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Commentary on Pharma & Biotech Oncology / Hematology New Product Development

Posts tagged ‘VEGF’

Video Report from 2012 European Association of Urology Congress in Paris

By on March 2, 2012

Amazingly, it’s been a year since I started doing conference highlight videos, with the first one rolling out at EAU meeting in Vienna last March. They’ve proven to be much more popular than expected! The good news is that the video recording, production and presentation skills have improved along the way.

Unlike last year, the 2012 EAU Congress wasn’t lit up with excitement about new data (abiraterone and MDV3100 dominated last year).  Instead, there were more reflective discussions about how to consider sequencing and combinations in a more crowded castrate resistant prostate cancer market going forward as well as some mention of new up and coming targets outside the androgen receptor (AR) such as ERG and Src.

Here’s the short (under 5 mins) video update:

If you can’t see the video, click here.

Meanwhile, the next conference update will be from the annual American Association for Cancer Research (AACR) meeting from March 31st-April 4th.

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

By 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:

  1. 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.
  2. 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.
  3. 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.
  4. 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.
  5. 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.
  6. 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:

ResearchBlogging.orgSennino, 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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Update from AACR Molecular Targets 2011 #2 – Angiogenesis

By on November 22, 2011

Angiogenesis inhibitors have seen a long and rather chequered history since Judah Folkman first propounded the concept that tumours grow by adding new blood vessels. Many of these inhibitors have ended up in the dog heaven scrap heap, so to speak, while others (some monoclonals, some small molecule inhibitors) have made it to market in some indications, but failed miserably in others.  All in all, it’s been a bit of a crapshoot at best for manufacturers trying to crack this particularly difficult nut.

Perhaps the most famous (some would say infamous) drug is bevacizumab (Avastin), a monoclonal antibody to VEGF-A, which has been approved for colon, lung, glioblastoma, renal cancers but just had its approval revoked in advanced breast cancer by the FDA due to a poor risk-benefit and efficacy profile.

Although Vascular Endothelial Growth Factor (VEGF) has been the target most associated with angiogenesis, there are quite a few other pathways involved in the process, including Platelet Derived Growth Factor (PDGF), Placental Growth Factor (PIGF), Fibroblast Growth Factor, Notch, angiopoeitins (eg Ang1-3 and Tie2) and many others.

Recently, at the European Multidisciplinary Cancer Conference (formerly ECCO and ESMO) in September, new data emerged on two new angiogenesis compounds in colorectal cancer, namely aflibercept (VEGF-Trap) from Regeneron and BIBF1120 (Vargatef) from Boehringer. Both drugs showed promising efficacy and tolerability data in a phase III (VELOUR) and a phase II trial, respectively.

I’m not going to go into details of those trials here, but to expand on the idea of angiogenesis further, because it makes logical scientific sense to target several aspects of the process to see if improved outcomes result. Closely related to this is lymphangiogenesis, which is the formation of new lymphatic vessels from pre-existing lymphatic vessels, in a similar way to blood vessel development or angiogenesis.

According to Tobler and Detmar (2006), a simplified angiogenic and lymphangiogenic mechanism is thought to look something like this:

angiogenesis

It was therefore with great interest that I came across Regeneron’s latest poster at the AACR-EORTC-NCI Molecular Targets meeting last week. They looked at the idea of combining aflibercept (VEGF) and (Ang2) to determine whether there was a synergistic effect. The angiogenesis process is described below (courtesy of Regeneron):

VEGFAng2

The answer, in short, was yes.

They found that combined blockade of both VEGF (aflibercept) and Ang2 (REGN910) promoted noticeable tumour necrosis and growth inhibition in colorectal cancer xenografts over either agent alone.

Of course, we don’t know which biomarkers will be useful predictors of response, but that’s a discussion in itself for another post.

Now, while these results are encouraging, it does not mean they will automatically translate to patients in the clinic, but I do think it looks like a promising dual targeting approach that is well worth exploring further.  In the research there appeared to be no obvious signs of additional toxicities with the combination.  This is one specific multi-targeted approach that we may see more of in the clinic going forward. What this space for progress!

