Prostate Cancer | Pharma Strategy Blog

ASCO GU Symposium 2011

By MaverickNY on February 16, 2011

Today, I’ll be heading off to Orlando to the Genito-Urinary Cancer meeting co-hosted by ASCO, ASTRO and SUO and runs through Saturday. This year promises to have some interesting data coming out on a variety of cancers, including renal cell and prostate cancers.

The official hashtag is #gusymposium, which is unfortunately rather long, when you consider there are only 140 characters for a tweet and medical meetings tend to contain a lot of complex information to parse on the fly. Like many, I’ll be using #ascoGU, which is much simpler and shorter when tweeting in a hurry. The widget below captures both to make following remotely easier.

If you have any questions, do tweet me @maverickny and I’ll do my best to answer them. ASCO also have a Twitter handle (@asco) if anyone has any logistics queries.

Update on PARP inhibitors including olaparib, iniparib and veliparib

By MaverickNY on January 28, 2011

Now that the dust has settled on the news from sanofi-aventis yesterday that iniparib did not achieve it’s primary survival endpoints in the phase III trial in newly diagnosed triple negative breast cancer (TNBC), it’s time to take stock of this class.

Yesterday was another major snow shovelling day in New Jersey so I missed the AstraZeneca year end conference call. A Pharma Strategy Blog reader kindly filled me in with some relevant information – the company discontinued the development of their PARP inhibitor, olaparib, in BRCA breast cancer – scroll down to the discontinued section to see the note.

Our source also listened to the Q+A and in response to questions on olaparib from the analysts, Martin Mackay, the Head of R&D observed that:

“We decided to focus on serious ovarian cancer, and really focus our attention to that in the first instance and wait to see how those results play out in Phase III. Then we’ll revisit… breast cancer.”

This raises some interesting questions about PARP inhibitors in general.

Yesterday, we noted the fine line that needs to be trod between potency/efficacy and tolerability. Last ASCO we saw how challenging it was to manage the toxicities with olaparib in combination with chemotherapy. Iniparib doesn’t appear to add to the adverse event profile in combination, but missed its efficacy endpoints.

Meanwhile, Abbott’s PARP inhibitor, veliparib, is being tested in the I-SPY breast cancer trial, so while it will be a while before we see any data, it will be interesting to see how it pans out given that it is also more potent than iniparib. Pfizer, BMS and Merck are also potential players in the PARP class, but their inhibitors are in earlier stage development. Based on the latest news with iniparib and olaparib it will be fascinating to see what they decide to do.

The latest developments in triple negative breast cancer also raise other critical issues:

Was the olaparib decision based on toxicities, lack of efficacy or being behind iniparib, since they recently announced their phase II results?
How will neliparib fare in the neoadjuvant setting and what toxicities might be expected?
TNBC are mainly basal cell histology so many will also be BRCA1 or 2 positive – did these women do better in the olaparib trial?
Will the Pfizer and Merck compounds have a better risk:benefit profile?
What biomarkers will emerge to indicate subsets or predict response to therapy?
If (5) does evolve, how will this develop from a diagnostics perspective?
What will happen in ovarian, lung and prostate cancers, all of which have a very small proportion of people who have the BRCA1 or 2 mutation.

The current situation with iniparib and olaparib raises more questions than answers, so it will be interesting to see what learnings emerge from the data and whether the once promising class is salvageable or dead.

All in all, 2011 is turning out to be an interesting year and we have yet to get past January.

10 Comments

Update on circulating tumor cells in colorectal cancer

By MaverickNY on December 28, 2010

Earlier this year we discussed some interesting papers on circulating tumour cells (CTC’s) in prostate cancer and how they are becoming a potentially useful surrogate marker in clinical trials for other cancers including lung cancer.

