Some are smart at life cycle management (GSK and Roche spring to mind), some think strategically about their portfolios, others get mired down in politics or – even worse – distracted by numerous committees focusing on what I call ‘fluffy puffy’ abstract things instead of moving the compounds rapidly through the pipeline to become safe and effective drugs that make a difference to patients lives.

The future of successful cancer drug development is likely going rest heavily on investment in basic science, molecular biomarkers and diagnostics, and novel-novel clinical trials that target multiple aberrations driving the disease.

Investors aren’t interested in any of these things, though; most just want a rapid or high return on their investment.  Spending less on R&D is much more in tune with their short term thinking:

Viebacher: If you sit down with investors, they clamor to stop spending on R&D, just do a buyback. #BIO2011

Tweet from Christiane True (PharmaLive) at BIO

The thing is, if pharma companies are going to rely on buying or licensing late stage compounds from Biotech, there is only so much small to medium Biotechs will be able to do going forward, because the future will mean more diagnostics and biomarkers, which are very expensive in cancer research, and in some cases, prohibitively so.  This will require closer, earlier collaboration with Academia and even different types of trials thanwe have been used to in the old chemotherapy world.

There are sometimes more challenges with clinical trial designs in small biotechs going from phase II to III, as Sanofi discovered with BiPar and iniparib and Novartis with Antisoma and ASA-404.  If we want to reduce the number of phase III failures, we have to get smarter about more iterative studies in phase II, better patient selection, incorporation of biomarkers, more logical combinations and yes, all of these will cost more dollars that will likely give investors insomnia.

Finding out more about the compound earlier will be the new name of the game – it is obviously better to abandon a weak agent on phase I or II than expensive phase III trials.

In the end, the companies who will win out in the long run are often those who think strategically, drive innovation, focus on science-based research, license earlier rather than later, invest in biomarker/diagnostic research, work in close knit cross-functional collaborative groups, avoid the twin pitfalls of bad karma and politics and ultimately ‘see’ things more clearly than the pack allows them to translate that into meaningful action.

It occurred to me that if you have to ask who the KOLs and experts are, then you have a long way to go and that doesn’t inspire confidence in the agent you’re developing.  If you have too much greed in the boardroom C-level that’s clearly going to hamper things as well, especially if they want to implement cuts down the line.  All of these myriad of factors surprisingly do matter when it comes to riding out patent cliffs and maintaining R&D momentum.

I should probably add ‘corporately ignore the short term investors for long term solid gains,’ but that would be a bit cheeky, perhaps 😉

Ultimately, what I would really like to see is less talk and more effective action:

A lot of talk about benefits and challenges with personalised healthcare but no mention of solutions #BIO2011

Tweet from Pieter Droppert in the Personalised Medicine session at BIO

I guess that’s why the American Association for Cancer Research (AACR) remains my favourite meeting in the annual conference calendar – at least Academic attendees are presenting data and discussing solutions in informal chats in corridors or poster sessions on how to address the practical issues of improving cancer research.  Inevitably, the smart companies are tapping into this resource and working alongside each other to unravel the complex mysteries.


The cancer research paradigm is slowly changing

By on June 14, 2011

Over the rest of this week I’m going to take some topics related to oncology and discuss them in more detail as part of a mini series about how cancer research is changing.

We all know that cancer isn’t one disease, but actually a myriad of different subsets, often even within each tumour type.  You can see the gradual shift aware from treating a type of cancer eg breast, lung, lymphoma, leukemia, melanoma etc to finding the driving the mutations and matching the patient to the therapy.

London Eye and Houses of Parliament

Having just returned from the European Hematology Association (EHA) meeting in London, I can say I was absolutely fascinated by the phase II data on brentuximab vedotin or Adcetris as it is now known (Seattle Genetics and Millennium), the antibody drug conjugate (ADC) in anaplastic large cell lymphoma (ALCL). Previously, we discussed the amazing data in Hodgkin Lymphoma but the photos of the patient responses in ALCL before and after treatment were amazing.

The connection?

Targeting the CD30 antibody on the surface of the cancer cells.

We can clearly see that as we learn more from basic research about the underlying mechanisms of growth, proliferation, survival and metastases, so our knowledge and ability to slow down disease progression and perhaps even stop the disease in it’s tracks also improves dramatically in some areas.

In the future, I can see triple negative breast cancer being segmented in various subtypes, for example, each with a different driving mutation and treating accordingly with carefully selected therapies, rather than treating them all as one homogenous subset of breast cancer, when they are in fact, heterogeneous.

There are several areas where we have made huge strides over the last five years:

  1. Earlier diagnosis
  2. Chemoprevention and slowing the inflammatory response
  3. Identifying biomarkers, both prognostic and predictive of responses
  4. Preventing metastases
  5. Translational scientist-clinicians

Over the next few days, I’m going to take a deeper look at these areas and discuss some of the new technology and research that is emerging in oncology as part of an updated landscape overview in cancer research.

If you have any other areas you would like covered, please do make suggestions in the Comments below.

