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Posts from the ‘Basic Research’ category

American Association for Cancer Research Meeting 2012

By on March 31, 2012

Today marks the kick off for one of my favourite conferences on the oncology-hematology calendar, with the annual meeting of the American Association for Cancer Research (AACR) being held in Chicago.  It’s all about the science and basic research here, although there are clinical sessions, usually on strategy and early emerging phase I/II data.

Wifi is usually pretty good at the AACR annual meeting, although it can be more variable at the smaller meetings.  Like many attendees, wifi permitting, I’ll be tweeting from the conference and blogging some of the interesting highlights over the next few days.

For those interested, you can follow the Twitter chatter using the conference hashtag #aacr from attendees and non-attendees alike, by clicking on the widget below:

AACR have a strong web and social media presence as well as webcasts of sessions (some free, some paid), thanks to the sterling efforts of Ron Vitale and his web team, who do a fantastic job.

They also have iPad/iPhone or Android apps for those interested in looking at the program on the go and an abstract app as well.  After all, what use is a CD-rom of the abstracts if you’re running around McCormick place with a mobile device?  These days, most conferences, I don’t even take a laptop anymore, so a CD is pretty useless with an iPad or tablet!

One of my favourite tools last year was the video app, which offers selections of short interview of some of the presenters giving the highlights of their talks or findings.  This is a great idea for getting key points out on topics of interest.

Huge doorstop abstract/reference books, CD-Roms and flash keys/memory sticks will soon be a thing of the past.  I confess to being a huge big fan of reading the program as a PDF, so that it can be easily read and bookmarked in iBooks, on a plane, bus, or while running round the poster halls.

All of these digital tools are much more practical and user-friendly – tailored towards the typical on-the-go use by attendees and I sincerely wish more conferences would follow AACR’s lead and move over to the web 2.0 world in this fashion.

The conference runs through Wednesday, so do check back daily for the Twitter updates and we’ll be blogging anything interesting either here on PSB (follow @maverickny) or on Biotech Strategy Blog (follow Pieter Droppert, @3NT).

 

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The importance of metabolism in cancer research

By on March 6, 2012

Cancer metabolism is fast becoming an area to watch out for in R&D.  Last month I tweeted that I was attending a one day meeting at NY Academy of Sciences on Cancer Metabolism with keynote speakers Drs Lou Cantley and Craig Thompson. Jonathan Mandelbaum (@biotechbaumer) responded saying it looked like a dress rehearsal of another related meeting he was attending the following week. That was too good an opportunity to miss, so I invited Jonathan to consider guest posting a summary of the Keystone event he attended here on Pharma Strategy. I’m delighted to say he kindly took me up on the offer and what follows is Jonathan’s synopsis, including some references he chose to illustrate the key points, most of which are open access.

Jonathan has the honour of being the first formal guest post from an industry scientist, although the first informal one went to Al Lalani, Ph.D of Regeneron, who sent in an excellent and very amusing summary of last year’s ASCO abstracts.  The original guest post was from an industry analyst, Adam Bristol, Ph.D.

I hope to post more guest blogs here from scientists going forward, as they add variety and different perspectives on the evolution of the cancer R&D process.

Jonathan Mandelbaum

To give you all some brief background, Jonathan is currently a postdoctoral fellow at Millennium Pharmaceuticals, Inc. based in Cambridge, MA. He received his Ph.D. in Cellular, Molecular and Biophysical Studies from Columbia University. His thesis focused on understanding the functional consequences of recurrent genetic lesions in human diffuse large B-cell lymphoma. Prior to Columbia University, he obtained his Bachelor of Science from McGill University in Montreal, Canada and spent his summers as a research student at the Campbell Family Institute for Breast Cancer Research within the Ontario Cancer Institute.

The 2012 Keystone Symposia on Cancer and Metabolism was a hot meeting, albeit in the cold mountains of Banff, Canada. Research into how cancer cells rewire their metabolism to cope with increased energetic and biosynthetic demands has been reinvigorated in recent years, in large part due to several prominent researchers that were featured at the meeting, such as Craig Thompson, Lou Cantley, Reuben Shaw and David Sabatini.

Talks and posters from Agios Pharmaceuticals, Inc., Novartis, Pfizer and Millennium Pharmaceuticals, Inc., provided additional insight into how industry is thinking of translating these latest findings into novel therapeutics. Without getting into much detail (since much of the data remains unpublished), I will summarize some main themes of the conference and takeaway thoughts on future directions for drug discovery.

