summarize this "Lew Cantley’s discovery of the PI3K pathway led to the development of a
whole class of drugs that target cancer metabolism. Three of these drugs,
known as PI3K inhibitors, have been FDA approved for certain relapsed
leukemias and lymphomas, and a fourth was approved in late 2019 for breast
cancer. But they haven’t seemed to work as well as predicted, based on
PI3K’s prominent role in the growth pathways of cancer cells. Also, they had
the annoying side effect of raising blood glucose, which in turn provoked a
jump in insulin levels and IGF-1 as the cell tried to work around PI3K
inhibition—the very thing we would want to avoid, under this theory.
This situation came up at a dinner in 2014, when I joined Cantley, who
was then director of the Meyer Cancer Center at Weill Cornell Medical
College in Manhattan, and Siddhartha Mukherjee, who is a practicing
oncologist, research scientist, and Pulitzer Prize–winning author of The
Emperor of All Maladies, a “biography” of cancer. I was a huge fan of Sid’s
work, so I was excited to sit down with these two giants in oncology.
Over dinner, I shared a story about a case where a PI3K-inhibiting drug
treatment had been enhanced by a kind of metabolic therapy. I couldn’t stop
thinking about it, because the patient was the wife of a very close friend of
mine. Sandra (not her real name) had been diagnosed with breast cancer six
years earlier. It had already spread to her lymph nodes and her bones.
Because of her poor prognosis, she qualified for a clinical trial of an
experimental PI3K-inhibitor drug, in combination with standard therapies.
Sandra was a very motivated patient. From the day of her diagnosis, she
had become obsessed with doing anything possible to stack the odds in her
favor. She devoured everything she could read on the impact of nutrition on
cancer, and she had concluded that a diet that reduced insulin and IGF-1
would aid in her treatment. So she worked out a regimen that consisted
primarily of leafy vegetables, olive oil, avocados, nuts, and modest amounts
of protein, mostly from fish, eggs, and poultry. The diet was just as notable
for what it did not contain: added sugar and refined carbohydrates. All along,
she underwent frequent blood tests to make sure her insulin and IGF-1 levels
stayed low, which they did.
Over the next few years, every other woman who was enrolled at her trial
site had died. Every single one. The patients had been on state-of-the-art
chemotherapy plus the PI3K inhibitor, yet their metastatic breast cancer had
still overtaken them. The trial had to be stopped because it was clear that the
drugs were not working. Except for Sandra. Why was she still alive, while
hundreds of other women with the same disease, at the same stage, were not?
Was she merely lucky? Or could her very strict diet, which likely inhibited
her insulin and IGF-1, have played a role in her fate?
I had a hunch that it may have. I believe that we have to pay attention to
these outliers, these “miraculous” survivors. Even if they are only anecdotal,
their stories may contain some useful insight into this lethal, mysterious
disease. As Steve Rosenberg used to say, “These patients help us ask the right
questions.”
Yet in his 592-page magnum opus on cancer, published in 2010,
Mukherjee had barely written a word about metabolism and metabolic
therapies. It seemed premature to write about it, he later told me. Now, as I
told this story over dinner, he seemed interested but skeptical. Cantley
grabbed a napkin and started scribbling a graphic: the problem with PI3K
inhibitors, he explained, is that by turning down the insulin-related PI3K
pathway, they actually end up raising insulin and glucose levels. Because
glucose is blocked from entering the cell, more of it stays in the bloodstream.
The body then thinks it needs to produce more insulin to get rid of all that
glucose, possibly negating some of the effects of the drug by activating PI3K.
So what if we combined PI3K inhibitors with an insulin-minimizing or
ketogenic diet?
From that crude drawing on a napkin, a study was born. Published in
Nature in 2018, with Mukherjee and Cantley as senior authors, the study
found that a combination of a ketogenic diet and PI3K inhibitors improved
the responses to treatment of mice that had been implanted with human
cancer tumors. The results are important because they show not only that a
cancer cell’s metabolism is a valid target for therapy but that a patient’s
metabolic state can affect the efficacy of a drug. In this case, the animals’
ketogenic diet seemed to synergize with what was otherwise a somewhat
disappointing treatment, and together they proved to be far more powerful
than either one alone. It’s like in boxing, where a combination often proves to
be much more effective than any single punch. If your first punch misses, the
second is already in motion, aimed directly at the spot where you anticipate
your opponent will move. (Mukherjee and Cantley have since partnered on a
start-up company to further explore this idea of combining drug treatment
with nutritional interventions.)
Other types of dietary interventions have been found to help improve the
effectiveness of chemotherapy, while limiting its collateral damage to healthy
tissues. Work by Valter Longo of the University of Southern California and
others has found that fasting, or a fasting-like diet, increases the ability of
normal cells to resist chemotherapy, while rendering cancer cells more
vulnerable to the treatment. It may seem counterintuitive to recommend
fasting to cancer patients, but researchers have found that it caused no major
adverse events in chemotherapy patients, and in some cases it may have
improved the patients’ quality of life. A randomized trial in 131 cancer
patients undergoing chemotherapy found that those who were placed on a
“fasting-mimicking diet” (basically, a very low-calorie diet designed to
provide essential nutrients while reducing feelings of hunger) were more
likely to respond to chemotherapy and to feel better physically and
emotionally.
