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Combined VEGF and MET inhibition in some cancers may be better than either alone

By MaverickNY on February 24, 2012

A couple of recent controversies in the field of angiogenesis have fascinated scientists and clinicians alike, namely:

Does VEGF inhibition lead to more aggressive tumours?
What drives metastases and invasion?
What is the role of tumour hypoxia in this process?

Data was originally presented in glioblastoma by Rubenstein et al., (2000), showing that anti-VEGF antibody treatment prolonged survival, but resulted in increased vascularity caused quite a stir. Several other groups subsequently demonstrated in preclinical models that VEGF signaling shrinks tumours, but also results in increased invasion and metastases (see Casanovas et al., (2005), Ebos et al., (2009), Paez-Ribes et al., (2009), for examples).

The mechanism for this process, however, remained elusive. A number of factors have been thought to be contributing, including:

Vessel pruning
Hypoxia
Increased expression of c-MET and/or HGF

The corollary of course, is that once we better understand the underlying biology, we can devise strategies to test new agents in clinical trials. The end result would hopefully be improved outcomes for patients undergoing cancer therapy.

Sennino et al., (2012) performed an elegant series of experiments that were published today in Cancer Discovery and sought to understand the roles of VEGF and c-MET signalling in invasion and metastases by using a variety of VEGF and MET inhibitors in transgenic mouse models of pancreatic neuroendocrine tumours. The paper makes for very interesting reading, which I highly recommend.

Here are some of the highlights:

Tumours treated with VEGF inhibitors such as an antibody (#AF-493-NA, R&D Systems) or sunitinib tended to shrink, but were more invasive as defined by irregular tumour border and presence of acinar cells.
Post treatment with VEGF inhibitors, proliferating cells were reduced in the tumour centre compared to control but there were more apoptotic cells compared to the control. This is consistent with what we would expect from anti-angiogenic therapy.
Interestingly, when looking at mesenchymal markers (eg Snail1, N-cadherin, vimentin) there were stronger bands in Western blots after VEGF therapy. EMT activity is usually a sign of invasion and early metastases in the microenvironment.
Tumours treated with anti-VEGF agents had fewer blood vessels than control, again consistent with expectations for anti-VEGF therapy. However, the reduced vascularity was also accompanied by more hypoxia and greater levels of HIF-1a.
c-MET staining was greatest in tumour cells, but not tumour vessels, after VEGF therapy compared with the controls. The latter is reduced as vessel pruning takes place.
Inhibition of c-MET with PF-04217903 and either sunitinib or the anti-VEGF antibody led to reduction in invasion and tumours with smoother contours, but not greater vascular pruning.

Other experiments were performed with both PF-04217903 and crizotinib (MET inhibitors), as well as cabozantinib, a dual inhibitor of MET and VEGF. When both targets were inhibited together, using either cabozantinib or PF-04217903 plus sunitinib, there was a consistent reduction in invasion and metastases. This also increased with tumour hypoxia and c-MET expression.

What does this data mean?

This is the first paper I’ve come across that convincingly suggests that targeting both VEGF and c-MET simultaneously reduces not only tumour size, but also invasion and metastases, thereby overcoming one of the limitations of treatment with VEGF inhibitors alone.

The work also advances our understanding of the anti-angiogenesic process which involves:

“A complex mechanism involving vascular pruning, intratumoral hypoxia, HIF-1a accumulation, and activation of c-MET in tumor cells.”

As a result, the data also suggest the value in combining VEGF and MET inhibitors with a therapy such as cabozantinib (XL184:

“Inhibition of both signaling pathways by XL184 also reduced tumor growth, invasion, and metastases, and prolonged survival.”

Overall, this was a very nicely put together piece of research and expands our understanding of angiogenesis. It also offers insight into how we can improve clinical strategies with combined VEGF and MET inhibition, which I think we will see more off rather than targeting either pathway alone.

Some of these agents are already approved (e.g. bevacizumab, sunitinib, crizotinib), while several others (MetMAB, tivantinib and cabozantinib) are in phase III clinical trials for various tumour types. It will be interesting to see how dual inhibition develops in the clinic and whether the animal studies can be confirmed in humans. I do hope so.

References:

Sennino, B., Ishiguro-Oonuma, T., Wei, Y., Naylor, R., Williamson, C., Bhagwandin, V., Tabruyn, S., You, W., Chapman, H., Christensen, J., Aftab, D., & McDonald, D. (2012). Suppression of Tumor Invasion and Metastasis by Concurrent Inhibition of c-Met and VEGF Signaling in Pancreatic Neuroendocrine Tumors Cancer Discovery DOI: 10.1158/2159-8290.CD-11-0240

Rubenstein JL, Kim J, Ozawa T, Zhang M, Westphal M, Deen DF, & Shuman MA (2000). Anti-VEGF antibody treatment of glioblastoma prolongs survival but results in increased vascular cooption. Neoplasia (New York, N.Y.), 2 (4), 306-14 PMID: 11005565

Casanovas O, Hicklin DJ, Bergers G, & Hanahan D (2005). Drug resistance by evasion of antiangiogenic targeting of VEGF signaling in late-stage pancreatic islet tumors. Cancer cell, 8 (4), 299-309 PMID: 16226705

Ebos JM, Lee CR, Cruz-Munoz W, Bjarnason GA, Christensen JG, & Kerbel RS (2009). Accelerated metastasis after short-term treatment with a potent inhibitor of tumor angiogenesis. Cancer cell, 15 (3), 232-9 PMID: 19249681

Pàez-Ribes M, Allen E, Hudock J, Takeda T, Okuyama H, Viñals F, Inoue M, Bergers G, Hanahan D, & Casanovas O (2009). Antiangiogenic therapy elicits malignant progression of tumors to increased local invasion and distant metastasis. Cancer cell, 15 (3), 220-31 PMID: 19249680

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Cancer Clinical Trials: Companion Diagnostics or Gene Sequencing?

Last year saw some interesting developments from MD Anderson Cancer Center in early phase clinical trials that may have a far-reaching impact on the future of cancer research as we know it:

At ASCO in June, Dr Tsimberidou presented the initial results from a phase I study run by the MD Anderson Department of Investigational Cancer Therapeutics group. Instead of testing patients with a given cancer (eg lung) for individual mutations eg ALK or EGFR and then offering patients a targted drug as we normally do, they ran a broad diagnostic panel across a multitude of patients with different cancers to determine what the tumour was telling them about the aberrations and selected appropriate targeted therapies. While the study was small in size, the results were better than random selection.
In September at the ECCO meeting in Stockholm, Dr Gordon Mills (Head of Systems Biology) stated in his keynote presentation that 30,000 cancer patients at MD Anderson would be screened and tested for aberrations using gene sequencing. This has huge implications for clinical trial efficiency, since they will effectively generate a powerful database that will enable them to match patients to studies based on the precise selection criteria, rather than looking at a protocol and testing new patients that subsequently come in the door for each target individually.

The other thing that many readers have asked about is companion diagnostics and whether they are the future following the recent approvals of crizotinib (Xalkori) and vemurafenib (Zelboraf) in ALK+ lung cancer and BRAFV600E melanoma respectively?