Central to the conference is the observation known as the Warburg effect, identified by Otto Warbug in 1924. Essentially, Warburg saw that cancer cells, despite being flush with oxygen, rely on aerobic glycolysis for their energy needs, resulting in an excess production of lactate. This phenomenon is common to normal proliferating cells, however, cancer cells have deregulated this process in part through activation of various oncogenic pathways (eg. PI3K, RAS-MAPK) and reliance on the M2 isoform of Pyruvate Kinase (PKM2) (see review by Vander Heiden et al., 2009). Many talks focused on how oncogenic activation of these pathways regulates the activity of different metabolic pathways (eg. glycolysis, the pentose phosphate pathway shunt, amino acid metabolism). For example, it’s known that cells transformed with MYC are dependent on glutamine metabolism for their survival (see Wise et al., 2008).

Is this metabolic rewiring simply an epiphenomenon of oncogene activation or is it truly important for tumorigenesis? Interestingly, mutations in several different metabolic enzymes have been found in certain cancers.  Fumarate Hydratase (FH) and Succinate Dehydrogenase (SDH), enzymes important for the TCA cycle, are inactivated by mutations in rare forms of cancer, implicating mitochondrial dysfunction in these tumors.  Additionally, recurrent gain-of-function mutations in isocitrate dehydrogenase (IDH1/2) have been found in a variety of tumor types, such as glioma and AML.  Most recently, PHGDH, an enzyme important for serine metabolism, was suggested to be the target of a locus recurrently amplified in melanoma (Locasale et al., 2011).

Several talks discussed how these mutations might be important for tumorigenesis. For example, FH-deficient renal tumors have a deregulated anti-oxidant response through activation of the Nrf2 transcription factor (Adam et al., 2011).  The authors suggest that increased fumarate in these cancer cells can promote a post-translational modification of proteins called succination, which can affect protein function.  Gain-of-function mutations in IDH1/2 result in excessive production of the metabolite 2-HG (Dang et al., 2009), which can inhibit the activity of histone demethylases, thus affecting the epigenetic regulation of gene expression (Figueroa et al., 2010).  At least for FH and IDH driven tumors, the common thread appears to be that metabolites can play critical roles in regulating a multitude of cellular processes outside of metabolism itself.

How might this basic research be translated into novel therapeutics?

Two obvious drug targets I mentioned, IDH1/2 and PKM2, are in fact drug programs being pursued by Agios Pharmaceuticals, Inc.  IDH1/2 presents an intriguing opportunity as the mutations are gain-of-function; drugs that can specifically target the mutant protein, akin to imatinib and vemurafinib, might be effective cancer therapeutics.

Although I did not discuss this topic, the autophagy pathway was another focus for several talks at the meeting. As this pathway is important for cells to cope with metabolic stress, and cancer cells face challenges such as hypoxia and nutrient deprivation, targeting autophagy might be a beneficial therapeutic strategy for cancer treatment.

Ultimately, understanding how different genetic dependencies in cancer reprograms cells to be specifically reliant on certain metabolic pathways, might provide synthetic lethal opportunities for drugs that target metabolic enzymes in those pathways.

From a drug discovery perspective, the conference highlighted for me two critical challenges going forward:

  1. What therapeutic window might exist for drugs targeting metabolic pathways? Jeff Rathmell emphasized an important observation that activated lymphocytes are dependent on glycolysis, similar to cancer cells, for their survival. Thus, agents targeting glycolysis might very well have immunological side effects.
  2. Many talks highlighted the plastic and redundant nature of metabolic pathways. Inhibiting one pathway can lead to adaptive flux through another pathway, or even drive metabolic enzymatic reactions in reverse, in order to compensate for that initial block. Understanding and overcoming these pathway redundancies (somewhat similar to the current state of signal transduction drug discovery) will be a key challenge going forward for cancer metabolism translational research.

Jonathan Mandelbaum is currently employed at Millennium Pharmaceuticals, Inc. The views expressed in this article are his own opinion and are not shared by his employer.

References:

ResearchBlogging.orgVander Heiden MG, Cantley LC, & Thompson CB (2009). Understanding the Warburg effect: the metabolic requirements of cell proliferation. Science (New York, N.Y.), 324 (5930), 1029-33 PMID: 19460998

Wise DR, DeBerardinis RJ, Mancuso A, Sayed N, Zhang XY, Pfeiffer HK, Nissim I, Daikhin E, Yudkoff M, McMahon SB, & Thompson CB (2008). Myc regulates a transcriptional program that stimulates mitochondrial glutaminolysis and leads to glutamine addiction. Proceedings of the National Academy of Sciences of the United States of America, 105 (48), 18782-7 PMID: 19033189

Locasale JW, Grassian AR, Melman T, Lyssiotis CA, Mattaini KR, Bass AJ, Heffron G, Metallo CM, Muranen T, Sharfi H, Sasaki AT, Anastasiou D, Mullarky E, Vokes NI, Sasaki M, Beroukhim R, Stephanopoulos G, Ligon AH, Meyerson M, Richardson AL, Chin L, Wagner G, Asara JM, Brugge JS, Cantley LC, & Vander Heiden MG (2011). Phosphoglycerate dehydrogenase diverts glycolytic flux and contributes to oncogenesis. Nature genetics, 43 (9), 869-74 PMID: 21804546

