Beautiful
Perhaps one of the most beautiful articles I’ve ever read on the internet:
“We all — in the end — die in medias res. In the middle of a story. Of many stories.”
You might want to have some tissues handy before reading.
Pharma Strategy Blog feed is back up
Last week’s post on ovarian cancer caused the blog feed that drives RSS, email alerts and the Kindle to fall over, apologies to all for that inconvenience! A stray and errant dot in one of the P values appears to have been the culprit for some strange reason.
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Update on MEK and AKT inhibition in RAS driven cancers
A couple of interesting developments have emerged over the last week with AKT and MEK inhibitors, specifically Merck’s MK-2206 and AstraZeneca/Array’s AZD6244, that are well worth discussing.
- At the ECCO/EMCC meeting in Stockholm last Tuesday, Johann De Bono discussed the combination data for MK-2206 and AZD6244 in KRAS driven colorectal cancer.
- Later the same week, Array Biopharma announced the initial results from a randomized phase II placebo-controlled study that compared the efficacy of selumetinib (AZD6244/ARRY-886) in combination with docetaxel compared to docetaxel alone in the second-line treatment of patients (n=87) with KRAS-mutant, locally advanced or metastatic non-small cell lung cancer (NSCLC).
Now, to be clear, I like the concept of AKT and MEK inhibitors, especially in select combinations, but the key thing here is the right combinations in the right context.
Let’s take a look at the lung cancer KRAS data first. One of the challenges I have with this approach, is that we’ve know for a while that BRAF and KRAS driven cancers behave rather differently according to Wee et al., (2009):
“Previous studies have found that whereas BRAF mutant cancers are highly sensitive to MEK inhibition, RAS mutant cancers exhibit a more variable response.”
Variable response is not an encouraging phrase when planning clinical trials!
Let’s take a look at the pathway itself:
We can immediately see that MEK is downstream of RAS, meaning that even if we target MEK, unfortunately RAS and KRAS is still largely untouched upstream. This is important to remember when considering the actual results later.
The other key factor to consider is what are the adaptive resistance pathways that might evolve as a result of treatment with a MEK inhibitor? In an ideal world, logical combinations would be tested that target both the primary driving mutation or aberration, as well as the adaptive resistance, to try and shut down the pathway more completely than targeting either alone. Another key question that needs to be addressed is what is driving the KRAS aberrant activity in the first place?
We’ve discussed MEK numerous times here on PSB, but the Wee et al., (2009) MEK paper stands out in particular. They identified a critical resistance pathway to MEK inhibition, namely PI3K. Although we discussed this originally in the context of BRAF driven tumours such as melanoma, it is well worth discussing again here in regards to KRAS driven tumours given a MEK inhibitor is being tested.
They observed that:
“Activating mutations in PIK3CA reduce the sensitivity to MEK inhibition, whereas PTEN mutations seem to cause complete resistance.”
It isn’t clear from the Array press release whether any of the patients with NSCLC exhibited PIK3CA mutations or loss of PTEN, but they definiely do occur in this disease. It will be interesting to see of more meta data is available at the forthcoming AACR Molecular Targets meeting next month.
I’m not a big fan of chemotherapy plus a single targeted agent, because as you can see from the evidence above, the pathway is not being shut down by one targeted agent and resistance is not being addressed at all. The chances of such a combination working (by that I mean increasing overall survival), I think would be fairly low.
According to the press release, the study did not see a significant improvement in overall survival (OS) but did show an encouraging response in the form of progression free survival (PFS):
“The key secondary endpoints of progression-free survival, objective response rate, and alive and progression-free at 6 months were all demonstrated with statistical significance, showing improvement in favor of selumetinib in combination with docetaxel versus docetaxel alone.”
Indeed, at the recent AACR and ASCO meetings, there was also some encouraging early signs from Genentech’s PI3K inhibitor, GDC-0941, as a single targeted agent with chemotherapy in NSCLC (a very small early trial), albeit not KRAS specific, but defined more broadly by squamous and non-squamous histology. Thus, all is not lost with the MEK agent yet – if we combined MEK and PI3K inhibitors in NSCLC patients previously treated with chemotherapy, we might have a better chance of succeeding and shutting down the pathway, based on evidence offered from Wee et al’s preclinical research:
“At the molecular level, the dual inhibition of both pathways seems to be required for complete inhibition of the downstream mammalian target of rapamycin effector pathway and results in the induction of cell death.”