More recently, we have seen numerous papers discussing the findings from massive parallel sequencing studies (more on that tomorrow) and developments in gene sequencing, including a dramatic announcement from Oxford Nanopore on Friday regarding its novel third generation sequencing progress.

I decided to discuss these issues with Dr Razelle Kurzrock, who heads up the Department of Investigational Cancer Therapeutics group at MD Anderson. Here’s the transcript of the interview. Please do check out the brief audio clip too, as this highlights a very important trend for the future with gene sequencing costs/time coming down.

PSB: Could you tell us a bit more about your phase I group and what you are doing with regards to matching therapies to targets?

Dr Kurzrock: Essentially we do phase 1 studies, which can be anything from new first in human drugs that are just going from animals to patients, or really any other phase 1. It might be in experimental drugs, or new combinations of two experimental drugs, combinations of an experimental and an FDA approved drug or combinations of FDA approved drugs. It is any new study that is just a new way of looking drugs is considered phase 1. That is really what we are doing. It is sort of a large scale, we have about 128 studies and we put over 1100 patients on study last year.

But I don’t think that has really gotten people interested or that we really are at the point that we are most excited about. The idea is to do molecular profiling on patients as they come in the door, then to try to match them with the appropriate targeted drugs. Of course people have done this for individual studies, like the ALK inhibitor crizotinib, the investigators and the company looked for ALK rearranged lung cancer patients.

The thing that we are doing differently is that we are not looking for one abnormality to match with one drug. We are looking at a panel of abnormalities as patients come in the door and then decide which drug to match them to. So it is a more generalized type of way of doing things and I am sure it is the way things will be done in the community in the future. It is a really simple concept, but nobody has done it like this before.

PSB: If you have more than one abnormality will you consider combination therapy or just target the main mutation first?

Dr Kurzrock: Well, I think it is either one. If you have more than one abnormality you can consider combinations or you can try and figure out what the main one is. The concept of looking for multiple abnormalities at once is really a diagnostic concept.

As an example if you had lung cancer, we know that there is ALK rearrangement in 4% of patients, then there might be an EGFR mutation in 5% of patients and probably when we look at al lung cancer there might be 20 different mutations, subsets of patients. There may be 50, we don’t know all of them yet.

This inevitably has implications of how we test and screen patients for clinical trials, as Dr Kurzrock astutely observed in the sound bite below:

PSB: I like the idea of doing the panel, and with over 100 studies, it must make it more efficient to assign patients to the appropriate clinical trials?

Dr Kurzrock: I think it is a lot more efficient. With the caveat that this was not a randomized study, what we saw in our pilot study was that we were getting response rates that were considerably higher than what we would expect in phase 1.

Our background response rates are about 5% of our patients will get a complete or partial remission if we just do things the old way, remembering that phase 1 patients are patients that have by definition failed all therapy. They are often in good shape, but have a highly resistant and lethal tumor.

But the response rates when we did the matching was 27%. Again, this isn’t a non-randomized trial so there are biases, but it could be actually biases that might lower the response rate or biases that might raise the response rates. But the bottom line is that it was much higher than what we would have anticipated. This of course needs to undergo more rigorous testing, but we were impressed that doing this was better for our patients and actually better for drug development.

PSB: So are you using next generation sequencing to drive your diagnostic panel?

Dr Kurzrock: That’s a good question. This is an area in very rapid flux. When we presented our data at ASCO 2011, we presented first generation data where we were just doing a very small panel of mutational analysis. Essentially we presented in mid 2011, data from 2010 mainly and the field has moved so quickly. The data was especially impressive because we used this primitive, first generation way of doing things. We are now expanding to using a Sequenom panel which looks at multiple different mutations, and I think the next generation panel is going to be the one that comes on line pretty soon. All exomic sequencing, while it can be done, the bioinformatics is still complicated and that is probably not quite ready yet. I think it will be ready maybe in a year or two years, but I think that is not quite ready to be used on large volumes of patients. But, Next Gen Sequencing, although you use the methodology, you only pick a set number of genes say 300, that is probably useable at this point.

PSB: I remember talking to Gordon Mills at ECCO and he said as the cost of sequencing costs come down, the analytical costs are going to go through the roof because it gets more and more complicated.

Dr Kurzrock: The analytical costs are now the problem. But, where I disagree is having seen how rapidly this field moves, what we need now is a jump in analytical capability. So if we assume there is not going to be a jump in knowledge, it is going to go through the roof.

I have a different assumption, I think there will be a leap. People are working on this. There is going to be a leap in the way we do things. We are going to be able to do the bioinformatics very quickly and the costs will come down just like the costs of sequencing.

In the early 1990s, I remember when everybody who knew anything said we would never sequence the human genome because it was too complicated. Then by the late 1990s we had sequenced the human genome, but it cost $3Billion dollars to sequence a patient. Now it costs $5000 and one company has said they will do it for $1000. This took leaps in technology that have occurred extraordinarily rapidly in 10 or 12 years. I absolutely think those leaps will occur in bioinformatics now, which is the sticking point.

PSB: Many oncology pharma companies seen to be going down the route of developing a companion diagnostic test with a targeted therapy e.g. crizotinib and vemurafenib, but I’m wondering is that really the way of the future?

Dr Kurzrock: I think that is not the way of the future, for the reason that I said. It is an interesting thing, the diagnostic panel is a great idea, but technology is moving so fast now that the diagnostic test is going to be outmoded, if it is not already outmoded.

And it is for the reason that I mentioned. A patient walks in the door, you can not see if that patient has whatever type of cancer whether it be breast cancer or lung cancer or whatever, you can not tell by look looking at that patient which diagnostic panel to do. You just can’t know. In essence you can choose to do one diagnostic test but that will probably be 4% of patients with that disease. So what you are going to have to do is multiple diagnostic tests to cover all the realms of possibility. If you license diagnostic tests one at a time and I have to do 20 or 50 or whatever tests, it is going to be hugely expensive, plus probably you will run out of tissue and you will have to rebiopsy the patient.

To me the way of the future will be a multi-assay panel whether it is Sequenom or next gen sequencing, probably it will be next gen sequencing or something like that, that will look at all the possible aberrations, rather than looking at them one at a time. Ultimately it is going to run up the cost if we do it that way [with individual diagnostic tests].

PSB: If we want to help more patients then we have to figure out what the aberrations are?

Dr Kurzrock: I think in the most simple sense, this is simply diagnosis. The reason we diagnose patients and we try to figure out whether you have breast cancer, you have lung cancer or colon cancer or some other cancer, is in order to give you the best treatment. That is the reason we give you a diagnosis, also to tell you the prognosis, but we want to tell you your best treatment.

Up till now, we the way we have diagnosed patients is with a light microscope that was invented back in 1590. In the simplest sense this is just a more sophisticated way of diagnosing patients, and it as at the molecular level. It is like using a molecular microscope except the molecular microscope is Next Gen Sequencing. So we really want to know when a patient walks in the door, what do you have, what is your disease at a molecular level? You can’t do that by using one probe at time, you have to look at all the relevant gene abnormalities and then figure out which one is abnormal.

