Today's post is going to be relatively short as I'm knee deep (literally) reviewing poster handouts from the recent AACR meeting, but while reading translational medicine data I came across a poster on sipuleucel-T basically explaining that it engages the immune system and activates or stimulates priming of T-cells in asymptomatic disease.
Like many out there I'm quietly wondering what will happen tomorrow with Dendreon's PDUFA date due on Saturday May 1st. We can reasonably assume a response on sipuleucel-T (Provenge) might be forthcoming on either Friday or Monday.
Given the gap in available treatments between castration resistance (CRPC) and stage IV metastatic disease, I'm hoping Provenge receives approval on the basis of the four month survival advantage after a somewhat rocky path along the journey. Approval could well kick off what may well turn out to be a new era, with other therapies also in late stage development, namely OrthoBiotech/Cougar's abiraterone and Medivation/Astellas' MDV3100, which are both seeking to test their efficacy and safety and in phase III trials for CRPC.
Non-approval could well be a disaster for a company who has invested so much into immunotherapy as their lead product, investors will likely be very unhappy and Monday could turn into a blood bath. I'm more inclined to be positive though, and my educated guess is that approval will be forthcoming given Dendreon met the pre-defined FDA targets.
We shall see.
{UPDATE: The FDA officially approved Dendreon's Provenge today 29-4-10, see comments below for FDA links and materials including the PI.}
There are a lot of clinical trials out there right with tyrosine kinase inhibitors; unfortunately many will fail because they were rushed into phase II or III trials without thinking through all the options. There are, however, some smart companies out there who do think.
What was noticeable at AACR this year, was the surfeit of posters and presentations regarding logical combinations designed to eliminate escape routes and hence resistance. For example, cross-talk is a common problem between ligands, eg IGF-1R and EGFR, so combining the two may reduce the problem but that isn't the whole story.
Feedback loops also exist, so targeting PI3-kinase alone is less likely to be effective than targeting both PI3-kinase and mTOR. Neal Rosen from MSKCC showed some interesting data to this effect and argued cogently that oncogenes tend to lead to constitutive negative feedback. He also noted that the BRAF mutation predicts for sensitivity to MEKi, for example. Michael Korn also discussed the feedback activation loop between the RAS-ERK and PI3K pathways and how the inhibition of autophagy (where cells self digest themselves) can enhance apoptosis and the anti-tumour effect with smart combinations.
Targeting both MEK and AKT may therefore also have more effect than either alone, as you can see in the chart below:
In a recent trial reported at the the ASCO GI meeting in January, Merck described an elegant design where IGF-1R, EGFR and AKT inhibitors were all combined to target advanced pancreatic cancer, with promising early results. I thought this was a prescient approach at the time, since it clearly sought to eliminate both cross-talk and feedback, so it was interesting to see numerous researchers advocating similar approaches in different tumour types based on the overexpression profiles at AACR last week. The design is based on rational biochemistry, which regular PSB readers will know I'm a big fan of, rather than randomly adding a kinase inhibitor to whatever is the standard chemotherapy of the day in a haphazard blunderbuss approach.
There are a number of MEKi and AKTi inhibitors out there (I counted nearly a dozen last time I checked), as well as a plethora of PI3-kinase and mTOR inhibitors, either alone or in combination. Merck and AstraZeneca announced an interesting deal earlier this year to jointly pursue research with their AKT (MK-2206) and MEK (AZD6244) inhibitors. This collaboration makes a lot of sense biochemically. Novartis (a client) have one of a broadest kinase pipelines in the industry and just added to it prior to AACR in a deal with Array BioPharma to license their MEK inhibitors, of which ARRY-162 is the lead candidate.
The compounds that ultimately win the race may not necessarily be the ones furthest ahead in clinical trials right now, but the ones with the smartest clinical trial designs to eliminate some of the issues associated with kinase inhibition - cross-talk, feedback, feed-forward loops and additional mutations.
MEKi and AKTi are two of my favourite kinase approaches right now because they offer the flexibility to add to existing TKI's such as erlotinib, sorafenib or everolimus, for example, potentially improving the outcomes further in a variety of different cancers, never mind the future combination possibilities. It's going to be a very interesting and hot area to watch in the near future, that's for sure.
If you have any thoughts or questions on this fascinating topic, please do add them in the comments below.
Despite the Europeans unfortunately stranded by the Icelandic volcano, business continued as usual with many presenters doing their talks by teleconference to live slides in the room. Quite a few researchers also FedExed their posters, so people could still peruse them and an envelope was provided for business cards or questions.
As we Brits say, "Keep calm and carry on."
There were approximately 18,000 delegates and 6,000 accepted posters this year, a sign of the times that the meeting is getting much bigger and cancer research is an active area of research.