As a result, they went onto to suggest a logical treatment approach:
“Our study provides molecular insights that help explain the heterogeneous response of KRAS mutant cancers to MEK pathway inhibition and presents a strong rationale for the clinical testing of combination MEK and PI3K targeted therapies.”
Of course, clinical trials like this always progress incrementally, such that we test a MEK or a PI3K inhibitor alone to determine safety and efficacy activity, then perhaps in combination, which requires another phase I dose finding study to determine the ideal dosages and whether they are too toxic or not combined.
So while either single agent targeted therapy with chemotherapy in and of itself is not a win, there are signs that combining the two may be more appropriate. I would still want to know what is driving the KRAS activity though, given MEK and PI3K are downstream of it. It is entirely possible that a third agent would be needed to shut down the pathway more completely in that patient subset.
At ECCO, De Bono (Royal Marsden) discussed the combination of AstraZeneca’s MEK inhibitor (AZD6244) and Merck’s AKT inhibitor (MK-2206) in RAS mutant colorectal (CRC) and lung (NSCLC) cancers. The results here were not a big win in the former, with 8/15 patients showing no antitumour activity to date.
There are several things we can conclude from the initial data:
- If we have the right combination for the right target in the right patient subset, then the therapeutic index of the agents is lacking and we need better drugs
- Are the targets (AKT and MEK) critical?
- Is something else driving the KRAS activity (see below)*?
- Are we shutting down the adaptive resistance pathways (escape routes?)
- Which patient subsets are most likely to respond and how do we best characterise them (ie need more biomarker data)?
And so on… there are always more questions than answers sometimes.
- * Note: This situation could well be similar to BRAF in malignant melanoma, where it is the V600E mutation that is driving the BRAF activity, thus specifically targeting ithe mutation rather than the kinase will have a greater clinical effect than targeting BRAF broadly. In this case, if we really believe KRAS is critical to the lung or colorectal tumour’s survival, then we need to figure out what is driving it before progress is made. Frank McCormick’s elegantly simple wac-a-mole concept for pathway inhibition is very apt here!
No doubt we will see more detailed data and an update soon, perhaps even at the forthcoming AACR Molecular Targets meeting next month.
References:
Wee, S., Jagani, Z., Xiang, K., Loo, A., Dorsch, M., Yao, Y., Sellers, W., Lengauer, C., & Stegmeier, F. (2009). PI3K Pathway Activation Mediates Resistance to MEK Inhibitors in KRAS Mutant Cancers Cancer Research, 69 (10), 4286-4293 DOI: 10.1158/0008-5472.CAN-08-4765
An in-depth review of the Phase II T-DM1 data in first-line metastatic breast cancer
The other day I highighted the phase II data from the T-DM1 (trastuzumab emtansine) trial as one of my top four abstracts at the ECCO European Multidisciplinary Cancer Conference (#emcc2011) in Stockholm.
For those of you interested in ADC technology, I wrote about the fascinating concept previously, if you want to check it out.
I think T-DM1 is a really exciting development for several reasons, so let’s take a look at the study in more detail.
- T-DM1 is an antibody drug conjugate (ADC), which combines the trastuzumab monoclonal antibody with a cytotoxic agent, maytansine, via a linker. This new molecule is stable and allows the structure to hold together until it reaches the cancer cells, wherein the chemotherapy is released in a much more targeted fashion than giving chemotherapy and Herceptin as separate drugs by infusion. With the traditional approach, it means that the chemotherapy will target normal cells as well as cancer cells, leading to significant side effects, including cardiotoxicity.
- ADC technology is designed to allow the combination to be delievered more specifically to the tumour, while also potentially reducing the side effects for patients.
- In this study (TDM4450g), T-DM1 was compared with the standard of care, trastuzumab (Herceptin) plus docetaxel in women with HER2+ metastatic breast cancer who had been previously untreated ie first-line therapy.
- It should be noted that maytansine is a very powerful cytotoxic that was originally seen as too toxic when given by traditional infusion. Combining it as an ADC therapy, however, reduces some of the associated adverse events since it can now given in a more localised fashion where it is most needed, ie in the tumour itself.