In summary…

There is no doubt in my mind that broad molecular gene profiling (or massively parallel sequencing as it is often called in research) to find aberrations in the tumours of cancer patients will be:

Faster
More effective

for patient clinical trial selection than the current approach of biopsies for individual targets based on a single diagnostic test. If we want to speed up clinical trials a broader screening approach will no doubt be a better starting point than searching for small needles in a haystack.

That said, the challenges going forward are still many. These include greater analytical and bioinformatic costs, as well as figuring out which aberrations really matter. After all, some will be drivers, but many will be passengers that merely add noise to the signal, so targeting every aberration that appears in a panel may not actually have any effect clinically and may even induce unwanted systemic side effects.

Until we determine which aberrations are the critical targets in each tumour type or subtype, as well as identify those that develop in response to therapy (adaptive resistance), then we still have a long way to go in terms of improving our understanding of the biology underlying the many diseases that make up ‘cancer’ and improving patient outcomes with therapeutic interventions.

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Raised platelets reduce survival in ovarian cancer

During my years in Pharmaland, I often sat in waiting rooms waiting to see the Principal Investigator (PI) for one of the studies we were doing. I would generally see them at the end of the clinic, preferring to arrive early and chat with some of the patients to learn of their experiences, the trials and tribulations of cancer therapy. This keeps your feet on the ground – drug development is not an academic exercise, there are real people involved after all.

Some of those patients were really sick, with quite advanced disease, maybe with a year or less to live by conventional estimates and yet they were entering a clinical trial, or seeking to get into one with great hope. Over time, one would meet some of those patients repeatedly, to be greeted with good cheer and the latest round in their stories. These shared moments are precious, you learn little snippets of their journey back to health and what it’s really like to go through various regimens. I cannot tell you how thrilling it was to meet some of the sickest patients several years later and learn that the greatest thing you ever hear in an oncologists surgery – that they were in remission.

To this day that still gives me goosebumps.

One of the things that often came up in those brief chats though, was the lab results, with various counts being up or down. Some of these matter, some don’t. The one that always puzzled me was raised platelets because on asking the doctors, few ever really seemed concerned about the levels, unless they were too low (thrombocytopenia) to undergo their next round of treatment. The scientist in me, however, always wondered about raised platelets – what do they do and do they have an impact on outcome?

This week, a paper has been published in the New England Journal of Medicine by Anil Sood’s group at MD Anderson Cancer Center that begins to address this very issue of raised platelets or thrombocytosis in cancer therapy.

The crux of the research was nicely summed in the MD Anderson press release:

“Highly elevated platelet levels fuel tumor growth and reduce the survival of ovarian cancer patients.”

Now that may sound a little dramatic but I was curious to know why does this happen, so this morning I talked to Dr Sood to find out more about his groups research:

PSB: This exciting research was about the impact of elevated platelets, can you tell us why this happens and what the consequences are?

Dr Sood: We looked at the clinical implications and found that patients who have higher platelet counts tend to live for a shorter time period and beyond that we asked how is it that these platelet counts are going up? We did a number of studies, including human material as well as laboratory experiments, and figured out that tumors can produce certain growth factors such interleukin-6 (IL-6) that stimulate the liver to produce this factor called thrombopoietin, which stimulates platelets counts. That’s the paracrine or complex circuit that promotes high levels of platelets in cancer patients.

PSB: What was the basic underlying mechanism behind this?

Dr Sood: The mechanism here was that the tumor derived IL-6 stimulates thrombopoietin production. Thrombopoietin will stimulate megakaryopoeisis through the bone marrow, which will then stimulate platelet production. We did some experiments to also figure out that if you could block this from occurring, could you reduce or could you block platelet levels from going up. We did a number of experiments using both siRNA as well as an antibody that blocks interleukin-6. If you block either of those you can abrogate the platelet counts from going up.

We also worked with collaborators in UK where they had used this same antibody that we used for animal experiments, in a clinical trial and they found that platelets come down when patients are treated with an IL-6 blocking antibody. That gave us further evidence that this mechanism seems to be operative where it is important for platelets.

PSB: Are there IL-6 antibody therapies available for community oncologists to treat their patients.

Dr Sood: Not yet. It is something, especially in the context of ovarian cancer, that is undergoing clinical development, so they need to be carefully developed.

The other question is an antibody such as that adequate in itself, or does it need to be combined with a cytotoxic or with a chemotherapy drug? In some of our preclinical experiments that we included here, there was the suggestion that combining it with chemotherapy was even more effective than just using the antibody alone.

PSB: When oncologists see patients with high platelet levels do they currently treat them in any way?

Dr Sood: Not really any differently. It is something that we have simply known for a long time. In this context, given especially that these patients tend to have aggressive behavior (of the tumour), there is a lot of potential clinical implications, but again this is relatively new, so I think we need to do additional work to really figure out what are the best approaches to treat these patients.

Is it better to combine an IL-6 antibody, specially in those patients who have high platelets, along with chemotherapy? Can drugs like even aspirin or things like that that interfere with platelet function, could those have implications? There are data that would suggest that patients who are on a daily aspirin tend to live longer in the context of cancer patients. These type of things need to be developed further.

PSB: Could the high platelets cause inflammation?

If you can’t see the soundbite audio clip, click here.

PSB: Where is your research going next?

Dr Sood: In many directions! This has opened a lot of questions for us. We found that platelets are not restricted to the blood system, but that they can in the tumor microenvironment also traffic. We want to understand how is that survival can be effected? I don’t think that the survival is effected just because these patients are getting more blood clots, or something like that. I think that the platelets can provide growth factors for cancers, which we are trying to understand.

Obviously, you don’t want to reduce or completely eliminate platelets because they are an essential part of our body, but if we can block this kind of abnormal thrombocytosis from occurring then that might have implications for therapy as well. The other thing we are asking is that since platelets are elevated in a fraction of cancer patients, can these be also useful as a biomarker, so we are trying to do studies to look at that aspect. There are many directions this research opens up.

Summary:

Although thrombocytosis has obviously been known for a long time, it’s really only now that we are starting to have a clearer idea of the potential negative impact of raised platelet levels in cancer patients. The survival curves between normal platelets and thrombocytosis in ovarian cancer were dramatically significantly different in the paper (P<0.001).

Obviously these results would need to be confirmed in randomised trials before making a more definitive conclusion from a patient perspective. That said, the results from Stone et al., (2012) do suggest that while raised platelets can influence survival in ovarian cancer, there may be some therapeutic options down the road to address this, possibly with an IL-6 antibody added to chemotherapy.

The anti-IL-6 antibody used in this elegant research (and the early study at Barts) was siltuximab (J&J), although a quick search of the clinical trial database revealed no US studies in ovarian cancer. In the paper data from UK patients were included (see also Coward et al., (2011) in the referencs below, as the MD Anderson press release noted:

“In a clinical trial conducted at the Barts Cancer Institute, Queen Mary, University of London, the team also found that treatment of 18 ovarian cancer patients in a phase I/II clinical trial with siltuximab, an antibody to IL-6, sharply reduced platelet counts over a three-week period.”