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Aggregating the 2011 American Association of Cancer Research AACR tweets

By on April 1, 2011

Every year I attend a numerous annual meetings associated with oncology and hematology, but the American Association of Cancer Research (AACR) event in April is one of my personal favourites.

It may be April Fool’s Day today, but this meeting is no joke – it’s for serious cancer researchers and a lot of fun to boot!

I’m looking forward to meeting a lot of people and catching up on the latest research advances. Last year, there was a credible number of us tweeting different sessions, around 130 of us in fact, from the CoverItLive statistics I collated from last year’s meeting.   This year the hashtag continues to be #aacr so you can follow along remotely, join in with questions and thoughts or tweet from some of the sessions. The sentiments are collated in the widget below for easy reading, so do check back periodically if you want to get a feel of what’s going on in Orlando this year:

You can also follow the sessions more easily from the online schedule that AACR have made available. In addition, they have also got an awesome lineup of podcasts and webcasts for those who cannot attend to follow remotely – check out the tools and services here.

Check back tomorrow, as I’ll be posting about the daily highlights from the meeting.

In the meantime, if you wish to receive the blog delivered daily by email (and only the blog) and don’t want to miss the updates, just enter your preferred email address in the box below:

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Cancer Biomarker Resources

By on March 29, 2011

Many regular readers will remember the interview with Dr Sue Desmond-Hellmann, the Chancellor of UCSF, on the I-SPY2 trial, a large neoadjuvant study that seeks to accelerate the pace of identifying effective novel agents for early breast cancer by incorporating biomarkers from the beginning and an adaptive conjoint design. Biomarkers is definitely something that is very much to the fore these days.

A great resource for scientists involved with research in the biomarker field is Biomarker Commons, curated by my friend Walter Jessen, who describes himself as,

“a computational biologist focused on biomarker discovery and prioritization”

Now that sounds like a fun job to me!

Walter has put a very nice site together in his spare time (he also runs Highlight Health a site dedicated to biomedical research as well as having a day job).  Biomarker Commons collates news, research and journal articles about biomarkers – it’s well worth checking out of you are interested in this field:

Biomarker Commons

I subscribe to the RSS feed for news items myself and find it very useful indeed, as well as loving the clean easy to use interface.

Another useful resource is the Biomarkers Consortium, which describes itself as:

“The Biomarkers Consortium is a major public-private biomedical research partnership managed by the Foundation for the National Institutes of Health with broad participation from stakeholders across the health field, including government, industry, academia and patient advocacy and other non-profit private sector organizations.

In addition to the Foundation for NIH, founding members include the National Institutes of Health, Food and Drug Administration and the Pharmaceutical Research and Manufacturers of America.”

The link above takes you to their active projects, which includes ISPY2, but if you are involved in cancer research, they welcome new project ideas and submissions too.

Related to biomarkers is companion diagnostics and this is something big Pharma and Biotech are both active in.  At least in high tech areas such as oncology.  As we identify and validate more biomarkers associated with disease, so the need for tests to measure them will increase.

In the long run, insurers in the US will also be happier because biomarkers will ultimately lead to fewer patients being treated with higher priced new therapeutics ie those most likely to benefit, rather than exposing thousands of patients to the systemic effects of a targeted therapy.

What was interesting though, was learning at European Association Urology meeting that in Germany, for example, bone mineral density measurements using DXA are not covered and patients must pay for them out of pocket.  These measurements are often required to determine the degree of bone loss.  For therapies that treat cancer-associated bone loss such as zoledronic acid (Zometa), which is currently approved and denosumab (Xgeva), which is pending approval in Europe, this may limit uptake of the drug.

This weekend I will be attending the annual American American of Cancer Research (AACR) meeting in Orlando and look forward to catching up on the various new developments not just in basic research, but also biomarkers and companion diagnostics. It promises to be an interesting meeting!

 

Nuclear Receptor expression defines a set of prognostic biomarkers for lung cancer

By on December 20, 2010

I’m on a lung cancer and systems biology roll at the moment, although partly that’s just how the interesting data rolls in the literature.

Here’s some new food for thought.  A group of respectable scientists published some fascinating data in PLOS Medicine (free article see reference below) entitled, “Nuclear Receptor Expression Defines a Set of Prognostic Biomarkers for Lung Cancer.”

Using PCR, they evaluated NR expression patterns associated with good and poor outcomes in patients with non-small cell lung cancer (NSCLC) and then validated the findings in lung adenocarcinomas (n=550) and squamous cell carcinoma (n=130) samples in three different analyses by comparing normal and lung cancer cells.  Two important factors emerged from the analysis:

“The prognostic signature in tumors could be distilled to expression of two nuclear receptors, short heterodimer partner (SHP) and progesterone receptor, as single gene predictors of NSCLC patient survival time, including for patients with stage I disease.”

The SHP protein was the better predictor of outcomes in patients with stage I disease; those with strong SHP expression had better overall survival rates of approx. 70% at 100 months compared with 45% among people with low SHP expression.  The survival curves in the paper were quite dramatic – check them out.  Interestingly, the same signatures were also predictive of recurrence based on normal tissue samples from the patients with NSCLC.  Progesterone receptor expression was, however, a much weaker predictor of any outcome based on this analysis.