One of the challenges with the T-DM1 trial, though, as Martine Piccard, the Discussant correctly pointed out, is the open label design. One must be careful in interpreting data from them, as Kaufman et al., (2007) observed:
“Placebo controlled, double-blind trials can reduce bias when efficacy is studied. Open label designs can falsely suggest efficacy and fail to uncover harmful effects. Placebo controlled trials are considered ethical when there is no standard treatment better than placebo, and when participants are informed about the use of a placebo.”1
Unless a trial is blinded, we can never completely be sure the patients weren’t selected to either arm without bias, even if unconscious. Now, I’m not saying that was the case here, merely that one must be aware of both the limits and potential possibilities.
That said, my least favourite studies are open label single arm trials, but that wasn’t the case here, since half the women were randomised to receive the standard of care, ie trastuzumab plus docetaxel, making it a good comparison to see if any improvement can be attained. However, a double blind placebo controlled (in place of docetaxel) randomized trial is always a more reassuring design than an open label one.
That said, unlike pills, it is much harder to give chemotherapy blinded because the dosing is calculated as per kilogram of body weight, a dead giveaway. Thus, T-DM1 is given as 3.6 mg/kg, while the trastuzumab dose is given per 6 mg/kg, whereas docetaxel (75 or 100 mg/m2) versus placebo can clearly be be more easily blinded.
We must also remember that this is an exploratory phase II trial designed to see whether there is an efficacy signal or not. The study endpoint was PFS. Phase III trial designs are often much more robust.
What do the results show?
The proof of the pudding is ultimately in the analysis, not the theory, though.
The good news is that Dr Sara Hurvitz (UCLA) presented data that was actually much better than I expected, which is very heartening to see. Usually, in metastatic disease, where there is a very high disease burden, we sadly see increments of ~2 months or less in many investigational agents, so anything more than that is a real standout.
In the TDM4450g trial, the efficacy and tolerability results were impressive:
- Patients lived a median of five months longer without their disease worsening ie the median progression free survival (PFS) was 14.2 months vs. 9.2 months (HR=0.59, P=0.035) in favour of T-DM1 over the standard of care.
- Note: any HR under 0.60 is scarily good news – that means a huge 41% reduction in the risk of the disease worsening or death was seen.
- Overall survival had not yet been reached at the time of the presentation in the T-DM1 arm, another good sign that the data are likely to be durable.
- Women in the T-DM1 arm generally experienced fewer adverse events compared to those who received Herceptin plus chemotherapy: the rate of Grade 3 or higher adverse events was reduced by nearly half (46.4% vs. 89.4%).
- In addition, more women on Herceptin plus docetaxel discontinued therapy due to side effects compared to T-DM1 (28.8% v. 7.2%).
Here’s a snapshot of the PFS curves – you can decide for yourself what you think:
So far, so good.
However, in the interests of fair balance, there were some side effects that appeared more in the T-DM1 arm, namely:
- Thrombocytopenia (30.4% v. 6.1%)
- Increased liver enzymes such as aspartate transaminase (AST) (39.1% v. 6.1%)
The most significant adverse event for me though, was cardiotoxicity, which is a well known side effect of standard Herceptin plus docetaxel therapy. Here’s how that data looked at the time of the analysis:
As you can see, it was less in the T-DM1 arm than the standard of care, which is most encouraging.
Patient sentiments are important
I did a quick search to see what patients in the trial were saying and came across these two heartfelt posts I encourage you all to read – it will put your day into perspective. Participating in clinical trials is not a bed of roses by any stretch of the imagination and I salute these brave women in their fight:
In conclusion…
These data from the phase II T-DM1 versus trastuzumab plus docetaxel study are an excellent start, with promising efficacy and safety signals in favour of the ADC over standard of care.
The big unanswered questions are whether the overall survival (OS) will also be better (I really hope so) and whether the data is reproducible in a large scale phase III trial (ditto). We will have to wait a while to see the more extensive phase III trial results.
- Kaufman et al., (2007) Issues in SMA clinical trial design The International Coordinating Committee (ICC) for SMA Subcommittee on SMA Clinical Trial Design http://www.columbiasma.org/docs/news/Kaufmann%20Muntoni%20Trial%20Design.pdf ↩
Social media at ECCO, ESMO, EMCC Stockholm 2011
Hopefully, by the time y’all read this we have arrived here we are in Stockholm after a nighmarish week with Continental and United messing up big time with flights booked six months ago. Sometimes big corporations really fail to understand the importance of communication and customer loyalty. Eventually, it is only when there is competition, they stop and wonder why many people used the Law of Two Feet and walked. Maybe that is a subconscious metaphor for Big Pharma 🙂
Anyway, enough of all that. Let’s take a look at some of the social media tools being used at the ECCO conference this week as it seems to be an increasing trend for conference organisers to incorporate social media into their event. They have taken several forms, including downloadable apps for the schedule, subscription to talks and webcasts on iTunes or encouraging open dialogue on Twitter and Facebook amongst participants.
