The Lucky Years: How to Thrive in the Brave New World of Health (10 page)

The other good news is that quicker access to experimental drugs will mean more people who are suffering from serious or life-threatening illnesses can potentially benefit. In 2015, the FDA moved to simplify the process for doctors to obtain such drugs, so that instead of a doctor needing one hundred hours to complete the forms necessary to apply for experimental treatments, it takes less than one hour. Not every patient who wants an experimental drug can get it. Patients are eligible when there is nothing else that can diagnose or treat their disease or condition and they cannot be enrolled in a clinical study testing the experimental drug. Risk must also be assessed, and it must be demonstrated that the probable risk from the disease exceeds the probable risk from the experimental drug. And the doctor must ensure that the manufacturer is willing to provide it. The FDA can’t compel the manufacturer to dispense the drug to an individual; it simply offers guidance on how to do it. Once an application has been filed, the FDA authorizes a vast majority of requests within days or even hours.

There will, however, be challenges to address in the pharmaceutical landscape going forward, starting with pricing. We have a system that assigns a cost to each pill or infusion. The longer a patient is receiving the treatment, the higher the costs. The costs are thereby spread out over long periods. But these new treatments may be given only once, thereby making “onetime opportunities,” so to speak, for pharmaceutical companies to profit. How do you assign a cost to such a treatment? No one is quite sure yet how a personalized cell therapy will be
commercialized on a large scale. One day it will probably be possible, for example, to scale immunotherapies and mass-produce off-the-shelf T cells or even do genetic engineering at a patient’s bedside that won’t cause anyone—neither the patient nor the drug company engineering the T cells—to go bankrupt. Some labs are working with instruments to pump genetic material into cells using electricity or pressure. Others have shown they can generate T cells in a lab dish and use them to cure mice, raising the possibility of T-cell factories. For now, though, all the engineered T-cell treatments in clinical testing use a patient’s own cells, and the process of creating these special cells is laborious and costly.

None of these hurdles will be impossible to overcome. They may, in fact, lead to new insights about the human body and maladies like cancer as we develop these technologies and aim to push costs down.

In 1970, Richard Peto, a British epidemiologist who helped established the importance of meta-analyses and is a leading expert on deaths related to tobacco use, introduced his namesake paradox. According to Peto’s paradox, there’s very little relationship between the size of an animal and cancer rates. Elephants can be eighty times the size of a human with proportionally more cells, but very rarely do they get cancer. The same goes for whales and the extinct woolly mammoths.

This seems to defy logic because the more cells an organism has, the higher the chance for mutations and resulting cancerous growth. So something else is going on to cause this phenomenon—and we finally gained some clues in 2015 when two different teams of scientists discovered that elephants’ cells have 20 copies (40 alleles) of the p53 gene, which is a now-famous gene associated with protecting us from cancer. We only have one copy (2 alleles).
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In fact, p53 has been referred to as the “guardian of the genome.”
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It’s what we call a tumor suppressor gene. It has three known functions: 1) it induces DNA repair mechanisms when it senses DNA alterations from the original genome; 2) it stops cells from dividing when it detects DNA alterations, thereby allowing for more efficient DNA repair; and 3) it pushes cells to self-destruct when there are too many DNA mutations to repair. Most human tumors are associated with a mutation in one of our two alleles
of p53. Loss of one of the alleles leads to Li-Fraumeni syndrome, which means more than a 90 percent lifetime risk for cancer, multiple primary tumors, and early childhood cancers. Although it isn’t yet proven that those extra p53 genes make elephants cancer-resistant, further research to confirm it could lead to new drugs to mimic the effect of p53 and new ways to protect people from cancer.

I’ve been accused of playing inside baseball when it comes to new discoveries in medicine. I’ll get excited at the smallest, most trivial of scientific findings that deserve publication in a prestigious journal but that the average person could not care less about because it’s not a cure. The difference between the number of p53 genes in elephants versus humans is but one example. But what many don’t realize is that these little wins—these seemingly small eureka moments and realizations—are much bigger than the sum of their parts. And they build upon one another, taking us closer to those cures we so desperately want.