The AACR staff did a fantastic job behind the scenes, were very responsive in whatever help or support was needed and also very active in social media, which was encouraged between delegates in order to share science and learnings with others in different sessions, those who were stranded and others who could not attend, but had an interest in the area.
In general, I think most of us used common sense and tweeted interesting and general highlight points made, but did not tweet material that was clearly labelled as unpublished, in press or from private discussions in poster sessions. If you want to find out more than the headlines, that's the point of travelling to the live meetings in person.
All this activity was very encouraging to see, because webcasts from key oral sessions and plenaries went up very quickly online for others to see. The missing Europeans possibly speeded this up, but AACR have a history of sharing science, as past meeting podcasts and interviews will demonstrate on the website. It also fosters comradeship and open science in the face of a common goal - curing cancer.
Here are the webcasts to date and also the link to podcasts and media teleconferences. Dr Ed Kim from MD Anderson did a superb job explaining the complexities of the BATTLE trial in simple, easy to understand language. I'm actually going to be listening to some of the webcasts and podcasts myself over the weekend because there were so many sessions one couldn't attend those in parallel, so it's really useful to see them up there.
If you are interested in cancer facts and figures, this short video from the AACR team may well surprise you:
It's always easy to criticise what organisations are doing if things are not exactly to our liking, but in this case, I genuinely want to say publicly, "Nice job, AACR!"
Twitter had several impacts for me at the meeting. I must confess that I dashed over to another session because Dr Naoto Ueno, an inflammatory breast cancer specialist at MD Anderson and a translational researcher, Dr Wafik El Deiry, at Hersey were both tweeting what looked to be a more interesting session than the one I was in (shhhh)! Such is the power of persuasive tweets. Twitter was also great for finding and meeting up with people one had been tweeting with, but not yet met. Chatting in the cloud is great, but meeting in real life also solidifies those relationships for the future and I was honoured to meet many really awesome people at AACR. I sincerely hope to catch those I missed at ASCO in June as it was a hectic meeting and trying to see everyone as well as attend sessions and posters was near nigh impossible.
It seemed particularly apt that a new Moleskine was christened at the beginning of the meeting for Dr Charles Sawyers opening plenary talk on prostate cancer and now the notebook is nearly a third full of chicken scratch notes already!
Still, many of you will be waiting with baited breath to hear what were the big picture emerging trends I noticed at this year's AACR?
Here are some quick thoughts of the top of my head:
The cancer genome is now dominant and understanding the biology is very much a focus, even from manufacturers.
Free plasma DNA is going to be critical for biomarker research.
RNA seems appear in almost every other abstract (more later).
GWAS is becoming more relevant, highlighting distinct subsets of patients who can then be evaluated for prognosis, biomarkers, efficacy and tolerability differences.
Combination targeted therapy is the smart way to go to eliminate cross-talk, feedback and feedforward loops. They may also reduce some acquired resistance, at least for a time.
Dr Bert Vogelstein noted that there are currently 12 critical pathways that impact cancer cell survival. Understanding these more will lead to new and better therapies.
Despite all the above, cancer is a heterogeneous disease and much work still needs to be done in unravelling the mysteries behind it.
Over the next few days, I'll be posting more in-depth thoughts about some of the key new TKI classes that are in the clinic, as well as some of the hot research topics that are emerging. I have a lot of notes and over 500 poster handouts to condense in a Zen-like fashion before that can be done, not to mention some glorious blisters from miles of walking!
Do feel free to add any thoughts, questions or immediate observations you may have from the meeting in the comments below in the meantime, it's always good to hear from others.
By strange coincidence this morning I was listening in to the Celgene R&D Day presentations including an update on their plans for their iMiD therapies thalidomide (Thalomid) and lenalidomide (Revlimid), while reading a couple of interesting papers about Millennium-Takeda's bortezomib (Velcade) that were just published in the Journal of Clinical Oncology last month and another this week for the treatment of multiple myeloma. All three of these drugs have changed the treatment of multiple myeloma from a certain death sentence to a treatable disease.
I'll post more about the Celgene pipeline in a later post, but the papers are well worth sharing and discussing. One report looked at the phase III data for the VISTA (Velcade as Initial Standard Therapy in Multiple Myeloma) trial. This study was presented at the recent American Society of Hematology (ASH) meeting in December (see previous post), but the paper now includes updated survival data in a large cohort of 682 people:
"With a median follow-up of 36.7 months, there was a 35% reduced risk of death with VMP versus MP (hazard ratio, 0.653; P < .001); median OS was not reached with VMP versus 43 months with MP; 3-year OS rates were 68.5% versus 54.0%. Response rates to subsequent thalidomide (41% v 53%) and lenalidomide based therapies (59% v 52%) appeared similar after VMP or MP; response rates to subsequent bortezomib-based therapy were 47% versus 59%.