Two excellent examples I’ve seen this year, in terms of well organised and integrated social media tools, have been the American Association for Cancer Research (AACR) and American Urological Association (AUA). While the American Society of Clinical Oncology (ASCO) inevitably gets the largest volume of tweets by dint of its sheer size, the smaller organisations have perhaps been more aggressive and creative in developing and utilising the tools more effectively for their members.
I’m really looking forward to seeing how things have progressed in Europe at the ECCO meeting, having had a very positive experience with planning most of my schedule on their new app. You can browse the sessions by day or type and add them easily to your calendar in local time in Stockholm. They appear in my calendar as ET but adjusted for the time zone. That’s a very nice touch many forget about and so the schedule goes wonky if you download it one time zone and attend the sessions in another! It looks like that will not be a problem with this app. Excellent!
Let’s take a look at what I could find in the ECCO program.
Social Media tools at ECCO
As mentioned yesterday, the official hashtag for Twitter is #emcc2011 and you can also follow the ECCO organisation on:
They also have some slick apps accessible by links or QR codes as preferred, to enable you to search and plan your schedule from the program:
- Apple iPhone/iPad
- Android phones
Tweets will most likely gather steam on Friday with the corporate symposia kicking off, as Thursday was the travel day for many.
Meanwhile, for those interested in following the conversations, as usual, we’re curating all the conference tweets below.
What’s hot at ECCO, ESMO, EMCC in Stockholm 2011?
After a wild day yesterday once we realised Continental had mysteriously and unaccountably changed our flights to Stockholm from Weds to Weds to Thurs to Tues, it seems that Cinderella will be going to the ball after all.
European Multidisciplinary Cancer Conference (EMCC) here we come, whew!
There are a couple of sessions I’m particularly looking forward to this year:
- Presidential Symposium on Sat 25th with talks from some of the leading lights in translational research:
- Tak Mak (U Toronto) on metabolism and cancer
- Jose Baselga (MGH) on the challenges of personalised medicine
- Gordon Mills (MDACC) on the future of personalised medicine
- Various abstract highlights include:
- Update on phase II ERIVANCE data for the Hedgehog inhibitor, vismodegib, in basal cell carcinoma (see phase I data from AACR)
- Biomarkers, including VEGF-A in the bevacizumab trials and an update on KRAS
- Phase II T-DM1 (trastuzumab emtansine) data in breast cancer
- Reversing drug resistance in breast cancer (Mon 27th)
- Updated data from the phase I and III (BRIM3) studies of vemurafenib (Zelboraf) in BRAF V600E-mutation positive metastatic melanoma (will be interesting to see how this compares to the ASCO data
- Update on therapies in prostate cancer, including new phase III Alpharadin data (see Biotech Strategy Blog)
- Scientific symposia on PARP inhibitors and PI3K inhibitors (both on Tues 28th). I’m gutted these two important sessions clash, as they are both key events I’d love to attend 🙁
All in all, it promises to be a fun and interesting meeting. For those interested, here’s the link to the full details of the EMCC programme.
Social media comes to ECCO
The official Twitter hashtag of the meeting is #emcc2011, a bit long I know, and I would much rather have the shorter, more descriptive and well known #ECCO or #ESMO, but it is a three organisation event afterall, with ECCO, ESMO and ESTRO all involved. You can also follow the EMCC conference organisers on Twitter (@EuropeanCancer).
This inevitably creates branding issues given it seems everyone in the industry has been seemingly asking me over the last two weeks if I’m going to ECCO or ESMO in equal measures! None outside of Twitter have mentioned EMCC at all. Ah well.
Using folate receptor alpha fluorescence imaging in ovarian cancer
The other day an interesting paper came to my attention entitled:
“Intraoperative tumor-specific fluorescence imaging in ovarian cancer by folate receptor-α targeting: first in-human results”
Thanks to my translational research friend Angela Alexander for highlighting it!