I was therefore intriqued to see another paper looking at the role of CTC’s in colorectal cancer (CRC) – see link below in the reference section at end of the article:

“Circulating tumour cells early predict progression-free and overall survival in advanced colorectal cancer patients treated with chemotherapy and targeted agents”

One of the challenges with some targeted therapies such as bevacizumab (Avastin) now routinely used for treatment of metastatic colorectal cancer is that while they improve overall survival, not all patients will actually respond to treatment.

While several studies have shown that the KRAS mutation status predicts response to EGFR therapy such as cetuximab (Erbitux) and panitumumab (Vectibix) in colorectal cancer, there is no known equivalent biomarker for determining who is most likely to respond to VEGF therapy with bevacizumab.

This situation creates a dilemma for the medical oncologist, because other than excluding those patients most at risk from the side effects (patients with cardiovascular disease, hypertension etc), perhaps 1 in five of the advanced CRC patients, there is no way to determine which of the remaining 4/5 people will respond, thus potentially exposing all to the not insignificant systemic effects of the drug with no idea who might be an ideal candidate.

Previously, research from Cohen et al., has shown in advanced CRC that the CTC at baseline and during treatment were prognostic for OS and PFS (see references below). These studies included a broad heterogeneous population of untreated and pre-treated patients who received different schedules of treatment, making it difficult to draw specific conclusions. That said, the research demonstrated that the technique is useful and can be measured from blood samples while not requiring invasive biopsies.

In this article, the researchers decided to see whether CRC’s would be a useful tool for predicting the responders from non-responders better in a more homogenous population.

What did the results show?

Perhaps the most interesting quote in this journal article was the finding that:

“The combined analysis of CTC and CT imaging provided a more accurate outcome assessment than either modality alone.”

Clearly, RECIST measurements are not going to go away, but combining the data with newer biomarker analysis that reflects the underlying biology may well be a good compromise.

What does this all mean?

Historically, physicians have used pathologic measures of measuring tumour response using RECIST criteria, but the problem with this approach is that tumour shrinkage alone does not always translate into an improvement in meaningful outcome for the patient. Sometimes patients can have no shrinkage and stable disease but still a reasonable and functional quality of life, as happens with some soft tissue sarcomas, for example.

New surrogate markers of survival are therefore needed that also tell us something about about the risk of recurrence. This new paper provides additional evidence that:

“The CTC count before and during treatment independently predicts PFS and OS in ACC patients treated with chemotherapy plus targeted agents and provides additional information to CT imaging.”

They based this conclusion on the results that demonstrated:

“The sensitivity and specificity of high CTC at baseline for the prediction of progressive disease on CT imaging were 16.7% and 70.1%, respectively, and of high CTC at 1–2 weeks after the start of treatment 20.0% and 95.1%, respectively.”

They also went on to note that:

“We demonstrate that CTC counts identify a small group of patients with unfavourable outcome early during treatment. However, whether a change in treatment on the basis of CTC count will result in a better survival for this group is yet unknown, and this issue should be addressed in a prospective trial. In such a design, it will also be worthwhile to investigate the cost-effectiveness of CTC testing.”

Unfortunately, although a reasonably large number patients were evaluated (n=467) in this study, half were treated with capecitabine, oxaliplatin, and bevacizumab and half received the same regimen plus weekly cetuximab, but the results were oddly described in the aggregate. We therefore have no idea whether CTC’s were more useful in the bevacizumab only arm, or when cetuximab was added. We do know that in the patients who did poorly, although their specific treatment is not described, they did have high CTC levels and poor disease control.

CTC’s are something we will likely hear a lot more about in research going forward from a biomarker perspective though, as researchers begin to incorporate their measurement into the design of more clinical trials.

