10th June 2021Cancer Models Forum
Next Generation of PDX and Cancer Mouse Models: Current Landscape and Future Directions
Dr. Vladimir Khazak is the co-founder and Chief Scientific Officer of NexusPharma, heading biology research and development. Particular areas of expertise include genetics and molecular oncology with a particular emphasis on protein-protein interaction, gene regulation expression and signal transduction. NexusPharma is a contract research organization established by Dr. Khazak in Philadelphia in 2004 and it is part of the Genesis Drug Discovery and Development group, a consortium of integrated CROs offering discovery through clinical services to support all stages of drug discovery and development. Dr. Khazak is offering his insight into the world of preclinical drug development and what the future holds for patient derived xenografts (PDX).
He will also be speaking in an upcoming PDX models webinar on Wednesday, 16th June. Registration is free, please see details at the bottom of this article.
Q1. What led you to found NexusPharma?
A: I was previously working as a Principal Investigator at Morphochem, another drug discovery company, where my research group was doing a very interesting project related to the inhibition of the KRAS oncogene in multiple cancers. Through our research, we devised a new class of compounds that we collectively decided to take into further development, which is how NexusPharma was born. One of our founders was working at the Fox Chase Cancer Center at the time, a comprehensive cancer centre in Philadelphia, and as a result the company has been uniquely organised around Fox Chase and we were even able to secure a rental space on the premises, which we continue to use and enjoy today.
Over the years of running NexusPharma, we’ve developed multiple animal models to test our new compound class, including many patient-derived xenograft (PDX) models, which we focused on later during the company’s development. For the last 5-6 years, our primary focus has been on developing new PDX models and testing them with investigational drugs or combinations of new drugs and chemotherapies for our clients.
Q2. NexusPharma offers access to many well-characterised preclinical cancer models. Multiple CROs out there offer similar models with patient derived xenografts and whole exome sequencing and RNA sequencing - what is different in your approach?
A: Firstly, because of the unique position of the company through our association with the Fox Chase Cancer Center, we have broad access to patient tumour tissues of various types from those being treated at the Center. Secondly, Fox Chase is involved in many clinical trials across various different oncology areas and those tissues are also available to us. This means we can develop models from patients undergoing clinical trials for new investigative drugs, which is important for the generation of new drug classes in pharmacology.
Our models have RNA seq and whole exome sequence data, which many other CROs are offering, however because of our close connection to Fox Chase, we also have access to extensive patient information regarding the tissues used in our models. This means we can follow-up with patients to see how they responded to their treatment (typically next-line chemotherapy or targeted therapy following surgery) and as a result, update models even after they have been developed.
In addition, many of our models have PDX-derived cell lines associated with them, so for instance, if a client is interested in taking a less expensive approach to test an agent via a cell-line based assay, we can offer that as well. We can also even do high-throughput or medium-throughput screenings using cell lines and then do follow-up studies in PDX models in vivo.
On the business front, we customize all our studies and are highly accommodating to our clients’ specific needs. Our clients tell us that they value us providing updates on a regular, periodic basis, and that we are very responsive when issues arise. A recent testimonial from Dr. Bruce Ruggeri, Vice President of Biology at Prelude Therapeutics, says that he really appreciates the honest and collaborative interaction with us, that our quality of work is excellent, and that he sees working with NexusPharma not just as a transaction, but a collaborative relationship as well. We are very proud that we retain all of our clients in follow-on studies.
Q3. What is unique about your portfolio and what are your most popular models?
A: Our most popular model requests tend to be for the Mesothelioma tumour type; these models are pretty rare and we have a relatively large collection of well characterised models with exome sequencing and RNA seq. Mesothelioma tumours are hard to treat and there are very limited options in the clinic, therefore these models provide a unique opportunity to test new drugs before they reach clinical trials.
Another model type that is very commonly asked for is lymphoma models. Lymphoma is an example of an indication where there are already multiple treatment options but some patients are still in need of further new treatments. We have a collection of 10 different non-Hodgkin’s lymphoma models, including for diffuse large B cell lymphomas, mantle cell lymphomas, Burkitt’s lymphoma and follicular lymphoma. Most of these are very aggressive fast-growing tumours and our models provide a unique window for investigators to test new drugs in this area.
Another unique model type I’d like to mention is pancreatic cancer models. Fox Chase has a very active pancreatic cancer service line and over the years, we have developed more than 30 pancreatic PDX models. Most of these are characterised using NGS and RNA seq for gene expression, and our model collection includes various types of pancreatic cancer from very common to quite rare.
Aside from these model types, we also have a relatively large collection of lung, gastric and esophageal tumours, as well as several unique hepatocellular carcinoma (HCC) models. Primary HCC models are rare because most HCC patients are not considered for surgery at the time they present for treatment in the hospital. Therefore, our models provide the unique opportunity to test new investigational drugs in an area of oncology with high demand for new treatments and we are excited to offer 3 HCC models to our clients.
Q4. How do PDX models compare to other preclinical cancer models?