It will be interesting to see if approach is subsequently tried in a larger scale trial with ovarian patients who have thrombocytosis to confirm the positive impact. Certainly, the clinical rationale is there. For those of you interested in the role of IL-6 in ovarian cancer further, a recent paper by Coward et al., (2011) from the group who did the phase I/II trial of siltuximab in ovarian cancer is well worth a read (see references below).

References:

Stone, R., Nick, A., McNeish, I., Balkwill, F., Han, H., Bottsford-Miller, J., Rupaimoole, R., Armaiz-Pena, G., Pecot, C., Coward, J., Deavers, M., Vasquez, H., Urbauer, D., Landen, C., Hu, W., Gershenson, H., Matsuo, K., Shahzad, M., King, E., Tekedereli, I., Ozpolat, B., Ahn, E., Bond, V., Wang, R., Drew, A., Gushiken, F., Collins, K., DeGeest, K., Lutgendorf, S., Chiu, W., Lopez-Berestein, G., Afshar-Kharghan, V., & Sood, A. (2012). Paraneoplastic Thrombocytosis in Ovarian Cancer New England Journal of Medicine, 366 (7), 610-618 DOI: 10.1056/NEJMoa1110352

Coward, J., Kulbe, H., Chakravarty, P., Leader, D., Vassileva, V., Leinster, D., Thompson, R., Schioppa, T., Nemeth, J., Vermeulen, J., Singh, N., Avril, N., Cummings, J., Rexhepaj, E., Jirstrom, K., Gallagher, W., Brennan, D., McNeish, I., & Balkwill, F. (2011). Interleukin-6 as a Therapeutic Target in Human Ovarian Cancer Clinical Cancer Research, 17 (18), 6083-6096 DOI: 10.1158/1078-0432.CCR-11-0945

A new fusion gene target in a rare soft tissue sarcoma

By MaverickNY on February 14, 2012

Every now and then my eye is caught by reports of new fusion genes being found in different cancers. Often these descriptions involve researchers across multiple laboratories due to the rarity of the target. Following a discussion on Twitter yesterday, a friend sent me the link to this interesting paper published in Science Translational Medicine. Naturally, one of the first things that came to mind was ‘is the identified target druggable?’

Source: wikipedia micrograph of epithelioid hemangioendothelioma (from the liver)

Tanas et al., (2011) used deep gene sequencing and conventional cytogenetics to identify two genes involved in chromosomal translocation in epithelioid hemangioendothelioma (EHE), a rare vascular sarcoma that arises out of endothelial cells, namely:

WWTR1, WW domain-containing transcription regulator 1 (3q25) and
CAMTA1, calmodulin-binding transcription activator 1 (1p36).

The researchers noted that:

“CAMTA1 encodes a transcription factor that is found in all multi- cellular organisms tested and is evolutionarily conserved from Arabidopsis to humans.”

What is its function?

“Little is known about the protein’s function in mammalian cells, but in humans, the gene is expressed almost exclusively within the brain and has been implicated in memory because high amounts of CAMTA1 mRNA have been identified in memory-related regions.”

Now, there are a couple of other things to note:

Not much is known about EHE, as the sarcoma was only described recently by Weiss and Goldblum (2008) in Enzinger and Weiss’s Soft Tissue Tumors. They appear to affect both sexes equally and are not age dependent, appearing in soft tissue, bone and visceral organs such as the liver and lungs.
There are no current treatment options for EHE, other than surgical removal.
Diagnosis of EHE is currently challenging and requires careful histological examination.

The paper is well worth reading for those interested in the challenges of fusion gene isolation, but what particularly struck me was the prevalence of the translocation in EHE compared with other sarcomas – it appears to be very distinctly different, since none of the others evaluated (nearly 30 of them, was found to have the translocation).

The presence of the fusion gene in EHE but not the other sarcomas strongly suggests a role in tumorigenesis, i.e. it’s an oncogene rather than a tumor suppressor gene.

“We anticipate that understanding the mechanism of WWTR1/CAMTA1 oncogenesis will be instrumental toward developing targeted therapy for EHE, for which none currently exists.”

There are some positive things that emerge from this research. In some ways, identification of the fusion gene in EHE may well change diagnosis and treatment options in the future for patients with the disease, much in the same way that imatinib helped to redefine the diagnosis and treatment of another rare sarcoma, gastrointestinal stromal tumours (GIST) in 2002. Hope, as they say, is always just around the corner.

If any scientists or pharma people following this blog have something in their pipeline that may target the WWTR1/CAMTA1 fusion gene, then please let me know – it would be useful if we could crowdsource potential therapies aimed at oncogenes actively involved in tumorigenesis of rare cancers.

{UPDATE: Bruce Shriver from the Liddy Shriver Sarcoma Initiative, patient support group since shared this link via Twitter on the background to the disease in plain English and further development of the fusion gene research – please check it out! }

References:

Tanas, M., Sboner, A., Oliveira, A., Erickson-Johnson, M., Hespelt, J., Hanwright, P., Flanagan, J., Luo, Y., Fenwick, K., Natrajan, R., Mitsopoulos, C., Zvelebil, M., Hoch, B., Weiss, S., Debiec-Rychter, M., Sciot, R., West, R., Lazar, A., Ashworth, A., Reis-Filho, J., Lord, C., Gerstein, M., Rubin, M., & Rubin, B. (2011). Identification of a Disease-Defining Gene Fusion in Epithelioid Hemangioendothelioma Science Translational Medicine, 3 (98), 98-98 DOI: 10.1126/scitranslmed.3002409

The role of the Androgen Receptor in breast cancer

By MaverickNY on February 10, 2012

This week I have been in Orlando for the American Association for Cancer Research (AACR) Special Conference on prostate cancer chaired by Drs Arul Chinnaiyan (U. of Michigan) and Charles Sawyers (MSKCC). It was a superb meeting, probably one of the best I’ve attended since the PI3K meeting that AACR hosted in February last year. I wrote nearly half a Moleskine of notes that vaguely resemble chicken scratch – there were so many good talks that stimulated new ideas and explained a few scientific things I also didn’t know too well. Learning is a continuous lifetime experience, after all.

During the meeting, I had a nice correspondence with one of our regular blog readers, the thoughtful Biomaven. Peter mentioned some data on the androgen receptor (AR) as a potential target in breast cancer following Medivation’s recent conference call. It’s an interesting topic and one well worth discussing. Here’s a map of the AR pathway for reference:

Source: wikipedia

The AR is not something one naturally and immediately thinks of in women, since testosterone is usually considered a manly thing. That said, it is present in women in both normal breast epithelial cells and ~70% to 90% of invasive breast cancers.

Until recently, the link, however between AR status and breast cancer survival is uncertain and perhaps a little controversial, but Hu et al., (2011) looked at the association between the AR status and breast cancer survival in the Nurses’ Health Study (NHS) – see references at the end for the link to the article.

What was the study about?

According to the authors:

“The NHS is a prospective cohort study established in 1976 when 121,700 female registered nurses from across the United States, aged 30 to 55 years, completed a mailed questionnaire on factors that influence women’s health.