References:

Tol, J., Koopman, M., Miller, M., Tibbe, A., Cats, A., Creemers, G., Vos, A., Nagtegaal, I., Terstappen, L., & Punt, C. (2009). Circulating tumour cells early predict progression-free and overall survival in advanced colorectal cancer patients treated with chemotherapy and targeted agents Annals of Oncology, 21 (5), 1006-1012 DOI: 10.1093/annonc/mdp463

Cohen, S., Punt, C., Iannotti, N., Saidman, B., Sabbath, K., Gabrail, N., Picus, J., Morse, M., Mitchell, E., Miller, M., Doyle, G., Tissing, H., Terstappen, L., & Meropol, N. (2009). Prognostic significance of circulating tumor cells in patients with metastatic colorectal cancer Annals of Oncology, 20 (7), 1223-1229 DOI: 10.1093/annonc/mdn786

Cohen, S., Punt, C., Iannotti, N., Saidman, B., Sabbath, K., Gabrail, N., Picus, J., Morse, M., Mitchell, E., Miller, M., Doyle, G., Tissing, H., Terstappen, L., & Meropol, N. (2008). Relationship of Circulating Tumor Cells to Tumor Response, Progression-Free Survival, and Overall Survival in Patients With Metastatic Colorectal Cancer Journal of Clinical Oncology, 26 (19), 3213-3221 DOI: 10.1200/JCO.2007.15.8923

4 Comments

$JNJ files NDA for abiraterone in castration resistant prostate cancer

By MaverickNY on December 20, 2010

At the recent European Society of Medical Oncology (ESMO) meeting, J&J and Centocor OrthoBiotech announced that they planned to submit the filing for abiraterone by the year end, following the presentation of the phase III data by Johann de Bono from the Royal Marsden. That moment finally came today with a press release announcing the news within the last half hour or so.

The filing, in castration resistant prostate cancer (CRPC) after treatment with a taxane (such as docetaxel), has apparently taken place in both the EU and US. For men with the disease in the US, approval of this agent could come within six months or even less, but the EMA will likely take a little longer, as they do not have an official priority review process.

It’s mixed blessings for me – too late to help my Dad or my friends Fathers, but hopefully it will represent good news and a new option for other men in their situation who have advanced disease and are too frail for chemotherapy.

You can read more about the data from ESMO here.

{Hat Tip to my buddy @adamfeuerstein of The Street for alerting me promptly to the news}

Wnt/β-Catenin Signaling in T-Cell Immunity and Cancer Immunotherapy

By MaverickNY on December 1, 2010

Recently, at the NY Chemotherapy Foundation symposium, Dr Phil Kantoff from Dana Farber gave a lecture on new therapeutic strategies in prostate cancer. Despite the unsociably early hour (7.30am), the room was almost packed.

While waiting for the session to start, over coffee I had some cheerful banter with some of the oncologists around me. They expressed a keen desire for more tolerable and effective therapies for their mostly elderly patients with prostate cancer, many of whom were too frail or disinterested to really consider chemotherapy once hormone therapies ceased to work.

Several of them were really interested in, but somewhat puzzled about, the recent spate of new data on hormone therapies (abiraterone) and immunotherapy (sipuleucel-T) and how they work, after all, as one pointed out – after a lifetime of treating thousands of patients with chemo and more recently, targeted therapy – getting their heads around new technologies such as vaccines was difficult and challenging to explain to patients in simple language:

“We know that it works, but how does it work? That’s what I’m stuck on.”

Another oncologist wondered why does abiraterone appear to work after failure of docetaxel chemotherapy? He wanted to know if the break from hormone therapy with chemotherapy meant that the androgen receptor (AR) was still driving tumour growth and whether re-treatment with any hormone therapy would actually be beneficial?

Fast forward to Kantoff’s lecture. He covered the basic ground well and also went through the recent trials, including the recent data from ESMO on abiraterone, the NEJM data on MDV3100 and several trials for sipuleucel-T, including the Small et al., (2006) data and the more recent IMPACT trial in asymptomatic and mild symptomatic metastatic castration resistant disease (CRPC) that showed a 4.1 month advantage over placebo, leading to approval by the FDA earlier this year.

