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Posts tagged ‘astrazeneca’

Developing a predictive biomarker for PARP inhibition

Today’s Science Friday post looks at the identification of a potential new biomarker and possible strategies for expanding use of PARP inhibitors in patients most likely to respond to them as a way to validate the the approach prospectively.  This has important implications for future clinical trial designs with this class of drugs.

Photo Credit: Ben Sutherland via flickr

Photo Credit: Ben Sutherland via flickr

Regular readers will be very familiar at my rants against broad catch-all studies and phase III trials with targeted agents that do not have a biomarker or even a logical well defined subset of patients because it’s akin to blindfolding an archer, turning him around 360 degrees and then asking him to hit a bullseye 50 or 100 yards hence.

How can you hit a target you can’t see?

PARP inhibitors have had a bit of a chequered history after the initial excitement was later followed by a series of rather disappointing clinical trial results, which occurred for a multitude of reasons.  Several of the approaches sadly fell into the category of ‘Five things not to do in R&D’ as delineated in my recent tongue-firmly-in-cheek post on the topic.  I’ll leave interested and curious readers to ponder at length exactly which of the no-nos they managed to break!

That said, we do know a few things of relevance:

  1. PARP1/2 inhibitors have produced sustained anti-tumor responses in patients with germ-line BRCA gene mutations
  2. Biomarkers other than BRCA1 and BRCA2 are clearly needed to predict responses to PARP inhibitors
  3. Catch-all trials without segmenting for BRCA mutations and biomarkers are highly unlikely to be successful (recall the spectacular phase III failure in triple negative breast cancer with iniparib, for example)
  4. Next generation PARP inhibitors have focused on more clearly defined subset populations with greater success (and potency).

Chris Lord and Alan Ashworth’s lab have recently published some nice work (open access, see Refs below) that is worthy of discussion. Bajrami et al., (2013) decided to dive a little deeper and look at what genes and mutations might affect the responses to PARP inhibition:

“In hypothesizing that additional genetic determinants might direct use of these drugs, we conducted a genome-wide synthetic lethal screen for candidate olaparib sensitivity genes.  In support of this hypothesis, the set of identified genes included known determinants of olaparib sensitivity, such as BRCA1, RAD51 and Fanconi’s anemia susceptibility genes.”

The main reason behind this approach quickly becomes apparent – there is a huge need for it:

“One of the major issues in the clinical development of PARP1/2 inhibitors is the identification of biomarkers other than BRCA1 and BRCA2 gene mutations that predict a favourable response to therapy.”

While patients with germline BRCA mutations have a greater tendency to respond, they don’t account for all the responses that have been seen in the clinic.  What else is involved?

What did they find?

“Integration of the list of candidate sensitivity genes with data from tumor DNA sequencing studies identified CDK12 deficiency as a clinically relevant biomarker of PARP1/2 inhibitor sensitivity.”

In other words, when CDK12 was low, PARP sensitivity was high, making it a potential predictive biomarker for response to therapy with a PARP inhibitor.

What does this mean?

“The appearance of CDK12 in our olaparib sensitization gene list, alongside the CDK12 mutational data, suggested the possibility that loss of CDK12 function could sensitize tumor cells to PARP1/2 inhibitors and that loss of CDK12 function in HGSOVCa could be a predictive biomarker for response to this developmental class of agents.”

In other words, it would be useful to evaluate loss of CDK12 as a biomarker of response for PARP inhibitors in prospective clinical trials in breast and ovarian cancers, with and without germ-line BRCA mutations.

CDK12 is only one of nine genes known to be mutated in high grade serous ovarian cancer (HGS-OVCa), for example, so should patients be identified upfront who have loss of CDK12, then it may be enough to ensure response to a PARP inhibitor, irrespective of BRCA status.  Clearly this work is still very early, but it creates a smart and well argued rationale that can be tested in clinical trials.

Should the approach be validated, then it could well expand the utility of PARP inhibitors in the clinic based on a predictive biomarker.  I would be interested to see what happens not only with olaparib, but also the new generation of PARP inhibitors from Abbott (veliparib), Biomarin (BMN 673) and Clovis (rucaparib), to name a few who are conducting trials in breast or ovarian cancers.

If this works, it will be a thing of beauty.

