Pharma Strategy Blog

Commentary on Pharma & Biotech Oncology / Hematology New Product Development

Posts from the ‘Strategy’ category

FGFR1 mutations in squamous cell lung cancer

By on June 17, 2011

“Using SNP array analysis, we found that a region of chromosome segment 8p11-12 containing three genes–WHSC1L1, LETM2, and FGFR1–is amplified in 3% of lung adenocarcinomas and 21% of squamous cell lung carcinomas.”

Dutt et al., (2011)

This snippet from a paper in PLoSOne caught my attention, because while we have seen a number of molecular targets identified and therapies developed for lung adenocarcinoma, none has yet been reported in squamous cell lung carcinoma.

Squamous cell carcinomas account for 25% of new lung carcinoma cases and 40,000 deaths per year in the United States, a not inconsiderable number of patients.

This isn’t a new finding per se, as we have discussed FGFR1 amplification in lung cancer previously on this blog.  However, what was also interesting and novel about the paper, is that the authors went on to note:

“Furthermore, we demonstrated that a non-small cell lung carcinoma cell line harboring focal amplification of FGFR1 is dependent on FGFR1 activity for cell growth, as treatment of this cell line either with FGFR1-specific shRNAs or with FGFR small molecule enzymatic inhibitors leads to cell growth inhibition.”

In this study, the pan-FGFR inhibitor PD173074 (Pfizer) was used to test whether cell growth was attenuated or not.  There are a number of FGFR inhibitors in development, which we discussed in the last blog post on this topic in December.

All this sounds very encouraging indeed, although there are caveats that should be stated, for example, preclinical research is no guarantee of success in the clinic and amplification of a mutation or gene (as opposed to mutation) does not mean that it is a driver of the disease – it could be a passenger or overexpression as a consequence of other things happening as a result of the tumour proliferation.

Still this is a promising finding well worth exploring, because as the authors rightly point out, “no FDA-approved targeted therapies for squamous cell lung cancer.”

The critical key to exploring mutations, amplifications and targeted therapies in the clinic going forward will be to have well designed iterative phase II trials with very careful patient selection based on the known biology to tease out the patients most likely to respond rather than catch-all studies where the chances of finding responders over non-responders is much lower.

Why do this?  Overall, I think it is better to have high response rates in a small subset than a low response rate in an unselected population where people who have no chance of doing well are exposed to the systemic side effects unnecessarily.

We can see this trend clearly emerging with the well designed trials ELM4-ALK translocations for crizotinib, for example.  Interestingly, ALK and lung cancer mutations (seen in adenocarcinomas) are very much in the news this month, following some excellent data at ASCO for Pfizer’s crizotinib that augers well for FDA approval and Ariad announcing that they are progressing their dual ALK-EGFR inhibitor, AP26113, into the clinic. Preclinically, this agent has also been shown to inhibit the T790M mutant that is resistant to EGFR inhibitors.  You can read more from Ariad on their EGFR-ALK inhibitor.

Oddly, Ariad’s other drug in phase II clinical development for CML, ponatinib, also inhibits FGFR and FLT3 as well as BCR-ABL, the critical target in CML; this will be an interesting company to watch out for over the next few years.

References:

ResearchBlogging.orgDutt A, Ramos AH, Hammerman PS, Mermel C, Cho J, Sharifnia T, Chande A, Tanaka KE, Stransky N, Greulich H, Gray NS, & Meyerson M (2011). Inhibitor-Sensitive FGFR1 Amplification in Human Non-Small Cell Lung Cancer. PloS one, 6 (6) PMID: 21666749

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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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BMS and Roche join forces in metastatic melanoma

By on June 2, 2011

Two of the most dynamic cancer markets at the moment are prostate cancer and metastatic melanoma, which is great news considering that neither has had much attention over the last decade compared to breast and lung cancers.

My colleague has posted an overview of what’s going on in advanced prostate cancer today, which you may be interested in checking out pre-ASCO.  However, what excited me this morning were announcements from BMS and Roche declaring their intent to pursue combination trials in BRAF metastatic melanoma with their therapies ipilimumab (Yervoy) and vemurafenib (PLX4032).

This is really great news, and a very logical approach that is well worth evaluating.

