What are radiation models of cancer?
Adrian: What we are trying to do is take a cancer model like the PDX model (patient-derived tumor xenograft), which is a human-derived cancer growing in an in vivo model and apply radiation to that model. What we are doing is very similar to how you would look at any other molecular targeted therapies for cancer but, in this case, we’re actually going to be using radiation in the delivery.
You can look at the effectiveness of radiation in an orthotopic tumor model rather than in a xenograft for example and really look at both basic schemes and combination therapies such as radiation combined with molecular targets. If you are using molecular targets such as drugs, then you can also assess the effect of radiation on the outcomes if the drug is delivered before radiation compared with if it is delivered afterwards.
Jean-Pierre: Generally, with drug discovery and development, most new drug candidates would be tested using an animal model. The idea is to learn a great deal about the molecule before it is tested in a human clinical trial. You learn about toxicity, efficacy and so forth. However, the traditional models were very poorly predictive, so you couldn’t really learn much about the drug candidate in question using older animal models.
With the new models, the more we test and use them, the more we realize that they are very, very predictive of how a compound is going to behave when used clinically.
Questions such as:
what is the best indication?
the best cancer to target?
which patient would benefit from a particular drug?
can all be answered.
That said, up until now, those models were mostly validated to be used with molecules or a combination of molecules but no good models were available for combining molecules and radiation.
With this collaboration between Xstrahl and CrownBio and with the use of their instruments together with our PDX technologies, we want to create those very predictive models, so that by the time a compound enters a human clinical trial, researchers really can be very knowledgeable about it and know how to develop it clinically and which patients might benefit the most from the therapy.
How can these models be used to develop more effective oncology therapies?
Jean-Pierre: The role of these types of models is to learn a great deal about the compounds before you commit to taking a molecule into a human clinical trial. Often, in the early stages of discovery, you are not sure about what the best indication is and whether you should you target lung cancer, for example, and if so, which type and so forth.
However, these new models would truly represent the diversity that you see in cancer patients and really help you decide what each agent is going to be most suitable for. The model will also do this at a patient level because each of these models truly represent a patient.
Crown has many models of each type, so let’s say you are interested in lung cancer, Crown has more than 150 lung cancer models representing a wide range of lung cancers. So you would test the compound very much like you would do in a clinical trial, except you would do it using the models. You would test the compound and find for example that it works in 22 of the models but not in 38 of the other models.
We can analyze the models and start to understand what is special about the models in which the molecule is working. Each model represents a patient, so it is possible to work out which patients specifically would benefit from the compound, therefore making the design of the trial so much more efficient - you know you’re not going to give those compounds to patients who are unlikely to respond to it.
Adrian: Considering 60-70% of cancer patients will receive radiation as a part of their treatment, enhancing the models would bring radiation into it as another modality but it would also help us to better understand the mechanisms at work throughout the entire treatment process.
At the moment, it is often that chemotherapy is given, stopped, and followed up with more radiation and chemotherapy. By using these models, you can actually predict which patients would actually benefit from some sort of combination therapy… which cancers would be more radio-resistant and therefore a better candidate for more molecular targets rather than the radiation approach.
The outcome of the radiation and initial chemo can also give an indicator as to what drugs will need to be given after radiation. What these models will allow these researchers to do is actually look at what really goes on in the clinic and look at the whole spectrum of the cancer treatment regimes.
Why have traditional preclinical models not closely reflected a patient’s condition?
Jean-Pierre: The earlier models were using cancer cell lines and to be able to use those cells you have to adapt them to in vitro conditions and, in doing so, a lot of the genes are modified and so forth until they eventually become less and less like the cells they were in the tumors. This means any conclusions drawn on studying the cells are often not very predictive.
Cancer is also very heterogeneous and the tumor contains many different types of cells that are transformed differently. If only one of those cell types is taken, it does not really represent the diversity of the tumor. Also, these cells might have changed because they have to be adapted to laboratory conditions. They may have changed quite a bit compared with the original cancer state.