References:

ResearchBlogging.orgBajrami I, Frankum JR, Konde A, Miller RE, Rehman FL, Brough R, Campbell J, Sims D, Rafiq R, Hooper S, Chen L, Kozarewa I, Assiotis I, Fenwick K, Natrajan R, Lord CJ, & Ashworth A (2014). Genome-wide Profiling of Genetic Synthetic Lethality Identifies CDK12 as a Novel Determinant of PARP1/2 Inhibitor Sensitivity. Cancer research, 74 (1), 287–97 PMID: 24240700

Photo Credit: Ben Sutherland

Update on MEK and AKT inhibition in RAS driven cancers

By on October 3, 2011

A couple of interesting developments have emerged over the last week with AKT and MEK inhibitors, specifically Merck’s MK-2206 and AstraZeneca/Array’s AZD6244, that are well worth discussing.

  1. At the ECCO/EMCC meeting in Stockholm last Tuesday, Johann De Bono discussed the combination data for MK-2206 and AZD6244 in KRAS driven colorectal cancer.
  2. Later the same week, Array Biopharma announced the initial results from a randomized phase II placebo-controlled study that compared the efficacy of selumetinib (AZD6244/ARRY-886) in combination with docetaxel compared to docetaxel alone in the second-line treatment of patients (n=87) with KRAS-mutant, locally advanced or metastatic non-small cell lung cancer (NSCLC).

Now, to be clear, I like the concept of AKT and MEK inhibitors, especially in select combinations, but the key thing here is the right combinations in the right context.

Let’s take a look at the lung cancer KRAS data first. One of the challenges I have with this approach, is that we’ve know for a while that BRAF and KRAS driven cancers behave rather differently according to Wee et al., (2009):

“Previous studies have found that whereas BRAF mutant cancers are highly sensitive to MEK inhibition, RAS mutant cancers exhibit a more variable response.”

Variable response is not an encouraging phrase when planning clinical trials!

Let’s take a look at the pathway itself:

We can immediately see that MEK is downstream of RAS, meaning that even if we target MEK, unfortunately RAS and KRAS is still largely untouched upstream. This is important to remember when considering the actual results later.

The other key factor to consider is what are the adaptive resistance pathways that might evolve as a result of treatment with a MEK inhibitor? In an ideal world, logical combinations would be tested that target both the primary driving mutation or aberration, as well as the adaptive resistance, to try and shut down the pathway more completely than targeting either alone. Another key question that needs to be addressed is what is driving the KRAS aberrant activity in the first place?

We’ve discussed MEK numerous times here on PSB, but the Wee et al., (2009) MEK paper stands out in particular. They identified a critical resistance pathway to MEK inhibition, namely PI3K. Although we discussed this originally in the context of BRAF driven tumours such as melanoma, it is well worth discussing again here in regards to KRAS driven tumours given a MEK inhibitor is being tested.

They observed that:

“Activating mutations in PIK3CA reduce the sensitivity to MEK inhibition, whereas PTEN mutations seem to cause complete resistance.”

It isn’t clear from the Array press release whether any of the patients with NSCLC exhibited PIK3CA mutations or loss of PTEN, but they definiely do occur in this disease. It will be interesting to see of more meta data is available at the forthcoming AACR Molecular Targets meeting next month.

I’m not a big fan of chemotherapy plus a single targeted agent, because as you can see from the evidence above, the pathway is not being shut down by one targeted agent and resistance is not being addressed at all. The chances of such a combination working (by that I mean increasing overall survival), I think would be fairly low.

According to the press release, the study did not see a significant improvement in overall survival (OS) but did show an encouraging response in the form of progression free survival (PFS):

“The key secondary endpoints of progression-free survival, objective response rate, and alive and progression-free at 6 months were all demonstrated with statistical significance, showing improvement in favor of selumetinib in combination with docetaxel versus docetaxel alone.”

Indeed, at the recent AACR and ASCO meetings, there was also some encouraging early signs from Genentech’s PI3K inhibitor, GDC-0941, as a single targeted agent with chemotherapy in NSCLC (a very small early trial), albeit not KRAS specific, but defined more broadly by squamous and non-squamous histology. Thus, all is not lost with the MEK agent yet – if we combined MEK and PI3K inhibitors in NSCLC patients previously treated with chemotherapy, we might have a better chance of succeeding and shutting down the pathway, based on evidence offered from Wee et al’s preclinical research:

“At the molecular level, the dual inhibition of both pathways seems to be required for complete inhibition of the downstream mammalian target of rapamycin effector pathway and results in the induction of cell death.”

As a result, they went onto to suggest a logical treatment approach:

“Our study provides molecular insights that help explain the heterogeneous response of KRAS mutant cancers to MEK pathway inhibition and presents a strong rationale for the clinical testing of combination MEK and PI3K targeted therapies.”

Of course, clinical trials like this always progress incrementally, such that we test a MEK or a PI3K inhibitor alone to determine safety and efficacy activity, then perhaps in combination, which requires another phase I dose finding study to determine the ideal dosages and whether they are too toxic or not combined.