The idea behind this concept is that fluorescence technology can be used to help guide ovarian cancer surgery more effectively, since the tumours tend to be small and hard to see for surgeons performing the excision:
“Tumor-specific intraoperative fluorescence imaging may improve staging and debulking efforts in cytoreductive surgery and thereby improve prognosis.”
Folate receptor-α as a tool for imaging originally came from an understanding of the biology of the disease:
“The overexpression of folate receptor-α (FR-α) in 90–95% of epithelial ovarian cancers prompted the investigation of intraoperative tumor-specific fluorescence imaging in ovarian cancer surgery using an FR-α–targeted fluorescent agent.”
This marker (FR-α) be easily detected either on tumour cells in ascites fluid or on tumor tissue obtained during staging laparoscopy or primary surgery.
What did the results show?
“In this limited series, we showed that the use of intraoperative tumor-specific fluorescence imaging of the systemically administered FR-α–targeted agent folate-FITC offers specific and sensitive real-time identification of tumor tissue during surgery in patients with ovarian cancer and the presence of FR-α–positive tumors.”
It was also encouraging to see further validity is also provided by negative results:
“One patient presented with a malignant tumor that did not express FR-α, and consequently, no fluorescence was detected.”
What do these results mean?
I think van Dam et al., (2011) encapsulated the significance of the imaging test nicely:
“The use of targeted fluorescent agents could provide a paradigm shift in surgical imaging as it allows an engineered approach to improving tumor staging and the technique of cytoreductive surgery and thereby improving the outcome in ovarian cancer.”
There are potential applications too associated with clinical research too, since Morphotek/Eisai are investigating farletuzumab, a humanized IgG1 antibody that targets folate receptor alpha in ovarian and other cancers. Using this imaging technique could be used to determine the drugs effectiveness in reducing the tumour in patients in a non-invasive fashion.
Of course, the initial trials are being undertaken in the metastatic setting, but if successful, I could see a role for the agent developing in neoadjuvant disease to shrink the tumour margins prior to surgery. Having an appropriate marker test, coupled with a valid imaging technique could well lead to improvements in survival down the line.
Overall, folate receptor-α could well be an interesting new development to watch out for over the next couple of years as data from the imagining and drug trials mature.
References:
van Dam, G., Themelis, G., Crane, L., Harlaar, N., Pleijhuis, R., Kelder, W., Sarantopoulos, A., de Jong, J., Arts, H., van der Zee, A., Bart, J., Low, P., & Ntziachristos, V. (2011). Intraoperative tumor-specific fluorescence imaging in ovarian cancer by folate receptor-α targeting: first in-human results Nature Medicine DOI: 10.1038/nm.2472
New developments in the biology pancreatic cancer
At the American Association for Cancer Research (AACR) Second Frontiers in Basic Cancer Research Conference this week, two interesting presentations on pancreatic cancer caught my eye. It has long been my belief that we will see no major breakthroughs for this devastating disease until our understanding of the biology advances.
Here’s a quick snapshot of each one:
EGFR Essential for the Development of Pancreatic Cancer
Barbara M. Gruener, a researcher at the Technical University in Munich, Germany stated that,1
“Originally, we wanted to characterize the known role of EGFR in pancreatic cancer to a higher extent so that EGFR targeted therapy could be more individualized.”
However, sometimes serendipity intervenes and some useful, unexpected, nuggets are revealed. In this case, she presented compelling evidence that demonstrated that:
- Despite KRAS, lack of EGFR blocks pancreatic cancer development
- EGFR plays an “unappreciated” central role early in the carcinogenic process
Now, while we know the mutation of the KRAS gene is an important factor in the development of many cancers, including pancreatic cancer, Gruener’s results suggests that despite the presence of KRAS, the development of preneoplastic precursor lesions and pancreatic ductal adenocarcinoma is blocked without the EGF receptor:
“EGFR seems to be involved in the early transdifferentiation processes of the pancreas in vivo and in vitro.”
What does this research mean in practice?
Firstly, these results were a surprise:
“With oncogenic active KRAS, you would expect that the lack of a receptor that is upstream of the KRAS signaling pathway does not impair the carcinogenic effects of KRAS almost completely.”
To me, the data strongly suggests that EGFR therapy might be a logical approach for early pancreatic cancer treatment than is currently undertaken, i.e. for advanced metastatic disease, when the tumor burden is much higher. Obviously, some clinical data will be needed to support and validate the preclinical findings, but this at least offers some pointers where we might start.