There was some discussion of the survival data, since disease progression, measured as progression-free survival (PFS), may often not be significant, but overall survival (OS) is. Why is this? Kantoff postulated that the time to the biological effect of sipuleucel-T may take longer than the time of measurement of progression (yes, but why?) PFS is also a difficult thing to measure in prostate cancer

The question for me, though, is what is the mechanism behind the delayed biological effect? How can this be explained?

In simple terms, vaccines such as sipuleucel-T rely on stimulating the bodies T-cells to fight the cancer. It doesn’t mean that there will necessarily be any effect on the tumour size, as measured classically by RECIST, but rather the overall impact is inevitably more on immunity effects, which are probably less well understood. Looking through the recent literature, though, I came across a most interesting article in Clinical Cancer Research:

“Wnt ligands are lipid-modified secreted glycoproteins that regulate embryonic development, cell fate specification, and the homeostasis of self-renewing adult tissues. In addition to its well-established role in thymocyte development, recent studies have indicated that Wnt/β-catenin signaling is critical for the differentiation, polarization, and survival of mature T lymphocytes. Here, we describe our current understanding of Wnt signaling in the biology of post-thymic T cells, and discuss how harnessing the Wnt/β-catenin pathway might improve the efficacy of vaccines, T-cell–based therapies, and allogeneic stem cell transplantation for the treatment of patients with cancer.”

We’ve covered Wnt on this blog before, so I’m not going to cover canonical signalling and the delights of Frizzled and Dishevelled in this post, but see here for more background if you’re interested in the biology. Of relevance to this discussion, though, is a quote from the article:

“… the discovery that Wnt/β-catenin signaling is a key regulator of T-cell immunity now raises the possibility that potentiating Wnt signaling could be used to improve cancer therapies through immune-based mechanisms.”

It will be interesting to see if prostate cancer vaccines such as sipuleucel-T actually have an effect on Wnt signalling, thereby explaining the enhanced T-cell effect.

Wnt signalling has also been shown to have a pivotal role in promoting stem cell self-renewal while limiting proliferation and differentiation (see Staal et al., and Fleming et al., 2008 in the references below). Inevitably, the biological effects on immunity can take time to take effect compared to the direct effects of say, DNA methylation or angiogenesis, and this may well explain the delay in efficacy with vaccines. The important thing for men with asymptomatic metastatic prostate cancer is that once it happens, the effect is both prolonged and durable, thereby offering them a new therapy option prior to chemotherapy.

As for the question about re-challenge with existing hormone therapies on the market, I don’t know the answer to that, but it’s a very good question, and perhaps best covered in another blog post unless some of the oncologists reading this have any practical experience to relate?

References:

Gattinoni, L., Ji, Y., & Restifo, N. (2010). Wnt/β-Catenin Signaling in T-Cell Immunity and Cancer Immunotherapy Clinical Cancer Research, 16 (19), 4695-4701 DOI: 10.1158/1078-0432.CCR-10-0356

Staal, F., Luis, T., & Tiemessen, M. (2008). WNT signalling in the immune system: WNT is spreading its wings Nature Reviews Immunology, 8 (8), 581-593 DOI: 10.1038/nri2360

Fleming HE, Janzen V, Lo Celso C, Guo J, Leahy KM, Kronenberg HM, & Scadden DT (2008). Wnt signaling in the niche enforces hematopoietic stem cell quiescence and is necessary to preserve self-renewal in vivo. Cell stem cell, 2 (3), 274-83 PMID: 18371452

1 Comment

Amgen receives approval for denosumab (Xgeva) in SRE for cancer

By MaverickNY on November 19, 2010

After hearing Amgen’s denosumab (Dmab) was approved late yesterday for skeletal related events (SRE) in the oncology solid tumour indications (but not multiple myeloma) and is now named Xgeva, I was tempted to write a Fun Friday post on how Pharma brand names make the mind boggle lately as you can see a few weird looking names have emerged this year alone. Seriously, some of them look as though they’ve been hastily put together from Scrabble tiles sometimes, or represent words more usually associated with the old Soviet Eastern bloc countries, never mind figuring out how they ought to be pronounced! {Update: this one is pronounced x-GEE-va not x-JAY-va as a European might think ;)}

