Accelerating Genomic Sequencing and Personalized Therapies for Young Patients

Interview with the Innovators

The Chan Soon-Shiong Children’s Precision Medicine Institute is a joint venture between Phoenix Children’s Hospital and Patrick Soon-Shiong

Dr Patrick Soon-Shiong is the founder of Nantworks, a company largely dedicated to applying genomic and proteomic analysis studies to translate diagnoses and cures more quickly and accurately. Historically, his efforts have been focused on adult populations. The recent creation of The Chan Soon-Shiong Children’s Precision Medicine Institute, which is a joint venture with Phoenix Children’s Hospital, will serve as the exclusive national hub for genomic research and precision medicine for pediatrics.

The partnership brings together the resources of renowned surgeon and healthcare technology visionary Patrick Soon-Shiong, MD, with Phoenix Children’s commitment to genomic research and access to a large pediatric patient base. The institute will transform the pediatric healthcare landscape by applying state-of-the-art genomic and proteomic technology to develop precision diagnostics, treatments, and cures for young patients facing serious illnesses.

At the heart of this revolutionary undertaking is next-generation sequencing of DNA, proteomics, supercomputers, and bioinformatics. Phoenix Children’s will be home to one of the few dedicated supercomputers in the country that can deliver genomic sequencing and analysis more quickly than ever before. Appropriate patients undergo genome sequencing and proteomics analysis in an unprecedented and rapid turnaround time.

Their mission is to develop innovative and effective diagnostics and therapies for young patients, while empowering physicians with the most up-to-date research and therapeutic models available, all to deliver potentially lifesaving treatments.

Often, existing treatment protocols lack efficacy for patients; this new genomic analysis will alter that dynamic through specific and targeted therapeutic remedies based on the individual’s unique genetic makeup. In time, next-generation sequencing will lead to a comprehensive genomic database platform, from which a shared information consortium will be integrated into a global diagnosis, treatment, and result-based methodology. A vast bank of pediatric patient data will be generated via a consortium of children’s hospitals, led by Phoenix Children’s.

The publishers of PMO spoke with Dr Nazneen Aziz about the joint venture between Phoenix Children’s Hospital and Patrick Soon-Shiong’s company and their vision of accelerating genomic sequencing and personalized therapies for young patients.

PMO To begin, tell us about your background in genetics and genomics?

Dr Aziz I began my career as a molecular geneticist, getting my doctorate in molecular genetics at MIT before the human genome project was initiated. I then joined Harvard as an assistant professor, and my research involved the cloning of new genes in polycystic kidney disease. I moved on from Harvard to the burgeoning biotech industry in Cambridge, MA, in the late ’90s when we were just beginning to understand that there are genetic variations in people and that therapeutics should be tailored to these differences—not everyone should be thought of as suited for the same drug.

Later, I was recruited to a professional organization, the College of American Pathologists (CAP) where I led strategic programs to help pathologists prepare for the era of genomic medicine. While with CAP, I led a committee called the Next-Generation Sequencing (NGS) Work Group where we developed standards for using NGS as a clinical test. The technology of NGS was published in 2005, and by 2010 this technology was being applied for clinical testing and thus this left a void in the clinical community as to how to use NGS in a safe and regulated way. My work on the development of NGS standards was therefore very well received by the clinical community, especially the diagnostic community.

After being at CAP for 4 years, I received the offer for my current, and very interesting, position at Phoenix Children’s Hospital as their Senior Vice President and Chief Research Officer. What interested me in this position was the vision of our CEO, Mr Bob Meyer. He understood that genomics is going to play a huge role in clinical care. I also learned that Phoenix Children’s had an opportunity for a joint venture with Dr Patrick Soon-Shiong, whose vision of using genomics to understand more about pediatrics merged nicely with Bob’s vision.

PMO Can you describe what would be an ideal level of knowledge that would be of practical use in helping the clinical oncologist frame their clinical strategies according to the science you’re describing?

Dr Aziz The basic message is that not everyone’s cancer is the same. Cancer should no longer be looked upon as a disease of the organ but really thought of as a molecular disease, because one can have a pancreatic cancer and a breast cancer due to the same gene mutation. Cancer is driven by mutations in genes that control cell division and the body’s ability to restrain the tumor growth. If we can identify those driver genes and mutations, it doesn’t matter in what organ the cancer is arising. Therefore, it is conceivable that the oncologist could give Herceptin, which is a breast cancer–targeted therapy, to his/her patient with pancreatic cancer if the patient’s cancer shows that the HER2/neu gene is amplified.

These are the concepts that oncologists have to grasp, and they have to further understand the importance of not relying solely on chemo and radiation, which is sort of a blunt force therapy that can sometimes do more harm than good. Eighty percent of certain pediatric AML [acute myeloid leukemia] patients will respond to chemotherapy, so that, understandably, is usually the therapy of choice. But we must then ask the question, at what cost? Children who are long-term cancer survivors may experience terrible side effects such as heart and other organ defects as a consequence of the chemo and radiation they’re exposed to. Yes, the response rate is high, but chemo can lead to a lot of downstream comorbidities. Hopefully we will move to an era where frontline genome analysis is routinely performed in children to determine whether we can give them targeted therapies.

This is the kind of research that we will be doing through our joint venture with Dr Patrick Soon-Shiong.

PMO What type of testing do you anticipate performing in pediatric cancers?

Dr Aziz In the near time, Phoenix Children’s is collaborating with a company called PierianDx to develop a unique NGS-based test for children’s cancer that is called the Complete Cancer Care Diagnostics (C3Dx).