Among patients treated with VMP (n = 178) and MP (n = 233), median survival from start of subsequent therapy was 30.2 and 21.9 months, respectively, and there was no difference in survival from salvage among patients who received subsequent bortezomib, thalidomide, or lenalidomide. Rates of adverse events were higher with VMP versus MP during cycles 1 to 4, but similar during cycles 5 to 9. With VMP, 79% of peripheral neuropathy events improved within a median of 1.9 months; 60% completely resolved within a median of 5.7 months."
The bold for emphasise is mine, but anytime you see a greater than 30% reduced risk of death from a treatment, one is bound to sit up and take notice, especially if you have a loved one suffering from the disease.
What do these results mean? Well, in practice they clearly demonstrate that VMP significantly prolongs OS versus MP after lengthy follow-up and extensive subsequent therapy for myeloma. What was particularly encouraging is that first-line bortezomib use does not induce more resistant relapse, which is also important for people sufffering from the disease.
The combination of VMP used upfront therefore appears more beneficial than first treating with conventional agents such as melphalan and prednisone and saving bortezomib and other novel therapies until relapse. Historically, oncologists often leave the big guns in their back pocket, but the data from this trial may well change their thinking about treatment strategies in multiple myeloma, at least.
The second paper examined the effect on minimal residual disease, by qualitative and real-time quantitative polymerase chain reaction (RQ-PCR), of a consolidation regimen that included the combination of bortezomib (Velcade), thalidomide (Thalomid), and dexamethasone (VTD) in people with multiple myeloma who responded to autologous stem-cell transplantation (auto-SCT). Although the results are more preliminary - this was a phase II trial with only a small number of patients (n=39) - they are very encouraging indeed.
This study is particularly important because it may be the first to document the occurrence of persistent molecular remissions (almost undetectable disease) in a proportion of people with multiple myeloma treated without allogeneic transplantation. To put this is context, until now, a transplant was the only known curative treatment that has been shown to induce molecular remission, so to achieve that state with therapy alone is something that will give many people goosebumps.
Why?
Because SCT are associated with 20% treatment related mortality alone, so if that number can be reduced by excluding the risk of death, then it offers hope not just for those who are ineligible for a transplant, but as another option for those who are.
The researchers also noted that:
"The major reduction in tumor load recorded by RQ-PCR after VTD suggests that unprecedented levels of tumor cell reduction can be achieved in MM thanks to the new nonchemotherapeutic drugs."
That's all sorts of awesome news, albeit in a small study, but it does augur well for the future if the results can be repeated in a phase III study.
Ladetto, M., Pagliano, G., Ferrero, S., Cavallo, F., Drandi, D., Santo, L., Crippa, C., De Rosa, L., Pregno, P., Grasso, M., Liberati, A., Caravita, T., Pisani, F., Guglielmelli, T., Callea, V., Musto, P., Cangialosi, C., Passera, R., Boccadoro, M., & Palumbo, A. (2010). Major Tumor Shrinking and Persistent Molecular Remissions After Consolidation With Bortezomib, Thalidomide, and Dexamethasone in Patients With Autografted Myeloma Journal of Clinical Oncology DOI: 10.1200/JCO.2009.23.7172
Mateos, M., Richardson, P., Schlag, R., Khuageva, N., Dimopoulos, M., Shpilberg, O., Kropff, M., Spicka, I., Petrucci, M., Palumbo, A., Samoilova, O., Dmoszynska, A., Abdulkadyrov, K., Schots, R., Jiang, B., Esseltine, D., Liu, K., Cakana, A., van de Velde, H., & San Miguel, J. (2010). Bortezomib Plus Melphalan and Prednisone Compared With Melphalan and Prednisone in Previously Untreated Multiple Myeloma: Updated Follow-Up and Impact of Subsequent Therapy in the Phase III VISTA Trial Journal of Clinical Oncology DOI: 10.1200/JCO.2009.26.0638
One of the new trends I've noticed recently has been the uptick in research on RNAi in basic oncology research. While searching for some information, this news release popped up from this morning:
"Tekmira and Pfizer will collaborate on evaluating Tekmira's stable nucleic acid-lipid particle (SNALP) technology to deliver small interfering RNA (siRNA) molecules provided by Pfizer. Tekmira will be responsible for preparing the SNALP formulations and Pfizer will evaluate the formulations in preclinical models. Financial terms of the collaboration were not disclosed."
Interesting.
Furthermore, the release went to explain more about RNAi technology:
"RNAi therapeutics have the potential to treat a broad number of human diseases by "silencing" disease causing genes. The discoverers of RNAi, a gene silencing mechanism used by all cells, were awarded the 2006 Nobel Prize for Physiology or Medicine. RNAi therapeutics, such as "siRNAs," require delivery technology to be effective systemically. Lipid nanoparticles (LNPs) are one of the most widely used siRNA delivery approaches for systemic administration.