47235-lo-osteoclast According to the NY Times, the Wholesale price for Dmab in the oncology setting will be $1650 per month, making it around double the price of Zometa (Novartis). Still, the good news for patients is that Amgen do have a patient assistance program for it and I understand from several sources that Amgen has a co-pay program that offers Xgeva to the patient with no co-pay the first month and only $25 afterwards. There are apparently no income limits to participate, which if true, would be most unusual. {Update: here is the link to actual details of the coupon program.}

At the NY Chemotherapy Foundation Symposium last week, several oncologists I spoke to said that a high price would be a significant barrier to use, so it would be reserved for those who do not respond or tolerate Zometa, or have poor renal function. Urologists would probably be more interested in Xgeva, since Zometa is an infusion product and they tend to refer patients to the oncologist for this. Xgeva, as a subcutaneous therapy, would therefore potentially be a more convenient option for urologists who have patients that progress to symptomatic metastatic prostate cancer.

The other interesting thing I noticed from the data presented on Dmab at the NY Chemotherapy Meeting, was that while time to SRE was significantly improved with Xgeva compared to Zometa, there was no difference in survival between either therapy, as measured by both progression-free survival (PFS) and overall survival (OS). There is a risk that oncologists will look at that data and see no meaningful benefit in survival at twice the price for their cancer patients. We’ll see what unfolds over the next few months, although the slow uptake of Prolia in the non-oncology setting does not portend well for Amgen.

Meanwhile, this week I’m in the office working on client reports instead of having fun at cancer conferences such as the EORTC-AACR-NCI Molecular Targets meeting that is currently ongoing in Berlin 🙂

A couple of interesting stories in preclinical or early phase development have caught my eye from the meeting so far.

The BBC wrote about nanocarriers and brain cancers, based on some research in mice, for example. We’ve previously covered nanotechnology at other AACR meetings (in pancreatic cancer), and this is probably one of my favourite disruptive technology concepts to emerge over the last twelve months. It may be a while before something is actually approved for use in human cancer though.

Another interesting item was data on a new PARP inhibitor, MK-4827, from Merck. I first posted on the science behind PARP inhibition way back in 2006, with quite a few subsequent posts on the clinical data since (you can find them all by using the Search widget on the right and typing PARP. Three main compounds have already emerged with a growing body of clinical data, mainly in breast and ovarian cancers:

Olaparib (KuDos/AstraZeneca)
Iniparib (BiPar/Sanofi Aventis)
Veliparib (Abbott)

We can now add the Merck compound to the growing list of PARP inhibitors with data in human trials from phase I and beyond. According to the ECCO press release, the new data extends beyond breast and ovarian cancers:

“In a Phase I trial conducted at the H Lee Moffitt Cancer Center (Tampa Florida, USA), University of Wisconsin-Madison (Madison, USA) and the Royal Marsden Hospital (London, UK), MK-4827 was given to 59 patients (46 women, 13 men) with a range of solid tumours such as non-small cell lung cancer (NSCLC), prostate cancer, sarcoma, melanoma and breast and ovarian cancers. Some patients had cancers caused by mutations in the BRCA1/2 genes, such as breast and ovarian cancer, but others had cancers that had arisen sporadically.”

These patients had metastatic, advanced disease, typically already received treatment with several other therapies and had experienced recurrence. In this setting, response rates are expected to be low given the high tumour burden:

“The researchers saw anti-tumour responses in both sporadic and BRCA1/2 mutation-associated cancers. Ten patients with breast and ovarian cancers had partial responses, with progression-free survival between 51-445 days, and seven of these patients are still responding to treatment. Four patients (two with ovarian cancer and two with NSCLC) had stable disease for between 130-353 days.”