Follow-up questionnaires have since been sent out every 2 years to the NHS participants to update exposure information and ascertain nonfatal incident diseases. Follow- up rate from 1976 to December 2007 is 98.9% in our study.”

Not to be confused with an population/epidemiology study from the NHS (National Health Service) in the UK! The main goal of this study was to:

“… determine the association of AR status with survival outcomes adjusting for covariates.”

What did the research find?

Out of all the breast cancers followed (n=1467), 78.7% were AR+. Additionally, amongst the ER+ patients (n=1,164), 88% were AR+:

“AR positivity was associated with a significant reduction in breast cancer mortality (HR, 0.68; 95% CI, 0.47–0.99) and overall mortality (HR, 0.70; 95% CI, 0.53–0.91) after adjustment for covariates.”

The situation was very different in women who were ER- (n=303) though:

“42.9% were AR-. There was a nonsignificant association between AR status and breast cancer death (HR, 1.59; 95% CI, 0.94–2.68).”

In other words, AR+ confers a better prognosis in ER+ breast cancer.

Now, the relevance of all this research is potentially important when considering possible mechanisms of resistance to aromatase inhibitor (AI) therapy in ER+ breast cancer. Recall that one mechanism of resistance to AI treatment is mTOR, which is why the BOLERO2 trial with an AI (exemestane) plus an mTOR (everolimus) in the relapsed setting did so well in ER+ women. Not all of the women in the trial responded to the treatment though, suggesting that other factors may play a role in acquired or adaptive resistance.

What is the importance of AR to therapies for breast cancer?

Normally, knowing whether a particular situation has a better or worse outcome isn’t particularly helpful for patients, since it doesn’t predict which therapy might be more appropriate. However, there is some other AR and breast cancer research from Cochrane et al., (2011) which was presented to the Endocrine Society Peter referred to that tells us a bit more of the AR story:

“We postulate that ER+ breast cancers that fail to respond or become resistant to current endocrine therapies (tamoxifen or AI) may do so because they have switched from growth controlled by estradiol (E2) and ER to growth controlled by liganded AR.

We therefore sought to determine if blocking AR activity could serve as a therapeutic intervention for such tumors.”

What did they do?

Cochrane et al, (2011) stated that:

“We used breast cancer cells that express ER and AR such as MCF7 cells and a cell line that we recently isolated that contains more AR than ER.

Our data indicate that although DHT does slightly inhibit E2-mediated proliferation, DHT alone is proliferative in cells such as MCF7 with both ER and AR, and is even more proliferative than E2 when AR is more abundant than ER.”

What did the results show?

The results were a) interesting and b) a little surprising:

“We found that while both the anti-androgen bicalutamide and the triple acting, non-steroidal, AR antagonist MDV3100 block DHT and R1881-mediated proliferation of breast cancer cells, we made the novel observation that MDV3100, but not bicalutamide, inhibits E2-mediated proliferation of breast cancer cells.”

These results led the authors to conclude that:

“Anti-androgens, such as MDV3100, may be particularly useful to treat patients whose tumors fail to respond to traditional endocrine therapy despite being ER+, or who have ER-/AR+ tumors.”

Not surprisingly, Medivation announced on their recent conference call this month that they will be seeking to explore this phenomenon in clinical trials. I think this is a logical and exciting development that is well worth a shot on goal. We know that not all the women in the BOLERO2 trial responded to exemestane and everolimus, so other mechanisms must be at play here. This is certainly worth exploring.

The question with the study design of me for me though, is patient selection. How do we determine which women whose initial AI therapy leads to relapse should go onto an mTORor an AR antagonist? I’m guessing that maybe biopsies will be part of the answer.

In conclusion…

On the positive side, it would be pretty cool if we could uncover two mechanisms of resistance to AI therapy in ER+ breast cancer and have some viable therapies to offer women once relapse or acquired resistance sets in. It would start to offer a) hope and b) potentially prolong outcomes further as we determine ways to shut down the various escape routes and signaling pathways. If the concept works, given that up to 30% of women with ER+ breast cancer may have AR+ signaling, then it would also be good news for Medivation and Astellas with MDV3100’s potential upside.

References:

Hu, R., Dawood, S., Holmes, M., Collins, L., Schnitt, S., Cole, K., Marotti, J., Hankinson, S., Colditz, G., & Tamimi, R. (2011). Androgen Receptor Expression and Breast Cancer Survival in Postmenopausal Women Clinical Cancer Research, 17 (7), 1867-1874 DOI: 10.1158/1078-0432.CCR-10-2021

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Is ARN-509 (Aragon) potentially better than MDV-3100 (Medivation) in advanced prostate cancer?

By MaverickNY on February 2, 2012

Many readers will have noticed that the advanced prostate cancer market is rapidly becoming crowded with three new therapies (cabazitaxel, sipuleucel-T and abiraterone) already approved and several more in late stage development, including Alpharadin (radium-223) and MDV3100, both likely to file this year. In addition, others are focused on bone complications, such as denosumab, which is expected to have a tough ODAC meeting this month, and cabozantinib, a multikinase inhibitor currently in phase III trials.

Unlike breast cancer, where progression-free survival (PFS) is a used as a surrogate measure of survival, in advanced prostate cancer, overall survival (OS) has pretty much become the gold standard by which prostate cancer trials are reviewed. This makes it much easier to judge whether the drugs are having a positive effect on true efficacy, i.e. do patients live longer as a result of treatment. PFS is particularly difficult to measure in prostate cancer, so it’s not surprising this approach has evolved as the standard measurement.

Interestingly though, Health Authority approval does not always mean reimbursement coverage, as NICE showed yesterday in declining to approve abiraterone in the UK on the grounds that it is too expensive. The BBC quoted a patient who had been on abiraterone for only three months, with a positive impact:

“I have my life back. I have a lot more energy and no pain. My quality of life is excellent. I wouldn’t even know I have cancer now, it’s that good.”

The BBC also quoted his wife, who had an excellent point:

“We know NICE has to take a lot of things into consideration, but when you have a terminal illness an extra four months is very precious.”

Source: BBC

Of course, it’s very much a case of balancing available resources with potential benefits and unfortunately, advanced stage patients will inevitably take the lion’s share in terms of budget for disease management. Post EMA approval, some local UK health providers permitted the drug to be used on an individual basis, raising the old contentious issue of the rather unfair post code lottery (zip code for Americans).

Going forward, no doubt there will be much political posturing and pressure, as you can see from Cancer Research UK, who helped fund the research, but hopefully a deal can still be struck between NICE and Janssen, the manufacturer, on price to enable British men broader access to the drug.

One of the things that has struck me lately, though, is how prostate cancer is attracting serious research focus, such that a heterogeneous disease is slowly being more segmented based on the underlying biology of the tumour. Examples include Arul Chinnaiyan’s superb work on the TMPRSS2-ERG fusion gene and Charles Sawyers’ work on the Androgen Receptor.