This test will examine children’s cancer very comprehensively, using exome sequencing—not only the tumor DNA but also the patient’s normal DNA as well as RNA sequencing. We’re combining all of these analyses within the test. The test is unique because it’s not off-the-shelf. Companies like Foundation Medicine or other clinical labs offering cancer NGS-based test will not be sufficient because their NGS-based tests were not developed specifically for pediatric cancer nor are those as comprehensive as C3Dx.

PMO Are the recent advances in immuno-oncology in any way involved with your research and vision?

Dr Aziz Personally, I have had experience with biotech companies that were involved in developing immunotherapy for cancers. In the end, many of these companies were not successful in clinical trials because our understanding and technology for cancer immunotherapeutics were not fully developed during that period.

It is becoming clearer that examining the tumor microenvironment rather than just the tumor cell itself is very important, meaning, what is it about the tumor microenvironment that’s allowing the tumor to grow. Much of it has to do with the body’s immune system being able to shield the cancer from being attacked by the immune system. Therefore, considering the immunotherapeutic aspect is very important.

We will certainly be looking at that in our clinical trials. When you’re looking at the genome or exome, you have the ability to look not only at all of the oncogenes and the tumor suppressor genes but also the immune system genes that are involved and whether there’s immunodeficiency in the child that’s letting the tumor escape. That concept is a part of the comprehensive genome analysis of our C3Dx test.

PMO Can you describe the extraordinary scope of this joint venture—The Chan Soon-Shiong Children’s Precision Medicine Institute?

Dr Aziz Our vision is large and focused exclusively on pediatrics precision medicine. We will be looking at pediatric diseases, be it children’s cancer or inherited diseases, and eventually chronic diseases such as obesity and type 2 diabetes that are more in the realm of complex genetics.

Our goal is to identify causative genes for childhood diseases and new pathogenic mutations within known genes that provide us the opportunity to identify new targets for drug development and manage pediatric disease better.

PMO How does the oncologist in the trenches, both at the academic and community-based level, stay abreast of the advances in this and have a working knowledge of the science to be able to participate meaningfully with the diagnostics and research community?

Dr Aziz You raise a very important point, and this is an issue I’ve been struggling with because there are academic medical centers where the doctors are very interested in diving deep into the mechanism and looking at the NGS data, and then there are others in the community setting where this is all too much. It’s too complex, too overwhelming. They just want to have someone tell them what the mutations are and how to proceed with it.

However, things will change over time. The future medical curriculum will incorporate a good understanding of genomic medicine, and the new generation of doctors will be very comfortable with the changes in their approach to cancer treatment and management and genomic tests. In the short term, we may see an understandable struggle among the oncologists to understand that cancer is a molecular disease and not merely a disease of the organ where it originates. In the future, genomic analysis of cancer, at the baseline and also during relapse, will become routine. In some clinical centers, this is already being done.

PMO Researchers are capable of answering just about any question that is brought to them. How do clinicians present “the right questions” for researchers to pursue?

Dr Aziz You are describing translations research, which is exactly what I’m proposing to support here in Phoenix Children’s Research Institute; researchers are collaborating very closely with our physicians who have, as you said, the right clinical questions. Physicians can provide the clinical problems, and the researchers with their analytical mindset and training can tackle the problem. This leads to discovering the new disease genes, new pathways, and identifying new targets and new solutions by conducting translational research.

We are envisioning researchers and laboratorians within the CSSCPMI interacting closely with physicians from the various clinical divisions within the hospital, eg, the heart center, the center for cancer and blood disorder, Barrow Neurological Institute, and many other of Phoenix Children’s clinical divisions. We also envision an important research resource will be to develop a “clinical grade” pediatric database where translational research can be conducted with the genomic and proteomic sequence information. In the longer term, there are plans to develop a consortium of children’s hospitals where we’re sharing all of the pediatric population data to make new discoveries.

Our vision is to encourage collaboration and data sharing, because the human genome is complex. Any individual’s genome will uncover about 3 to 4 million variants where they differ from another individual. So we know that, with this level of complexity, large numbers of genomes are needed to make discoveries and so the more pediatric patients that we can enroll in research studies, not just at Phoenix Children’s but through a consortium of many children’s hospitals, knowledge will progress at a much faster pace and ultimately help our patients.

PMO Can you expand on your thoughts about basic research and the way science is evolving?

Dr Aziz In the current academic model, research is very removed from clinical applications, and it takes 14 to 20 years before it’s applied to clinical practice. That model just won’t work any longer. On the other hand, translational research has the potential to produce a return very quickly, but only where there’s tremendous collaboration and data sharing. It’s moving away from the old pattern of satisfying the individual needs of scientists wanting the sole glory of making a discovery. That model will change to crowd sourcing where there will be shared databases that will be accessed by numerous hospitals, researchers, or academic institutions to make discoveries together.

So, we are entering the big data era. The only way we can build knowledge at a fast pace is when we share all of these data and when researchers and clinicians come together closely to talk about the problem. Working together, physicians and researchers can produce great results. But having a line of close communication is key. We are reaching, I think, an age where there will be some blurring of lines between the researcher and clinician because, when examining a patient’s genome, that level of close interaction is needed. The complexity of genome analysis and meaningful clinical interpretation require that laboratorians, researchers, and clinicians work very closely together on their patients.

PMO Final thoughts on the mission of the Children’s Precision Institute at Phoenix Children’s Hospital?

Dr Aziz All I would like to say is I’m really glad to be a part of this because this is truly precision medicine that is focused on children, and there’s a great satisfaction in this line of research and children’s care. I’m fortunate to be part of it, and I’m hopeful that within a couple of years we can give you success stories from the Precision Medicine Institute.

PMO Thank you. The work you’re doing is inspired.

Dr Aziz It is deeply satisfying when you love what you’re doing, and I’m so glad that we’re in a day where we’re seeing precision medicine being applied specifically for children’s treatment and care.

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