References:

ResearchBlogging.orgTobler, N. (2006). Tumor and lymph node lymphangiogenesis–impact on cancer metastasis Journal of Leukocyte Biology, 80 (4), 691-696 DOI: 10.1189/jlb.1105653

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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

What's hot in molecular diagnostics and biomarkers? AACR #1

By on October 5, 2010

One of the biggest challenges with Vascular Endothelial Growth Factor (VEGF) therapy to date has been the singular lack of either predictive or prognostic biomarkers.

This means that we have no idea which patients are most likely to respond to therapy (ie predictive) when selecting either a monoclonal antibody (eg bevacizumab) or a small molecule tyrosine kinase (eg sorafenib, sunitinib or pazopanib), nor do we will know what their likely prognostic outcome might be in terms of survival.

In an ideal world, we would be able to predetermine and monitor therapy for specific subtypes, thereby avoiding exposing thousands of patients to the systemic effects (and costs) of a drug that may not work for them.

Of course, we all know that developing biomarkers is:

  1. not easy
  2. could be rather expensive

I was therefore greatly cheered while at the AACR meeting Denver on Molecular Diagnostics and Cancer Therapeutics last week to come across a little gem of a poster from the scientists at AVEO Pharmaceuticals.

AVEO ($AVEO), a biotech based in Boston, are developing an oral VEGF inhibitor called tivozanib, currently in phase III for renal cell cancer, and appear to have developed a method to predict which patients are more likely to respond to the compound. Whoa!

I've been watching this company for a couple of years now and have been impressed with what I see so far. Two years ago I met their CMO Bill Slichenmyer over lunch at the AACR meeting in Denver when he was at Merrimack Pharma and kept track of what was happening at AVEO when he moved there. Both companies have interesting technology platforms and smart scientists.

Aside from the poster, AVEO's head of translational medicine, Murray Robinson, also presented the data during an oral session. What was particularly interesting was that the findings were not what one might expect – at all. They wondered if the potential biomarker they identified in animal studies might be reproduced in humans.

AVEO found their biomarker by inserting specific oncogenes and other engineered genes altered in numerous cancer types into the tissue of animals then studying the variety of tumours that were produced. One example of this approach was to genetically alter the HER2 gene, resulting in tumours that naturally expressed different pathways for growth.

They then looked at 600 tumour samples in clinical trials across eight different tumour types and realised that essentially the same biomarker identified in their breast tumour model was indeed associated with clinical activity in a set of kidney tumour patients from a previous Phase II kidney cancer trial. This biomarker was associated with white blood immune cells that are recruited into the tumour to produce angiogenic growth factors and leads to intrinsic resistance to tivozanib.

I confess to being kind of awed by this sort of research.

For some time, clinicians have been grumbling about not having a biomarker for Avastin, Sutent or Nexavar to better help choose which patients would be most likely to respond, thereby avoiding the need to treat everyone to gain a benefit in a few. Here we have three big pharma companies and no biomarker. A little biotech comes along with some smart ideas, a rational approach to the problem and some creative thinking to developing a biomarker for their compound, which is not yet on the market.

Of course, this biomarker is specific to AVEO's tivozanib, as no work has been completed to show that the myeloid component they identified is relevant in the others.

The good thing is that it's now the first biomarker associated with a VEGF therapy.

The bad news is that we will have to wait a little longer to see if the results of the phase III trials in kidney cancer are good enough for approval, but hopefully that won't be too long now.

Imagine one step further.  

Currently, the FDA is reviewing Roche's Avastin in breast cancer and deciding whether or not to withdraw the application given the marginal data currently available from trials such as AVADO. Suppose Roche/Genentech had a biomarker that was relative to Avastin and could be helpful for either prognostic or better still, predictive purposes? Then you could actually make better use of the drug based on a biomarker.