I’m delighted to see the two companies seeking to work together on this to see if the combination can improve outcomes further than what we have seen for vemurafenib alone, which already showed impressive responses in poor prognosis patients.

How vemurafenib works in BRAF V600E metastatic melanoma

Vemurafenib has been shown to target the BRAF V600E mutation, as you can see in the graphic.

Ipilimumab is an immunotherapy that targets the CTLA-4 antigen and was approved by the FDA in March as a treatment option for newly diagnosed patients with metastatic melanoma.

A phase I/II trial is planned initially, which is a relatively low risk study – if the results look good we will hopefully see a larger scale phase III trial emerge.  If not, at least we will know a quick answer on the combination.

Meanwhile, these two drugs will be presented in the plenary session at ASCO this weekend comparing either to the current standard of care, dacarbazine (DTIC), in advanced newly diagnosed metastatic melanoma.

I’m really looking forward to writing more on those trials on Monday morning – so do check back then for an update of the phase III data!

 

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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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Making a difference to the lives of cancer patients: An interview with Dr Charles Sawyers

Advanced prostate cancer has been quite a hot topic lately, with several new and relatively late stage compounds in the pipeline garnering attention from promising data. One of those agents, abiraterone acetate (Zytiga) only just received FDA approval on Friday and has been designated for accelerated review by the EMEA.

Following on from previous interviews in the Pharma Strategy Blog “Making a Difference” series with Dr Sue Desmond-Hellman (Chancellor of the University of California, San Francisco), Alain Moussy (CEO of AB Sciences) and Dr Ross Camidge (University of Colorado), it seemed most timely to extend the next round of the series to prostate cancer.

It was therefore a pleasure to talk with Dr Sawyers about his current research in the prostate cancer last week and discuss how he approaches some of the challenges involved with incorporating translational medicine into clinical research.  He is co-inventor of two drugs currently in clinical trials for prostate cancer, namely MDV3100 (Medivation) and ARN-509 (Aragon Pharmaceuticals).

Charles L. Sawyers, MD is Chair of the Human Oncology and Pathogenesis Program at the Memorial Sloan-Kettering Cancer Center (MSKCC), and an Investigator with the Howard Hughes Medical Institute.  In 2009, he received the Lasker-Debakey Clinical Medical Research Award along with Drs Brian Druker and Nick Lydon, for their work on molecular targeting that led to the development of imatinib (Gleevec/Glivec), a drug that revolutionized the treatment of Chronic Myeloid Leukemia (CML) and turned it from deadly cancer into a manageable, chronic disease.

In full disclosure, I had the great privilege of working with Drs Sawyers and Druker while bringing imatinib to market at Novartis Oncology.

Pharma Strategy Blog: Charles, you and I have known each other for over ten years, when we first met you were at UCLA. What made you move to the East Coast and MSKCC?

Dr Sawyers: Harold Varmus who was the Director here at MSKCC, before he moved to the NCI, made me a job offer I couldn’t refuse.  Memorial had built up an impressive cadre of basic scientists, but there was this missing piece of physician scientists who could capitalize on translational opportunities. He was able to convince “the powers that be” to build a new research tower with 21 floors of lab space, that opened in 2006.  He offered me 3 floors and the opportunity to be Director of a brand new program called “Human Oncology.”

My mission was to recruit the best and brightest physician scientists either locally or around the country.  I also saw, after my imatinib work, that the most important contributions I could continue to make from my laboratory work were not going to be in CML, and I wanted a new challenge.  I had started to work on prostate cancer for many reasons, mostly scientific, and I needed to be at a place where clinical care and clinical trials infrastructure was much more integrated than it was at UCLA.  So, it was not that hard a decision to make the move.

Pharma Strategy Blog: One of the drugs that you discovered at your lab was MDV3100, what are you thoughts on when this may be used?

Dr Sawyers: I am very much involved in asking translational questions about MDV3100 and whether it works beyond castrate resistant disease.  Does it work up front in the neo-adjuvant setting, prior to surgery to shrink the tumor? Would it synergize with radiation? All kinds of interesting questions are coming up that we are working to answer.

Pharma Strategy Blog: Why does MDV3100 block the androgen receptor better than bicalutamide?