Essentially, this means the study demonstrated:

“NR expression is strongly associated with clinical outcomes for patients with lung cancer, and this expression profile provides a unique prognostic signature for lung cancer patient survival time, particularly for those with early stage disease.”

What are nuclear receptors, you may be wondering?

“The NR superfamily contains 48 transcription factors (proteins that control the expression of other genes) that respond to several hormones and to diet-derived fats.  NRs control many biological processes and are targets for several successful drugs, including some used to treat cancer.”

Still, it’s not something that immediately springs to mind as a possible or logical prognostic biomarker.

That said, out of the 48 transcription factors, two were found to be related to poorer patient outcomes.  They were NGFIB3, a receptor associated with nerve growth factor, and NR3C2, a mineralocorticoid receptor protein:

“This study highlights the potential use of Nuclear Receptors (NRs) as a rational set of therapeutically tractable genes as theragnostic biomarkers, and specifically identifies short heterodimer partner and progesterone receptor in tumors, and NGFIB3 and MR in non-neoplastic lung epithelium, for future detailed translational study in lung cancer.”

Going forward, we still need to see more research to find out whether these particular NRs or others were involved with tumour development and growth.  If  they do, then NR’s may potentially offer new therapeutic targets for future research and development.

References:

ResearchBlogging.org Jeong, Y., Xie, Y., Xiao, G., Behrens, C., Girard, L., Wistuba, I., Minna, J., & Mangelsdorf, D. (2010). Nuclear Receptor Expression Defines a Set of Prognostic Biomarkers for Lung Cancer PLoS Medicine, 7 (12) DOI: 10.1371/journal.pmed.1000378



What's hot in molecular diagnostics and biomarkers? #aacrMD #2

By on October 8, 2010

At the AACR meeting on Molecular Diagnostics and Cancer Therapeutics meeting in Denver, there was quite a bit of interesting scientific data coming out on cancer biology and biomarkers, so here is a quick synopsis of what appealed to me:

1. IGF-1R is over expressed in a subset of triple negative breast cancers (TNBC)

This presentation, from Witkiewicz et al., was interesting because they showed that IGF-1R might be a useful prognostic biomarker in TNBC. Usually, TNBC, which occurs in 15-20% of all breast cancers and is associated with a poorer prognosis, so finding a subgroup that might actually do better could be useful. Gene amplification was seen in 23% of the cases investigated. Caution must be exercised here, however, just because something is over expressed or amplified, does not mean that it is mutated, and therefore a potential druggable target with a therapeutic as we saw with the negative phase III results with figitumumab, an IGF-1R inhibitor in lung cancer.

What I would like to know though, is how many women with TNBC also have the BRCA1 or 2 mutation and have amplified IGF-1R? We know that targeting a cancer with one drug at one or two mutations in solid tumours has modest effects. But what if we target several things with a combination therapy, for a specific subset, then that might possibly yield different results altogether.

2. Molecular biomarker analysis using circulating tumour cells (CTCs)

Siminder Atwal, a Genentech scientist, presented her work on CTCs, with the idea of determining whether they could be used as a predictive biomarker by correlating CTCs with HER2 status in archival tumour samples. CTC's in theory should match tumour biopsies since they are cells that have shed from the primary tumour.  The Genentech scientists found that they were indeed correlated, with a high concordance (95%) using the CellSearch system. Of course, EpCAM expression can vary in some tumour types, complicating analysis and interpretation, but it looks like they saw some early hints that molecular biomarker status in CTCs are indeed reflecive of the biomarker status in patient tumours.

Predictive biomarkers allow us test whether a patient is likely to benefit from a given treatment, so the obvious and leading question is whether this work could be extended to look at eg CTC's in colorectal, lung or breast cancers to determine whether a patient is more likely to respond to bevacizumab (Avastin) or not. It would probably be easier in breast (lots of biopsy samples) and colorectal (lots of surgery providing samples).

At the moment, there is no way of telling who is most likely to respond to Avastin, so a predictive biomarker test would be really useful for clinicians before deciding on treatment, rather than having to expose thousands of patients to the systemic side effects. Given that the FDA have to make a decision by the year end on the full approval of Avastin in breast cancer, it is a shame that they likely won't have this sort of data to help guide a decision.  

3. BRCA1 mutations in prostate cancer

Gerhardt Attard gave an enlightening talk entitled, "Circulating tumor cells: Potential uses, pitfalls and challenges in their use as pharmacodynamic markers" but what struck me was not so much the fascinating information about CTCs as his mention that a subset of prostate cancer patients have the BRCA1 mutation. They tested the impact of olaparib, a small molecule PARP inhibitor from AstraZeneca, and found that all three responded.

A study open for men with prostate cancer and either BRCA1 or 2 mutations is currently recruiting patients. Given the interest with PARP inhibitors in breast and ovarian cancers, I'll be following this development with great interest.

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