Thanks to Sawyers work we now know that the old terminolgy ‘androgen independent’ prostate cancer is an incorrect way of descibing advanced disease because as Clegg et al., (2012) described Scher et al’s original research findings in 2005:

“Despite administration of androgen-depleting therapies, continued androgen receptor (AR) signaling is a common feature of CRPC, attributed to AR gene-amplification, AR gene mutation, increased AR expression or increased androgen biosynthesis in prostate tumors.”

In other words, the AR is very much an oncogenic driver of the tumour’s survival.

This week, we saw promising data for MDV3100, an AR antagonist in the post chemotherapy setting but what of the pipeline beyond abiraterone and MDV3100?

Previously, we came across Aragon’s ARN-509 AR antagonist, which is much further behind in phase I/II clinical trials. Sawyers and Michael Jung, the co-inventors of MDV3100 while at UCLA also developed (along with several other scientists) additional AR compounds, the most promising of which became ARN-509. Aragon is a privately held company formed out of the UCLA discovery with the intent of developing and commercialising this compound.

The obvious question arises – is it a ‘me-too’ or potentially better than MDV3100?

Preclinical data has just been published in Cancer Research by Clegg et al., (2012) addressing this issue. They argued that, based on their findings:

“In a clinically valid murine xenograft model of human CRPC, ARN-509 showed greater efficacy than MDV3100.”

Of course, preclinical data doesn’t always translate to the clinical setting, but my first reaction was ‘Whoa!’

Let’s take a look at the agent in more detail. ARN-509, like MDV3100, is a pure antagonist of the androgen receptor, unlike bicalutamide (Casodex), which has both agonist and antagonist properties. The idea behind this is that there will be less resistance and greater therapeutic potential for more comprehensive binding with the receptor.

We know from work in Sawyers lab that MDV3100 targets splice variants, which have been shown to cause resistance in CRPC, but we don’t yet know how ARN-509 will fare on that front.

So why did Clegg et al., (2012) suggest that ARN-509 might be superior to MDV3100?

“Maximal therapeutic response in this model was achieved at 30 mg/kg/day of ARN-509, whereas the same response required 100 mg/kg/day of MDV3100 and higher steady-state plasma concentrations.

Thus, ARN-509 exhibits characteristics predicting a higher therapeutic index with a greater potential to reach maximally efficacious doses in man than current AR antagonists.”

In other words, it’s much more potent and has a greater therapeutic index; these things are important clinically. It also has a longer half-life:

“ARN-509 exhibits low systemic clearance, high oral bioavailability and long plasma half-life in both mouse and dog, supporting once-daily oral dosing.”

Androgen deprivation therapies are more commonly used in castrate-sensitive disease, so this begs the question of whether there is anti-androgenic activity in the non-castrate setting:

“At higher doses of 30 mg/kg/day, robust tumor-regression (>50% reduction in starting tumor volume) was observed in 6/8 ARN-509-treated animals, similar to regressions observed in mice castrated on the day treatment initiated.”

The promising results led the researchers to conclude that:

“ARN-509 is a next generation anti-androgen selected for pre-clinical and clinical development based on its efficacy and pharmacodynamic profile in mouse xenograft models of CRPC.”

They also stated that:

“Unexpectedly, given a similar in vitro profile, ARN-509 is more efficacious per unit dose- and per unit steady-state plasma-level in mouse models of CRPC than MDV3100.”

In other words, ARN-509 is a next generation AR antagonist with a good efficacy and PK profile in mouse xenograft models of CRPC. It’s clinical development, although further behind abiraterone and MDV3100, will be well worth watching over the next few years.

In summary…

While there has been a lot of activity in the advanced prostate cancer market lately with new approvals making a difference to the lives of men with prostate cancer, there are also several other promising near term agents in development, as well as some potentially more potent and effective treatments in early clinical development. What we have seen to date is merely the beginning of new advances in R&D.

The early and advanced prostate cancer markets are likely to see some significant changes over the next 24 months, as new products based on rational drug design and an improved understanding of the biology of the disease make it to market.

More on prostate cancer coming soon!

All this new data is very timely, considering on Monday I’m off to the AACR Special Conference on Prostate Cancer, jointly chaired by Drs Chinnaiyan and Sawyers. I’ll be interested to learn what new events are emerging as biological targets and what factors can help us predict response to treatment. If you’re going to this meeting do stop and say hello, it’s always good to meet new people in the field.

References:

Clegg, N., Wongvipat, J., Tran, C., Ouk, S., Dilhas, A., Joseph, J., Chen, Y., Grillot, K., Bischoff, E., Cai, L., Aparicio, A., Dorow, S., Arora, V., Shao, G., Qian, J., Zhao, H., Yang, G., Cao, C., Sensintaffar, J., Wasielewska, T., Herbert, M., Bonnefous, C., Darimont, B., Scher, H., Smith-Jones, P., Klang, M., Smith, N., de Stanchina, E., Wu, N., Ouerfelli, O., Rix, P., Heyman, R., Jung, M., Sawyers, C., & Hager, J. (2012). ARN-509: a novel anti-androgen for prostate cancer treatment. Cancer Research DOI: 10.1158/0008-5472.CAN-11-3948

Scher, H. (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

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Update on Medivation’s MDV3100 in advanced prostate cancer

This weekend heralds the annual American Society of Clinical Oncology (ASCO) Genitourinary (GU) meeting in San Francisco, although ASCO held their press briefing today to provide an update on some of the key topics.

For those of you interested in Alpharadin (radium-225) in castrate-resistant prostate cancer (CRPC), check out the update of Dr Oliver Sartor’s presentation, which is covered on Biotech Strategy Blog.

The key topic that most interested me though, was Dr Howard Scher’s update on Medivation’s Androgen Receptor antagonist, MDV3100, in CRPC. Previously, Medivation announced that the data showed an improvement in median overall survival (OS) of 4.8 months and this is still solid (Note: J&J’s abiraterone was approved by the FDA based on an OS of 3.9 months in the same population and must be taken with prednisone).

Three new things were important in this presentation though:

There has been some previous concern about the risk of seizures, after they were reported in an earlier trial, but that was at much higher doses. In this study, the now standard (and much lower) 160 mg dose of MDV3100, demonstrated low levels of seizures (0.6%), which is very reassuring and not something I think many will worry too much about.
MDV3100 has a nice effect not only on OS, but also median time to confirmed PSA Progression, i.e. 8.3 months vs. 3.0 months for placebo (HR 0.248, P<0.0001). Yes, I had to do a double take at that HR – it’s quite phenomenal!
Aside from PSA drops, patients often like to know if their tumour is shrinking or not as evidence of activity and progress. Dr Scher showed the soft tissue response by CT/MRI imaging. There was a 28.9% response rate with MDV3100 compared with 3.8% for placebo (P<0.0001).

From this data we can definitely say that patients lived longer, saw a positive impact on their PSA levels, and felt better compared to placebo. In terms of serious adverse events, there were fewer in the MDV3100 arm (28.4%) versus the placebo arm (33.6%). There were also slightly more discontinuations in the placebo (7.0%) than MDV3100 (3.8%) cohort.