Tekmira's SNALP (stable nucleic acid-lipid particles) technology is the leading class of LNPs being used in clinical development. SNALP technology encapsulates siRNAs with high efficiency in uniform lipid nanoparticles which are effective in delivering RNAi therapeutics to disease sites in numerous preclinical models."
April heralds the annual AACR meeting in DC and while browsing the program last night, it was clear that this is an emerging area. More on RNAi technology developments will be updated after the meeting next month; it looks like a fascinating new platform that is well worth exploring.
Of course, this is not news to my cancer researcher buddies, many of whom have been working in this area for some time, but it's always good to see things begin to reach the more mainstream consciousness too. Novel nanotechnology ideas were discussed at the AACR Molecular Targets meeting last November so we'll see what the next meeting brings.
If anyone is going to AACR in DC, do let me know - it would be great to meet up in person.
Every now and then, something lands in my Google Reader that makes me stop and gasp, or at least eagerly look a little more closely. Today's head turner was:
"Scripps Research scientists find two compounds that lay the foundation for a new class of AIDS drug"
Whoa!
On more careful examination, it seems that a team of scientists at The Scripps Research Institute really has identified two compounds that act on novel binding sites for an enzyme used by the human immunodeficiency virus (HIV), the virus that causes AIDS. The discovery apparently lays the foundation for the development of a new class of anti-HIV drugs to enhance existing therapies, treat drug-resistant strains of the disease, and slow the evolution of drug resistance in the virus.
I've written about AIDS and HIV previously and how the disease evades treatment in the past, but if this new finding holds true, we could potentially have a new approach that will add to the current pool of treatment regimens that slow down the path to drug resistance and improve patient outcomes.
Current HIV-protease drugs mimic the shape of certain regions of the HIV protein chain, known as the "cleavage sites" and bind to the active site in the hollow center of protease. Once this site is blocked by the drug, the protease is disabled, and HIV cannot make new infectious particles. Protease drugs therefore impede the spread of the HIV infection to other cells within a patient.
The researchers decided to look at drug-resistant strains of the virus. They then conducted computer simulations of the movement of a particularly nasty multi-drug-resistant mutant strain of HIV (V82F/I84V) to see what happened and if they could learn from it.
The results showed that the flaps of the drug-resistant protease molecule tended to be open more often than their counterparts and they were also more flexible. While the anti-HIV drugs still fit into the active site binding pocket, more energy was needed to close the flaps than the drugs could muster. The drugs wouldn't stay in the binding site and the pocket remained available for the HIV protein chain, which was still able to close the flaps and go on to create new infectious particles.
We can now see that a new type of drug might be able to bind to alternate sites on the sides of the protease, restraining the flaps from their ends and providing the current anti-HIV drugs enough help to close the flaps and disable the protease. Instead of blocking the protease's active site, these compounds would be "allosteric fragments" ie small molecule building blocks that shift the dynamics of the molecule, allowing a different conformation or shape.
How are these two compounds different from currently approved drugs for HIV?
Well, in plain English, current treatments target HIV protease, however, the two new agents in development are small chemical units or "fragments," which bind with the two specific parts of the molecule where they identified resistance occurring.
Essentially, this approach is an important proof-of-concept that the protease molecule has two non-active site binding pockets or 'allosteric sites', which can be exploited as a powerful new strategy to combat drug-resistance in HIV.
Overall, there is a long way to go yet, including extensive clinical trials to determine the safety and efficacy of the compounds, but in theory, with this approach, future drugs incorporating the fragments' novel structural elements may offer new angles that can be exploited biochemically.
Once you have finished comtemplating, please re-read the quote at the top of the post. The more we understand about the science and biology of disease, the more awed I feel.
Perryman, A., Zhang, Q., Soutter, H., Rosenfeld, R., McRee, D., Olson, A., Elder, J., & David Stout, C. (2010). Fragment-Based Screen against HIV Protease Chemical Biology & Drug Design, 75 (3), 257-268 DOI: 10.1111/j.1747-0285.2009.00943.x
As we learn more about the biology of cancer, I'm finding that rather becoming simpler, it actually seems much more complex and sophisticated than we may have first realised.
Sometimes, we don't know what we don't know.
Take for example, the recent AACR meeting on the molecular origins of lung cancer that I attended and wrote a few summary posts on (with more to come!)
There was a particularly fascinating lecture from Robert Kerbel, who looked at the role of tyrosine kinase inhibitors (TKIs) in metastatic cancer. He noted that there have been many successful trials with TKI's, with a two month improvement in survival being typical. There have also been failures, such as bevacizumab (Avastin) in 1st line pancreatic cancer, 2nd and 3rd line breast cancer and adjuvant colorectal cancer.
Numerous theories associated with how anti-angiogenic agents work, including the normalisation of blood vessels, allowing more drug to be delivered to the tumour and several other hypotheses have also been floated around.
