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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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Raised platelets reduce survival in ovarian cancer

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

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

To this day that still gives me goosebumps.

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

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

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

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

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

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

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

PSB: What was the basic underlying mechanism behind this?

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

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

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

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

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

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

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

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

PSB: Could the high platelets cause inflammation?

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

PSB: Where is your research going next?

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

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

Summary:

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

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

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

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

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

References:

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

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

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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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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A new opportunity for vemurafenib in BRAFV600E colon cancer

By on January 26, 2012

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

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

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

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

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

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

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

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

So what actually happens in melanoma?

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

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

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

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

Note: bracketed bold addition mine.

What does this data tell us?

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

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

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

References:

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

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miRNA as a potential biomarker for early breast cancer

By on January 16, 2012

One way to potentially improve long term cancer statistics is earlier detection, and in high risk patients, appropriate initiation of earlier treatment, since it is well known that the survival in stage II or III breast cancer is noticeably better than that for stage IV metastatic disease.

A critical question then, is how do we improve earlier detection?

There are a number of ways to achieve this:

  1. Imaging techniques
  2. Prognostication
  3. Diagnostics
  4. Biomarkers

Historically, breast cancer has often been picked up using classic, but rather crude, imaging techniques such as mammography and ultrasound, although both have their limitations and challenges. Biopsies are also challenging and invasive, especially in early stage disease when the tumour(s) may be very small. I’m particularly interested in biomarkers because it offers a lot of untapped near-term promise. We know that as tumours begin to develop, they leave tell tall signs and signatures – how can we develop ways to detect these earlier and with greater accuracy than at present?

Source: wikipedia

I was fascinated to read a paper in PLoSONE (open access, see references below) this morning looking at circulating microRNAs (miRNA) as a potential blood based marker for early stage breast cancer detection.

miRNA were defined by Schrauder et al., (2012) as:

“MicroRNAs (miRNAs, miRs) are a class of small, non-coding RNA molecules with relevance as regulators of gene expression thereby affecting crucial processes in cancer development.”

They were first described by Lee et al., (1993) in C. elegans (open access, see references below) and have since been found to be stable in blood, making them ideal biomarker material.

In the current research, the authors set out to determine whether miRNA could discriminate early stage breast cancer (n=48) from healthy controls (n=57) using microarray analysis.

What did the research show?

The initial results appear promising:

“We found that 59 miRNAs were differentially expressed in whole blood of early stage breast cancer patients compared to healthy controls. 13 significantly up-regulated miRNAs and 46 significantly down-regulated miRNAs in our microarray panel of 1100 miRNAs.”

Two of the miRNAs (miR-202, miR-718) were subsequently validated by RT-qPCR in an independent cohort.

What do these results mean?

I thought these results were encouraging, although it should be noted that there is no doubt that blood-based miRNA-profiling is behind the improvements seen in tissue-based miRNA-profiling. The advantage though, of blood-based profiling, is that it clearly offers:

“The potential for early, non-invasive, sensitive and specific BC detection and screening.”

Of course, there is a long way to go yet, although similar early studies have been performed in other tumour types such as lung cancer (Foss et al., 2011; Boeri et al., 2011), ovarian cancer (Häuser et al., 2010) and others.

Using miRNA as a potential biomarker for early detection is not without its challenges, though. Shrauder et al., noted that Chen et al., (2008) observed that:

“Comparing serum and blood cells from the same healthy individual an almost identical miRNA profile can be found, but in cancer patients the profiles differ.”

Other studies have not shown complete congruence in the results or findings, so it may well be a while before some clarity emerges with miRNA as a potential diagnostic, most likely with improved standardisation of sample handling, protocols, detection methods and patients (stage of disease, etc).

That said, miRNA looks to be a promising but fledgling area for biomarker research in the early detection of cancer. No doubt this field will evolve further with new and more sensitive techniques.

References:

ResearchBlogging.orgSchrauder, M., Strick, R., Schulz-Wendtland, R., Strissel, P., Kahmann, L., Loehberg, C., Lux, M., Jud, S., Hartmann, A., Hein, A., Bayer, C., Bani, M., Richter, S., Adamietz, B., Wenkel, E., Rauh, C., Beckmann, M., & Fasching, P. (2012). Circulating Micro-RNAs as Potential Blood-Based Markers for Early Stage Breast Cancer Detection PLoS ONE, 7 (1) DOI: 10.1371/journal.pone.0029770

Lee, R., Feinbaum, R., & Ambros, V. (1993). The C. elegans heterochronic gene lin-4 encodes small RNAs with antisense complementarity to lin-14 Cell, 75 (5), 843-854 DOI: 10.1016/0092-8674(93)90529-Y