Adam J, Hatipoglu E, O’Flaherty L, Ternette N, Sahgal N, Lockstone H, Baban D, Nye E, Stamp GW, Wolhuter K, Stevens M, Fischer R, Carmeliet P, Maxwell PH, Pugh CW, Frizzell N, Soga T, Kessler BM, El-Bahrawy M, Ratcliffe PJ, & Pollard PJ (2011). Renal cyst formation in Fh1-deficient mice is independent of the Hif/Phd pathway: roles for fumarate in KEAP1 succination and Nrf2 signaling. Cancer cell, 20 (4), 524-37 PMID: 22014577

Dang L, White DW, Gross S, Bennett BD, Bittinger MA, Driggers EM, Fantin VR, Jang HG, Jin S, Keenan MC, Marks KM, Prins RM, Ward PS, Yen KE, Liau LM, Rabinowitz JD, Cantley LC, Thompson CB, Vander Heiden MG, & Su SM (2009). Cancer-associated IDH1 mutations produce 2-hydroxyglutarate. Nature, 462 (7274), 739-44 PMID: 19935646

Figueroa ME, Abdel-Wahab O, Lu C, Ward PS, Patel J, Shih A, Li Y, Bhagwat N, Vasanthakumar A, Fernandez HF, Tallman MS, Sun Z, Wolniak K, Peeters JK, Liu W, Choe SE, Fantin VR, Paietta E, Löwenberg B, Licht JD, Godley LA, Delwel R, Valk PJ, Thompson CB, Levine RL, & Melnick A (2010). Leukemic IDH1 and IDH2 mutations result in a hypermethylation phenotype, disrupt TET2 function, and impair hematopoietic differentiation. Cancer cell, 18 (6), 553-67 PMID: 21130701

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nab-Paclitaxel and its potential role in pancreatic cancer

By on March 5, 2012

Back in 2009 at the American Association for Cancer Research (AACR) Molecular Targets meeting, a researcher (Anirban Maitra) from Boston had a most interesting poster about the use of nanotechnology to deliver nab-paclitaxel (Abraxane) to pancreatic adenocarcinomas in a more targeted fashion.  You can read about it in more detail from the meeting coverage at that time.

Essentially, one of the things that stops chemotherapy being more effective in advanced pancreatic cancer is that the stromal layer forms a physical, almost impenetrable layer, that slows drugs from getting through to the tumour.

Using nanotechnology, the MIT researchers were able to direct nab-paclitaxel to the stromal layer more effectively, wiping it out and allowing subsequent gemcitabine to be more effective in their animal models.

Fast forward two years and there has been a new paper in Cancer Discovery by a different group (see Frese et al., (2012) from the University of Cambridge in the references) looking at the mechanistic role of nab-paclitaxel in pancreatic adenocarcinomas.

Their findings were as follows:

  • Combination of nab-Paclitaxel and gemcitabine causes tumour regression and reduces metastasis
  • Treatment with nab-Paclitaxel targets tumour epithelial cells
  • nab-Paclitaxel promotes elevated intratumoural gemcitabine levels
  • nab-Paclitaxel decreases cytidine deaminase protein levels

Taken together, the authors concluded that, mechanistically:

“Paclitaxel reduced the levels of cytidine deaminase protein in cultured cells through reactive oxygen species–mediated degradation, resulting in the increased stabilization of gemcitabine.

Our findings support the concept that suboptimal intratumoral concentrations of gemcitabine represent a crucial mechanism of therapeutic resistance in PDA (pancreatic ductal adenocarcinoma) and highlight the advantages of genetically engineered mouse models in preclinical therapeutic trials.”

In an AACR press release, the leader author, David Tuveson, was quoted as saying:

“We predict from this mechanistic study that nab-paclitaxel may be most effective if we administer it first, and delay administration of the gemcitabine. The next step is to test this prediction, since it could help a great deal with patient treatment.”

Based on the earlier Boston research in 2009, I think that this sequencing approach makes logical sense, because the nab-paclitaxel will wipe out the stromal layer and create an opportunity for the subsequent gemcitabine infusion (or other therapy) to be more effective.

What are significance of these findings?

Firstly, there are a number of trials ongoing in pancreatic cancer, including a phase III trial of gemcitabine plus nab-paclitaxel, which is expected to mature next year. Based on the promising interim data, I’m hopeful that this combination may move the needle in terms of improved survival (as measured by OS) for patients with this devastating cancer.