Virus Shows Promise for Imaging and Treating Pancreatic Cancer
The second abstract that really appealed to me was from Dana Haddad (MSKCC), who talked about the potential for an oncoloytic virus in pancreatic cancer 2
I confess that my first reaction was a little sceptical, as vaccines and viruses have yet to show dramatic activity in solid tumours, never mind a difficult to treat one such as pancreatic cancer. That said, let’s take a look at Dr Haddad’s research in detail.
First of all, she specified what an oncolytic virus actually is and what it does:
“Defined as viruses that selectively replicate in cancer cells with consequent direct destruction via cell lysis.
Leaves non-cancerous tissue unharmed.”
So a targeted approach, rather than a broad non-specific effect (I’m warming up already!)
One of the challenges though, is that biopsy is currently the gold standard for monitoring viral therapy in clinical trials, but these repeated biopsies are invasive and often difficult. There is therefore a need for new and improved methods for:
- non-invasive monitoring
- real time assessment of response to therapy
- monitoring of potential viral toxicity
Haddad et al., looked at the feasibility of systemic virotherapy, together with monitoring radiotherapeutic response of pancreatic cancer xenografts treated with a vaccinia virus encoding the human sodium iodide symporter (hNIS), GLV-1h153.
hNIS is a cell surface protein that mediates transport of iodine mainly in thyroid gland. The value of this approach is that it has:
- imaging potential by using several carrier free radionuclide probes
- therapeutic potential by combining radioiodine with viral therapy
GLV-1h153 was injected systemically or intratumorally into pancreatic cancer xenografts in nude mice and 124I-positron emissions tomography (PET) was used image tumors.
The results clearly showed that:
- PET signal intensity correlated with antitumor response
- Colonization of tumors with GLV-1h153 facilitated uptake of radioiodine at potentially therapeutic doses
- Combining GLV-1h153 with 131I led to enhanced tumor kill compared to either treatment alone
What do these findings mean in practice?
Dr Haddad summarized this nicely:
“It has been shown, for the first time, that vaccinia virus construct GLV-1h153 facilitates:
non-invasive long-term deep tissue monitoring of viral therapy, monitoring of tumor therapeutic response,
potential for targeted radiotherapy.”
She also went on to suggest that:
“GLV-1h153 can be directly translated to human clinical trials:
parent virus already in phase I clinical trials,
radiotracers and imaging modalities FDA approved.”
I think that we will see more clinical research evolve on GLV-1h153, since it appears to be a promising oncolytic agent, based on the data thus far. That’s good news for the San Diego biotech company, Genelux Corporation, who were involved with this oncolytic research. It’s still very early days, but the data looks promising enough to pursue clinical trials in humans further. A phase I trial has recently been completed by the Royal Marsden Cancer Centre in the UK, with preliminary data presented at ASCO earlier this year.
Can monoclonal antibodies target oncoproteins directly in the cancer cell?
This week a fascinating paper appeared in one of my favorite journals, Science Translational Medicine. Until now, it had been assumed that antibodies only bind to proteins found on the cancer cell surface, largely because of the size of the molecules:
“Because antibodies are viewed as too large to access intracellular locations, antibody therapy has traditionally targeted extracellular or secreted proteins expressed by cancer cells.”
Not so fast!
Guo et al., (2011) have now demonstrated that proteins hidden within cells can be attacked by antibodies as well.
This paper is first to report that antibodies can actually directly target intracellular oncoproteins such PRL-3 that reside within cancer cells, thereby suppressing cancer growth:
“As proofs of concept, we selected three representative intracellular proteins as immunogens for tumor vaccine studies: PRL-3 (phosphatase of regenerating liver 3), a cancer-associated phosphatase; EGFP (enhanced green fluorescent protein), a general reporter; and mT (polyomavirus middle T), the polyomavirus middle T oncoprotein.
A variety of tumors that expressed these intracellular proteins were clearly inhibited by their respective exogenous antibodies or by antigen-induced host antibodies (vaccination).”
In plain English, the data clearly showed that the antibodies induced tumour regression in mice.
What fascinated me was that the tumour regression depended on the presence of immune B cells, which are responsible for antibody production, potentially by improving entry of the antibodies into the tumor cell. Vaccination with the intracellular proteins spurred production of specific antibodies by the host, which also led to tumour regression.
What are the potential mechanisms involved in the therapeutic antibody effect?