Foss KM, Sima C, Ugolini D, Neri M, Allen KE, & Weiss GJ (2011). miR-1254 and miR-574-5p: serum-based microRNA biomarkers for early-stage non-small cell lung cancer. Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer, 6 (3), 482-8 PMID: 21258252

Boeri M, Verri C, Conte D, Roz L, Modena P, Facchinetti F, Calabrò E, Croce CM, Pastorino U, & Sozzi G (2011). MicroRNA signatures in tissues and plasma predict development and prognosis of computed tomography detected lung cancer. Proceedings of the National Academy of Sciences of the United States of America, 108 (9), 3713-8 PMID: 21300873

Häusler, S., Keller, A., Chandran, P., Ziegler, K., Zipp, K., Heuer, S., Krockenberger, M., Engel, J., Hönig, A., Scheffler, M., Dietl, J., & Wischhusen, J. (2010). Whole blood-derived miRNA profiles as potential new tools for ovarian cancer screening British Journal of Cancer, 103 (5), 693-700 DOI: 10.1038/sj.bjc.6605833

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What’s hot at SABCS – Update 2 – advanced breast cancer

By on December 10, 2011

After a number of basic research and science sessions over the last two days (see the Update 1 post on the science that intrigued me for more details), but the last two days heralded some excellent clinical sessions, in both oral and poster forms. These included the presentation of the much anticipated update to the BOLERO-2 trial, which was also published in the New England Journal of Medicine online and the CLEOPATRA study, also published in the same journal.  One of the more impressive posters that caught my eye was the ENCORE 301 study, which provided an update to the entinostat data in ER/PR+ HER2- advanced breast cancer.

Many of you will have read the wire and news articles released in a barrage on Wednesday evening with the NEJM publications ahead of the presentations on Thursday and Friday, but I wanted to put them in context of what we know so far and why these studies are both elegant and important.

Why am I fascinated by these particular studies?

Drug resistance can develop either upfront or is acquired in response to treatment over time.  The latter is also known as adaptive resistance, as the tumour evolves certain strategies to ensure it’s survival.  This is one reason why many people will have a different response to the same treatment.

In simple terms, if we can figure out ways to:

  1. Either delay the development of resistance up-front in treatment naive patients by enabling more comprehensive pathway suppression
  2. Or switch to a new logical combination regimen once resistance has developed

then we may be able to prolong patient outcomes and survival further.  To me, these kind of rational approaches make much more sense than merely throwing random chemotherapy doublets of choice at the problem.  These two strategies are very much at the heart of the three impressive studies mentioned above.  Let’s look at them in a little more detail.

BOLERO2

BOLERO-2 is the acronym for the breast cancer trials of oral everolimus and the updated safety and efficacy data were reported here at the San Antonio Breast Cancer Symposium (SABCS), although it should be noted that the NEJM article is based on the phase III ECCO data previously presented by Jose Baselga in September.

The trial design, though, remains the exactly same – patients were randomised to receive with everolimus plus exemestane versus placebo plus exemestane to determine whether the mTOR added anything to the AI alone.

The rationale behind this trial is that mTOR is a known cause of resistance to AI therapy, so the combination targets both the ER, which is driving the tumour proliferation, and mTOR targets the adaptive resistance pathway.  Shutting down both pathways should lead to improved survival, which we clearly saw at ECCO (6.5 months extra survival as measured by PFS).

The latest data presented by Dr Gabriel Hortobaygi (MDACC) confirmed that the responses continue to be durable, with an improvement in the PFS with the combination arm now up to 11.0 months, up from 10.6 months at ECCO. The results for the exemestane control arm remained the same at 4.1 months. This means that the improvement in survival with the mTOR now offers a median 6.9 months extra benefit.  OS had not yet been reached and therefore was not reported.

My view? These are excellent results from a well designed trial with a logical and elegant design given that we know mTOR is one of the adaptive resistance mechanisms to AI therapy and confirm that the original hypothesis was a valid one.

That said, what we don’t know is who will most benefit from the combination i.e. which women are more likely to respond. I’d love to know whether the really good responders had higher mTOR levels or overexpression or whether there is something else that would help us determine the likely responders for several reasons:

  • mTOR isn’t the only acquired resistant pathway to AI – there are others – so hopefully a way to determine who would be the ideal candidate for mTOR therapy will emerge from retrospective analysis.
  • A quarter (26%) of both arms received prior chemotherapy – did these women do better or worse when given the AI-mTOR combination compared with those who only received hormonal therapies?
  • This combination will not be cheap, considering the likely costs of everolimus alone without the AI could easily be ~$7K/month and the cost of exemestane must be added to that.