So while either single agent targeted therapy with chemotherapy in and of itself is not a win, there are signs that combining the two may be more appropriate. I would still want to know what is driving the KRAS activity though, given MEK and PI3K are downstream of it. It is entirely possible that a third agent would be needed to shut down the pathway more completely in that patient subset.

At ECCO, De Bono (Royal Marsden) discussed the combination of AstraZeneca’s MEK inhibitor (AZD6244) and Merck’s AKT inhibitor (MK-2206) in RAS mutant colorectal (CRC) and lung (NSCLC) cancers. The results here were not a big win in the former, with 8/15 patients showing no antitumour activity to date.

There are several things we can conclude from the initial data:

  • If we have the right combination for the right target in the right patient subset, then the therapeutic index of the agents is lacking and we need better drugs
  • Are the targets (AKT and MEK) critical?
  • Is something else driving the KRAS activity (see below)*?
  • Are we shutting down the adaptive resistance pathways (escape routes?)
  • Which patient subsets are most likely to respond and how do we best characterise them (ie need more biomarker data)?

And so on… there are always more questions than answers sometimes.

    * Note: This situation could well be similar to BRAF in malignant melanoma, where it is the V600E mutation that is driving the BRAF activity, thus specifically targeting ithe mutation rather than the kinase will have a greater clinical effect than targeting BRAF broadly. In this case, if we really believe KRAS is critical to the lung or colorectal tumour’s survival, then we need to figure out what is driving it before progress is made. Frank McCormick’s elegantly simple wac-a-mole concept for pathway inhibition is very apt here!

No doubt we will see more detailed data and an update soon, perhaps even at the forthcoming AACR Molecular Targets meeting next month.

References:

ResearchBlogging.orgWee, S., Jagani, Z., Xiang, K., Loo, A., Dorsch, M., Yao, Y., Sellers, W., Lengauer, C., & Stegmeier, F. (2009). PI3K Pathway Activation Mediates Resistance to MEK Inhibitors in KRAS Mutant Cancers Cancer Research, 69 (10), 4286-4293 DOI: 10.1158/0008-5472.CAN-08-4765

4 Comments

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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Glioblastoma recurrence after VEGF therapy: lack of rebound vascularisation as a mode of escape

By on January 3, 2011

One of my favourite journals, Cancer Research, has a new paper available via open access (i.e. free to the public, thank you AACR), which you can obtain from the link in the Reference section below.

It caught my attention because there was a fascinating symposium on angiogenesis at ESMO this summer with some heavyweight debates from Robert Kerbel (accelerated metastasis) and Lee Ellis (normalisation of tumour vessels) taking different viewpoints on the pros and cons of VEGF inhibition.  I took a few photos of the slides for private study and reflection, as they were going too fast for me to keep up with the key points with unreadable chicken scratch notes, but sadly my iPhone went missing in the exhibit hall less than an hour afterwards before I could download the photos :(.  That said, both sides argued with very compelling data for their perspective that I’m not sure which way I roll on the issue.

In this latest paper, di Tomaso et al., from Boston discuss the concept of recurrent glioblastomas and the tendency to relapse after VEGF therapy.  They noted that there are two current theories for how this might happen:

  1. Switch to VEGF-independent angiogenic pathways
  2. Vessel co-option

They therefore decided to investigate these mechanisms in patients with relapsed glioblastoma using a pan VEGF inhibitor, cediranib.  Now, it should be noted that cediranib (Recentin) is not yet approved and is a small molecule inhibitor, whereas another VEGF inhibitor, bevacizumab (Avastin), is a monoclonal antibody approved for relapsed GBM, so I’m sure why they didn’t use that instead.  It does make extrapolation of the findings a little more tricky though, as you cannot always assume a class effect.

Here are the key findings:

  • Endothelial proliferation and glomeruloid vessels were decreased
  • Vessel diameters and perimeters were reduced to levels comparable to the unaffected contralateral brain hemisphere
  • Tumour endothelial cells expressed molecular markers specific to the blood–brain barrier, indicative of a lack of revascularization despite the discontinuation of therapy
  • Cellular density in the central area of the tumour was lower than in control cases and gradually decreased toward the infiltrating edge, indicative of a change in growth pattern of relapsed GBM after cediranib treatment
  • Cediranib-treated GBMs showed high levels of PDGF-C (platelet-derived growth factor C) and c-Met expression and infiltration by myeloid cells, which may potentially contribute to resistance to anti-VEGF therapy

The authors therefore concluded that:

“rGBMs switch their growth pattern after anti-VEGF therapy—characterized by lower tumor cellularity in the central area, decreased pseudopalisading necrosis, and blood vessels with normal molecular expression and morphology—without a second wave of angiogenesis.”