Of course, it’s still early days yet in a phase I trial, but it will be interesting to see how this new class of cancer agents evolves over the next couple of years.

Photo Credit: Amgen

2 Comments

#ESMO 2010 round-up #2

By MaverickNY on October 12, 2010

"Do or do not. There is no try."

Master Yoda

2010 looks to be a good year for prostate cancer after a six year wait since the last therapy (docetaxel) was approved for what was then known as hormone refractory (now called castrate resistant) prostate cancer, or CRPC, for short.

This year has already seen two new approvals for the disease, namely:

Sipuleucel-T (Provenge) from Dendreon in asymptomatic or mildly symptomatic CRPC prior to chemotherapy.
Cabazitaxel (Jevtana) from sanofi-aventis in docetaxel failure CRPC.

In addition to these, we have also seen new data for two other novel hormonal therapies, namely abiraterone (Cougar/J&J) and MDV3100 (Medivation/Astellas) in the CRPC setting.

MDV3100 is now entering phase III trials in the 2nd line and asymptomatic setting, while the phase III data was presented on abiraterone here at ESMO yesterday in the Presidential Symposium.

Abiraterone was originally developed by the Institute of Cancer Research (ICR) in the UK and is a CYP17 steroid inhibitor that prevents the biochemical conversion of cholesterol to testosterone. Testosterone is secreted by the testes, adrenal gland and prostate tumour to ensure it's growth and survival via androgen receptor (AR) signalling. The simple idea here is that biochemically inhibiting the key pathways with both abiraterone and a steroid such as prednisone or dexamethasone, will lead to improve outcomes for men with prostate cancer.

The proof of the pudding lies in a randomised phase III trial to determine whether the combination is both safe and effective.

The results were interesting, to say the least.

The overall survival (OS) was as follows:

Abiraterone + prednisone: 14.8 months
Placebo + prednisone: 10.8 months

The PSA response also favoured the treatment arm:

Abiraterone + prednisone: 38.0%
Placebo + prednisone: 10.1%

Adverse events with abiraterone treatment were obviously higher than for placebo, but in general it appeared well tolerated and an important common side effect was fluid retention (30.5% of patients, with 2.4% of them being severe ie grade 3/4 in severity).

No data on the circulating tumour cells was given at this meeting, but the analysis is underway and will be published in 2011.

The big questions that spring to my mind are how do these results stack up against what we have and is the control arm ideal?

Cabazitaxel was approved earlier this year in combination with prednisone versus mitoxantrone plus prednisone, with an OS benefit of 2.8 months. Previously, mitoxantrone was approved in 1996 with a survival benefit over prednisone. Other therapies were not so lucky – GPC's satraplatin showed no benefit at all over prednisone.

If we look in the absolutes, the 3.9 month benefit for abiraterone sounds great until we look at the relative vales and comparators in more detail:

2nd line metastatic setting:

Satraplatin vs prednisone: 14.3 vs 14.3 months
Cabazitaxel + pred vs mitox + pred: 15.1 vs 12.3
Abiraterone + pred vs prednisone: 14.8 vs 10.9

Mitoxantrone generally offers some benefit over prednisone, based on the original head to head trial, leading it to become the first chemotherapy to be approved for advanced prostate cancer by the FDA. I've no idea why mitoxantrone plus prednisone was not used as the control group instead of prednisone alone, but we can only evaluate what we have.

You have to say, based on this top line overview, GPC were really unlucky to have a placebo group do uncommonly well! An OS of 10-12 months for prednisone might well be a most logical expectation, but that's how clinical research goes sometimes.

It's odd, but had the abiraterone control group done as well as satraplatin's control, the outcome difference would likely be minimal and not significant. Such is the crapshoot we call R&D! Overall, my sense is that mitoxantrone plus prednisone does better in terms of OS than prednisone alone, so we would expect abiraterone's control group to be lower than cabazitaxel's, making the relative difference higher, and that is indeed the case based on the data so far.