Dr Sawyers: The most interesting property that MDV3100 has, and what I think is the most likely explanation for its superior performance, is that when you treat cells with this compound the androgen receptor is completely incapable of binding DNA.  We have shown this recently using ChIP-Seq technology that is very powerful at annotating all the binding sites for any transcription factor across the genome.  With bicalutamide, the androgen receptor still binds with the drug very tightly on many thousands of binding sites, whereas with MDV3100, we cannot find it binding anywhere.  It has a profoundly different effect on the receptor.

Pharma Strategy Blog: How did the discovery of MDV3100 come about?

Dr Sawyers: We had been using mouse models to understand why the tumor became resistant to castration and bicalutamide.  What came out of that was the level of expression of the androgen receptor was consistently up, about 3 to 5 fold, in the castrate resistant sub lines of otherwise sensitive tumors.  Then we showed by either over-expressing the androgen receptor at about that level or knocking it down in castrate resistant lines, that it was both necessary and sufficient for this resistance phenotype. Quite dramatically, when you overexpress the receptor at that level and treat cells with bicalutamide, bicalutamide is now a weak agonist rather than antagonist.  So, you can trick the cell into responding differently just by manipulating the level of the androgen receptor.

All of that led me to approach a couple of companies that were interested in prostate cancer, with the idea that we should do a screen for compounds that are selected based on their ability to inhibit androgen receptor signaling in this context of higher expression.  Everybody that I talked to in the pharma industry pretty much thought that the androgen receptor was not really all that relevant a target in castrate resistant disease.  There seemed to be a mindset, that had built up over decades, that castrate resistant disease was really androgen independent disease, and therefore hormone therapy is no longer going to be effective.

That’s why we had to do it academically, and the approach that worked was based on a friendship that I had made with a chemist at UCLA named Mike Jung.  Rather than do high-throughput screens, he said there’s tons of chemistry already done on the androgen receptor, let’s explore that literature and try to find compounds that bind with extremely high affinity that others have described that aren’t antagonists and then do some SAR to figure out how to make them antagonists.  He found this compound that was described in an old patent that has extremely high binding affinity for the androgen receptor, never went anywhere because it is a potent agonist, but it was about two orders of magnitude tighter than bicalutamide.  So he made it, we tested it and of course it didn’t work.  Then we started making derivatives of that compound, tested 200 over a year and half, and stumbled upon MDV3100.

Pharma Strategy Blog: What is the current state of development for MDV3100?

Dr Sawyers: MDV3100 is now in a phase 3 registration trial that is fully accrued and is supposed to read out later this year, maybe early 2012.

Pharma Strategy Blog: What do you think of Circulating Tumor Cells (CTCs) as a surrogate marker in prostate cancer instead of PSA response?

Dr Sawyers: Measuring CTCs using a standard Veridex platform is very nice, the answer that is not so clear is whether a CTC drop is predictive of a long-term clinical benefit?  There are a number of clinical trials in prostate cancer moving along with traditional survival endpoints in which the CTC data is being collected in parallel.  Hopefully, over another a year or two these kind of correlates can be drawn to see if it is a surrogate marker of response that could lead to faster registration.

Pharma Strategy Blog: Could CTCs replace PSA as a measure of response?

Dr Sawyers: I think in the case of MDV3100 we are targeting the androgen receptor, which regulates the expression of PSA, so it is almost a given that if your drug is engaging the target effectively you have to see a PSA drop.  If you don’t you probably haven’t hit the target correctly.  In essence, PSA is a pharmacodynamic endpoint.  If you are able to sustain PSA down for 12 weeks, with a drop of at least 50%, that is considered a pretty significant effect that is likely to be predictive of some other longer-term benefit.  Not many drugs have done that in the past, so I wonder if PSA actually might be more valuable than we give it credit for, if we just set the bar higher for what we call a PSA response.

Pharma Strategy Blog: Can you tell us more about the other prostate cancer compound that came out of your lab that is being developed by Aragon?

Dr Sawyers: “Son of Medivation” is what some people call it.  It came out later than MDV3011 and is more potent, and has what we think is a better safety profile. It is called ARN-509 and is in the clinic now. It is still in the dose-escalation stage of a phase I study at Sloan Kettering that Howard Scher and colleagues are running. There is a lot of excitement around it and we are pushing as fast as we can.  The challenge now is that the prostate cancer space is becoming crowded.