Commentary:

What intrigued me in particular was not the lack of rebound vascularisation effect but the myeloid component.  Many of you will remember the AACR meeting last September on Molecular Diagnostics in Cancer Therapeutics, where AVEO presented data on their VEGF inhibitor in development and found that the myeloid component acted as a useful biomarker of response for tivozanib in renal cell cancer. You can read more about that here if you missed it.

This raises several interesting questions for me:

  1. Is the myeloid marker that AVEO found with tivozanib actually more useful and applicable to VEGF therapies in general?
  2. Does the myeloid component indicate acute inflammation, as we have seen with respiratory and other diseases?
  3. If PDGF and MET expression rise as resistance sets in, does that suggest logical combination therapies for the treatment of GBM?
  4. How can we better overcome the blood brain barrier, which is a physical impediment to improving outcomes.

Time will tell but clearly the research in relapsed GBM has a-ways to go before we figure out how best to approach it yet.

References:

ResearchBlogging.org di Tomaso, E., Snuderl, M., Kamoun, W., Duda, D., Auluck, P., Fazlollahi, L., Andronesi, O., Frosch, M., Wen, P., Plotkin, S., Hedley-Whyte, E., Sorensen, A., Batchelor, T., & Jain, R. (2011). Glioblastoma Recurrence after Cediranib Therapy in Patients: Lack of “Rebound” Revascularization as Mode of Escape Cancer Research, 71 (1), 19-28 DOI: 10.1158/0008-5472.CAN-10-2602

Metastatic melanoma – what’s new on the horizon?

By on November 3, 2010

Metastatic melanoma is quite a hot topic right now with a rich pipeline of products in development after a decade of little or no progress.  Of course, it is a bit like three London buses coming along at once after an hour long wait in the winter weather, but better late than never.

Many of you will remember the recent data from ipilimumab (BMS), an immunotherapy that showed increased survival, albeit with some severe adverse events, from the phase III trial in newly diagnosed metastatic melanoma presented at ASCO in the plenary session earlier this year, followed by a publication in the NEJM.  The FDA filing was subsequently submitted on the basis of the positive data.

Yesterday, BMS announced that the FDA have moved the PDUFA date back 3 months from Dec 25th to March 26th, 2011.  A precise reason for the delay wasn’t given , but the company did say:

“In response to an FDA request, Bristol-Myers Squibb submitted further analysis of data pertaining to the current application for pre-treated advanced melanoma and the agency considers this to be a major amendment to the drug’s BLA.”

I’m not going to speculate on the reasons for the extra review time or what the new data was, but it is an interesting and unexpected development.

Meanwhile, there’s also been a lot of buzz around targeted BRAF inhibition in melanoma lately, specifically around the initial stunning results seen with PLX4032 (Plexxikon & Roche).  So far, it seems that responses of around 6-12 months, with a median of around 8 months are possible with an kinase inhibitor that specifically targets the V600E mutation associated with BRAF, although there two problems:

  1. The responses are not durable as resistance (eg associated with MEK or AKT amplification) sets in.
  2. Inhibiting CRAF as well as BRAF appears to lead to an unwanted excess proliferation of squamous cells, which is reversible on withdrawal of treatment.

In the first case, a couple of recent papers have looked at mechanisms of resistance around BRAF inhibition that give us some clues of where to go next.

Gopal et al., (2010) decided to see what happened with AZD6244 or selumetinib (Array and AstraZeneca), a MEK and MAP/ERK inhibitor, and whether it would have any impact in mitigating BRAF resistance, given the potential close interaction within the RAS-RAF-MAPK pathway and downstream events that could be impacted through cross-talk and feedback loops:

“We analyzed a panel of Braf mutant human cutaneous melanoma cell lines for their sensitivity to growth and survival inhibition by AZD6244. We compared these effects with the baseline activation status of signaling pathways in the cells, and with AZD6244 treatment–induced changes in signaling networks.

These studies have identified the phosphoinositide 3-kinase (PI3K)-AKT pathway as a critical regulator of the efficacy of AZD6244 in Braf-mutant melanomas, including in cells without baseline activation of the pathway.”

In order to determine possible mechanisms of resistance in the cell lines, they compared the effects of AZD6244 treatment on their signaling pathways with effects in sensitive cell lines and found:

“Although all four of these Braf-mutant cell lines showed similar degree and duration of MAPK inhibition and several other proteins, the resistant cell lines increased their P-AKT levels following exposure to AZD6244, which was not observed in the sensitive cell lines.”

