We have discovered that in many instances, mutations identified in cancer gene panels may not be expressed at the RNA level, and, hence, these mutations are not translated to protein, which is the key target to identify for targeted therapeutic intervention.
—Patrick Soon-Shiong, MD, FRCS(C), FACS
Only through collaboration with sharing of outcomes data on a global scale can we hope to rapidly advance the field and unravel the complexity of the biology of this disease.
—Patrick Soon-Shiong, MD, FRCS(C), FACS
The ability to interrogate cancer cells at the genomic, proteomic, immunologic, and metabolomic levels will transform oncology care from one that relies mainly on trial-and-error treatment strategies based on the anatomy of the tumor to one that is more precisely based on the tumor’s molecular profile at the proteomic level, enabling many cancers to be turned into manageable chronic disease, and providing patients with long-term high quality of life, according to Patrick Soon-Shiong, MD, FRCS(C), FACS, who is returning to academia as visiting professor at the Imperial College of London and pending appointment as Adjunct Professor of Surgery at the University of California, Los Angeles (UCLA).
Dr. Soon-Shiong is the inventor of nab-paclitaxel (Abraxane), the first U.S. Food and Drug Administration (FDA)-approved nanotechnology-based chemotherapeutic agent. He is also the Founder and CEO of NantWorks and its subsidiary NantHealth, a cloud-based biomolecular medicine and bioinformatics company that uses high-frequency, high-throughput tumor genome sequencing to analyze the DNA, RNA, and protein levels of an individual patient’s cancer cells.
During this year’s ASCO Annual Meeting, Dr. Soon-Shiong presented results from a study that used his GPS (genome/proteome sequencing) next-generation sequencing technology to analyze genomic (DNA) and transcriptomic (RNA) sequencing data to identify driver variants between somatic and germline DNA.1 Using this technology, Dr. Soon-Shiong and his colleagues determined expression of identified mutations in a cohort of 3,784 patients to establish therapeutic relevance of the mutated genes overcoming the limitations of the cancer gene panels. The study, which included sequencing on 19 anatomic tumor types, found that genetic mutations in gene panels do not always result in protein expression and concluded that “an informed molecularly driven clinical treatment decision requires insight into downstream protein expression and not just DNA alterations alone.”
Dr. Soon-Shiong also presented findings from his study integrating whole-genome and RNA sequencing with quantitative proteomics to inform treatment selection.2 In this study, over 50 unique tumors from primary and metastatic disease were selected for panomic tumor profiling. The investigators found that many mutations showed little or no expression at the transcriptomic level. Because the molecular signature of a patient’s cancer is independent of the anatomic tumor type and since many gene mutations were not expressed, the study authors again concluded that clinical treatment decisions need to be based on both downstream protein expression and DNA alterations.
Advancing the Next Paradigm of Cancer Care
To advance cancer care for patients based on the latest innovative molecular science, Dr. Soon-Shiong has established an omics network—an international cadre of clinicians, scientists, pharmaceutical manufacturers, employers, patient advocates, and health insurance companies—to build a think tank of thought leaders who can define and implement “the next paradigm of cancer care in the era of genomics, proteomics, and immuno-oncology.”
Late last year, Dr. Soon-Shiong launched the Chan Soon-Shiong Institute of Molecular Medicine, a nonprofit medical research organization designed to support and fund the delivery of personalized, data-driven, molecular-based medicine to patients with cancer. To date, the Institute has provided grants to the University of Oxford in London and Phoenix Children’s Hospital in Arizona. Over the next 2 years, Dr. Soon-Shiong has committed a $1 billion philanthropic fund to make grants available to cancer institutions throughout the United States and in countries around the world to provide the financial resources necessary for more patients with cancer to benefit from genomic sequencing.
The ASCO Post talked with Dr. Soon-Shiong about his vision for oncology care based on highly sophisticated molecular science.
Evolving Concept of Cancer
You have said that the ability to sequence the cancer genome is turning every cancer into a rare disease. Please talk about the implications of that premise.
The commonly held belief that cancer is a single clonal disease is a misplaced assumption. With the advent of next-generation sequencing, the realization has emerged that patients with cancer face the enormous challenge of inter- and intrapatient tumor heterogeneity. It has only recently become clear to us that cancer progression is a result of genetic expression of a multiclonal disease—driven not just by one genetic mutation, but in many instances driven by tens and even hundreds and perhaps thousands of mutations, rearrangements, and structural changes in the genome, dynamically changing across time and space.