What struck me though, was that the switch to a different concept, one where there are early indications that anti-angiogenic therapy actually promotes invasion and metastasis, for example in glioblastoma. Dr Kerbel then showed some scans clearly showing disease progression and growth and asked whether bevacizumab actually increases the aggressiveness of a metastatic tumour over time?
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The evidence for this concept came from an paper published in Cancer Cell in 2009 by Paez-Ribes et al.,:
"The realization that potent angiogenesis inhibition can alter the
natural history of tumors by increasing invasion and metastasis
warrants clinical investigation, as the prospect has important
implications for the development of enduring antiangiogenic therapies."
This invasion effect has been shown in bevacizumab and sunitinib (Sutent), both potent inhibitors of VEGF, so clearly the effect is a class one.
Kerbel discussed what else could explain the results other than increased tumour hypoxia?
Another idea looked at dose dependent circulating levels of plasma VEGF, which Ebos et al., proposed and was subsequently noted with sunitinib in phase II human breast cancer trials reported by Harold Burstein.
The issue then becomes one of potential consequences. Thus, plasma VEGF levels may explain drug resistance seen with anti-angiogenic agents, rapid tumour regrowth and rebound revascularisation may occur once therapy is stopped and an increase in malignant aggressiveness may be seen as invasion and metastasis increases.
The other question on my mind is why is there differences observed in adjuvant and metastatic disease as we have discussed previously with the negative bevacizumab results in adjuvant colorectal cancer. It is possible, based on these observations that treatment with anti-angiogenic agents may have the opposite effect to that intended by hastening progression and thus such therapies may be better suited to the metastatic setting.
The big question now is figuring out how to overcome the drug resistance seen with these agents while minimising the vascular stimulation effects seen.
Pà ez-Ribes, M., Allen, E., Hudock, J., Takeda, T., Okuyama, H., Viñals, F., Inoue, M., Bergers, G., Hanahan, D., & Casanovas, O. (2009). Antiangiogenic Therapy Elicits Malignant Progression of Tumors to Increased Local Invasion and Distant Metastasis Cancer Cell, 15 (3), 220-231 DOI: 10.1016/j.ccr.2009.01.027
Ebos, J., Lee, C., Cruz-Munoz, W., Bjarnason, G., Christensen, J., & Kerbel, R. (2009). Accelerated Metastasis after Short-Term Treatment with a Potent Inhibitor of Tumor Angiogenesis Cancer Cell, 15 (3), 232-239 DOI: 10.1016/j.ccr.2009.01.021
Loges, S., Mazzone, M., Hohensinner, P., & Carmeliet, P. (2009). Silencing or Fueling Metastasis with VEGF Inhibitors: Antiangiogenesis Revisited Cancer Cell, 15 (3), 167-170 DOI: 10.1016/j.ccr.2009.02.007
Ebos, J., Lee, C., Christensen, J., Mutsaers, A., & Kerbel, R. (2007). Multiple circulating proangiogenic factors induced by sunitinib malate are tumor-independent and correlate with antitumor efficacy Proceedings of the National Academy of Sciences, 104 (43), 17069-17074 DOI: 10.1073/pnas.0708148104
Burstein, H., Elias, A., Rugo, H., Cobleigh, M., Wolff, A., Eisenberg, P., Lehman, M., Adams, B., Bello, C., DePrimo, S., Baum, C., & Miller, K. (2008). Phase II Study of Sunitinib Malate, an Oral Multitargeted Tyrosine Kinase Inhibitor, in Patients With Metastatic Breast Cancer Previously Treated With an Anthracycline and a Taxane Journal of Clinical Oncology, 26 (11), 1810-1816 DOI: 10.1200/JCO.2007.14.5375
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
The cancer stem cell (CSC) concept has important implications for understanding carcinogenesis as well as for the development of cancer therapeutics. According to this concept, tumors are initiated and maintained by a cellular subcomponent that displays stem cell properties. These properties include self-renewal, which drives tumorigenesis, and differentiation (albeit aberrant), which contributes to tumor cellular heterogeneity. The existence of CSCs has been described in a variety of hematologic and solid tumors including those of the breast, brain, colon, pancreas, lung, liver, and head and neck.
Cancer stem cells (CSC) are thought also to contribute to tumor spread (metastasis) and recurrence after treatment, so many researchers are looking at ways of targeting them therapeutically.
Why is this important? According to the article (click on the jci.org link above to access it):
"In addition to intrinsic pathways regulating stem cell functions, normal and malignant stem cells are regulated by extrinsic signals generated in the microenvironment or CSC niche."
What does this mean in simple terms? Well, in breast cancer, the niche is composed of immune cells, mesenchymal cells (fibroblasts, endothelial cells etc) and these aspects play a important role in both normal breast development and carcinogenesis. Thus, if the microenvironment plays a critical role in the regulation of CSC growth, then looking at ways of interfering with the processes could affect the very production of CSC's.