They went on to note:

“The functional significance of AKT activation is supported by the fact that inhibition of AKT activity, either by AKT knockdown or concurrent treatment with the mTORC1/2 inhibitor AZD8055, resulted in synergistic cell killing in the resistant cell lines.”

AstraZeneca and Merck have an ongoing partnership with their MEK (AZD6244) and AKT (MK-2206) kinase inhibitors, so combining them in a clinical trial to try and reduce resistance via feedback loops here would be an interesting approach worth trying.  Such a combination trial is currently recruiting in advanced solid tumours, not melanoma per se.  It is, however, a classic catch-all phase I study to see what kinds of cancers might respond and determine the MTD, but I would be very interested to see the data from patients with metastatic melanoma if they are enrolled.

Now, it has been shown in breast cancer cell lines showed that MEK inhibition resulted in cross-activation of the EGFR tyrosine growth factor receptor, but EGFR has not been shown to be relevant in melanoma, so Gopal et al., considered what other receptors might be responsible for mediating the effects.   In the discussion, an interesting snippet caught my eye:

“AZD6244 treatment induced a slight increase of IGF-I secretion by the cells, and knockdown of IGF-I also blocked P-AKT induction by AZD6244.  Supporting a specific role for the pathway in cell survival, recombinant IGF-I treatment blocked AZD6244-induced cell death, but not growth arrest, in the sensitive WM35.”

This might also suggest another useful combination approach to consider in clinical trials.

Previously, it has been shown that targeting BRAF can not only inhibit the important driver in melanoma, the V600E mutation, but it can also stimulate cellular signaling through the MEK-ERK pathway by activating the related family member C-RAF. This may explain the squamous cell proliferation seen in some patients with PLX4032. The more ideal BRAF inhibitor would therefore specifically target BRAF V600E, without activating CRAF at the same time.

Related to the subject of malignant melanoma, Kamata et al., (2010) just published a paper that looked at the relationship between BRAF and CRAF in the disease.  Previously it has been shown that D594A BRAF lacks kinase activity, but can induce the related gene product CRAF in addition to the mitogen-activated protein/extracellular signal-regulated kinase (ERK) kinase (MEK)/ERK pathway.  What they found was really interesting.  In a nutshell:

“We show that the aneuploid phenotype is dependent on Craf. Treatment with the MEK inhibitor U0126 did not attenuate the emergence of aneuploidy but prevented the growth of aneuploid cells.  These results provide a previously unidentified link between Craf and chromosomal stability, with important implications for our understanding of the development of cancers with driver mutations that hyperactivate Craf.”

Aneuploidy is an abnormal number of chromosomes and can lead to genetic instability, a key cancer hallmark. It’s an important concept here because Kamata et al., have offered a different reason for the CRAF proliferation observed with some BRAF inhibitors:

“Impaired activity BRAF mutants are frequently coincident with oncogenic RAS mutations in human cancers (26) and in these, albeit rare, cancers, we may expect the hyper-activated CRAF induced by the combination of both oncogenes to enhance the aneuploidy response compared with mutation of either oncogene alone.  Such a situation is likely to be highly detrimental to the individual and, indeed, this mechanism may well account for the highly aggressive melanomas we observed following the combined expression of D594A Braf and G12D Kras in melanocytes.”

All in all, this is a very complex yet fascinating area of research and for those of you interested in this field, I would highly recommend reading the latest papers.

Photo Credit: Wikipedia

References:

ResearchBlogging.org Boni, A., Cogdill, A., Dang, P., Udayakumar, D., Njauw, C., Sloss, C., Ferrone, C., Flaherty, K., Lawrence, D., Fisher, D., Tsao, H., & Wargo, J. (2010). Selective BRAFV600E Inhibition Enhances T-Cell Recognition of Melanoma without Affecting Lymphocyte Function Cancer Research, 70 (13), 5213-5219 DOI: 10.1158/0008-5472.CAN-10-0118

 

Garnett MJ, Rana S, Paterson H, Barford D, & Marais R (2005). Wild-type and mutant B-RAF activate C-RAF through distinct mechanisms involving heterodimerization. Molecular cell, 20 (6), 963-9 PMID: 16364920

Gopal, Y., Deng, W., Woodman, S., Komurov, K., Ram, P., Smith, P., & Davies, M. (2010). Basal and Treatment-Induced Activation of AKT Mediates Resistance to Cell Death by AZD6244 (ARRY-142886) in Braf-Mutant Human Cutaneous Melanoma Cells Cancer Research, 70 (21), 8736-8747 DOI: 10.1158/0008-5472.CAN-10-0902