Still, we also have to think about this from the patient perspective. Many men are like my own Father was – they would much rather pop a pill or have an injection than go through chemotherapy and risk feeling sick and have their hair fall out. Indeed, I suspect he was typically of many 70 year olds who declined chemotherapy, but might have considered abiraterone or sipuleucel had they had been available ten years ago.

If you're wondering what will happen next, well according to the press releases, J&J will be submitting the filing to the regulatory authorities by the end of the year, which means we should know some time in 2011 whether we will have a 3rd active drug approved for this cancer.

1 Comment

What's hot in molecular diagnostics and biomarkers? #aacrMD #2

By MaverickNY on October 8, 2010

At the AACR meeting on Molecular Diagnostics and Cancer Therapeutics meeting in Denver, there was quite a bit of interesting scientific data coming out on cancer biology and biomarkers, so here is a quick synopsis of what appealed to me:

1. IGF-1R is over expressed in a subset of triple negative breast cancers (TNBC)

This presentation, from Witkiewicz et al., was interesting because they showed that IGF-1R might be a useful prognostic biomarker in TNBC. Usually, TNBC, which occurs in 15-20% of all breast cancers and is associated with a poorer prognosis, so finding a subgroup that might actually do better could be useful. Gene amplification was seen in 23% of the cases investigated. Caution must be exercised here, however, just because something is over expressed or amplified, does not mean that it is mutated, and therefore a potential druggable target with a therapeutic as we saw with the negative phase III results with figitumumab, an IGF-1R inhibitor in lung cancer.

What I would like to know though, is how many women with TNBC also have the BRCA1 or 2 mutation and have amplified IGF-1R? We know that targeting a cancer with one drug at one or two mutations in solid tumours has modest effects. But what if we target several things with a combination therapy, for a specific subset, then that might possibly yield different results altogether.

2. Molecular biomarker analysis using circulating tumour cells (CTCs)

Siminder Atwal, a Genentech scientist, presented her work on CTCs, with the idea of determining whether they could be used as a predictive biomarker by correlating CTCs with HER2 status in archival tumour samples. CTC's in theory should match tumour biopsies since they are cells that have shed from the primary tumour. The Genentech scientists found that they were indeed correlated, with a high concordance (95%) using the CellSearch system. Of course, EpCAM expression can vary in some tumour types, complicating analysis and interpretation, but it looks like they saw some early hints that molecular biomarker status in CTCs are indeed reflecive of the biomarker status in patient tumours.

Predictive biomarkers allow us test whether a patient is likely to benefit from a given treatment, so the obvious and leading question is whether this work could be extended to look at eg CTC's in colorectal, lung or breast cancers to determine whether a patient is more likely to respond to bevacizumab (Avastin) or not. It would probably be easier in breast (lots of biopsy samples) and colorectal (lots of surgery providing samples).

At the moment, there is no way of telling who is most likely to respond to Avastin, so a predictive biomarker test would be really useful for clinicians before deciding on treatment, rather than having to expose thousands of patients to the systemic side effects. Given that the FDA have to make a decision by the year end on the full approval of Avastin in breast cancer, it is a shame that they likely won't have this sort of data to help guide a decision.

3. BRCA1 mutations in prostate cancer

Gerhardt Attard gave an enlightening talk entitled, "Circulating tumor cells: Potential uses, pitfalls and challenges in their use as pharmacodynamic markers" but what struck me was not so much the fascinating information about CTCs as his mention that a subset of prostate cancer patients have the BRCA1 mutation. They tested the impact of olaparib, a small molecule PARP inhibitor from AstraZeneca, and found that all three responded.

A study open for men with prostate cancer and either BRCA1 or 2 mutations is currently recruiting patients. Given the interest with PARP inhibitors in breast and ovarian cancers, I'll be following this development with great interest.