Having discovered multiple abnormal variants from a single patient, the critical question we have explored is, which of these variants transcribe downstream and drive tumor growth or cell immortality? Thus, it’s not just about the identification of mutations and genomic hotspots, some of which may be expressed while others remain dormant, but the protein products expressed downstream that are important to identify in order to improve decision-making and optimize treatment options.
We have discovered that in many instances, mutations identified in cancer gene panels may not be expressed at the RNA level, and, hence, these mutations are not translated to protein, which is the key target to identify for targeted therapeutic intervention. Clearly, it is those mutations that are expressed and, therefore, affect downstream signaling of the protein pathways that should be uncovered to better inform clinical treatment decisions.
We established the GPS Cancer test to address this challenge. The GPS Cancer test is a comprehensive single test that analyzes the entire genome of both normal and cancer tissue samples from the same patient, combined with a whole-exome analysis to identify variants in the tumor exome to normal tissue from the patient, in addition to expression analysis that measures transcription of the mutated downstream molecules through RNA sequencing. This comprehensive test will thus provide the necessary data to more accurately identify the protein pathway driving tumor growth in that patient and finally match this comprehensive molecular information to FDA-approved drugs or drugs in clinical trials.
Recognizing that practicing physicians will find it impossible to keep up with this deluge of scientifically complex data key to the patient’s care, we began building the infrastructure over the past decade and an oncology knowledge database to provide physicians with validated evidence-based information. To address the challenge of large-scale deployment of this decision support engine, we have partnered with large insurance companies such as Blue Cross to provide this actionable information at the point of care in the form of a downloadable decision support app called Eviti. This system is now available in all 50 states and will drive an adaptive learning system at scale, since we will now have the capability to measure outcomes over the life of the patient and drive transformational innovation utilizing real-world clinical care experience.
As to why we now consider cancer as a set of rare diseases, the unfortunate reality is that the pathways involved in cancer are hugely complex and result in multiple mechanisms of cell growth. That is what I mean about cancer being divided into rare diseases, based not just on its genomic variation but also on the pathway clusters.
One of the serious implications of adjusting to this concept of cancer as a set of rare diseases is that no single institution will have enough patients with that particular pathway or abnormal signature to enable the validation of a treatment regimen based on the patient’s unique molecular signature. We are now faced with not just a subset of patients, but a subset of a subset of a subset of patients, and in order to achieve sufficiently high numbers of patients to test therapies and compare outcomes, we need a large collaborative omics network—a molecularly sophisticated network of oncologists to share outcome data and create an “adaptive learning system.”
This will require an infrastructure for sharing of outcomes in real time as well as an infrastructure to receive an in-depth whole-genome, RNA, and proteome sequence analysis in a timely manner to take advantage of real-time knowledge that may better inform a clinical decision. Supported by our family foundation and NantHealth, the global omics network was established to serve that purpose.
Nab-Paclitaxel and Beyond
If cancers are divided into many types of rare diseases, how will drugs be discovered and tested for individual patients?
That is the issue we started addressing in 2001, when we conceived [nab-paclitaxel] as a “protein-based cell-signal transduction delivery platform.” We had this view that cancer in the metastatic phase is what I call a “dance of proteins,” and it is how and why we developed nab-paclitaxel to treat different cancer types—because we believed that the “nab” [nanoparticle albumin-bound] addresses a fundamental dance of a gp60 albumin receptor, caveolin-1, and caveolae formation at the endothelial cell level to initiate transcytosis and drive the paclitaxel molecule to the tumor microenvironment.
Most importantly, we believed this would occur independent of the cancer type. From 2001 to 2005, this idea that a single taxane molecule could have a significant effect on tumors as diverse and challenging as triple-negative breast cancer, stage IV pancreatic cancer, and squamous cell lung cancer was met with great skepticism.
We persisted in the belief that we were addressing a fundamental biology of overexpressed gp60 proteins occurring during the dynamic changes of metastatic disease—and that this biology was ubiquitous across all tumor types. We launched tens of phase II trials and multiple randomized phase III trials in breast, lung, and pancreas indications simultaneously to prove this hypothesis.