These points aside, I do think these results are impressive and good news for an advanced population of women who may not want to even consider chemotherapy – the current data suggests that many will get more time with this approach.  Expect to see Novartis filing for everolimus approval in advanced breast cancer with the FDA before the year is out.

ENCORE 301

In the same patient population of ER/PR+ HER2- women, there was an update to the phase II ENCORE 301 trial with the HDAC inhibitor, entinostat, that we blogged in more detail at the recent AACR Molecular Targets meeting.

What was new about the data here was an update on the overall survival (OS) data. Remember, in San Francisco the PFS for the entinostat arm (comparable to the everolimus-exemestane arm in BOLERO2) was 8.5 months in the women with high acetylation, an excellent predictive biomarker of response.

Now, I was wondering why the OS has still not yet been met in the BOLERO2 trial here and realised why with the updated entinostat data:

 

Entinostat OS in ENCORE 301

As you can see above, based on a medium follow-up of 23 months, the OS has improved in these patients in the phase II trial from 19.8 to 26.9 months, an improvement of 7.1 months of life.

We’ve all seen so many trials where the benefit is a mere 1-3 months, so to see several trials in advanced breast cancer where the survival is measured in 6-7 months is breathtaking.  Long may this trend continue with more rationally designed combinations and robust trial designs!

The entinostat phase II data certainly provides a good efficacy and safety signal to continue development and I was delighted to see that Syndax are moving forward to a confirmatory phase III trial in 2012.  I’m very much looking forward to watching how this study progresses, although we obviously won’t know the results for a while.

CLEOPATRA

The CLEOPATRA study looks at a completely different patient population than BOLERO and ENCORE.  In this situation, it’s looking at women were treatment naive, not refractory, who also needed to be HER2+ to enter the study.

As discussed in the What’s Hot at SABCS review prior to the meeting, pertuzumab is similar to trastuzumab in that it is a monoclonal antibody to HER2, but also differs in that it acts in a different part of the HER domain from Herceptin and also prevents pairing of HER2 and 3 dimersiation:

HER dimerization, source: NEJM

The idea behind combining pertuzumab and trastuzumab upfront is to enable a more comprehensive shutdown of the HER2 pathway and delay the resistance setting in.  By doing this, PFS should increase.

Dr Jose Baslega presented the results of the CLEOPATRA trial for the first time to a packed and highly excited audience in San Antonio.  Unfortunately, I wasn’t there as I was en route to the American Society of Hematology (ASH) meeting, but like many, I was eagerly reading the tweets and reactions from the attendees.

The Roche press release summed up the essence of the data nicely:

“The median PFS improved by 6.1 months from 12.4 months for Herceptin and chemotherapy to 18.5 months for pertuzumab, Herceptin and chemotherapy.

Overall survival (OS) data are currently immature, with a trend in favour of the pertuzumab combination.”

In short, another stunning six month leap in survival in an entirely different patient population of advanced breast cancer.  This is the sort of data those of us working in the industry live for and hopefully, things will continue to get better because clearly thought leaders such as Martine Piccart (at the the NY Chemotherapy Symposium) and Jose Baselga (at SABCS) are already dreaming and envisioning a world in which women with HER2+ breast cancer can be treated without chemotherapy at all.  Now that would be a wonderful thing indeed and I really hope to see it happen sooner rather than later.

One thing that hasn’t been factored into the equation is the antibody drug conjugate T-DM1 and how that relates to pertuzumab and trastuzumab.  The phase III trial MARIANNE is currently enrolling patients and may offer us an answer to that question in a couple of years time.

For those of you interested in some expert commentary, the NEJM published an excellent editorial from Dr William Gradisher (Northwestern, Chicago) accompanying the BOLERO2 and CLEOPATRA studies which is well worth reading (see references below).

In summary…

These three studies all show how rationally designed and elegant studies based on solid science can lead to large leaps in improvement in survival in the clinical setting.  Roche have already filed the BLA for pertuzumab and Novartis are expected to file everolimus in advanced breast cancer soon.  Syndax are already planning their phase III trial for entinostat.

It’s a very good period for ER/PR+ HER2- and HER2+ advanced breast cancers – from that perspective, this year’s San Antonio Breast Cancer Symposium was very uplifting and one of the more exciting meetings of the last five years.

