This is the first in a three-part series, “Winning the Cancer War,” by Patrick Soon-Shiong, MD, FRCS(C), FACS
In 2003, government agencies proclaimed we solved cancer because we solved the human genome. We thought we could halt cancer in its tracks by targeting mutations in our DNA and stopping those “cancer drivers.” This spurred the great genomics buildout over the last ten years. Hundreds of academic medical centers and companies began developing their own gene panels—everything from 40 DNA gene panel to 500 gene panels, from breast cancer panels to lung cancer panels, and everything in between—all in a tremendous race to treat cancer with targeted drugs.
Large pharma and biotechs joined the bandwagon. They invested billions of dollars and utilized insights from limited gene panels as the only counter-intelligence for the “tricks that cancer cells play,” continuing the trend of high-dose chemotherapy but supplementing with targeted, single-agent therapies as the weapon of choice…so-called targeted therapy or “smart bombs.” Thirteen years later, it turns out that genomics is only part of the story. And single-agent targeted therapy alone is sadly doomed to failure. The cancer cell has too many redundancies. We have now learned that the only thing constant about a cancer cell is its ability to morph and change.
When you look at what cancer really is, it’s the natural evolution of our normal human cell regenerative processes. A provocative thought, but one I have come to believe is true based on over 25 years of research into stem cells. Each day our bodies generate cancer cells. We are our cancer! Fortunately, the evolutionary power and the exquisite God-given sophistication of our immune systems—the orchestration of dendritic cells, T cells, and natural killer cells—ward them off and keep us healthy. However, when our physiological processes go a little haywire and our immune system is tricked, cancer cells, I firmly believe, hijack normal cellular mechanisms and prevent the immune system from doing its job. So cancer is effectively breaking the contract with one’s body. To overcome this, we need to find a way to re-educate and reignite the immune system so it can go after tumors. We need to look beyond the information stored in DNA as the single source of truth.
Unfortunately, we’re still stuck in dogma. We continue to live in a world where the standard of cancer care is built on the naïve, almost arrogant, assumption that simply understanding the gene is the only important thing. Or that understanding 50 genes or even 500 genes will give us all the information to unlock the secrets of cancer cell metastasis. But our research is beginning to show that this is no longer the case. The bottom-line is that the biology of cancer is extraordinarily complex. It’s so complex that the output of the gene—specifically, the downstream networks of proteins within our bodies—is even more important than the gene itself.
We continue to live in a world where the standard of cancer care is built on the naïve, almost arrogant, assumption that simply understanding the gene is the only important thing.
Compounding this is cancer cell heterogeneity. We recently discovered that when you take a biopsy from a patient with triple negative breast cancer, from different sites on the body (for example, the breast, the lymph node, or a site of spread) and measure the DNA, there are actually completely different mutations present in each biopsy depending on the site of the biopsy, all present in the same patient on the same day. So the question arises—what do you target? If you simply try to target a site with single-agent targeted therapy, it’s only a matter of time before the cancerous subclone, which may have been missed by the targeted therapy, repopulates. This is the concept of “resistance mutations.”
This means we must go beyond DNA alone. We must understand what I like to call the complex interplay or “dance of proteins.” This means looking not just at DNA, but also the RNA, the protein network, the protein pathway and the actual quantitative level of the proteins present on the cancer cell itself. This will help us better figure out all the intricate mechanisms that the cancer cell has hijacked, as well as where and when to intervene. This is the depth of intelligence our oncologists need in the battlefield.
To do this effectively, the scale and size of the battlefield is immense. Just look at the numbers:
• We have 3 billion base pairs of DNA that control more than 20,000 genes.
• These 20,000 genes and other genes (called “junk DNA” by the scientific community who didn’t recognize the immense role the rest of the DNA played) control something called transcription, which involves 200,000 rRNA (ribosomal DNA) molecules.
• The rDNA is involved in transcribing millions of proteins that interact with each other and create over 10,000 different network pathways.
So our challenge is to integrate this information to enable the analysis of 3 billion base pairs, times 20,000 genes, times 200,000 rRNA molecules, times 10,000 pathways, all in a quest to find that single protein pathway that is enabling a cancer cell to thrive.
This means we need to elevate the current course and speed of genetic sequencing to look beyond just 500 genes. We need to expand our current thinking to look at whole genome sequencing (more than 20,000 genes) and combine that with RNA sequencing so we can gain real relevance into the DNA alterations and protein expression by the cancer cell. We also need to apply the richness of quantitative proteomics so we can measure the actual amounts of clinically relevant proteins that are the targets for various therapies. This will help us understand how well those therapies will work together. That’s where I believe the future of cancer treatment lies—utilizing genomics and proteomics to make us smarter, so we can unlock the power of our immune systems to fight off the disease. This deepest intelligence will enable oncologists to fight a lifelong war on behalf of their patients.
So let’s return to the DNA story. What will be most important in fighting cancer is overcoming the current dogma and incorrect assumptions that we have held for some time. We have to let go of the thinking that more information will clutter our minds and merely confuse our approach. This dogma is our greatest challenge to advancing our insight and has prevented us from winning the war against cancer. With the completion of the human genome project in 2003, the assumption was “we were done” and can now cure cancer. Public announcements were made by government agencies and officials leading the science in the USA and UK proudly announced that cancer as we know it is over. That was 2003.
Today, the potential of genomics and proteomics is fully within our grasp. And with that comes promising new ways to combat cancer (in essence, combination immunotherapy), whose very success is optimized when we understand the complete molecular profile of a patient—from the DNA, to the RNA, to the protein. The challenge is as large as discovering “God’s particle,” except it’s compounded with the need to solve this for millions of cancer patients every day. We have built the fiber and supercomputing infrastructure to meet this challenge, and we can now derive an answer for literally thousands of sets of sequencing data every day.
With this critical counter-intelligence in place, my next blog talks about various ways to arm the battlefield by looking at the vast potential of combination immunotherapy as the critical weapon for outsmarting this disease. Through this next-generation test, which we have coined “GPS Cancer,” we will find the ultimate target, the neo-epitope. But that is a topic for another day.
Patrick Soon-Shiong is the Chairman and CEO, NantWorks