Fortunately, we were proven correct in this unconventional thinking, and today the drug is approved globally in all three indications. What is most gratifying is recent data from a head-to-head trial against weekly paclitaxel in neoadjuvant breast cancer, presented late last year at the San Antonio Breast Cancer Symposium.3 These data showed a remarkable and statistically significant improvement with nab-paclitaxel in triple-negative breast cancer.
This year marks the 10th anniversary since [nab-paclitaxel] was approved, and the lesson I have learned is that we, meaning the collective oncology community and the pharmaceutical industry, have an urgent need to completely rethink the strategy of cancer treatment.
With regard to long-term remission, rather than short-term gains, we need to address the cancer stem cell as well as the proliferating metastatic cell. The cancer stem cell, the progenitor cancer cell, and the metastatic cancer cell may be hugely different in their molecular profile and, more importantly, in their biology—both in terms of proliferation and metabolism. For the first time, we now have the molecular tools to gain insights into the biology and immunology of cancer at these multicellular levels.
In 2005, we began a movement at our organization to identify how to address each of these cell types independently and began building the tools required to perform genomic, proteomic, immunologic, and metabolomic interrogation at the cellular level. We spent almost a decade building this molecular infrastructure as well as the omics network needed to implement the studies, and we now have these tools as well as a committed network of global collaborators to begin to address a whole new paradigm of cancer care.
Perhaps most importantly, a change in our thinking must include the recognition that under the misconception that cancer was a single clonal disease, drug development and clinical trials have evolved under what I strongly believe is a flawed model of testing and administrating a single dose of chemotherapy at its maximum tolerated dose. Unfortunately, this flawed model may have contributed to the sad fact that we have not won the war against cancer and, in many cases, unnecessarily harmed the patient with toxic and ineffective therapies.
How do we effectively attack this multiclonal disease that changes its gene expression over time and space? I believe the way to do that is to explore ubiquitous pathways driving proliferation and metabolism of the cancer cell, to attack both the stem and metastatic cancer cells, to recognize that the biology of these two cell types differ, and to use multiple drugs focused on multiple points of attack, targeting the cell’s nucleus, DNA, cell signal pathways, and metabolism all simultaneously. We must pursue a path of combination therapy and immunotherapy, which I term “quantum oncotherapeutics,” to address the need for combination therapies that will change over time in step with the inevitable dynamic molecular changes that will occur in response to our treatment.
Through constant molecular interrogation and through the application of liquid biopsies, we can establish predictive modeling and be prepared for the almost inevitable resistance. Furthermore, instead of using high-dose chemotherapy in the standard regimens, which impairs the patient’s immune system, the model we should pursue is to use metronomic, low-dose combination therapy that maintains the already impaired immune system of a patient afflicted with cancer and perhaps, if administered correctly, a regimen that may actually stimulate the immune system.
For example, low-dose fluorouracil (5-FU) has been known to stimulate the immune system, and low-dose paclitaxel may increase the activity of natural killer cells. We are now working on an exciting program involving the development of allogeneic, off-the-shelf activated natural killer cells, which have the capability of being grown in a blood bag, doubling every 28 to 52 hours. By targeting these natural killer cells with specific human antibodies against epitopes unique to the tumor cell, we may successfully achieve direct killing, while also exploiting the innate immune system to destroy both proliferating cells and cancer stem cells. We are about to enter phase I and phase II trials in multiple indications, in both blood and solid tumor cancers, using these techniques.
The way we are going to create drugs for this vast array of multiple rare diseases is by finding the ubiquitous pathways of the cancer cell, by going after the cancer stem cells as well as the metastatic cells, and by enhancing the patient’s immune system. I think we will then have a chance of changing the paradigm of how we manage cancer patients. Eventually, by more deeply understanding the biology of the cancer stem cell, we will provide long-lasting remission and get closer to a cure for cancer.
How soon will you be able to treat patients with the method you described?
We will begin a phase II clinical trial very soon with low-dose metronomic nab-paclitaxel combined with 5-FU and combination regimens. We will be launching natural killer cells to enhance the innate immunity of patients receiving these low-dose combinations. We have supported a next-generation “basket” clinical trial, the PANGEA (Personalized Antibodies for Gastro-Esophageal Adenocarcinoma) trial, at the University of Chicago Medicine under Daniel Catenacci, MD [Assistant Professor of Medicine]. He is performing next-generation sequencing and proteomic analysis to identify the molecular profile of patients to enter into the appropriate treatment arm based on this comprehensive molecular analysis.