One of the therapeutic strategies being pursued to target CSC's involves inhibition of self renewal or survival pathways in these cells. Normal cells die due to a process known as programmed cell death or apoptosis but in cancer, the cells continue to proliferate, thereby producing tumours.
It now appears that critical pathways involved may include NOTCH, Hedgehog, and WNT. Researchers in Michigan, US and Marseille, France have utlised this knowledge to target human breast cancer stem cells, leading to decreased tumor growth and metastasis in mice xenotransplanted with human breast cancer cells using this approach.
In essence, they found that inhibiting the cell surface protein CXCR1, with either an antibody or a small molecule known as repertaxin, selectively depleted the cancer stem cell population in two human breast cancer cell lines in vitro. Loss of the cancer stem cells was followed by extensive death of many of the remaining tumour cells.
Treatment with repertaxin had similar effects in mice xenotransplanted with human breast cancer cells and cancer stem cells were selectively depleted leading to a reduction in tumor growth and metastasis.
It is possible that strategies targeting CXCR1, the soluble protein that binds to it, or the signaling pathways downstream of it, may provide a new approach to deplete breast cancer stem cells, retarding tumour growth and reducing metastasis.
It will be very interesting indeed to see where this research goes in the future.
Priority Review designation may be granted by the FDA to an NDA for drugs that offer major advances in treatment, or provide a treatment where no adequate therapy exists. This designation has the potential to expedite the NDA approval process by reducing the target review period for the application from approximately 10 months to six months. Based on the Prescription Drug User Fee Act (PDUFA), the FDA has set an action date for the NDA of May 4, 2010.
Idiopathic pulmonary fibrosis (IPF) is a disease characterized by progressive scarring, or fibrosis, of the lungs, which leads to their deterioration and destruction. It occurs in older patients (aged 50-70 years) and has a median survival of approximately 2-5 years from diagnosis.
Pirfenidone is an orally active small molecule drug that may inhibit collagen synthesis, down regulate production of multiple cytokines and block fibroblast proliferation and stimulation in response to cytokines.
Phase II and III trials have been completed and it will be interesting to see what the FDA and it's advisory committee make of the data when they review it in a few months.
That was the key question posed by Gail Roboz during her improvised talk at the recent Greenspan Chemotherapy Foundation meeting in New York. She was standing in for Janice Gabrilove who was unfortunately sick, but managed to put together 16 mins of incredible thoughts for where things could head next in the near future with this disease.
The ideas Dr Roboz expressed gave me a lot of food for thought, so I thought I would try and summarise a brief synopsis. If you want to hear the presentation and see the slides yourself, I would highly recommend checking out the Chemotherapy Foundation website in the link above.
If we take a look at the response rates in younger AML patients, we see some very high complete responses (CR) or remissions in the 70-80% range, yet 5 year survival is only in the 30% range:
A similar trend exists in the elderly AML group, although the corresponding numbers are a dispiriting 40-50% and 10-20% for complete response and 5 year overall survival respectively.
The answer, according to Dr Roboz, lies in understanding the role of the leukemia stem cells, which are largely quiescent and not killed by conventional chemotherapy. They persist after treatment and probably most likely to be responsible for or involved in relapse.
Currently, there are no standard post remission therapies in AML. Options include chemotherapy consolidation and allogeneic stem cell transplantation (SCT). However, what is surprising is that minimal residual disease (MRD) evaluation and maintenance strategies showing a survival benefit are standard in ALL, but not AML.
Given the poor results seen with maintenance chemotherapy in AML, Dr Roboz suggested it was time for a change in approach. She noted that many targeted drugs with good science but do not work alone in active AML could be considered for maintenance therapies in CR, via clinical trials to determine their effectiveness. These agents include the following:
In conclusion, her recommendations to try new ideas and novel approaches to the treatment of AML looks at ways of keeping the patients who achieve a complete response in remission for longer, thereby impacting the overall survival. The suggestions for personalised treatment of AML included the following:
Given that this was an impromptu presentation at very short notice, it was very well thought through and delivered. In fact, I would go so far as to say it was the one presentation that had the most vivid impact on me from the meeting, and there were many good ones over the course of four days.
Sometimes, we learn more and perhaps can see a better vision or approach when when someone articulates the issues and focuses on some new areas for consideration. I wish more researchers thought strategically like this!
I'm looking forward to seeing some Pharma companies consider the idea of targeted therapies taken as maintenance therapies in patient with AML who have achieved complete remission. If we can impact the 5 year survival rate for the better, that would be a wonderful thing indeed.
At the AACR molecular targeting meeting in Boston, several key presentations have focused on lessons learned from previous kinase studies and using them to help guide future developments.