Pharma Strategy Blog: Does ARN-509 have a similar mechanism of action to MDV3100?

Dr Sawyers: Yes, very similar. We don’t yet know if ARN-509 will work in those patients who don’t respond to MDV3100 or have resistance to it. If it does work in that setting in the clinic, then it is a straightforward path to approval.  What I think is more likely is that ARN-509 will work in a similar same patient population as MDV3100 but might produce a higher percentage of responders or maybe longer duration of response. It will take at least a year if not a little more to know with confidence what those numbers are for ARN-509 compared to MDV3100, and by then Medivation will be approved.

Pharma Strategy Blog: How do androgen receptor antagonists such as MDV3100 and ARN-509 compare to abiraterone acetate (Zytiga) that was recently approved by the FDA?

Dr Sawyers: Abiraterone is targeting the androgen receptor pathway differently. Even though all these men remain on a testosterone lowering agent, testosterone is still produced primarily by the adrenal gland.  Abiraterone targets the enzyme Cyp17 that is critical in maintaining that residual level of testosterone. It is the same target of ketoconzole, a drug that has been used in this space, but has a fairly unpleasant side-effect profile. Abiraterone is looking great and showed a survival advantage in the same kind of trial as the Medivation one.  A very obvious question is whether it would make sense to target the androgen receptor pathway at two points i.e. abiraterone plus MDV3100.  Scientifically it makes beautiful sense and I think that combination trials will happen.

Pharma Strategy Blog: Would it make sense to potentially sequence them?

Dr Sawyers: I am always a believer of going up front with your best shot, so scientifically favor using a combination.

Pharma Strategy Blog: What are some of the challenges that remain in prostate cancer?

Dr Sawyers: We have a good understanding of the prostate genome, but it is very challenging to obtain tissue from patients in trials so that we can subset them into molecular subgroups.  The benefit of that is so crystal clear in other tumor types. It is a challenge that we are still struggling how to execute in prostate. One reason for this is that the trials are typically done with end-stage patients with bone disease, so tissue is not easily obtainable.  Even if patients give consent, technically, it is a challenge to isolate the tumor and analyse it.

Pharma Strategy Blog: It is a very exiting time to be in this field.  Hopefully, we will learn more at the AACR special meeting on Prostate Cancer that you are organizing in Orlando next year.  Thank you, Dr Sawyers, for sharing your thoughts and insights.

 

References:

ResearchBlogging.orgScher, H., & Sawyers, C. (2005). Biology of Progressive, Castration-Resistant Prostate Cancer: Directed Therapies Targeting the Androgen-Receptor Signaling Axis Journal of Clinical Oncology, 23 (32), 8253-8261 DOI: 10.1200/JCO.2005.03.4777

Watson, P., Chen, Y., Balbas, M., Wongvipat, J., Socci, N., Viale, A., Kim, K., & Sawyers, C. (2010). Inaugural Article: Constitutively active androgen receptor splice variants expressed in castration-resistant prostate cancer require full-length androgen receptor Proceedings of the National Academy of Sciences, 107 (39), 16759-16765 DOI: 10.1073/pnas.1012443107

 

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MEK mutations confer resistance to MEK and BRAF inhibitors in melanoma

By on April 21, 2011

The other day, we discussed resistance in melanoma and how COT can reactivate BRAF signalling through MAPK reactivation.  Previously, we reviewed how MEK inhibitors may potentially be useful when combined with BRAF inhibitors in overcoming resistance due to cross-talk.  There are also other methods of preserving this oncogenic activity, which are highly relevant to current clinical development.

At the recent American Association for Cancer Research (AACR) meeting, Levi Garraway (Dana Farber) presented at the plenary session on “Navigating the interface of tumor biology and therapeutic development through integrative genomics.” He first discussed the history and context of targeted therapy, then focused on the progress in metastatic melanoma, highlighting some dramatic responses to the BRAF inhibitor PLX4032 (vemurafenib) using before and after pictures of his patients.

The talk was very well done indeed and I was so engrossed in following the story, I forgot to make notes – that’s how good it was!  The good news is that AACR captured the excellent slides and audio in a free webcast.  If you have 20 minutes, please do take some time to check this one out – it was one of my highlights of the meeting.