XMRV in prostate cancer and chronic fatigue syndrome

By MaverickNY on September 23, 2010

Every now and then I come across a really nice write-up by some one else, and rather than do my own commentary, you can check out this well reasoned and balanced synopsis by Edward Winstead at the NCI on XMRV:

XMRV Researchers Discuss the State of the Science

Although my interest was focused on the relevance of the XMRV virus to prostate cancer, the potential role in chronic fatigue syndrome was also covered. The NIH have posted a webcast of the Q&A session for those of you who are interested in this topic.

If you're on Twitter, you can follow Ted and his colleague, Carmen Phillips, who both write well researched articles for the NCI Cancer Bulletin, one of my regular weekly reads.

Keep up the great work, guys!

Photo Credit: xandxmrv

Selective cell death mediated by small conditional RNAs

By MaverickNY on September 9, 2010

Cancer cells are characterized by genetic mutations that deregulate cell proliferation and suppress cell death. To arrest the uncontrolled replication of malignant cells, conventional chemotherapies systemically disrupt cell division, causing diverse and often severe side effects as a result of collateral damage to normal cells. Seeking to address this shortcoming, we pursue therapeutic regulation that is conditional, activating selectively in cancer cells.

via www.pnas.org

This was an interesting paper that caught my eye in PNAS last night. Further reading demonstrated that the process uses small RNA molecules. The idea behind this approach was that the small RNA molecules can be programmed to attack only specific cancer cells; then, by changing shape, those molecules cause the cancer cells to self-destruct.

Normal cells die after a period of time and are replaced by new ones, a process called programmed cell death or apoptosis. In a tumour, the cells continue to proliferate and form a mass, growing new blood vessels to feed the structure via angiogenesis.

One of the things that has absorbed researchers for years is how to stop that process and induce cell death in cancer cells without killing a lot of normal cells at the same time. To do this, we need to find ways of distinguishing cancerous from normal cells, thereby inducing a more targeted and selective approach to destruction and reducing unwanted side effects. ]

This is not as easy as it sounds though!

In the PNAS study, the researchers took small conditional RNAs, which are less than 30 base pairs in length and are hairpin shaped molecules as shown in the photo below.

The press release from Caltech described the concept as thus:

"The researchers' method involves the use of two different varieties of small conditional RNA. One is designed to be complementary to, and thus to bind to, an RNA sequence unique to a particular cancer cell—say, the cells of a glioblastoma, an aggressive brain tumor.

In order to bind to that cancer mutation, the RNA hairpin must open—changing the molecule from one form into another—which, in turn, exposes a sequence that can spontaneously bind to the second type of RNA hairpin. The opening of the second hairpin then reveals a sequence that binds to the first type of hairpin, and so on.

In this way, detection of the RNA cancer marker triggers the self-assembly of a long double-stranded RNA polymer."

Essentially, this is a clever way to use small conditional RNAs to the trick cancer cells into self-destructing by selectively forming long double-stranded RNA polymers that mimic viral RNA.

The researchers tested the RNA concept in the lab in xenograft models derived from three types of cancers: glioblastoma, prostate carcinoma, and Ewing's sarcoma so far, with some success:

"The molecules caused a 20- to 100-fold drop in the numbers of cancer cells containing the targeted RNA cancer markers, but no measurable reduction in cells lacking the markers."

Now clearly this approach has a long way to go before we see it in clinical trials, but there's nothing like starting off your day with exciting new technology approaches that may have application in the near future.

We need more creative research like this in oncology!

Photo Credit: Caltech

Venkataraman, S., Dirks, R., Ueda, C., & Pierce, N. (2010). Selective cell death mediated by small conditional RNAs Proceedings of the National Academy of Sciences DOI: 10.1073/pnas.1006377107

3 Comments

Pharma Strategy Blog

Commentary on Pharma & Biotech Oncology / Hematology New Product Development

Posts from the ‘Prostate Cancer’ category