Kamata, T., Hussain, J., Giblett, S., Hayward, R., Marais, R., & Pritchard, C. (2010). BRAF Inactivation Drives Aneuploidy by Deregulating CRAF Cancer Research, 70 (21), 8475-8486 DOI: 10.1158/0008-5472.CAN-10-0603

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Gefitinib or Chemotherapy for Non–Small Cell Lung Cancer with Mutated EGFR

By on June 28, 2010

AstraZeneca's Gefitinib (Iressa) has had a bit of a chequered history since it's fast track approval by the the Japanese Health Authority in 2002 and the FDA in 2003 for non-small cell lung cancer (NSCLC). However, since the phase III trials did not appear to generate a significant overall survival advantage, it has been available in the US, Canada and Switzerland under strict labelling restrictions based on the ISEL study since 2005.  A patient assistance program is available for suitable patients in the US:

"In the light of positive survival data with other agents including another oral EGFR inhibitor, physicians should use other treatment options in advanced non-small cell lung cancer patient populations who have received one or two prior chemotherapy and are refractory or intolerant to their most recent regimen." 

Source: US Iressa PI

The IPASS study (IRESSA Pan-ASia Study) subsequently demonstrated superiority of gefitinib's efficacy over doublet chemotherapy in EGFR mutation positive patients in 2008.  In Europe, this led to gefitinib being finally approved for the treatment of adults with locally advanced or metastatic NSCLC with activating mutations of EGFR-TK across all lines of therapy in 2009.

The latest data, from the North-East Japan Study Group, published in this weekend's NEJM, showed some interesting new results in a study of 239 newly diagnosed Asian patients with NSCLC and EGFR mutations when they compared standard chemotherapy of carboplatin plus paclitaxel to gefitinib as a single agent.

Essentially, in this front-line setting, treatment with the EGFR tyrosine kinase inhibitor gefitinib resulted in progression-free survival (PFS) that was twice as long as treatment with standard chemotherapy, ie PFS of 10.8 months in the gefitinib group compared with 5.4 months in the chemotherapy group. Response rates were also improved in the gefitinib arm compared to chemotherapy (73.7% vs. 30.7%). Side effects were as expected for the two treatments (rash and elevated aminotransferase in the gefinib group and neutropenia, anemia, loss of appetite and neuropathy in the chemotherapy group).

However, the median overall survival (OS) of 30.5 months vs 23.6 months was not significantly different between the two groups.  

It is clear from both IPASS and the NE Japan studies that in a select sub-population of lung cancer patients, patients could elect to receive biologic therapy such as gefitinib rather than chemotherapy and have a reasonable quality of life.  

However, given the lack of over survival benefit with Iressa but has been demonstrated with Tarceva (erlotinib) in other studies, I'm not sure where this leaves AstraZeneca. It is unlikely that the restrictions on the US or Canadian approvals will change as a result of this study. 

Why Tarceva led to a survival benefit in EGFR mutated NSCLC and Iressa does not is still unclear at this stage.

ResearchBlogging.org

Maemondo M, Inoue A, Kobayashi K, Sugawara S, Oizumi S, Isobe H, Gemma A, Harada M, Yoshizawa H, Kinoshita I, Fujita Y, Okinaga S, Hirano H, Yoshimori K, Harada T, Ogura T, Ando M, Miyazawa H, Tanaka T, Saijo Y, Hagiwara K, Morita S, Nukiwa T, & North-East Japan Study Group (2010). Gefitinib or chemotherapy for non-small-cell lung cancer with mutated EGFR. The New England journal of medicine, 362 (25), 2380-8 PMID: 20573926

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Gefitinib first-line treatment of locally advanced or metastatic non-small cell lung cancer

By on May 27, 2010

After the news yesterday about Bayer's sorafenib being rejected by NICE in liver cancer comes another oncology decision, this time a positive one, and good news for AstraZeneca and gefitinib (Iressa).

The new guidance states:

"Gefitinib is recommended as an option for the first-line treatment of people with locally advanced or metastatic non-small-cell lung cancer (NSCLC) if: 

• they test positive for the epidermal growth factor receptor tyrosine kinase (EGFR-TK) mutation and 

• the manufacturer provides gefitinib at the fixed price agreed under the patient access scheme."

Iressa has had a somewhat chequered history over the last few years, first with the fast track approval in the US on promising phase II data and then the down side of phase III trials failing to show any clear improvement in outcome while OSI/Roche's erlotinib (Tarceva) demonstrating a small but significant survival benefit.

It looks like Iressa is coming back from the dead after all, at least in Europe.