Dr Garraway also drew the audience’s attention to a poster from Wagle et al., (2011) based on new research from his lab looking at a new mechanism of resistance in melanoma, namely mutations in MEK.  Unfortunately, I missed the poster that morning, but the group kindly referred me to their publication in Journal of Clinical Oncology last month (see references below), which offers more detail for discussion here.

Essentially, they used a genomics approach to see if they could advance our understanding of mechanisms of de novo and acquired resistance to RAF inhibition, which are poorly understood.  To put things in context, the same patient that Dr Garraway refers to in the webcast above was also the subject of the genomics profiling in the paper:

“We performed massively parallel sequencing of 138 cancer genes in a tumor specimen from a melanoma patient who developed resistance to PLX4032 after a dramatic initial response.”

Initially, the patient responded to therapy:

“A profound clinical response ensued, including nearcomplete regression of all subcutaneous tumor nodules at 15 weeks on drug.”

The pictures of the patients torso in the webcast were dramatic.  There were several involuntary sharp intakes of breaths from the audience around me in the session.

Unfortunately, it wasn’t all good news:

“After 16 weeks on PLX4032, the patient experienced widespread disease relapse, which by 23 weeks involved most previous sites of visceral and subcutaneous disease.”

The pictures in the webcast also showed the physical impact of this sad news.  The key question then, is why did the patient relapse?

The genomic profiling undertaken by the group addressed this question and uncovered something unexpected:

“The resulting profile identified a novel mutation in the downstream kinase MEK1 that was absent in the corresponding pre-treatment tumor.

This MEK1 mutation was shown to increase kinase activity and confer robust resistance to both RAF and MEK inhibition in vitro.”

What are the implications of this research?

This was a very nice piece of work that sought to uncover the reason for a responding patient becoming resistant to treatment with PLX4032.  The researchers found a downstream MEK1 mutation was responsible for inducing resistance.

The implications of the finding, however, are slightly scary.

Why?  Because as the authors concluded in their paper, the MEK1 mutation found in this patients is cross-resistant to allosteric MEK inhibitors (eg AZD6244), even though the patient has never been exposed to a MEK inhibitor.  It also implies a mechanism by which melanoma may become resistant to combination RAF and MEK inhibitors (eg PLX4032 + AZD6244) with just a single mutation.

In other words, we still have a ways to go figuring out all the potential combinations and methods of resistance that could take place in this disease.  The good news is that research into mechanisms of resistance is running parallel with clinical development in metastatic melanoma and will hopefully continue to do so.

References:

ResearchBlogging.orgWagle, N., Emery, C., Berger, M., Davis, M., Sawyer, A., Pochanard, P., Kehoe, S., Johannessen, C., MacConaill, L., Hahn, W., Meyerson, M., & Garraway, L. (2011). Dissecting Therapeutic Resistance to RAF Inhibition in Melanoma by Tumor Genomic Profiling Journal of Clinical Oncology DOI: 10.1200/JCO.2010.33.2312

Biology of indolent B-cell lymphomas and chronic lymphocytic leukemia

By on April 14, 2011

We all know the importance that inflammation and the immune system plays in the early development of many cancers, but this is not a ubiquitous finding.  Indeed, some hematologic malignancies arise out of immunodeficiency, such as myelomas and chronic lymphocytic leukemia (CLL).  I haven’t written much about this topic in the past, so thought it would be useful to explain some of the underlying biology of CLL given that we can expect new (hopefully positive) data emerge at the American Society of Clinical Oncology (ASCO) meeting in June.

Several studies have shown specifically that immune activation can promote development and progression of lymphoma.  Extranodal marginal zone lymphomas (eMZLs), for example, originate at the site of chronic inflammation under the influence of T-cell help (see Suarez et al., 2006).

Hervé et al., (2005) have previously shown that antigen receptor repertoires exist in B-cell lymphoma and additionally, autoantigen recognition by CLL-derived immunoglobulin may suggest a role for antigen receptor signaling in lymphomagenesis.

In addition, an increase in circulating regulatory T cells (Tregs) has been reported in myeloma, CLL, and other B-cell lymphomas by Breyer et al., (2005) and confirmed by others.  This may well explain why the combination of fludarabine and cyclophosphamide (FC) is a useful strategy in reducing immunosuppression prior to cancer immunotherapy with rituximab (R).  The FCR combination is now very much the bedrock of treatment for patients with CLL and is based on a very solid rationale.