Joan (pronounced Joe-ahn) Massagué Solé is the director of the Sloan Kettering Institute and chair of the Cancer Biology and Genetics Program at Memorial Sloan Kettering Cancer Center. I admire him greatly for the contributions he’s made in my world of oncology. His work is proof that radical changes to the treatment of cancer that will extend the lives of millions are possible, for they are taking shape in labs the world over today. Massagué has been dubbed “the unintentional scientist”; he never thought he’d stay in America after landing here from his native Spain in 1979 to do a two-year postdoctoral fellowship at Brown University.
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But two years later, he decided not to go back home, where he probably would have joined his pharmacist parents in their drugstore. Instead, he stuck it out to pursue more science in a country that loved to cater to his competitive streak and fierce determination.

And that perseverance paid off. He’s gone down in history as the man who succeeded in understanding the code to the TGF-beta (transforming
growth factor beta) pathway, an intricate and highly regulated affair that’s essentially a molecular “conversation” through which cells tell one another to stop multiplying, among other actions. Since cancer is a disease of mad cellular copying, where cells don’t know how to stop dividing, Massagué knew he was on to something when he began to study this important “conversation.”

Growth factors in general are biological messengers that cells release into the space between one another. These chemical couriers then travel to nearby cells to deliver their message by locking on to them through a door on the surface of the cell called a receptor. But that’s just the beginning in a long cascade of events whereby the message is passed to a number of different players before it culminates in the intended effect, or outcome, of the message. For a long time, we didn’t know much about TGF-beta, its message, its receptor, and what happened once the details of its message got relayed. It was so complicated that even people in the field didn’t bother to spend time and effort investigating it. Good thing Massagué dedicated much of his professional life to this particular “telegram,” although he didn’t intend for that to happen either. He found himself uniquely driven to know the whole story of TGF-beta. It became, in his words, his “playground.”

A protein secreted by cells, TGF-beta has many functions in most cells, but for the most part, it controls cellular proliferation and differentiation—dictating when cells can multiply and what they will become when they grow up. It plays a role in not just cancer but also in immunity generally and a spectrum of illnesses, from the relatively mild, like asthma and diabetes, to the severe, such as heart disease, Parkinson’s disease, multiple sclerosis, and AIDS. In normal cells, TGF-beta halts the cell cycle at a certain point through its signaling pathway to stop proliferation, induce differentiation, or trigger programmed cell death (apoptosis). When a cell becomes a cancer cell, however, parts of the TGF-beta signaling pathway are changed, and TGF-beta no longer controls the cell. These cancer cells are then able to multiply without any brakes.

In addition to telling the story of TGF-beta, Massagué has worked
tirelessly on another characteristic of cancer that has evaded scientists for centuries: metastasis, or the process by which cancer cells exit the mothership (the tumor of origin), travel to distant tissues, and invade. Massagué’s work has also been helped by the contributions of one of my mentors, Dr. Larry Norton, a breast cancer oncologist also at Memorial Sloan Kettering Cancer Center. The combination of a biologist like Massagué and a clinician like Norton has led to surprising new insights into the anatomy of cancer and its body-snatching ingenuity.

The ancient Egyptians knew about metastasis. The word owes its origins to the Greek verb for “change,”
methistanai
. In the late sixteenth century, it took on a rhetorical meaning: “rapid transition from one point to another.” Which is what metastasis is all about. It’s still the biggest challenge in cancer—the boogeyman. If it weren’t for metastasis, cancer would not be what it is today; you’d just excise the tumor like you extract a bad tooth or trim a hangnail and you’d go home. The whole point of chemotherapy and radiation after surgery is mostly to avoid or treat metastasis.