Rethinking the Paradigm
Based on this multipronged approach, do you think it will it be possible to cure more cancers or convert them into chronic diseases people can live with?
I think the first issue we need to address is the terrible quality of life patients endure when diagnosed with “incurable” metastatic disease. In that disease setting, the standard of care is to give patients multiple high doses of chemotherapy in a linear fashion—see what happens, then try again. If the treatment fails, the patient enters a difficult end-of-life course.
That entire paradigm can and must be changed by rethinking the current strategy of ordering the maximum tolerated dose of single chemotherapy. Encouraging early results of this paradigm shift are seen in our current management of patients with advanced pancreatic cancer, where we are administering low-doses of nab-paclitaxel, 5-FU, and oxaliplatin to attack the cancer at its different cellular levels. Attacking the tumor in this way and stimulating the immune system completely change the paradigm and take us down a path to a potential cure for cancer.
Together with colleagues at UCLA and UCSF, we are testing this low-dose combination therapy in patients with stage IV metastatic pancreatic cancer. In early-stage case studies, we are seeing very encouraging results, and, this year, we will be implementing a formalized phase II trial called PANGENA (Pancreatic Genomic Abraxane).
Will sophisticated genomic sequencing provide physicians with more effective methods for earlier detection of cancer, for example, with liquid biopsies?
We are looking at a number of different aspects of liquid biopsies currently. One of our established liquid biopsy programs is developing technology that simplifies the procedure of transforming tumor and normal cells embedded in formalin-fixed paraffin sections and converting these laser-dissected cells into liquid lysate to allow us to measure the protein level in the tumor.
As an example of this early research work, we can now quantitatively measure protein biomarkers, such as HER2/HER3, and we have shown that these findings are significantly more accurate compared with immunohistochemistry and even fluorescence in situ hybridization tests.
The second element of our liquid biopsy platform is our ability to analyze a cancer patient’s blood sample to detect circulating tumor cells and use this information to understand the disease biology, determine treatment, and anticipate the resistance factor that is going to be generated as a consequence of the treatment. We are also looking deeply at the role that cell-free tumor DNA plays in cancer.
The entire GPS Cancer, whole-genome, whole-exome, and RNA platform will shed new light on circulating tumor cells, cell-free tumor DNA, and the role that these diagnostic tests will play in the continuum of cancer care across the dynamic of quantum oncotherapeutics.
What do you think is the greatest impediment to advances in oncology care?
The challenge now is to overcome the long-held dogma that cancer is a single clonal disease rather than a multiclonal disease and understand cancer to be many rare diseases. We need to unlearn the standard of single-agent maximum tolerated dose and empiric trial and error.
I believe overcoming dogma and the “comfort” of pursuing “tried-and-true” regimens is going to be the largest impediment to advances in cancer care, but, hopefully, we will be able to overcome that dogma and drive cancer advances based on 21st century molecular science. To achieve that objective, there is a need to establish an adaptive learning system to validate molecular-driven cancer care.
Only through collaboration with sharing of outcomes data on a global scale can we hope to rapidly advance the field and unravel the complexity of the biology of this disease. I sincerely hope that the omics network we have established will contribute to this common cause. ■
Disclosure: Dr. Soon-Shiong is the majority shareholder in NantWorks and its affiliated companies: NantHealth, NantOmics, and Conkwest, a natural killer cell immunotherapy company.
1. Benz SC, Rabizadeh S, Sanborn JZ, et al: Protein expression by genetic mutations identified in gene panels (hotspots) and efficacy of targeted treatments. 2015 ASCO Annual Meeting. Abstract 11005. Presented June 1, 2015.
2. Rabizadeh S, Benz SC, Burrows J, et al: Genomics, transciptomics, and proteomics in the clinical setting. 2015 ASCO Annual Meeting. Abstract 11093. Presented May 31, 2015.
3. Untch M, Jackisch C, Schneeweiß A, et al: A randomized phase III trial comparing neoadjuvant chemotherapy with weekly nanoparticle-based paclitaxel with solvent-based paclitaxel followed by anthracyline/cyclophosphamide for patients with early breast cancer (GeparSepto); GBG 69. 2014 San Antonio Breast Cancer Symposium. Abstract S2-07. Presented December 10, 2014.