Guo et al., (2011) suggested several possibilities:
- A small fraction of intracellular antigens may be released due to necrosis or cancer cell lysis.
- Some intracellular antigens may be externalized and displayed on the surface of cancer cells by unconventional secretion.
- Binding of antibodies to surface-exposed intracellular proteins may then trigger immune responses such as ADCC to destroy the cancer cells.
- Antibodies could be taken up by the cancer cells in an antigen-specific manner.
- Complement-mediated events may also be involved.
In other words, it could be highly complex with several factors involved. These will no doubt be studied further to elucidate the mechanisms more precisely.
What are the implications of this research?
Remember – tumours targeted with unrelated antibodies usually produce no beneficial response – which was also seen in this research.
Overall, I think if the concept of targeting targeting intracellular oncoproteins with antibody therapy or vaccination were to be reproducible in human research, then new, highly specific cancer targets may well emerge in clinical trials, much in the same way the HER2 protein was used as a highly specific target for a subset of breast cancer patients.
In order to have higher response rates from cancer therapeutics, we need to have better, more specific targets than we currently see in the clinic. I’ll be following this development to see where it goes, whether new translational research and also specific monoclonal antibodies will emerge, as a result of these findings from the basic research.
It might take a little while, but that would be great news for cancer patients.
References:
Guo, K., Li, J., Tang, J., Tan, C., Hong, C., Al-Aidaroos, A., Varghese, L., Huang, C., & Zeng, Q. (2011). Targeting Intracellular Oncoproteins with Antibody Therapy or Vaccination Science Translational Medicine, 3 (99), 99-99 DOI: 10.1126/scitranslmed.3002296
iPad apps for science and medicine
One of the nicest things about about going to scientific meetings is that you get to meet interesting people. Instead of swapping cards and going about your way, in the modern world social media allows you to stay in touch more frequently personally while sharing cancer and scientific information over time. The discussions can be very insightful and enriching.
Two recent PhDs from MD Anderson Cancer Center (MDACC), Drs Angela Alexander and Jeannine Garnett are two of those research scientists I met while at cancer meetings and now keep in touch with – congratulations on your well earned doctorates this summer, ladies!
Angela recently started a nice blog The Cancer Geek and posted an extensive review of how she uses her iPad during the day, including a summary of some of her favourite apps. Check it out, it’s well worth reading!
Funnily enough, I use many of the same apps and a few different ones too. Not surprisingly, our workflow is a little different, given the diversity of things we’re both involved with. Since there’s no active bench research here at Icarus, there’s no need to order supplies. However, I thought for fun it would be a idea to take a leaf out of Angela’s book and take look at what’s on my iPad and how I use it. Here’s my home screen:
After much trial and error, I decided to keep the top most used apps on the main screen (they do change over time with usage and circumstances eg the ESPN Fantasy Football app disappears when the season is over) and organise all the other less used ones into folders in a library screen. On the other two screens I dragged and dropped things into folders such as tools, productivity, books, audio etc and use Search on the home screen to find things quickly like this:
This is much more productive than scrolling through looking for the app you need in a multitude of folders. The app usually comes up in the list after 2-3 letters are typed. Some basic caveats – at home or in the office the iPad is mainly used as a consumption devise to browse (on Safari or Atomic), read (iBooks, Goodreader, AACR Journals), check RSS and blog feeds (BW RSS, Feedly, Reeder), see what hot in Twitter (Echofon and Flipboard) or listen (iPod or Spotify for music, Science podcasts, AACR Webcasts app, Instacast for podcasts such as one of my favourites, MacPowerUsers).
The reason for focus on consumption over creation is that the desktop and laptop are much more powerful and heavy duty for content creation. However, there are some cool tools for capturing drawings and scribbles such as Penultimate and Listary, which is excellent for syncing a quick To-Do list between the iPad and iPhone.
On the road though, the iPad becomes a very nifty and efficient creation tool that fits my workflow at scientific congresses nicely. Yes, I have taken just the iPad to conferences and left the laptop behind without much difficulty. That was liberating!
There are some nifty productivity To Do apps out there such as Things and OmniFocus (I prefer the latter) in addition to password security, which I highly recommend in case your iPad goes missing – 1Password is my personal favourite.