Previous work in 2004 by Christopoulos et al., observed a significant reduction in peripheral T helper cells in patients with untreated FL and eMZL.  The question remains as to what happens to the T-helper cells in untreated CD4+ subpopulations.

Christopoulos et al., (2011) therefore conducted a prospective open label study recently to look at the underlying immune system in patients with CLL or monoclonal gammopathy of unknown significance (MGUS).  According to the Mayo Clinic:

“Monoclonal gammopathy of undetermined significance (MGUS) is a condition in which an abnormal protein (monoclonal protein, or M protein) is in the blood.”

In terms of the selection criteria, patients with prior antineoplastic therapy, including corticosteroids, and patients with evidence for preexisting autoimmunity or immunodeficiency were excluded from the study.

The current study is interesting, because the results demonstrated:

“substantially reduced circulating T helper cells, predominantly naive CD4+ cells, in patients with nonleukemic follicular lymphoma and extranodal marginal zone lymphoma, but not in monoclonal gammopathy and early CLL.”

They went to to say that:

“Gene expression profiling of in vitro–stimulated CD4+ cells revealed an independent second alteration of T helper cell physiology, which was most pronounced in early CLL but also detectable in follicular lymphoma/extranodal marginal zone lymphoma.”

What new therapies are emerging for CLL?

Rituximab has been a very useful addition to the basic FC regimen in CLL.  A number of other therapies are also being evaluated in the disease, including fostamatinib, a SYK inhibitor from AstraZeneca and lenalidomide, a widely used immunotherapy for the treatment of multiple myeloma from Celgene.

Friedberg et al., (2010) published their data on fostamatinib in CLL and NHL last year based on the promising results previously presented at ASCO in 2009.  I wrote about the data at that meeting here for those interested.  Lenalidomide is being evaluated as a maintenance therapy for CLL in clinical trials (see my notes on the previous data presented at ASH) and given it is now 18 months to two years since we saw the initial data, I’m hoping there will be an update in Chicago this year, including some information on the optimal lenalidomide dose (see Wendtner et al., 2010).

Although CLL is a relatively indolent disease, patients can cycle through multiple therapies and combinations over time, so there is still a need for new drugs to mix up the combinations and extend life for this chronic condition further.

A future update will appear on this topic at ASCO in June – watch this space!

References:

ResearchBlogging.orgChristopoulos, P., Pfeifer, D., Bartholome, K., Follo, M., Timmer, J., Fisch, P., & Veelken, H. (2011).  Definition and characterization of the systemic T-cell dysregulation in untreated indolent B-cell lymphoma and very early CLL Blood, 117 (14), 3836-3846 DOI: 10.1182/blood-2010-07-299321

Suarez F, Lortholary O, Hermine O, & Lecuit M (2006). Infection-associated lymphomas derived from marginal zone B cells: a model of antigen-driven lymphoproliferation. Blood, 107 (8), 3034-44 PMID: 16397126

Hervé M, Xu K, Ng YS, Wardemann H, Albesiano E, Messmer BT, Chiorazzi N, & Meffre E (2005). Unmutated and mutated chronic lymphocytic leukemias derive from self-reactive B cell precursors despite expressing different antibody reactivity. The Journal of clinical investigation, 115 (6), 1636-43 PMID: 15902303

Christopoulos P, Follo M, Fisch P, & Veelken H (2008). The peripheral helper T-cell repertoire in untreated indolent B-cell lymphomas: evidence for antigen-driven lymphomagenesis. Leukemia : official journal of the Leukemia Society of America, Leukemia Research Fund, U.K, 22 (10), 1952-4 PMID: 18385751

Friedberg JW, Sharman J, Sweetenham J, Johnston PB, Vose JM, Lacasce A, Schaefer-Cutillo J, De Vos S, Sinha R, Leonard JP, Cripe LD, Gregory SA, Sterba MP, Lowe AM, Levy R, & Shipp MA (2010). Inhibition of Syk with fostamatinib disodium has significant clinical activity in non-Hodgkin lymphoma and chronic lymphocytic leukemia. Blood, 115 (13), 2578-85 PMID: 19965662

Wendtner CM (2011). Lenalidomide in CLL: What Is the Optimal Dose? Clinical advances in hematology & oncology : H&O, 9 (3), 220-4 PMID: 21475128

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What's hot at the 2011 AACR meeting?