Studying metastasis isn’t as easy as you might expect. Cells are not efficient at metastasis, so it’s hard to find the ones that hold the key controls. Original tumors dump millions of cells every day into the bloodstream, but not all of those cells have the power to metastasize. If you die from metastatic cancer, you don’t die of millions of metastases. Massagué and Norton injected into mice some cells from the tumor of a woman who had died of breast cancer. These mice were engineered to have weak immune systems that wouldn’t notice the foreign cells, so their cancer would grow. Then Massagué and Norton collected the cells that traveled to the bone, which is where breast cancer cells like to go and take root. Next, the researchers took breast cancer cells that had metastasized to the mouse bones and injected those into a second group of mice. Bone tumors developed in those mice in half the time one would expect. This meant that Massagué and Norton had isolated the cellular boogeymen—the cells that hold the controls to metastasis.

Massagué and Norton’s work has revealed many new facts about
these offenders. Although we used to think that cells were either born with the capability to metastasize or acquire it later, we know now that cells both start out with the power to metastasize
and
gain it later. Cancer cells that leave their tumor of origin and become seeds for new tumors elsewhere in the body aren’t necessarily confined to their new home. We also know now that the craftiest of circulating tumor cells can not only go out to metastasize, but can also travel back home to their tumor of origin in a process called self-seeding. Massagué and Norton performed an experiment on a mouse in which they put green-colored breast cancer cells into one breast and uncolored cells into the other. After sixty days, the green-colored cells were found in both breasts. These cancer cells are akin to scouts, and they might be transmitting important messages back to the tumor about the patient when they return.

The discovery that tumor cells are swimming in our blood has paved the way for liquid biopsies: minimally invasive blood tests that can detect cancer cells or DNA that have been shed into the bloodstream from tumors. So instead of removing pieces of tissue from the tumor itself in a traditional biopsy, doctors simply draw blood from almost all patients with metastatic cancer and isolate cancer cells. These cells can be profiled molecularly, just like the tumor biopsy I described earlier. While this is certainly much easier for the patient, most important, it also facilitates frequent monitoring of the cancer’s molecular changes. This kind of technology will help us stay ahead of any cancer that is out scouting for a new address in a distant, vital organ, and allow us to change treatments as soon as we see those changes.

Massagué and his team are also credited with discovering that many of the genes that lead to metastasis work together. Activating just one or two of them doesn’t achieve their goal of spreading cancer. In 2003, Massagué presented the gene combination he identified in breast cancer cells that are prone to spread to the bone. Then in 2007, he published findings on four genes that control blood vessel growth and are likely critical to the transmission of breast cancer to the lungs. Mice experiments showed that censoring these genes individually decreased the
cancerous cells’ ability to park themselves and proliferate in the lungs, and that deactivating them all essentially shut the tumor down. His team has also found that certain microRNAs, which are small RNA molecules found in cells that suppress gene function, are few and far between in some metastatic cells. Once again, this suggests that a brake has been turned off or released somewhere. Adding these microRNA brakes back to cells seems to turn off genes involved in cellular copying and movement. In other words, these microRNAs neutralize the bad cells’ ability to spread.

Perhaps the most astounding part of these discoveries is that the drugs to flip the “off” switch in these genes and halt their activity, and thus the cancer growth, were already on the market when Massagué published his findings. And some of these drugs were not traditionally used to treat cancer and had been developed for other illnesses! One of these was celecoxib (Celebrex), a nonsteroidal anti-inflammatory that was originally approved to treat pain and inflammation often caused by arthritis. In another unrelated study that emerged in 2015, researchers discovered that a common and generic heart drug called a beta-blocker, which targets a receptor protein in heart muscle and blocks the effects of the stress hormone epinephrine, may actually prolong ovarian cancer patients’ survival.
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This underscores my belief that we may already have the vast majority of drugs we need to combat most illnesses, including cancer.

Massagué and Norton aren’t the only ones demystifying cancer and deconstructing genes to find ways to fight it. Given the extent to which cancer is now understood to be influenced by drugs and even human physiology, it’s hardly surprising that scientists are turning their attention to how cancer can be crushed in ways unimaginable when I was training. Biologists and clinicians at Sloan Kettering are among countless researchers adding volumes of new data in the Lucky Years. And these dedicated people will keep asking the tough questions and exploring areas of biology doctors used to shy away from.