Before anyone in big pharma jumps up and down and starts moaning about the cost and the difficulty, take a look at AVEO's logical, sensible technical approach to the problem. You realise that what we really need is more imagination and creativity in R&D and less objections to progress.

Now suppose the biomarker AVEO identified in their breast cancer models turns out to be useful in breast cancer for women on their compound? If you can clearly show an association between different subsets, who is likely to develop resistance and who is more likely to respond, plus better outcomes, what's not to like?  The overall response rates will be higher in some subsets and lower in others, rather than a crapshoot of "well, it helps some women" or how about the vague "many women clearly benefitted". Great, but which ones and why?

In my opinion, AVEO have done a great job identifying a relevant biomarker for their compound which may actually increase rather than lessen the chances of successful approval down the road.

May the force be with them!

 

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Angiogenesis, angiopoeitin and Glioblastoma Multiforme (GBM)

By on September 21, 2010

Read and writing about malignant brain cancers, gliomas or glioblastoma multiforme (GBM) always makes me sad as life span from diagnosis is often only a year. Over the last decade we have seen many advances in surgery, radiation, chemotherapy and targeted therapies in many cancers, yet this one remains largely immune to significant progress.

Background

Angiogenesis inhibitors targeting the VEGF signaling pathway have been shown to be effective both in preclinical cancer models and in clinical trials. This has led to the approval of several agents targeting VEGF in cancer, including bevacizumab (Avastin), sorafenib (Nexavar) and sunitinib (Sutent). To date, bevacizumab, has been approved for the treatment of relapsed glioblastomas in the US, at a dose of 10 mg/kg IV every 2 weeks. The approval in GBM was based on objective response rate, not survival.

There have been concerns in the past about the use of anti-angiogenic therapy (see references below) with malignant gliomas, principally malignant progression of the tumours with increased local invasion and distant metastasis. In other words, the cancer become more aggressive, which is not a good thing.  Still, the concerns and risk involved must be balanced with the severity of the disease and relatively poor prognosis. Development of resistance is also an ongoing problem.

This morning though, I was a little more cheered about the topic after someone kindly sent me a new clinical paper on angiogenesis and GBM.  

Angiogenesis 

Brunkhorst et al., (2010) looked more closely at the mechanisms underlying tumour angiogenesis, principally angiopoeitins, and found some interesting relationships:

"We establish that Ang-4 is upregulated in human GBM tissues and cells. We show that, like endothelial cells, human GBM cells express Tie-2 RTK."

In simple terms, angiopoietins (Ang-1, Ang-2, and Ang-4) are the ligands of the Tie-2 receptor tyrosine kinase (RTK). More details can be found in an excellent review of angiopoietins and Tie2 in a review by Huang et al., (2010).  While the roles of Ang-1 and Ang-2 are reasonably well known, little is understood about the role of Ang-4, so Brunkhorst et al., set out to research this in more detail.

What they found was really interesting:

"Our results establish the novel effects of Ang-4 on tumor angiogenesis and GBM progression and suggest that this pro-GBM effect of Ang-4 is mediated by promoting tumor angiogenesis and activating Erk1/2 kinase in GBM cells.

Together, our results suggest that the Ang-4–Tie-2 functional axis is an attractive therapeutic target for GBM."

The pipeline

There aren't too many inhibitors of Tie-2 in development, as this is a relatively new area of research.  That said, I did find a couple in my database:

  • ARRY-614 (Array): inhibits p38, Abl, Tie2 and VEGFR2, research in MDS
  • XL-184 (Exelixis): inhibits VEGFR-2, MET, c-KIT, FLT-3, and Tie2
  • ABT-869/linifarnib (Abbott): Inhibits VEGF, FLT3, Tie2, c-FMS, PDGF, c-kit
  • AP-24534/ponatinib (Ariad): inhibits BCR-ABL, FLT3, VEGFR, FGFR, Tie2 
  • AMG-386 (Amgen): inhibits angiopoeitin 1 and 2, thus Tie2 is indirectly inhibited.