Charles Sawyers from MSKCC put together a particularly nice presentation looking at the lessons learned from CML and prostate cancer. He noted that 75% of CML patients respond to imatinib and attain a complete cytogenetic response, with only a small number, 20% relapsing by 5 years. The question is why and what can be done to change this?
Firstly, the natural course of the disease predicates that mutations will occur as the cancer finds ways to re-activate BCR-ABL in order for the leukemic cells to survive. New kinase therapies in development now target not only BCR-ABL, but also the other mutations that evolve with time. Both dasatinib and nilotinib not only have different conformations than imatinib, but also inhibit most of the other mutations that have been recognised to date. However, neither targets the T315i mutation, but fortunately other compounds in R&D including AP24534, omacetaxine and others do.
Neil Shah from UCLA also made similar points in his talk and emphasised that as more therapies become available for the treatment of CML, so the ability to personalise therapy for each patient based on their particular mutation analysis now exists by choosing a kinase that is sensitive to the mutations arising. This is especially so in CML with a growing number of drugs available either commercially or through clinical trials. This is great news for patients, because this cancer was once a death sentence but is now a chronic treatable disease that can be kept under control with targeted therapies.
Hilary Calvert from University College London discussed PARP inhibitors, which target the BRCA1 and BRCA2 mutations and also potentiate the effect of some chemotherapy drugs in vivo such as temozolomide. He covered a number of these interesting agents in development, including olaparib and AG014699, and how tumour shrinkage occurs but drug resistance ultimately ensues due to intragenic deletion activity of BRCA2. Despite platinum resistance developing in ovarian cancer, however, responses to olaparib have still been seen, so much work still needs to be done in this area to figure out what resistance mechanisms are in play and what strategies can be used to overcome them. BRCA1 and BRCA2 mutations occur in both breast and ovarian cancers, so these cancers have been the primary targets for the PARP class of drug initially and represent an interesting new approach.
Kapil Bhalla from the Georgia Cancer Center described a novel new approach in breast cancer that made me stop and think. The cancer cell is always looking for ways to survive and find alternative escape routes to achieve this despite chemotherapeutic drugs targeting it's death through apoptosis. They forced the cancer cell in the mammary fat pad of mice into autophagy, and then pulled the rug away by adding an autophagy inhibitor. This was achieved by targeting heat shock response protein with panobinostat combined with an autophagy inhibitor, thus allowing apoptosis to continue instead of being inhibited.
In this novel approach, Dr Bhalla described it succintly as,
"The panobinostat accentuates stress, causes autophagy and sets up the cell to be eliminated by autophagy inhibitors."
It will be interesting to see how this approach translates into humans and if it works, we may see more autophagy inhibitors developed that are tumour specific.
AACR have launched a series of podcasts from the meeting, including one with Charles Sawyers, which you can find here and download to listen to on your MP3 player or computer. They make for very interesting listening, especially if you were unable to attend the meeting in person.
Scientists have published an interesting article in the Federation of the American Societies for Experimental Biology (FASEB).
Basically, a gene therapy vector is used to deliver a therapeutic gene or a portion of DNA into a cell nucleus similar to how a syringe is used to inject medicines. To create the new gene therapy vector, the researchers used pieces of different genes to create a protein called a "modular DNA carrier" that can be produced by bacteria. This protein carries therapeutic DNA and delivers it to a cell's nucleus, where it reprograms a cell to function properly.
In the laboratory, these carrier proteins were combined with therapeutic DNA and attached to cell membrane receptors and the nuclear import machinery of target cells. The packaged DNA moved into the cell through the cytoplasm and into the nucleus.
Applications for this approach include inherited genetic diseases, which tend to respond well to gene therapy. This new approach may lead to more a more efficient and effective delivery mechanism by borrowing from the vector approach that uses the same machinery that viruses use to transport their cargo into our cells.
Glover, D., Ng, S., Mechler, A., Martin, L., & Jans, D. (2009). Multifunctional protein nanocarriers for targeted nuclear gene delivery in nondividing cells The FASEB Journal, 23 (9), 2996-3006 DOI: 10.1096/fj.09-131425
A recent paper published in the Proceedings of the National Academy of Sciences by scientists from the University of Rome has shown that the administration of nerve growth factor (NGF) stabilizes or reduces the damage to the optic nerve caused by the raised intra-ocular pressure (IOP) associated with glaucoma.
Glaucoma is an eye disease that is the world’s leading cause of blindness affecting 77 million people around the world and causes irreversible damage to vision. An easy to use eye drop that stabilizes or reduces damage to retinal ganglion cells and the optic nerve cells offers exciting potential and is research that will be watched closely by companies with an ophthalmology portfolio.