References:

ResearchBlogging.orgBaselga, J., Campone, M., Piccart, M., Burris, H., Rugo, H., Sahmoud, T., Noguchi, S., Gnant, M., Pritchard, K., Lebrun, F., Beck, J., Ito, Y., Yardley, D., Deleu, I., Perez, A., Bachelot, T., Vittori, L., Xu, Z., Mukhopadhyay, P., Lebwohl, D., & Hortobagyi, G. (2011). Everolimus in Postmenopausal Hormone-Receptor–Positive Advanced Breast Cancer New England Journal of Medicine DOI: 10.1056/NEJMoa1109653

Baselga, J., Cortés, J., Kim, S., Im, S., Hegg, R., Im, Y., Roman, L., Pedrini, J., Pienkowski, T., Knott, A., Clark, E., Benyunes, M., Ross, G., & Swain, S. (2011). Pertuzumab plus Trastuzumab plus Docetaxel for Metastatic Breast Cancer New England Journal of Medicine DOI: 10.1056/NEJMoa1113216

Gradishar, W. (2011). HER2 Therapy — An Abundance of Riches New England Journal of Medicine DOI: 10.1056/NEJMe1113641

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What's hot at SABCS – Update 1

By on December 8, 2011

Yesterday evening brought a flurry of news around the New England Journal of Medicine articles for the BOLERO2 and CLEOPATRA trials, but out of respect to the presenters, I hate talking about the actual data before its being presented. Call me old fashioned if you like, but it seems odd moving up deadlines for the publication ahead of the presentations instead of releasing them on the day and is a little disrespectful of the journal towards the presenter and attendees.

I will therefore discuss the data for BOLERO2 and CLEOPATRA studies in detail after they have been presented today and tomorrow, respectively. For those of you interested in the study designs and their potential implications, you can check out my brief video highlights in the meantime.

Yesterday at the San Antonio Breast Cancer Symposium (SABCS) brought some really intriguing biology data that are well worth discussing:

  • Notch inhibition to reduce AI resistance
  • HER2 mutants
  • Targeting HER3 with an antibody and impact of ErbB3 expression on luminal cells

Notch inhibition

Perhaps one of the most intriguing presentations (to me) yesterday at SABCS looked at combining a Notch inhibitor plus an AI to reduce breast cancer resistance in preclinical models.

This is an interesting idea that is worth exploring because resistance to oral therapies, including AIs, is a common problem. Understanding the potential mechanisms of resistance should therefore lead to new trial designs and logical combinations.

In this research, the presentation focused on early data on combining MK-0752 (notch) plus hormone therapy. Interestingly, it also finally mentioned the magic word, biomarkers! I think this is a combination we will here much more about going forward.

In his award lecture, Dr Carlos Arteaga correctly observed that the medical community has not done a good job with ER+ drug-resistant disease. This situation is slowly changing as the BOLERO2 data has shown and other mechanisms of resistance will no doubt follow now that more attention is being focused on it.

HER2 mutants

Dr Boulbes from MD Anderson presented the results of some elegant research identifying three mutants to HER2, namely:

  • D808N
  • V794M
  • L726F

All three phenotypes displayed aggressive tendencies. Both the V and L phenotypes showed a dramatic lack of phosphorylation and the latter may be related to the development of HER2 resistance. Data was shown in relation to lapatinib, a HER2 small molecule TKI, which is known to develop resistance to treatment over time.

This is the first time I think HER mutant phenotypes have been reported to my knowledge and if validated clinically, they will represent a breakthrough in our understanding of how HER2 resistance develops, but more importantly, suggest directions for potential therapeutic strategies to overcome it.

Targeting HER3 with an antibody and impact of ErbB3 expression on luminal cells

HER3 has not received a lot of attention relative to its more popular HER2 cousin, largely because it is tricky to target. However, at this meeting, Dr Garner et al., showed that an anti-HER3 antibody (Novartis) nicely shrank breast cancer tumours in immunocompromised mice.

The presenter observed that the alpha-HER3 mAB recognizes and stabilizes HER3 in the inactive conformation. I was left wondering whether HER2 and 3 pairing / dimerization was shut off or something else was going on?

Dr Cook subsequently showed some clear data whereby HER3 is required for HER2 cancer growth in genetic engineering animal model. This was a very nice piece of research.

What was interesting was that Dr Garner also showed that alpha-HER3 can combine w/ trastuzumab plus a PI3K inhibitor to improve efficacy in trastuzumab-resistant settings. This caught my attention because earlier this year at the AACR PI3K special meeting, Neal Rosen (MSKCC) noted that targeting PI3K activated HER3 as one mechanism of resistance in the breast cancer model they were using and thus speculated that combined inhibition of HER3 and PI3K would lead to reduced resistance. Looks like his hypothesis was correct 🙂

And that was just the first full day of presentations with much more to come!

In the meantime, you can follow the conversations remotely using our tracking tool, accessible here on the blog.

Check back tomorrow for more updates on cancer biology and clinical trials from SABCS.

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