Insights

Regarding the relationship between angiopoetin and Tie2, Herbst et al., summarised it succinctly:

"AMG 386 is an investigational peptide-Fc fusion protein (ie, peptibody) that inhibits angiogenesis by preventing the interaction of angiopoietin-1 and angiopoietin-2 with their receptor, Tie2."

Mita et al., (2010) have generated some initial research looking at this compound in a catch-all phase I trial in advanced solid tumours with the standard combinations and dose finding approach. It's too early to say whether the agent will pan out, but some evidence of anti-tumour activity was seen.

In the original article on GBM and angiopoeitins, Brunckhorst et al., (2010) demonstrated that Ang-4 promotes GBM progression by promoting tumour angiogenesis. What was also clear from their data is that Ang-4 seems to display a more potent proangiogenic activity than Ang-1.  

More importantly, they found that GBM cells express Tie-2 and thus there may be a novel role for Ang-4 in promoting Erk1/2 kinase activation in GBM cells and in enhancing GBM cell viability.

Clearly, we still have a long way to go in figuring out the precise details around the broader angiogenesis process involved in tumour growth and development, but expanding the potential targets beyond VEGF into angiopoeitins, Tie2 and even platelet derived growth factor (PDGF), fibroblast growth factor (FGFR) and others will hopefully yield some productive bench to bedside success in the near future. 

 

References

ResearchBlogging.org Brunckhorst, M., Wang, H., Lu, R., & Yu, Q. (2010). Angiopoietin-4 Promotes Glioblastoma Progression by Enhancing Tumor Cell Viability and Angiogenesis Cancer Research, 70 (18), 7283-7293 DOI: 10.1158/0008-5472.CAN-09-4125

Verhoeff, J., van Tellingen, O., Claes, A., Stalpers, L., van Linde, M., Richel, D., Leenders, W., & van Furth, W. (2009). Concerns about anti-angiogenic treatment in patients with glioblastoma multiforme BMC Cancer, 9 (1) DOI: 10.1186/1471-2407-9-444

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), 220-231 DOI: 10.1016/j.ccr.2009.01.027

Herbst, R., Hong, D., Chap, L., Kurzrock, R., Jackson, E., Silverman, J., Rasmussen, E., Sun, Y., Zhong, D., Hwang, Y., Evelhoch, J., Oliner, J., Le, N., & Rosen, L. (2009). Safety, Pharmacokinetics, and Antitumor Activity of AMG 386, a Selective Angiopoietin Inhibitor, in Adult Patients With Advanced Solid Tumors Journal of Clinical Oncology, 27 (21), 3557-3565 DOI: 10.1200/JCO.2008.19.6683

Mita, A., Takimoto, C., Mita, M., Tolcher, A., Sankhala, K., Sarantopoulos, J., Valdivieso, M., Wood, L., Rasmussen, E., Sun, Y., Zhong, Z., Bass, M., Le, N., & LoRusso, P. (2010). Phase 1 Study of AMG 386, a Selective Angiopoietin 1/2-Neutralizing Peptibody, in Combination with Chemotherapy in Adults with Advanced Solid Tumors Clinical Cancer Research, 16 (11), 3044-3056 DOI: 10.1158/1078-0432.CCR-09-3368

Huang, H., Bhat, A., Woodnutt, G., & Lappe, R. (2010). Targeting the ANGPT–TIE2 pathway in malignancy Nature Reviews Cancer, 10 (8), 575-585 DOI: 10.1038/nrc2894

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New potential targets in ovarian cancer?

By on August 26, 2010

Treatment for ovarian cancer hasn't changed much in the last ten years, reflecting the lack of biomarkers and biochemical targets for the disease. Chemotherapy with a platinum (carboplatin or cisplatin) and a taxane (paclitaxel or docetaxel) has therefore formed the bedrock of therapy, along with other options such as gemcitabine or pemetrexed, as illustrated in the latest NCCN Guidelines.

The good news is that the use of paclitaxel-based combination chemotherapy has been shown to increase progression free survival (PFS) and overall survival (OS) in women with primary peritoneal or ovarian cancers.