Overall, I wasn’t at all surprised when the host, Dr Nicholas Vogelzang (Medical Director of the Developmental Therapeutics Committee of US Oncology) exuberantly said he had only one comment to Dr Scher’s presentation of the MDV3100 data,

“Wow, that’s very impressive! It’s unprecedented.”

For once, I thought that ‘impressive’ was actually an understatement to apply to a cancer drug.

I also talked to Dr David Hung, CEO of Medivation afterwards. Many readers will remember my interview with Dr Charles Sawyers, the co-inventor of MDV3100, last year about the science behind the development. It was nice to see Medivation’s side of the R&D story, which has gone pretty rapidly so far.

PSB: Are you going to be filing soon based on this data?

David Hung: We are having a pre-NDA meeting with the FDA. Once we have that meeting we will be able to give much more concrete guidance on when we will be filing.

PSB: Some of the pre-chemo trials have started, would they be due to report some data soon?

David Hung: We haven’t given any timelines on any of our other trials.

PSB: When I interviewed with Charles Sawyers previously, he said that many pharma companies were not interested in what is now MDV3100. What did you see in it when many others said “no”?

David Hung: Charles didn’t approach me. I found him! I had read, with great interest, his work on the AR. I was very familiar with his Nature Medicine publication in 2004 showing that overexpression of the AR is a significant molecular change in patients with castration resistant disease. While I think a lot of people thought that targeting the AR would create just another AR antagonist, like casodex, the data suggested to me there was more here.

Because, in Charles’ lab by being able to over-express the AR, we were able to much more carefully assay and screen compounds for their ability to block androgen receptor signaling very thoroughly. And we found in the process that a number of compounds in the series that we were testing had ability to not only block just AR binding by testosterone, which is something that Casodex does, but unlike Casodex these compounds were able to inhibit nuclear translocation as well as DNA binding and activation by the AR.

I am an oncologist by training and was pretty familiar with this area, so when I saw the compounds and saw the data in more detail, I didn’t agree that it would just be another casodex like molecule. I thought the mechanisms suggested that this drug could be special, so when I went ahead and licensed the drug back in 2005. We then took the program forward rapidly through development. We had to do all the standard pharmacokinetics, metabolism, tox, formulation work, then take it into a clinical trial as quickly as we could, led by Howard Scher. So, we were able to develop the molecule very quickly.

One of the differences with MDV3100 over weaker AR antagonists such as bicalutamide, is it’s ability to target splice variants. This was a surprising but important finding. I asked Dr Hung about them:

PSB: Does that potentially mean that the patients in the current trial data presented by Dr Scher, may actually do better over time or is the 4.8 months OS probably going to be the final number?

David Hung: Well, I won’t know the answer to that until I unblind the PREVAIL trial. What is very interesting from our phase 1 / 2 data is that the time to PSA progression in post-chemo patients in that data set is about 203 days. Yet, the time to PSA progression in the pre-chemo patients was 4x longer than that, 812 days, suggesting that the drug may have even more robust activity upstream than it does downstream. Downstream it already has robust activity. We will be greatly looking forward to seeing the PREVAIL data, because that is the pre-chemo population. If we can recapitulate our phase 1 / 2 results, that would be great news for patients.

PSB: At AUA last year, I heard from Charles Sawyers that if you inhibit the androgen receptor, you often activate the PI3-Kinase pathway. His colleague Neil Rosen had also noticed that if you inhibit PI3K, you activate androgen receptor in prostate models. So Charles was saying in their joint paper that the logical thing to do would be to combine an androgen receptor inhibitor and a PI3K-inhibitor to potentially reduce the resistance and hopefully improve outcomes. Is that the kind of combination you might consider in the future?

David Hung: We actually are. You point out exactly the kind of things that we think about. We look to see how our drug works and we look to see what mechanisms might possibly complement our drug. That is the way we think about potential combination studies that we might do.

All this is very exciting news for both Medivation (and commercial partner Astellas), as well as patients with advanced prostate cancer. I hope that the discussions with the FDA go well and we will see a filing, perhaps even with Accelerated or Priority Review in the near future. Based on the data so far, the data clearly shows that MD3100 can make a difference to the lives of men with advanced prostate cancer.

Next week, I’ll be at the American Association for Cancer Research (AACR) Special Conference on Prostate Cancer, jointly chaired by Charles Sawyers (MSKCC) and Arul Chinnaiyan (Michigan) to learn more about the biology of prostate cancer. It promises to be both a timely and exciting meeting!

References:

Chen CD, Welsbie DS, Tran C, Baek SH, Chen R, Vessella R, Rosenfeld MG, & Sawyers CL (2004). Molecular determinants of resistance to antiandrogen therapy. Nature medicine, 10 (1), 33-9 PMID: 14702632

Carver, B., Chapinski, C., Wongvipat, J., Hieronymus, H., Chen, Y., Chandarlapaty, S., Arora, V., Le, C., Koutcher, J., Scher, H., Scardino, P., Rosen, N., & Sawyers, C. (2011). Reciprocal Feedback Regulation of PI3K and Androgen Receptor Signaling in PTEN-Deficient Prostate Cancer Cancer Cell, 19 (5), 575-586 DOI: 10.1016/j.ccr.2011.04.008

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On KRAS, NF-kB activation and pancreatic cancer

By MaverickNY on January 31, 2012

Pancreatic cancer as many readers know, is one of those cancers that is generally diagnosed later than most in stage IV and as a result, has a poor prognosis, often only a year or so from diagnosis.

It has been known for a decade that constitutive Kras and NF-kB activation is one of the signature changes in the disease in the majority (80-95% ) of patients. Kras is a particularly important gene because it is often involved with on-off signaling of other genes. In addition, mutational inactivation of a key tumour suppressor gene (Ink4a/Arf) also occurs in over half (50-75%) of pancreatic adenocarcinomas. What is not known, however, is what are the key signaling pathways downstream of Kras and how they relate to pancreatic cancer.

Earlier this month though, Ling et al., (2012) published some new data in Cancer Cell advancing our knowledge in this area:

“Our findings reveal that KrasG12D-activated AP-1 induces IL-1a, which, in turn, activates NF-kB and its target genes IL-1a and p62, to initiate IL-1a/p62 feedforward loops for inducing and sustaining NF-kB activity.”

They also noted the impact of this process, namely:

“IL-1a overexpression correlates with Kras mutation, NF-kB activity, and poor survival in PDAC patients.”

In other words, dual feedforward loops of IL-1a (induced by AP-1) and p62 are responsible for the IKK2/b/NF-kB activation by KrasG12D.

The group also observed:

“Our results show that TSC1 and FOXO3a pathways are involved in Kras-induced PDAC.”

In other words, they promote tumorigenesis.

What does this data mean?

In practice, this research suggests that several approaches might be potentially useful:

Inhibiting mutated Kras (specifically KrasG12D) may be a viable therapeutic target in pancreatic cancer.
Since IL-1a overexpression correlates with poor survival in PDAC patients, pharmacologic targeting of IL-1a may also be a useful strategy to consider.