According to FiercePharma, a deal was successfully struck with the agency:

"The lung cancer pill got a recommendation from the cost-effectiveness watchdog for use by the National Health Service, but only after the company offered an unusual fixed-price arrangement. Iressa will be supplied to the NHS at £12,200 ($17,560) per patient, regardless of how long treatment lasts. And the NHS won't pay at all for patients who use Iressa for less than three months."

So in the UK, sorafenib would cost around £27K, whereas gefitinib would cost £13K, both offering a couple of months increased survival in liver and lung cancer, respectively.  The difference in the two situations is that patients can be now screened for the EGFR mutation in lung cancer (which wasn't known at the time of the original approval), thereby preselecting which patients are most likely to respond. There is no biomarker associated with VEGF therapy yet, as far as I'm aware.

As to what will happen in the US, we'll have to wait and see.

ASCO 2010 Preview #2: PI3K and mTOR inhibitors

By on May 12, 2010

One of the interesting things about scientific conferences such as AACR and ASCO is that everyone looks at the same data differently as if it were through a kaleidoscope.

Brand marketers focus on their competition by tumour type or disease, scientists look at specific mechanisms or pathways, investors look at particular companies and so on. 

Someone asked me the other day how I analyse the data.  I hadn't really thought about it much until then, but on reflection what I'm interested in is trends and how research evolves from a big picture science view so that means I look at pathways like a true biochemist.  This also teaches us where the gaps are and what opportunities may arise in the future.  It's not exactly rocket science, but it is a useful approach sometimes.

Phosphoinositide 3-kinasesImage via Wikipedia

One of the clear trends emerging at AACR the other week is that dual inhibition of both the PI3K-mTOR and RAS-ERK pathways may be necessary in some cancers such as melanoma to reduce cross-talk, feedback and feedforward loops, drug resistance and loss of PTEN gain of function, just as one might also target IGF-1R and EGFR to reduce cross-talk and add in another inhibitor, eg MEK or AKT.

Given the increasingly critical role of MEK and AKT in various combinations in the future to reduce the potential for drug resistance occurring, this bodes well for a host of companies.  I wasn't, therefore, surprised to see Novartis snap up Array's MEK inhibitor (ARRY-162) given they already have an mTOR on the market (everolimus, Afinitor), two PI3-kinases in development and others including a RAS inhibitor.  Having a MEK inhibitor as well may therefore give them a lot of flexibility with different combinations in multiple cancer types if this approach pans out. 

Merck are also following a similar approach with their mTOR inhibitor, ridaforolimus, which they have finally grabbed commercial control of from their partner, Ariad.  Let's not forget they also have an AKT inhibitor, dalotuzumab and a MEKi through their partnership with AstraZeneca to play with too.

This is all good news for several biotech companies though, if some big Pharma companies start catching onto the trend and realise they need may a PI3K-mTOR inhibitor and a MEK or AKT inhibitor to stock up in their pipeline before the field gets too crowded.

Which companies might have new and interesting data in this area?

Well, Keryx and Aeterna Zentaris, Semafore, Calistoga, Intellikine and a few others all have PI3K inhibitors in development, while Exelixis have a deal in place with sanofi-aventis for XL147 and XL765 and Roche/Genentech have a pan-PI3K inhibitor, GDC-0941.  Novartis have two (BEZ235 and BKM120). Some of these compounds are single PI3K inhibitors and some are dual inhibitors of PI3K-mTOR.

Looking at the ASCO abstract titles, Exelixis appear to have the most abstracts in this area this year, so it will be interesting to see what sort of data they have across a range of different tumour models and early phase I results in solid and hematologic malignancies, with a variety of different combinations. 

One session I'm really looking forward to at this year's ASCO is a Clinical Science Symposium entitled, "Paths for Clinical Development of PI3K Inhibition" with some of the heavyweights in the field such as Neil Rosen (MSKCC), Skip Burris (Sarah Cannon), Jose Baselga (Spain) and Carlos Arteaga (Vanderbilt).  Arteaga is presenting a talk in that session entitled, "Next steps in clinical development of PI3K inhibitors?"

More later on this blog after the posters and the data become available at the meeting.

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BIO 2010: A place for new biotech deals emerging?

By on May 6, 2010

I've been following the annual Biotechnology Industry Organisation (BIO) Conference being held in Chicago remotely on Twitter (check out the hashtag #BIO2010) while busy with client work this week and secretly thanking my lucky stars that I'm office bound and not whinging about sore feet myself as McCormick Place has hard floors and miles of corridors!  Much of the lifestream seems to be a lot of moaning about the limited/almost non media access to the keynotes and grumbling about the general lack of social media savvy of the organisation. No surprises there.