The PDX models use a three dimensional tumor. We have collaborations with many hospitals and we receive fragments of fresh tumors from the hospital that represent the diversity and the heterogeneity of the original tumor. And those are what we inplant directly to generate the PDX model. In a number of cases, the human tumor is going to grow and we can verify that the tumor in the model maintains the original characteristics and heterogeneity of the original cancer very well.
Adrian: Radiobiology research has been using radiation on cell lines, in vitro or xenograft or subcutaneous models but only a few studies actually look at an actual orthotopic tumor growing in the organ itself.
If you want to study the effect of radiation on a lung cancer then you really want to be treating a lung cancer in a lung rather than on a flank, for example. Radiation biology research has always been frustrated by the fact the lack of good orthotopic tumor models for them to target and they didn’t really have the equipment to target those tumors either.
What we have been able to do is allow researchers to mimic what happens in the clinic, which is actually defining a dose field and delivering a dose to that particular target in a pre-clinical model. And we can get a much better understanding of the mechanisms of how the cancer is going to grow and how effective the treatment is going to be.
With just a normal cell line you are not looking at the full picture and also without having radiation you are not looking at the full picture either because, as I said, 60-70% of the cancer patients are going to receive radiation. So bringing these modalities together really allows you to irradiate the tumor and see what the effects of the radiation are on the tumor, along with the molecular therapies as well. So, it’s a good combination of treatments that is really translational.
What excites you most about current radiation biology research?
Adrian: I’m really passionate about the use of radiation. I have been in this field for quite a long time and whenever you talk about radiation to people they think about the Incredible Hulk or anybody that has been modified by radiation. If you talk to cancer patients or families of cancer patients, they associate for radiation with dying so people see it as an entirely negative treatment.
Actually, radiation has really moved on, especially in the last ten years. In previous years, it used to be a bit like whacking a walnut with a sledgehammer, but nowadays the clinical machines have been able to really tone down the dosage solution to the exact target. There are now machines, for example, that monitor your breathing, monitor the movement of the head and can really target a brain tumor.
What excites me is that we are finding with the use of today’s equipment, that it is possible to actually really mimic what is going on during treatment. I think that now, radiobiologists are actually able to really look at how radiation is interacting with the tissue around it, the mechanisms, and the DNA damage and repair that happens with radiation.
It’s going to be a much more viable treatment for patients because in the case of inoperable tumors that are resistant to chemo, radiation is pretty much your only chance. The fact that we can now enhance the biology and the combination therapy means we can enhance treatment and actually stabilize those patients... and I find that really exciting.
Jean-Pierre: The field has come a long way. It’s really amazing what they can do now.
Adrian: It used to be that in the field of radiotherapy, you saw the tumor as almost like a golf ball inside somebody that we needed to give a certain amount of radiation because that was the only mechanism we had for reducing the cancer.
Now, radiobiology is actually looking at what’s really going on inside the tumor. They have been looking at this for many years with the models that are available now, such as those you can get from CrownBio, and you can actually look at that tumor and distinguish an area of necrosis from an area of hypoxia, for example, or decide to target a certain part of the tumour to see what happens if only the growing part is treated.
There is so much going on in radiobiology now that really is a growing area. I also think radiation treatment is becoming more viable in the clinic and that is causing more people to go into radiobiology and actually look at how they can really enhance treatments for patients. . I am really passionate about that.
How can we close the gap between radiation biology and current clinical techniques?
Adrian: In the clinic, they use imaging guidance now. So, physicians will not be estimating where a tumor is – a patient has a CT scan….a PET/CT…a PET/MR… and then treatment is designed around those images.
Then, when it is time for their treatment, they will be screened again to check they are in the correct position before targeting the radiation through the patient.