While a proportion of ovarian cancers have been shown to be highly chemosensitive, a large number unfortunately fail to respond to primary taxane therapy, leading to the emergence of resistant disease.

The big unanswered questions are therefore why does this happen and what can be done about it to improve outcomes and overall prognosis?

It was with great interest that I read about the findings of a new study just published in Cancer Cell from researchers at MD Anderson (see e-link in the references below).  According to the MD Anderson news alert:

"For the first time, Salt Inducible Kinase 2 (SIK2) has been found to play a critical role in cell division and to regulate the response of some ovarian cancers to chemotherapy."

It's not often when you see the mention of both a potential target and prognostic/predictive biomarker mentioned in the same sentence as ovarian cancer, so this is huge news!  The press release went on to claim:

"Researchers found that depleting SIK2 from ovarian cancers sensitized the cancer cells to paclitaxel, a commonly prescribed chemotherapeutic agent that inhibits cell division, making the drug more effective in stopping the cancer's growth. Levels of the SIK2 protein are increased in approximately 30 percent of ovarian cancers and are associated with poorer survival in women with the disease."

The researchers analysed nearly 780 pools of siRNAs to identify proteins that alter sensitivity to paclitaxel. They found that SIK2 regulates sensitivity to paclitaxel and prevents cell division. This means that SIK2 may offer a useful therapeutic target for pipeline drugs to be developed in ovarian cancer.

What was even more fascinating was that another related article on ovarian cancer from Bast's group appeared in the same journal. In essence, they used siRNA-loaded nanoparticles to stifle a protein, Zeste homolog 2 (EZH2), which is associated with poor survival. This resulted in inhibition of angiogenesis (formation of new blood vessels) to the tumour and caused a steep reduction in the tumour burden in a mouse model of ovarian cancer.

In this study, the authors looked at human 180 ovarian cancer tumours and found that the protein was overexpressed in the tumour samples (66%) and in the endothelial cells (67%). It is relevant to note that endothelial cells line the inside of blood vessels and play a crucial role in angiogenesis.

In practice, they found that women with increased EZH2 levels in their tumours had a median survival of 2.5 years compared to 7.33 years for those without. Looking at overexpression in the endothelial cells, the difference was 2.33 years versus 8.33 years for those with normal levels.

Like me, you're probably wondering how these nanoparticles work.  According to MD Anderson:

"The nanoparticles accumulate in the cancer cell and vasculature passively as they circulate in the blood stream. Chitosan nanoparticles are so small that they can flow through tiny holes in the tumor vasculature. They also accumulate in other organs, so the researchers are working to add a targeting molecule that will limit nanoparticle uptake to tumors and their vasculature."

Targeting EZH2 may have application beyond ovarian cancer, since it been associated with the progression and spread of bladder, breast, prostate and gastric cancers and cancer of the pharynx.

All in all, a really interesting pair of papers from Bast's group, which may have clinical promise and real application to the future treatment of ovarian cancer.

 

ResearchBlogging.org Ahmed, A., Lu, Z., Jennings, N., Etemadmoghadam, D., Capalbo, L., Jacamo, R., Barbosa-Morais, N., Le, X., Vivas-Mejia, P., & Lopez-Berestein, G. (2010). SIK2 Is a Centrosome Kinase Required for Bipolar Mitotic Spindle Formation that Provides a Potential Target for Therapy in Ovarian Cancer Cancer Cell, 18 (2), 109-121 DOI: 10.1016/j.ccr.2010.06.018

Lu, C., Han, H., Mangala, L., Ali-Fehmi, R., Newton, C., Ozbun, L., Armaiz-Pena, G., Hu, W., Stone, R., & Munkarah, A. (2010). Regulation of Tumor Angiogenesis by EZH2 Cancer Cell, 18 (2), 185-197 DOI: 10.1016/j.ccr.2010.06.016

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Exelixis and BMS part ways over XL184

By on June 21, 2010

It came as no big surprise this morning to hear that Exelixis and BMS have announced they are terminating their agreement over XL184.  The compound is being tested in medullary thyroid cancer, glioblastoma multiforme (GBM) and non-small cell lung cancer (NSCLC).  This is a small molecule that inhibits several targets, namely MET, RET and VEGFR2.

