You are looking at what is a big hurdle when you’re using next generation hormone therapy but also potentially could be a hurdle with re-treating patients with metastatic castration resistant prostate cancer, even with taxane therapy. So what is it that you’ve been trying to investigate here?

The Holy Grail for advanced prostate cancer is figuring out which patients respond to the therapies that we give them and which patients might be resistant from the get-go; we call that primary resistance. It’s important to know that ahead of time because if you do know that you can prevent that patient from receiving a futile therapy. So our work has focussed on the androgen receptor splice variants, also known as ARVs, and there are many splice variants, about twenty. The only one that we think is important in humans is the AR splice variant 7, which is called ARV7.

Now we’re going to be talking about this so I should get you to explain what is a splice variant and how does it fit in to cancer therapy?

An androgen receptor splice variant is only relevant in the setting of prostate cancer. We’ve known for about seventy years that the androgen receptor is a key target in prostate cancer because androgens, which are the male sex hormones, feed and fuel prostate cancer. Now, the androgen receptor in its normal form has a section called the ligand binding domain, it’s the part to which the androgens bind but it’s also the part to which many of our drugs, including the anti-androgens, bind. We have new therapies now which have been very successful, they work in the majority of patients. The first one is abiraterone which decreases the amount of androgen and the second is enzalutamide which directly binds to the ligand binding domain. So for these two drugs to work they require the ligand binding domain. The AR variants, including ARV7, are an abnormal form of the androgen receptor which is missing the ligand binding domain, in other words that part is deleted.

And then the drugs don’t work.

And then the drugs have nowhere to bind. So the drugs are missing their targets because this abnormal androgen receptor is missing the ligand binding domain.

So what you’re hoping is that they can still be susceptible to chemotherapy?

That is correct. So our initial observation which has now been published is that if patients have ARV7 in their circulating tumour cells, the vast majority of them are resistant to both enzalutamide and abiraterone. So the question remains, what do these questions respond to? We have a number of drugs in the clinic that are called taxane chemotherapies, docetaxel is one of them and cabazitaxel is a second one. We know that across the board these drugs work. So the question is, if a patient does happen to possess this ARV7 splice variant will he also be resistant to the chemotherapy, and that’s what we studied in this particular project.

You’ve been focussing on ARV7, what did you find?

What we found was that the presence of ARV7 is not associated with resistance to taxanes. In other words, patients that do have the ARV7 may still respond, in some cases quite favourably, to either docetaxel or cabazitaxel. That was actually a big relief and the reason was we know these patients have very, very poor responses to enzalutamide and abiraterone and now the good thing is we have a drug that is already FDA approved in this country, available in many countries across the world, that we can use right now, even before we wait for pharma to develop new drugs that may potentially target the ARV7 we’ve already got one.

So how should doctors be using this knowledge then right now?

If our findings are replicated by other groups and further prospective studies confirm what we have found, because right now we’re the only group that has reported this, if this becomes mainstream knowledge and if a commercial test is available to detect the ARV7 then it would stand to reason that if you were a patient and you had a circulating tumour cell which expressed ARV7, that patient should probably receive a chemotherapy such as docetaxel and not an androgen receptor targeting therapy such as enzalutamide or abiraterone.

So what should doctors take home from all of this, progress?

Progress is great and the field is moving very rapidly. The next hurdles are, number one, getting this test done in a CLIA certified laboratory; that means that the test results can be given to patients and they can be used to make clinical decisions. Right now the test is a research test so even at our institution, Johns Hopkins, right now the test is only being done under the auspices of research. Within a few months this test will be CLIA certified, meaning that a patient will be able to have the test done and the results reported. After that this needs to be developed by a commercial company such as a biomarker company and then made commercially available to a wider population of patients.

Do you think this then could become a treatment selection marker that’s used routinely?

I think within the next 12-18 months this could be a very promising treatment selection marker, at least in my opinion.