Dear Maria,

there is a major difference between preclinical findings and clinical effectiveness.

Nowadays you may find hundreds of compounds or "targets". Looking into the literature, you will find that almost every day the next oncogene / target is identified. But now the real problems start, as several have already stated here:

1. Finding a potent inhibitor (not just one which works in vitro or in mouse studies).

2. Pharmacodynamics, Pharmacokinetics. Specificity,

3. In vivo efficacy, off-target effects

4... and so on.

You see there is a major difference between what we find in vitro and the reality in the clnics. Would it be that easy, pharma companies would not "waste / spend" each year billions of $ / Euro in finding a drug from which only one or two is released if at all..

I think the problem has been the development of the appropriate delivery vehicle for this. Most studies use virus based delivery systems in mice. That isn't always the best type of delivery system for humans.

Yes I agree with Julio Morales, Need better delivery system.

The biggest challenge is indeed delivery.

When it is inside the cell it will do his job, they have tried to use different tags (PTD4 for example)

I also know that some groups started experiment with nanoparticles, curious to see what comes out of that

I think this may because of the molecular mechanisms is still unclear. In fact, our study found the protein of apoptosis also has a little effects on normal cell. Is there any body found this same results?

I see, thank you, delivery seems to be tricky.

@Bo - have you tested it on your own and saw an induction of death in the normal cells as well? I found several reports on the mechanistic underlying mechanisms, Akt-triggered activation of cyclin-dependent kinase 2 is apparently the main one and here (http://www.biomedcentral.com/1471-2407/13/488/) the authors tested several truncated apoptin proteins to find out the functional one in parallel with non-cancerous cells via cytoplasmic microinjection. They also report on partial death of "normal" cells.

We have developed polysaccharide nanoparticles (PSNP) for cancer cells treatment. Animal experiments (mice) show very good targeting, we have 3-5 times higher concentration of PSNP in cancer as compared to other organs. They easily enter cell interior and now we are looking for drugs to put inside. We started with doxorubicin, may be we can also try with apoptin, shell we try / cooperate?

@Maria：My own experiments found that apoptin protein could also induce a tiny death in normal cells. However, its induction of death in cancer cells is more obvious. This two groups have a significantly difference .

Very interesting, Tomasz!! There is a call from Volkswagen Stiftung (http://www.volkswagenstiftung.de/en/funding/challenges-for-academia-and-society/experiment.html Experiment!), where creative ideas, written in 1000 words, can be submitted. Could you please contact me via [email protected]

I think the problem for not seeing it in clinic yet is that pharmaceutical companies show no interest in natural products since they are not patentable. What you cannot make money out of is not worth investing in it!!! There was a similar story out a few weeks ago about the benefits of concurrent treatment of vitamin C and chemotherapy, which didn't draw the attention of investors since vitamins are not patentable!

@Mehrad in this case apoptin was patented in some way (i dont know the exact details in here but i do know that there was a patent concerning apoptin (VP3).

evendo it is still not just in the clinics it did open a complete new field.

it led to the discovery of multiple protein with a similar 'function', like HAMLET

most of them are mainly unstructured/unfolded amino acid chains (also apoptin).

We are currently looking at the efficacy of apoptin and endostatin in experimental mouse models of beta-amyloid induced neurodegeneration. I suppose there are many issues which need to be looked into and considered such as its pharmacology, toxicology and clinical effects i.e risks and benefits.

It doesn't make sense that more studies are not being done with Apoptin - good luck Maria with this......

Dear Maria,

there is a major difference between preclinical findings and clinical effectiveness.

Nowadays you may find hundreds of compounds or "targets". Looking into the literature, you will find that almost every day the next oncogene / target is identified. But now the real problems start, as several have already stated here:

1. Finding a potent inhibitor (not just one which works in vitro or in mouse studies).

2. Pharmacodynamics, Pharmacokinetics. Specificity,

3. In vivo efficacy, off-target effects

4... and so on.