According to Exelixis, the CEO stated in their press release:

"We certainly understand BMS' need to make pipeline and prioritization decisions."

It looks as if they couldn't agree on the priorities for the clinical development, which would be a little odd given the $240M invested in XL184 and XL281 in 2008, with the same indications planned.

It could also be a question of risk management for several reasons:

  1. Thyroid cancer is slow growing and thus development times will be relatively long, lung cancer is notoriously difficult to crack, as is GBM.
  2. BMS also have another VEGF inhibitor in late stage development called brivanib (BMS582664), which is in phase III and inhibits both VEGFR2 and FGFR.  This compound is being tested in a number of indications, including liver and colon cancers.

Recent BMS analyst meetings from have focused on brivanib as one of the promising new oncology agents in the pipeline, so my suspicion is that they probably decided they only needed one VEGF inhibitor and killed the Exelixis agent rather than their own homegrown one.  These things happen all the time. Sometimes you develop several molecules in the hope that one looks more promising in trials.

A few years ago, I remember reading about an incredibly brave and strong patient in one of the early brivanib trials, for advanced cancer.  In this case, the feisty young lady had a non-differentiated spindle cell sarcoma and blogged about the encouraging impact of her new treatment:

"My Scans came back with wonderful results. The Brivanib pills are working! My tumors are stable and haven't grown since my last scan! One tumor in my lymph node has actually died! There is no blood flow to the tumor! This is the best news I could get. My doctor is so happy with these results. 

I will be on the pills for 12 weeks. After that I will be given either a Placebo or continue on the pills. Because it is a trial it's a 50, 50 shot that I could get the Placebo. Booooo! I will know right away by how I am feeling. The reaction happens within 15 minutes after I take the pills. I am a walking zombie. If I do get the Placebo, I can then go back on the trial."

You can follow her incredible journey back to health here; it's an inspiration to us all.  

Thankfully, she's still blogging 2 years later, a testament to her resolve and ability to fight the disease. Long may she continue! Not everyone who gets cancer is elderly, often many people are diagnosed in their teens, twenties and thirties too.

I don't know about you, but I love happy stories and hope to be following her blog for a very long time.

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Bench to Bedside: How can we speed up cancer drugs to the clinic?

By on March 18, 2010

After yesterday's post about the I-SPY trials in neoadjuvant therapy for breast cancer and how they may speed up the process of bringing new innovative cancer drugs to the clinic faster, I was reflecting on my own experiences with imatinib (Gleevec).   

The Philadelphia Chromosome was first identified in 1960 by Nowell and Hungerford. Gleevec was finally approved by the FDA in May 2001, 41 years later.   

Between 1999, when I arrived in the US and working in New Product Development at Novartis until 2001 when Gleevec was launched, I attended scientific meetings including AACR, ASH and ASCO. Often, Dr Judah Folkman, a scientific researcher from Harvard, would talk about angiogenesis and hypothesised that was the principal mechanism by which tumours grew. I listened to his ideas many times because I was curious and found the concept both fascinating and intuitive. There was a long line of drugs that failed to work though, and every meeting seemed to bring yet more negative results.

Now, Folkman first advanced the angiogenesis theory in 1971 in the New England Journal of Medicine, but it wasn't until 2002, when bevacizumab (Avastin), a VEGF inhibitor that prevented angiogenesis from happening, was finally approved for the treatment of colon cancer.   At that point you go, 'oh wow' and realise that Folkman's theory was indeed proven correct.

Thus a tale of two incredible cancer drugs that both took a relatively long time to evolve from scientific idea to effective treatment in people with cancer.  Or perhaps they were actually relatively 'quick' compared to others, but why it takes this long is something we can surely do better at. 