This flies in the face of traditional practice, which is to try to get patients
on chemotherapy to eat as much as they can tolerate, typically in the form of
high-calorie and even high-sugar diets. The American Cancer Society
suggests using ice cream “as a topping on cake.” But the results of these
studies suggest that maybe it’s not such a good idea to increase the level of
insulin in someone who has cancer. More studies need to be done, but the
working hypothesis is that because cancer cells are so metabolically greedy,
they are therefore more vulnerable than normal cells to a reduction in
nutrients—or more likely, a reduction in insulin, which activates the PI3K
pathway essential to the Warburg effect.
This study and the Mukherjee-Cantley study we discussed earlier also
point toward another important takeaway from this chapter, which is that
there is rarely only one way to treat a cancer successfully. As Keith Flaherty,
a medical oncologist and the director of developmental therapeutics at
Massachusetts General Hospital, explained to me, the best strategy to target
cancer is likely by targeting multiple vulnerabilities of the disease at one time,
or in sequence. By stacking different therapies, such as combining a PI3K
inhibitor with a ketogenic diet, we can attack cancer on multiple fronts, while
also minimizing the likelihood of the cancer developing resistance (via
mutations) to any single treatment. This is becoming a more common
practice in conventional chemotherapy—but for it to be truly effective, we
need more efficacious treatments to work with in the first place, ones that do a
better job of singling out cancer cells for destruction while leaving healthy
cells, and the patient, unharmed.
In the next section, we’ll look at how the once-outlandish notion of
immunotherapy has yielded multiple potentially game-changing cancer
therapies that could fit this bill.
The Promise of Immunotherapy
Like metabolism, immunotherapy did not figure in The Emperor of All
Maladies. It was barely on the radar when the book was published in 2010.
But when Ken Burns made his documentary based on the book just five years
later, both immunotherapy and Steve Rosenberg were featured very
prominently, which speaks to the degree to which our thinking about cancer
and especially immunotherapy has begun to change, just in the last decade.
The immune system is programmed to distinguish “nonself” from
“self”—that is, to recognize invading pathogens and foreign bodies among
our own healthy native cells, and then to kill or neutralize the harmful agents.
An immunotherapy is any therapy that tries to boost or harness the patient’s
immune system to fight an infection or other condition (example: vaccines).
The problem with trying to treat cancer this way is that while cancer cells are
abnormal and dangerous, they are technically still our cells (“self”). They
have cleverly evolved to hide from the immune system and specifically our
T cells, the immune system’s assassins that would ordinarily kill foreign cells.
So for a cancer immunotherapy to succeed, we essentially need to teach the
immune system to recognize and kill our own cells that have turned
cancerous. It needs to be able to distinguish “bad self” (cancer) from “good
self” (everything else).
Rosenberg wasn’t the first person to try to harness the immune system
against cancer. Back in the late nineteenth century, a Harvard-trained surgeon
named William Coley had noticed that a patient with a serious tumor had
been miraculously cured, apparently as a result of a major postsurgical
infection. Coley began experimenting with bacterial inoculations that he
hoped would trigger a similar immune response in other patients. But his
medical colleagues were appalled by the notion of injecting patients with
germs, and when others failed to reproduce Coley’s results, his ideas were
sidelined and condemned as quackery. Yet cases of spontaneous cancer
remission—like the one Rosenberg had observed as a young resident—kept
occurring, and nobody could really explain them. They offered a tantalizing
glimpse of the healing power of the human body.
It wasn’t an easy problem to solve. Rosenberg tried one approach after
another, without success. A cancer “vaccine” went nowhere. He spent many
years experimenting with interleukin-2 (IL-2), a cytokine that plays a major
role in the immune response (it basically amplifies the activity of
lymphocytes, white blood cells that fight infection). It had worked in animal
models of metastatic cancer, but results in human subjects were more mixed:
patients had to spend days, if not weeks, in the ICU, and they could very
easily die from its massive side effects. Finally, in 1984, a late-stage
melanoma patient named Linda Taylor was put into remission by high-dose
IL-2 alone.
This was a huge turning point, because it showed that the immune system
could fight off cancer. But the failures still outnumbered the successes, as
high-dose IL-2 seemed to be effective only against melanoma and renal cell
cancers, and only in 10 to 20 percent of patients with these two cancers.
[*2] It
was a shotgun approach to a problem that required more precision. So
Rosenberg turned his attention to the T cells directly. How could they be
trained to spot and attack cancer cells?
It took many more years and several iterations, but Rosenberg and his
team adapted a technique that had been developed in Israel that involved
taking T cells from a patient’s blood, then using genetic engineering to add
antigen receptors that were specifically targeted to the patient’s tumors. Now
the T cells were programmed to attack the patient’s cancer. Known as
chimeric antigen receptor T cells (or CAR-T), these modified T cells could be
multiplied in the lab and then infused back into the patient.
In 2010, Rosenberg and his team reported their first success with a CART treatment, in a patient with advanced follicular lymphoma who had
undergone multiple rounds of conventional treatments, including
chemotherapy, as well as a different kind of immunotherapy, all without
success. Other groups pursued the technique as well, and finally, in 2017, the
first two CAR-T-based treatments were approved by the FDA (making them
the first cell and gene therapies ever approved by the FDA), one for adult
lymphoma and another for acute lymphoblastic leukemia, the most common
cancer in children. It had taken nearly fifty years, but Steve Rosenberg’s onceoutlandish theory had finally yielded a breakthrough.
"