More recently, Infinity reported that their phase II trial with their Hedgehog inhibitor (saridegib) plus gemcitabine was stopped for futlity. I wasn’t surprised to hear this based on the 2009 data mentioned above, because without blasting out the stromal layer, neither the TKI nor gemcitabine can impact the tumour cells effectively. Another Hedgehog inhibitor, vismodegib (Genentech/Roche) is being evaluated in a triple combination trial with gemcitabine and nab-paclitaxel. I like this trial design a lot better, but we will have to see whether sequencing is also important, as shown in this latest research, ie nab-paclitaxel first, followed by gemcitabine (plus the Hedgehog inhibitor).

All in all, Frese et al., (2012) provide novel insights into the antitumour activity of nab-paclitaxel. They also offer a potential mechanism for improving gemcitabine delivery to pancreatic tumours that deserves research in the clinical setting. This more targeted smart approach to trial design may well yield improved results in the clinic, rather than the old method of throwing random doublets and triplets at the (tumour) wall hoping something will stick.

References:

ResearchBlogging.orgFrese, K., Neesse, A., Cook, N., Bapiro, T., Lolkema, M., Jodrell, D., & Tuveson, D. (2012). nab-Paclitaxel Potentiates Gemcitabine Activity by Reducing Cytidine Deaminase Levels in a Mouse Model of Pancreatic Cancer Cancer Discovery DOI: 10.1158/2159-8290.CD-11-0242

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We the People…

By on February 29, 2012

I don’t do this very often, but here’s a worthy cause for scientists and cancer researchers to rally around – Dr Steven Meltzer at Johns Hopkins established an online petition to the White House to increase funding to the NIH – the current proposal is to maintain the budget at a flat $30.7 billion.

Supporting the petition taught me something interesting – NIH funding created 350,000 jobs and contributed $50 Billion to the national economy in 2007 alone.

The problem, though, with flat budgets is that every 7 years the value of money halves, so the NIH budget has essentially been decimated over the last decade. This is sad for science, for progress and also for patients.

I was signature 7K odd, but this week has already seen an influx in new supporters that now rank nearly 10.5k strong, which is great progress.  Please take a moment to help support science and research – every vote counts!

Here’s the link to the White House NIH petition.

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Will combining custirsen and MDV3100 reduce resistance in advanced prostate cancer?

By on February 26, 2012

EAU-2012-Congress-Paris-View-of-Eiffel-Tower-By-NIght

Sights of 2012 EAU Congress

Greetings from the European Association of Urology (EAU) congress in Paris. Despite the grey drizzle typical of Europe in winter, this is actually quite an interesting meeting with lots of poster presentations.

One poster that caught my eye yesterday was from Martin Gleave’s group on clusterin knockdown synergising MDV3100 activity. Previously, we discussed on this blog how inhibiting clusterin with custirsen (OGX-011) potentiated docetaxel. At the AUA meeting last year, the issue of whether the same would happen with MDV3100 was suggested, as you can see in the short video blog.

Clusterin is also known as testosterone-repressed prostate message-2 or TRMP-2, and has been shown by Miyake et al., (2000) to be important in advanced prostate cancer. This is because the treatment of choice in hormone-sensitive disease, androgen deprivation therapy (ADT), can lead to clusterin upregulation, thereby causing castrate resistance.

The group’s latest study at EAU looked at whether clusterin knockdown sensitised MDV3100 activity and evaluated potential mechanisms for how this might work.

The results showed that:

  1. Neither MDV3100 or custirsen alone affected AR levels, but in combination, the AR protein levels were reduced.
  2. The combination synergistically suppressed LNCaP (human prostate cancer cell lines) in vitro and in vivo compared to monotherapy with either alone.
  3. Inhibition of the AR has been shown to activate the PI3K-Akt pathway, but the combination prevented this from occurring.
  4. Dual treatment also increased AR instability via decreased levels of the AR chaperone, FKBP52.
  5. AR degradation occurred with combination therapy via the proteasome, leading to synergistic repression of AR transcription.

While these data offer a very nice and logical preclinical rationale for considering a combination of MDV3100 and custirsen to overcome castrate resistance in advanced disease, we also need to see clinical evidence in advanced prostate cancer before getting too excited. I like the idea scientifically but Oncogenex, the manufacturers of custirsen, have not exactly been swift at moving their previous trials along, as Luke Timmerman noted his Xconomy article last year.

Ultimately, the proof is always in the (clinical) pudding.

References:

ResearchBlogging.orgMiyake H, Nelson C, Rennie PS, & Gleave ME (2000). Testosterone-repressed prostate message-2 is an antiapoptotic gene involved in progression to androgen independence in prostate cancer. Cancer research, 60 (1), 170-6 PMID: 10646870

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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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The role of the Androgen Receptor in breast cancer

By 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:

ResearchBlogging.orgHu, 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 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:

ResearchBlogging.orgClegg, 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:

  1. 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.
  2. 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!
  3. 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:

ResearchBlogging.orgChen 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 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:

ResearchBlogging.orgLing, 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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