By on April 1, 2011

At the recent American Association of Clinical Research special conference on the PI3K-mTOR pathway, it was very clear that this area of research is becoming a hot topic. At the annual meeting starting tomorrow, there are over 330 abstracts on PI3K alone – a huge increase over the last couple of years. This is one area where a systems biology approach to understanding the disease is bearing fruit.

We’ll be posting some highlights of each day during the meeting along with some video interviews with some experts on different topics.

In the meantime, we put together a short trailer for the AACR meeting – check it out:

Nanotechnology and cancer research: can it improve therapy for cancer?

By on March 31, 2011

Way back in November 2009 at the American Association of Cancer Research (AACR) Molecular Targets meeting in Boston, there was a fascinating poster on the early promise for nanotechnology as a new form of efficient drug delivery for cancer therapeutics (see the blog post here).

Fast forward 18 months and my attention was drawn to a new article published in Cancer Research about how nanotechnology has been used preclinically to deliver therapy for breast cancer into the cancer cells rather than to the cells.  This is a subtle, but important, difference.

For those of your wondering what nanotechnology is, my colleague Pieter Droppert reviewed some basics earlier this month in a blog post:

“Nanotechnology is the application of science and engineering to materials that are between 1 and 100 nanometers (nm) in size.”

He went on to put this in layman terms:

“1nm is one-billionth of a meter.   To put this in context, 1nm is one seven-thousandth of the width of a red blood cell or one eighty-thousandth of the width of a human hair.  These are unimaginably small materials that are engineered to operate at the molecular and atomic level.”

The approach in the latest preclinical research (see references below) is to take trastuzumab (Herceptin) and combine it with biodegradable polymers to form nanoconjugates that are small enough to enter cancer cells because they are more water soluble rather than attack the outside of the cells, thereby potentially reducing toxicities associated with the therapy.

The same group also tried this technique with brain cancer (see references below), allowing the nanocells to cross the usually impenetratable blood-brain barrier, which:

“resulted in a marked inhibition of tumor angiogenesis and growth.”

In the breast cancer research, the group compared the results of their polymer-trastuzumab conjugate with trastuzumab alone in mice:

“Our experiments confirmed that a proper design of the lead nanobiopolymer was possible for efficient blocking of HER2/neu-positive breast tumor growth through dual inhibition of HER2/neu and Akt phosphorylation, and as a result, promoting enhanced tumor cell apoptosis.

The nanobiopolymer’s unique combination of features resulted in highly specific drug accumulation in the tumor tissue and inside tumor cells.”

It will be most interesting to see if this idea is developed clinically in human trials and whether the results will be reproducible or not.

Significance of the findings:

The nanoconjugate concept has promise, not just in allowing a novel drug delivery system to cross impenetrable barriers, but also in reducing the toxicities associated with systemic targeted therapy.  Randomised clinical trials in patients with cancer are required to determine if there is viability in humans.

References:

ResearchBlogging.orgInoue, S., Ding, H., Portilla-Arias, J., Hu, J., Konda, B., Fujita, M., Espinoza, A., Suhane, S., Riley, M., Gates, M., Patil, R., Penichet, M., Ljubimov, A., Black, K., Holler, E., & Ljubimova, J. (2011). Polymalic Acid-Based Nanobiopolymer Provides Efficient Systemic Breast Cancer Treatment by Inhibiting both HER2/neu Receptor Synthesis and Activity Cancer Research, 71 (4), 1454-1464 DOI: 10.1158/0008-5472.CAN-10-3093

Ljubimova, J., Fujita, M., Ljubimov, A., Torchilin, V., Black, K., & Holler, E. (2008). Poly(malic acid) nanoconjugates containing various antibodies and oligonucleotides for multitargeting drug delivery Nanomedicine, 3 (2), 247-265 DOI: 10.2217/17435889.3.2.247

Ding, H., Inoue, S., Ljubimov, A., Patil, R., Portilla-Arias, J., Hu, J., Konda, B., Wawrowsky, K., Fujita, M., Karabalin, N., Sasaki, T., Black, K., Holler, E., & Ljubimova, J. (2010). Inhibition of brain tumor growth by intravenous poly( -L-malic acid) nanobioconjugate with pH-dependent drug release Proceedings of the National Academy of Sciences, 107 (42), 18143-18148 DOI: 10.1073/pnas.1003919107

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Accelerated approval and cancer drugs

By on March 24, 2011

There is a provocative article in this week’s New England Journal of Medicine asking whether the accelerated approval process should be used for more cancer drugs:

“The striking results of recent phase 1 trials of targeted cancer drugs have provoked serious discussion about shortening the road to drug approval.”