Still, in a world where life seems to be increasingly on 24/7, this interesting little snippet from the San Francisco Business Times was much more revealing:

"Big drug makers are ready to make a deal.  

With some facing a multibillion-dollar patent cliff and others just trying to expand their focus, big biotech and pharmaceutical companies are reaching out to capture potential products from other companies. 

That played out at the recent Biotechnology Industry Organization convention in Chicago. While smaller, privately held companies continued to dominate the number of 15-minute pitches, South San Francisco-based biotech biggie Genentech Inc. and German goliath Bayer Schering Pharma AG also spun out appeals to smaller companies to sell out or partner up.
The list of big companies taking time slots to make similar pitches included the likes of Pfizer, Merck AstraZeneca, Eli Lilly and GlaxoSmithKline."


It's a few weeks post AACR and a month before the run-up to ASCO, also oddly in Chicago, and thus companies interested in oncology will have been evaluating the latest AACR data and thinking about whether or not to make a move before the competition do.

Of course, with many companies facing a potential perfect storm of patent cliffs and a shortfall in the in-house pipelines over the next few years, everyone is desperately hunting for 'breakthroughs'.  These are never a sure fire thing and are very hard to predict.

Increased activity and competition for licensing deals also means good news for the little companies as supply and demand may well drive prices up.  It will certainly be interesting to see who pounces over the next few weeks and many investors will be scanning their crystal balls hard for clues.  

Who do you think will be snapped up?

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#AACR10: The Kinase Dilemma

By on April 26, 2010

There are a lot of clinical trials out there right with tyrosine kinase inhibitors; unfortunately many will fail because they were rushed into phase II or III trials without thinking through all the options.  There are, however, some smart companies out there who do think.

What was noticeable at AACR this year, was the surfeit of posters and presentations regarding logical combinations designed to eliminate escape routes and hence resistance.  For example, cross-talk is a common problem between ligands, eg IGF-1R and EGFR, so combining the two may reduce the problem but that isn't the whole story.

Feedback loops also exist, so targeting PI3-kinase alone is less likely to be effective than targeting both PI3-kinase and mTOR.  Neal Rosen from MSKCC showed some interesting data to this effect and argued cogently that oncogenes tend to lead to constitutive negative feedback.  He also noted that the BRAF mutation predicts for sensitivity to MEKi, for example.  Michael Korn also discussed the feedback activation loop between the RAS-ERK and PI3K pathways and how the inhibition of autophagy (where cells self digest themselves) can enhance apoptosis and the anti-tumour effect with smart combinations.

Targeting both MEK and AKT may therefore also have more effect than either alone, as you can see in the chart below: 

Picture 10Source: Array Biopharma

In a recent trial reported at the the ASCO GI meeting in January, Merck described an elegant design where IGF-1R, EGFR and AKT inhibitors were all combined to target advanced pancreatic cancer, with promising early results.  I thought this was a prescient approach at the time, since it clearly sought to eliminate both cross-talk and feedback, so it was interesting to see numerous researchers advocating similar approaches in different tumour types based on the overexpression profiles at AACR last week. The design is based on rational biochemistry, which regular PSB readers will know I'm a big fan of, rather than randomly adding a kinase inhibitor to whatever is the standard chemotherapy of the day in a haphazard blunderbuss approach.

There are a number of MEKi and AKTi inhibitors out there (I counted nearly a dozen last time I checked), as well as a plethora of PI3-kinase and mTOR inhibitors, either alone or in combination.  Merck and AstraZeneca announced an interesting deal earlier this year to jointly pursue research with their AKT (MK-2206) and MEK (AZD6244) inhibitors.  This collaboration makes a lot of sense biochemically.  Novartis (a client) have one of a broadest kinase pipelines in the industry and just added to it prior to AACR in a deal with Array BioPharma to license their MEK inhibitors, of which ARRY-162 is the lead candidate. 

The compounds that ultimately win the race may not necessarily be the ones furthest ahead in clinical trials right now, but the ones with the smartest clinical trial designs to eliminate some of the issues associated with kinase inhibition – cross-talk, feedback, feed-forward loops and additional mutations. 

MEKi and AKTi are two of my favourite kinase approaches right now because they offer the flexibility to add to existing TKI's such as erlotinib, sorafenib or everolimus, for example, potentially improving the outcomes further in a variety of different cancers, never mind the future combination possibilities.  It's going to be a very interesting and hot area to watch in the near future, that's for sure.

If you have any thoughts or questions on this fascinating topic, please do add them in the comments below.

 

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