A: Over my 20-year career working in the oncology space, I’ve seen a lot of frustration in the clinical development cycle associated with investigating new drugs, and it’s mostly related to failure in the final stages of preclinical development, specifically in in vivo cancer trials. This is because investigators often test compounds that show activity in ex vivo cell-based assays using xenograft models developed from the same cell lines, but these cell lines represent only a single clone from a very complex organism, which is a tumour. This means that when you later try and treat patients, the drug typically faces multiple problems due to high levels of heterogeneity among cancer cells.
To be effective, a drug should be able to kill or inhibit growth for all cancer cell clones, however if the drug is tested preclinically using cell-line models, it will have only been tested on a single clone. This is why PDX models provide an absolutely unique opportunity to verify whether an investigational drug would be able to work against a heterogenous population, which very closely recapitulates the patient tumour environment. If a drug works in PDX and you have a patient whose genomic profile is very similar to the PDX model then there is a 90%+ chance that the drug will work on the patient. This makes the PDX platform critical for development of new drugs in oncology.
Q5. You mentioned you have over 20 years of experience in drug development. Can you tell us about any changes you see happening in drug development? Have you noticed any upcoming trends or shifts?
A: Over the years, researchers in preclinical oncology and oncology drug discovery have gone back and forth with developing new platforms for fighting malignancies. In the last 15 years or so, it has become very popular to develop drugs that target certain genomic abnormalities in tumours, as opposed to non-specific chemotherapies that inhibit proliferation of all quickly dividing cells. This involves looking for certain vulnerable points in a patient’s tumour and addressing it with a targeted therapy, and has provided a basis for personalised or precision medicine.
Another recent new trend or evolution in preclinical oncology is the development of immuno-oncology drugs to treat patient tumours by activating their own immune response, and this requires having the right target, the right tumour and the right drug.
Q6. As you mentioned, immuno-oncology (IO) is one of the biggest trends in the drug discovery market. For both IO and non-IO therapies, you need to show significant evidence of efficacy and safety, so the large scientific question behind the preclinical development of each is similar but the platforms used are different. Can you tell us about models that are required for IO studies?
A: PDX can be critical for validating immuno-oncology drugs in specific precision groups of patients. At NexusPharma, we are trying to address the unmet need for new models by developing models from cancer types that have been approved for treatment with immuno-oncology drugs. If a client is interested in developing new agents for PD-L1 checkpoint inhibitors, we can also provide information on the expression of PD-L1 antigen in our tumours. This gives clients a better understanding of the tumours and the possibility of a drug working successfully in the model. It is also becoming more important to know the HLA-typing of a tumour for certain types of immune-oncology drugs, and we routinely provide HLA-genotyping for the models we are using in immune-oncology drug trials.
There are also other approaches, in addition to PDX, that can be used in the development of immuno-oncology drugs; for example, several publications in peer-reviewed journals have shown that cell-based xenografts (CDX) can be successfully treated in humanised mice. These cell lines have been established in NexusPharma’s sister company, Invivotek, and are readily available for clients to carry out studies on new checkpoint inhibitors or any other immune-oncology drugs.
In addition, we can offer multiple syngeneic models which can be used in immune-proficient, normal mice to verify the activity of immuno-oncology drugs in cancer applications.
Q7. Talking about preclinical cancer models, can you tell us how PDX models have changed over the years?
A: PDX models have become a very popular and trusted platform for preclinical and translational research in oncology. Over the years, we have learned how to use the models better and what models need to be developed. Currently, there is a trend towards developing ‘hard-to-make’ PDX models, such as prostate or breast models, and at NexusPharma, we are using foetal bone chips to develop these rare PDX models for testing new anti-cancer agents. Nowadays, it has also begun to be extremely critical that models be complete with genomic information (mutation profile, gene expression, presence of biomarkers, protein expression, etc.). This has become a really important trend amongst PDX models, and it allows selection of specific models with specific genetic abnormalities or a given gene expression profile.
Q8. What potential do PDX models hold for drug development and how do you see this technology evolving in the coming years?
A: PDX models are extremely well positioned to support drug development and advise on the efficacy of oncology drugs. For drug development purposes, PDX models have begun to be an absolutely necessary step in the very late stages of drug development. PDX models are commonly used to verify the probability of drug success in clinical trials and they allow for testing to be done in a safer and more economical way than directly in the clinic with patients.
I believe in the future no new cancer drugs will be developed without testing in PDX to confirm efficacy and I think we are probably just at the beginning of this evolution in oncology drug development. With new drugs, indications and approaches in oncology, I don’t see PDX models being replaced and I believe this platform has a very promising future. I am very hopeful that this will make a huge difference in the next few years in preclinical and clinical development of new anti-cancer drugs.
Dr. Khazak is speaking in an upcoming webinar “NexusPharma - Xenopatient Discovery Platform for Precision Cancer Therapy” on Wednesday, 16th June.
Attendance is free, please click here for more information and to register: https://us02web.zoom.us/webinar/register/6816219547135/WN_qd8adMoMT8eEX5xFLUy6oA