The main thrust of the argument was that it takes on average seven years from entering human trials to approval if phase III trials are included in the oncology drug development process.

“Of the 23 oncologic drugs given accelerated approval between 1993 and 2008, two were ultimately withdrawn from the U.S. market — gemtuzumab because of toxicity and gefitinib because of lack of efficacy.”

The author argues that:

“Phase 3 trials are expensive and time-consuming, usually taking at least 2 to 3 years to reach survival end points. The news of a highly successful new compound in phase 1 or 2 rapidly reaches physicians and patients, creating demand for early access.”

While we have seen some successes with the Accelerated Review process with imatinib (Gleevec), erlotinib (Tarceva), cetuximab (Erbitux), bevacizumab (Avastin) and others, there has also been a flood of promising phase II agents that duly flopped in randomised phase III trials, with Pfizer’s figitumumab, Novartis/Antisoma’s ASA404 and sanofi-aventis’ iniparib to name a few off the top of my head.

One of the challenges here is that companies often take a targeted therapy but strangely test it in an unselected patient population, which will increase the chances of failure in a more rigorous randomised phase III trial.  In an ideal world, several carefully designed adaptive phase II trials would help develop logical combinations and markers of response, thus increasing the chances of success in phase III studies.

The big problem as I see it then, is that while we have exciting new agents likely to be approved in 2011 such as:

  • crizotinib in lung cancer
  • ipilimumab (Yervoy) and PLX4032 (vemurafenib) in metastatic melanoma
  • brentuximab vedotin in Hodgkin Lymphoma
  • abiraterone acetate (Zytiga) in prostate cancer

we don’t always know how to carefully select patients to enable treatment based on the underlying molecular basis of the disease.

Of those mentioned above, with crizotinib (ALK), vemurafenib (V600E BRAF) and brentuximab (CD30) we clearly do, but with abiraterone and ipilimumab the issue of patient selection seems less clear at the moment.  Sadly there are not any biomarkers available to tell us which patients are most likely to benefit from treatment in targeted therapies already approved such as bevacizumab.

The fate of bevacizumab in breast cancer has yet to be determined.  It was approved under the FDA Accelerated Review process based on the initial phase II data, with the assumption that the phase III trials would show an improvement in overall survival.  The AVADO and RIBBON1 trials showed a benefit in progression free survival or PFS (ie a surrogate marker of event free survival), but unfortunately were not positive for overall survival, which is the ultimate measure of disease progression and the condition required to be met under the fast track process.

The FDA are therefore recommending withdrawal based on the lack of overall survival as per the accelerated agreement and Roche offering the counter argument that there was evidence of patient benefit.  That issue will no doubt continue to be debated for much of 2011 until the public hearing later this year.  There is an excellent analysis of the impact of the FDA recommendation on bevacizumab uptake in the US in Oncology Business Review for anyone interested in trends.

Ultimately, we need have a better understanding of the molecular basis of the cancer types and drugs developed to target that aberration in a more carefully selected patient population.  The arguments for and against accelerated review will run and run – probably for longer than the debate about how to pronounce some of the new names!

My position on the accelerated review process?

When it works, it works well.  However, problems can arise when you get phase III trials that do not support the full approval due to a lack of a proven overall survival advantage in the population evaluated.  The FDA can find themselves in an impossible position especially given the high emotions that run in breast cancer, for example.  The onus should be on the company to do further research or trials better defining the patients who are most likely to respond rather than risk exposing thousands of patients to the systemic effects of a drug that may not offer meaningful benefit to the majority.

References:

ResearchBlogging.orgChabner, B. (2011). Early Accelerated Approval for Highly Targeted Cancer Drugs New England Journal of Medicine, 364 (12), 1087-1089 DOI: 10.1056/NEJMp1100548

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