What we’ve enabled with our device is for exactly the same thing to be done in a pre-clinical model. Now we can actually get clinical doses into our pre-clinical models that we can use to really replicate what the patients are going through. Having availability of the actual human derived tumors means that we can really mimic exactly what’s happening in the patients and really try to pinpoint delivery of irradiation.
Jean-Pierre: In general, people say the drug industry’s not producing many new drugs and I think that those models can really change the whole efficiency of the process. We should now see more successful drug development, with very targeted drugs being developed for specific patients. I think that’s a great development.
The prevalent type of anti-cancer treatment for many years has been chemotherapy. Do you think radiation will be used more frequently going forwards?
Adrian: I think the future really is in combination therapy. There won’t be this kind of primary chemo and radiation approach. Treatment will be more combined and based on your genome and what the cancer looks like inside you, for example.
So, the use of radiation will probably be at a similar level, but it will be more effective because it will be bolstered by the combination therapy and will minimize normal tissue toxicity because it will be more targeted.
I think radiation will be used more on inoperable cancers and would give people who probably wouldn’t otherwise survive a much better survival chance because you would be able to enhance the delivery of the radiation and enhance the combination of therapy.
Jean-Pierre: Almost every cancer patient is different. Unfortunately, in the past, many of those patients have received the same treatment. I think it is important to really adjust each treatment for each patient.
To be able to achieve that, we need to characterize each patient in great detail and find out exactly what type of cancer they have. We need to add therapies that will fit each situation. We need to understand the different therapy options and match it to each cancer so that each patient can receive treatment that is safe, non-toxic and efficacious.
What are Xstrahl’s and CrownBio’s plans for the future?
Jean-Pierre: Each patient will be characterized to a great extent individually to understand what specific cancer is really driving the process. Hopefully, a patient would then have a collection of available treatments and the most suitable treatment for the specific cancer could be picked, which would most likely be a combination of drug and radiation or a cocktail of drugs. That is the end goal I think. We still have a long way to go but I think that these models that we are discussing today will be a big help in getting there.
Adrian: Our vision is that in the future, the patient gets personalized treatment through healthcare and increased survival. We are a technology company providing instruments and technology to enable researchers to get to that point. So, we are enhancing our technology to make it more accurate and moving that forward and also looking at what biomarkers can be introduced, especially through imaging and through enhancing the imaging available with our system.
We are partnering with other imaging companies so that imaging can be used in a more effective way with radiation, to see the effects of radiation immediately after delivery and also to help target the radiation.
Where can readers find more information?
About Adrian Treverton and Jean-Pierre Wery
Adrian Treverton holds a Physics degree and Master of Science from Imperial College London. He followed his MSc in optics to take a technical sales role in a major optical components company; from there he went onto selling more advanced optical systems throughout the world.
In 2003 he was recruited by a radiotherapy company they had developed an optical system for external patient monitoring during treatment. Seeing a need for enhanced imaging, he then commercialized 3D ultrasound technology from Cambridge University, allowing the correlation of internal and external anatomy for radiotherapy planning.
He joined Xstrahl in 2006 as Sales Director, leading the sales and marketing of their Orthovoltage x-ray therapy systems. In 2009 he was instrumental in commercialising the SARRP from Johns Hopkins University and then moved to the USA in 2011 to continue to expand their life science division.
Prior to joining CrownBio, Dr. Wery was Chief Scientific Officer at Monarch Life Sciences, a company dedicated to the discovery and development of protein biomarkers.
Prior to joining Monarch, Dr. Wery spent three years at Vitae Pharmaceuticals, Inc. where he was VP of Computational Drug Discovery.
Before joining Vitae he worked for 12 years at Eli Lilly and Company in various scientific and management positions.
Dr. Wery received his B.S. and Ph.D. in Physics from the U. of Liege, Belgium. Following his Ph.D., he did postdoctoral studies at Purdue University with Prof. Jack Johnson. Dr. Wery has authored more than 50 abstracts and publications.