One important point to note – I truly detest the shackles of Microsoft Office and have never been a big fan of the bloatware it has become. Years ago, while doing my PhD, the Physiology unit started migrating from WordPerfect, with its fast keyboard shortcuts and better graphic integration tools, to Word. The constant fiddling with autochanges to formatting, size and scaling drove me potty then and I still scowl if I have to use any of the apps with the exception of Excel, although the simplicity of Lotus 1-2-3 and its macros and keyboard slashkeys is a happy memory to this day.
PC and Windows users are very much stuck in the world of files organised into folders, but many Mac tools and the iPad in particular don’t work this way, so the thinking behind it is rather different. Think cloud apps and sync through Dropbox or searching for things based on Tagging, much in the same way that other apps such as Gmail, various text editors and Evernote work. This is the way of the future for many and is a much more efficient way to find and store data.
With this in mind, most of my writing (and I do a lot of it as a consultant and blogger) is done in plain text – simple, elegant and infinitely more useful. It took me a while to settle down with one system, but now I’m very happy with Simplenote on the iPad, iPhone or desktop and Notational Velocity Alt (nvALT) on the desktop. They sync beautifully together once you enter your username/password. This guarantees a natural backup will always be there. Some of the data is also synced to Dropbox.
Surprisingly, I now have thousands of blog posts, snippets, text and notes accrued in this handy text sync system. While walking around at cancer meetings, I take quick notes of interesting things from the posters or add quotes from chats with presenters straight into Simplenote on the iPad. For oral presentations, these go much faster than my typing skills allow, so I write long hand in my Moleskine and add notes manually in a quiet moment later so that they become searchable and re-usable.
John Gruber’s awesome Markdown syntax (discussed in Daring Fireball) and Fletcher Penny’s Multimarkdown are tools I make use of a lot, especially as conversion tools allows me to preview the text and then convert it to html for cutting and pasting into WordPress, the platform used for this blog. Text Expander Touch on the iPad uses the same master shortcut file as the desktop/laptop versions and makes repetitive typing of various tumour types, for example, so much faster!
Text or RTF files created in apps on the iPad can be synced via Dropbox for later use and aggregation in various desktop apps. I save Markdown notes and snippets as text files in Simplenote or Elements and once on a laptop, drag them to Marked, a cocoa desktop app from Brett Terpestra to preview and convert into html for blog posts or text for reports.
Scrivener is my Word Processor of choice these days, not Word, because it is simply superb for technical research and writing. I can’t wait for the makers to come out with an iPad app! For now, I use different creating tools on the iPad since Scrivener supports a host of different inputs from TXT or RTF files that have been created on the iPad, whether from Simplenote, Index Cards (great for creating an outline), iThoughtsHD (a mind map tool) or Evernote, where I clip and store interesting websites.
Creating short and long form articles, posts and reports is really easy and much faster in Scrivener when you are focusing on the content and not the formatting. Since the export function is very versatile, you can also create different documents formatted as PDFs, LaTeX or epub format (for the Kindle), whichever you choose to apply. Overall, I have found this tool to be extremely versatile and saves me a lot of time.
Other iPad apps I enjoy using include iKinase, which provides a handy tool for finding protein and chemical structures for small molecules and Molecules, which shows 3D molecular structures that you can manipulate with your fingers – very cool.
When travelling, I love the TripIt app for keeping me straight on flight and hotel details, which it picks up from emails sent to my business account and creates itineraries automatically. On the road, though, I tend to use the iPhone more than the iPad for viewing the details as it is smaller and more mobile while waiting at a taxi line. The maps produced from the destination are useful for finding your way around or telling the cab driver where to go!
Another app I have on both my iPhone and iPad are QR code readers but the reality is that it’s much easier to get the code from an iPhone, especially if the code is awkwardly placed on a poster.
Need an app for curating your expenses on the road? iXpenseIt is useful for tracking cash receipts rather than losing or forgetting about them. Many banks also now have iPhone and iPad apps that are worth checking out for scanning checks and checking expenses.
Wondering what one of my favourite apps is? Try the Howard Hughes Medical Institute (HHMI) quarterly bulletin – a truly beautiful combination of art and science that is a pleasure to read. Reading medical journals on the iPad is also a delight – I read Nature, NEJM and AACR journals regularly on the iPad and download articles as PDFs for easy reading offline while travelling in iBooks.
Overall, I love my iPad as a consumption tool and travel with it regularly to cancer conferences along with my Moleskine and also a laptop for more heavy duty work. There is something about the iPad that makes it hard to put down.