NGF was discovered by Stanley Cohen and Rita Levi-Montalcini, who received the 1986 Nobel Prize in Physiology. NGF may have a neuroprotective and repair function within the body, which could explain its ability to stabilize nerve damage caused by raised IOP.
In the paper published by Bonini and Levi-Monalcini they administered eye drops with NGF to rats and three human subjects. This caused an reduction in retinal ganglion cell death in the rats, and the patients who received NGF had improvements in their visual field and visual acuity.
The data is extremely promising, but in view of the small subject numbers and the fact that rat models do not always translate into humans, more extensive clinical trials data are needed to validate it as a potential new treatment.
Hopefully more data will be available for presentation at the ARVO (Association for Research in Vision and Ophthalmology) annual meeting in May next year.
Lambiase, A., Aloe, L., Centofanti, M., Parisi, V., Mantelli, F., Colafrancesco, V., Manni, G., Bucci, M., Bonini, S., & Levi-Montalcini, R. (2009). Experimental and clinical evidence of neuroprotection by nerve growth factor eye drops: Implications for glaucoma Proceedings of the National Academy of Sciences DOI: 10.1073/pnas.0906678106
Twitter is turning out to be a fantastic resource for science and oncology information, if you follow the right people.
@jackmctique sent me this link to a video about how human embryonic stem cells (hESC) could kill cancer cells in a variety of mouse models. I was awestruck. This is the sort of exciting news you live to hear about as a life scientist.
Check out the simple video for yourself - it's exceedingly easy to follow:
@alexey will be delighted to hear that this vignette has motivated me to research the topic more and is overcoming some of my slight scepticism about whether cell therapies will have any practical utility in cancer treatments.
I'm sure there is some other useful stuff out there on this topic, so time to do some research when I have a few spare moments.
I'm now wondering how long it will be before we some of this new technology reach the clinic?
After recently writing about Dendreon's Provenge and other prostate cancer drugs, the long awaited survival data has finally been revealed in a late breaking abstract at the American Urological Association.
Unfortunately, when I tried to access the abstract online, the sign-up form said it would take several days for someone to get back to me. Huh? Obviously they have a ways to go in communicating data compared to their efficient brethen at ASH and ASCO, who allow guests, patients and interested parties to sign in and freely read the abstracts from the meetings.
The snapshot of the data is therefore summarised here courtesy of Forbes, Dendreon's press release and the WSJ app on my iPhone (the website will frustratingly only give you the first paragraph or so).
Essentially, Provenge prolonged the lives of men with advanced prostate cancer who had failed hormone therapy and were not responding to treatment with hormonal therapy. Taxotere was previously approved after failure of hormone therapy with improved survival by 3 months over placebo and a response rate of approx. 18%. Provenge extended life by 4.1 months in previously pre-treated patients (25.8 vs. 21.7 months), a statistically significant result (P<0.032).
However, the trial design makes it difficult to compare whether Provenge exerted any effect over Taxotere alone. Therapy was started with either
with placebo or Provenge. As soon as tumours grew, men on placebo
got a frozen version of Provenge, followed by Taxotere. Those who started on Provenge also got Taxotere
when they stopped responding to initial treatment. There was no Taxotere only arm to determine the incremental effect of Provenge, as might be expected. Therein lies the rub for ODAC and the FDA.
In 2007, the FDA declined to approve the vaccine, preferring to wait for survival confirmation from the 512 patient IMPACT study presented today. Those discussions led to a target of a reduction in risk of death by 22%. The IMPACT data just squeaked in at 22.5%. There is no guarentee that approval for Provenge will be a dead cert given the marginal improvement, unconventional trial design and likely exhorbitant price.
The main advantage of Dendreon's Provenge over chemotherapy is better tolerability, since the most common side effect was flu-like symptoms but not heightened stroke or cerebrovascular events, whereas Taxotere can cause severe myelosuppression, fatigue and occasionally, febrile neutropenia.
The next six months will be interesting as a) Dendreon can expect to file with the FDA later this year and b) ODAC can give biotech companies with fuzzy trial designs a run for their money; remember GPC/Spectrum and satraplatin? I'd sure love to be a fly on the wall for the Dendreon ODAC meeting...
Disclosure: To avoid confusion, I should add that while I don't normally tend to post immediate news about drugs or pharma on this blog, my particular interest stems from having lost a dear father to the disease 9 years ago. It is my hope that one day others will have a better opportunity for an improved quality of life after being diagnosed with advanced cancer. Most advances are inevitably incremental, rather than being a lengthy improvement in quality of life and survival, as Gleevec was for CML patients. As for Dendreon's Provenge, I'm not sure that flu-like symptoms and a high price tag will be the panacea that many patients and their families were hoping for :(
This blog is published by: Sally Church, PhD of Icarus Consultants, Inc. The contents of this blog are the intellectual property of the author and all rights are reserved. No commercial use, copying or distribution is permitted without the author's express permission.
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