You see there is a major difference between what we find in vitro and the reality in the clnics. Would it be that easy, pharma companies would not "waste / spend" each year billions of $ / Euro in finding a drug from which only one or two is released if at all..

Thank you, Behzad, I agree - not every identified molecular "target" is translated directly into the clinics, that´s true. We first start with the cell lines experiments and extrapolate maybe sometimes promissing results into wider dimension of "making a pill" out of it.

But this example with apoptin is somewhat extraordinary, at least when you read the reports - it really seems to kill specifically malignant cells based on their "special" features which we perhaps do not really understand yet. But, on the other hand - if it would really appear to be an "all-in-one remedy from cancer" we would hear about it earlier, I guess. But who knows, maybe delivery is indeed too challenging..

Dear Aman Shah Abdul Majid - could you please share some more details about your experiemnts on the neurodegenration model? Do you want to help cells to escape from death by applying apoptin and endostatin?

As I look at it, with my experience in studying apoptosis, the signalling pathways for apoptosis and cell survival are intricately linked with complex signalling molecules having dual roles, cross-talks, including involvement of stress pathways (ROS). And as you mention, with all reports confirming the role of apoptin as an apoptotic inducing agent in malignant cells, still it is has not reached the clinics, as its mechanism of action is complex and needs to be further delineated, or it will be difficult to bring specificity in targetting the cancer cells only, as it uses also the SAPK/JNK-ATF2 pathway. Studies are ongoing as it remains to be a potential candidate. Some refs below may be of help, to understand the complexity of signalling.

http://www.nature.com/cddis/journal/v4/n12/full/cddis2013475a.html

http://www.nature.com/mt/journal/v11/n1s/abs/mt2005427a.html

There are actually a couple of clinical trials going on with Apoptin.

We, the discoverer of Apoptin Mathieu Noteborn and I, have written a review about those "Anticancer Genes":

http://www.cell.com/trends/molecular-medicine/abstract/S1471-4914(10)00003-1

An update will be given in a book on Anticancer Genes that will be published later this year by Springer.

Hope that this helps.

Wow, how amazing, thank you Stefan for your input. Could you share perhaps how your colleague, Mathieu Noteborn, came into cross with this protein. Was is happy serendipity experiment or somehow predicatble observation?

I think you can call it an educated guess. Mathieu found that Apoptin can induce apoptosis in tumour cells and in the PNAS paper he then showed that it cannot do that in normal, untransformed cells:

http://www.pnas.org/content/94/11/5843.long

this pathway (apoptosis) is already mutated in more than 50% of cancers, others would include its suitability for human micro-environment such as Pharmacodynamics, Pharmacokinetics.

Hi, Maria,

Did you find better answer for your question so far? I am also very interested in the study of Adoption, but unfortunately it is not very easy to study the recombinant protein as it is unstructured and aggregated, also it is oligomerized... There is a nice review of the adoption I have read is: http://www.sciencedirect.com/science/article/pii/S1471491414001166#

Apoptin is not only found from chicken anemia virus but also from human gyrovirus. So far, there are only a few publications on the human gyrovirus Apoption. I would like to know if any of you know anything about the recent progress on the apoption studies. Any clinical progress?

@Stefan Grimm, I have read your review paper, which is very nice written. But I can't get the full text of the book online. Do you mind directing me to get a copy of it, please? http://link.springer.com/chapter/10.1007%2F978-1-4471-6458-6_3

Thanks very much.

Dear Maria

We are making various types of polysaccharide nanoparticles. After iv administration they are able to accumulate in the tumor area and quickly enter tumor cells (mice). Nanoparticles will protect apoptin from destruction in the circulatory system. But we don’t have experience with apoptine and similar apoptosis triggering agents, we are rather nanoprticle engineers…

Dear all,

I am interested in this protein but I would like to have a more clear overview about the topic: do you know if is there any clinical trial regarding this protein?

Thank you very much.

We don't have much knowledge on protein, we have experience in various nanoparticles.

t.ciach#ichip.pw.edu.pl