Kras mutations appear in a number of cancers, including pancreatic and colon cancers, where in the latter case, they have been shown to cause resistance to EGFR inhibitors. To date, strategies to target Kras have been disappointing at best. There are also a number of MEK and other inhibitors being evaluated in pancreatic and other cancers, but I’m not sure that targeting downstream of RAS will have any effect in these cases, if mutated RAS upstream is the main issue:

Source: ReactionBiology

MD Anderson summed up this data in pancreatic adenocarcinoma nicely in a succinct press release describing the feedforward loops as a ‘vicious circle’ i.e.:

“A self-perpetuating loop of molecular activity that fuels pancreatic cancer by promoting inflammation, development of new blood vessels and blocking programmed cell death.”

References:

Ling, J., Kang, Y., Zhao, R., Xia, Q., Lee, D., Chang, Z., Li, J., Peng, B., Fleming, J., Wang, H., Liu, J., Lemischka, I., Hung, M., & Chiao, P. (2012). KrasG12D-Induced IKK2/β/NF-κB Activation by IL-1α and p62 Feedforward Loops Is Required for Development of Pancreatic Ductal Adenocarcinoma Cancer Cell, 21 (1), 105-120 DOI: 10.1016/j.ccr.2011.12.006

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FDA approves Roche hedgehog inhibitor vismodegib/Erivedge in basal cell carcinoma

By MaverickNY on January 30, 2012

It’s been quite a roller coaster ride for Hedgehog inhibitors of late.

Last week, brought negative data as Infinity announced that their phase II trial with saridegib (IPI-926) had been stopped for futility in pancreatic cancer. This trial sought to determine the impact of the hedgehog in combination with gemcitabine over gemcitabine alone in advanced pancreatic cancer. Unfortunately, the trial was stopped for futility, meaning the control arm was doing better than the treatment arm.

All is not lost for pancreatic patients though, as Roche/Genentech have a phase II trial currently recruiting patients with the triple combination of gemcitabine, nab-paclitaxel and vismodegib. Previously, we have discussed the impact of Abraxane on removing the stromal layer in pancreatic cancer in animal models using nanotechnology to enable therapy to work and I think this may be a more promising approach in the long run.

In contrast, there was good news this morning as the FDA approved Roche/Genentech’s vismodegib, now known as Erivedge, in advanced basal cell carcinoma (BCC) who are not candidates for surgery or radiation and for patients with metastatic disease.

The original PDUFA date was scheduled for March 8th, so this is an early approval, but one that is not entirely unexpected given the promising results previously presented at medical conferences over the last 12-18 months.

The goal of the trial was to measure overall response rate (ORR). In final analysis, the results showed that 30% of the metastatic patients experienced a partial response (PR), while 43% of patients with locally advanced disease experienced a complete (CR) or partial response. These results represent a clear advance for patients with this disease and studies are also ongoing looking at new combinations to overcome resistance and hopefully, extend outcomes further.

For those of you interested in pricing, it looks as though Erivedge will be $7500/month so that would be estimated $75,000 for typical 10-month course of treatment (HT Ruth Coxeter, CNBC).

Links:

FDA Press Release

Genentech Press Release

A new opportunity for vemurafenib in BRAFV600E colon cancer

By MaverickNY on January 26, 2012

There’s been quite a flurry of commercial news on the Pharma front this morning, with Amgen buying Micromet (whose leading product is blinatumumab in ALL) and Celgene announcing their acquisition of Avila Therapeutics who have a Bruton Kinase Inhibitor (BTK) AVL-292 in phase IB development for lymphomas, which was all the rage at the recent American Society of Hematology (ASH) meeting last month.

The big news for me today, though, wasn’t the commercial acquisitions but a gem of a paper relating to science and its significance for future cancer treatment.

One of the unsolved scientific conundrums that arose in my interview with Dr Gordon Mills (MDACC) at the European Multidisciplinary Cancer Congress (EMCC) meeting in Stockholm last September centred around the RAS pathway, and the BRAFV600E mutation, in particular.

Dr Mills astutely noted that while vemurafenib (Zelboraf) has shown activity in patients with advanced melanoma with the BRAFV600E mutation, he raised the important question why did we not see similar activity in mutated colon cancer? Of course, one obvious conclusion might be that the target isn’t critical to the tumour’s survival… or is it? The challenge though, is that these patients do particularly poorly, and usually that is a sign that the mutation is actively driving aberrant activity. Therein lies the quandary, leaving many researchers such as Dr Mills puzzled at the discrepancy and asking why?

This week I’ve been doing a series on colorectal cancer and it is quite by coincidence that today we learn more about the science of colon cancer and BRAFV600E mutations since Pralahad et al., (2012) have just published a Letter in Nature explaining that their research actually suggests that resistance mechanisms might be one of the culprits:

“We performed an RNA-interference-based genetic screen in human cells to search for kinases whose knockdown synergizes with BRAF(V600E) inhibition. We report that blockade of the epidermal growth factor receptor (EGFR) shows strong synergy with BRAF(V600E) inhibition.”

This finding surprised me because melanoma typically has low levels of EGFR expression, unlike more epithelial cancers:

“We compared EGFR expression in a panel of BRAF(V600E) mutant melanoma, colon cancer and thyroid cancer cells. Melanoma cell lines indeed express low levels of EGFR.

So what actually happens in melanoma?

“Mechanistically, we find that BRAF(V600E) inhibition causes a rapid feedback activation of EGFR, which supports continued proliferation in the presence of BRAF(V600E) inhibition.”

Ah, our old friend, feedback loops! These have an uncanny knack of popping up in advanced cancers, as the cancer attempts to ensure it’s survival and overcome the targeted therapy, causing adaptive resistance to treatment in their wake.

You may be wondering how common is this mutation in colon cancer then? Well, Pralahad et al., (2012) observed:

“Our data suggest that BRAF(V600E) mutant colon cancers (occur in) approximately 8–10% of all colon cancers.

Note: bracketed bold addition mine.

What does this data tell us?

In short, a combination of vemurafenib and an EGFR inhibitor, such as erlotinib, cetuximab or gefitinib, might be a useful clinical approach to try therapeutically in patients with colon cancer harbouring the BRAFV600E mutation. Of course, Roche/Genentech have both vemurafenib and erlotinib (Tarceva) in their portfolio, so it would be interesting to see whether proof of clinical concept could be established quickly in a phase I clinical trial. EGFR inhibitors tend to be rather quirky though, and it remains to be seen whether a small molecule (erlotinib, gefitinib, afatinib) or a monoclonal antibody (cetuximab, pantitumumab) would be the ideal partner for vemurafenib in this setting.

While there is much yet to be done in R&D to advance the scientific research, this important finding teaches us that there is hope for this subset with a generally poorer prognosis yet.

I look forward to following the future clinical progress to see if a viable new combination treatment emerges in BRAF V600E mutated colon cancer – watch this space!

References:

Prahallad, A., Sun, C., Huang, S., Di Nicolantonio, F., Salazar, R., Zecchin, D., Beijersbergen, R., Bardelli, A., & Bernards, R. (2012). Unresponsiveness of colon cancer to BRAF(V600E) inhibition through feedback activation of EGFR Nature DOI: 10.1038/nature10868

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