Last night I was researching ideas for drug development and innovation since the concept of bench to bedside fascinates me and came across this enlightening video from a lunchtime talk that Dr Susan Desmond-Hellmann gave last year at UCSF. Oddly, she seems to have trodden similar thought processes and asked why and how can we speed things up as well. 

The short lecture is well worth listening to for those interested in drug development – the good doctor explains the bench to bedside concept far better than I: 

Sources for scholars and clinical scientists:

The NEJM doesn't appear to go back beyond 1993 online, but the original reference to Folkman's article is at: 

Folkman J. Tumor angiogenesis: therapeutic implications. N Engl J Med 1971;285:1182-1186.

A more recent one from 1995, which provides an update is available online at: NEJM

Afinitor extends life for renal cancer patients

By on October 9, 2008

A new drug in development, Afinitor (everolimus, RAD001) appears to extends life without tumour growth by almost 5 months compared to 1.9 months with placebo.  In addition, a quarter of the patients in the study remained progression free beyond 10 months of treatment.  This is the first therapy to show significant benefit after failure with initial tyrosine kinase therapy (Sutent or Nexavar).  It is currently being reviewed by the FDA for treatment of advanced kidney cancer after failure of initial therapy.

Initial therapy with kinase inhibitors has demonstrated signifcant progression free survival (PFS).  Nexavar, for example, demonstrated a doubling of median PFS in patients with no prior
cytokine therapy of 25 weeks vs. 12 weeks with placebo.   Sutent was compared to interferon-alpha and demonstrated a PFS of 47.3 weeks compared to 22 weeks with interferon-alpha.

What makes Afinitor different and why does it appear to work well, even in patients who have failed stand therapy?  Well, the answer lies in it's mechanism of action.  Both Sutent and Nexavar are multiple kinase inhibitors, principally of Vascular Endothelial Growth Factor (VEGF), that appears to be important in renal cell cancer.   Solid cancers survive by extending their network of tumour vasculature, a process known as angiogenesis. Inhibiting VEGF therefore inhibits the tumours ability to grow.  They also inhibit Platelet Derived Growth Factor (PDGF), which is important in cell proliferation.

Afinitor, on the other hand, inhibits the mammalian target of rapamycin (mTOR) is an intracellular protein that
acts as a central regulator of multiple signaling pathways (IGF, EGF,
PDGF, VEGF, amino acids) that mediate abnormal growth, proliferation,
and angiogenesis in cancer.  mTOR is a critical component of the PI3K/AKT pathway, a key signaling pathway that is frequently dysregulated in many cancers.

RAD001_IMG

Image courtesy of Novartis Oncology

By targeting a different pathway, the activity of the tumour can be further reduced, even after patients have stopped responding to their initial therapy.  This is one of the new key approaches to attacking cancer – find multiple inhibitors of different critical pathways and then determine the best sequencing for the regimens, thereby improving survival.

All three drugs mentioned so far are oral therapies, which are convenient and easy for cancer patients to take each day.  Another drug approved for renal cancer is Torisel (temsirolimus), a mTor inhibitor that is given by intravenous infusion over 30-60 minutes on a weekly basis.  This drug significantly extended survival in renal cancer patients compared to interferon-alpha treatment (10.9 vs. 7.3 months).  When standardised in weeks to enable comparison to Sutent, this means the PFS was approx. 49 weeks compared to 47 for Sutent.

It should be noted that rare bowel perforations are possible with these therapies, a class effect of inhibiting the VEGF pathway.  Sutent and Nexavar have also been asssociated with raised blood pressure and hypertension, whereas Torisel may result in hyperglycemia and hyperlipemia. This may result in the need
for an increase in the dose of, or initiation of, insulin and/or oral
hypoglycemic agent therapy and/or lipid-lowering agents, respectively.

Additional new results with these agents are expected at the Annual Society of Clinical Oncology meeting in mid 2009.  Afinitor is currently being evaluated by the FDA and EMEA for approval and could be available on the market by March-April 2009.

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