Subject: The Exceptional: What Miraculous Recoveries Can Teach Us About Beating Cancer
From: "Eric Schwerin" <[email-masked]>
To: "Hunter Biden" <[email-masked]>, "Alexander S. Mackler" <[email-masked]>
Date: Tue, 27 Oct 2015 17:13:44 -0400

Not sure who is the point person on the cancer stuff for your Dad, but this would be something to put in the file and maybe follow up on.   David Solit is a Cheltenham grad but more importantly graduated from Penn in the same class as Beau and me.  He’s been doing some amazing stuff in Cancer research and now heads the Center for Molecular Oncology and Sloan Kettering which was funded by $100m from Henry Kravis. 

> http://www.popularmechanics.com/science/health/a17577/exceptional-breakthrough-awards-2015/ <http://www.popularmechanics.com/science/health/a17577/exceptional-breakthrough-awards-2015/>
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> The Exceptional: What Miraculous Recoveries Can Teach Us About Beating Cancer
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> After a cancer patient loses the battle, when the funeral has ended and the mourners have returned home, the cancer remains. It doesn't go where the body goes, to the funeral home or the crematorium. The hospital doesn't throw it away. Usually a pathologist freezes a piece of a tumor, or bathes it in an embalming fluid called formalin and sends it out to be fixed in a paraffin block. Then he seals it in a clear biohazard bag, puts it on dry ice, and adds it to a stockpile of other samples, their identities stripped to random sequences of numbers and letters, all awaiting a journey to a biorepository, a tissue bank for samples such as these. There the cancer will wait among thousands of other samples, until a doctor somewhere thinks of a reason to want it.
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> These warehouses are catalogs of the difficulties inherent in treating the disease oncologist Siddhartha Mukherjee famously called the emperor of all maladies: Of the hundreds of drugs that move into development annually to treat cancer, only a few are safe and effective enough to receive Food and Drug Administration approval. Despite advances in chemotherapy, proton therapy, and immunotherapy, techniques that employ drugs, radiation, and the immune system, respectively, to shrink tumors, more than 585,000 people succumb to the disease every year. Their tumors, fresh, frozen, or fixed in wax, build up in the tissue bank.
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> Oncologist–researchers, the united human front line against cancer, are accustomed to disappointment. They tend to be driven by the conviction that cancer can be beaten, in spite of the massive trove of evidence to the contrary. David Solit, an athletic forty-six-year-old with eyes as blue as a work shirt, is a perfect example. In medical school he chose oncology because his aunt had died of breast cancer. "I wanted to find better treatments for people who had incurable tumors," he says. He is not intimidated by the word incurable.
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> "It would be nice if we could predict who will respond to which drugs."
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> Back in 2010 Solit was in a meeting on the fourth floor of the Kimmel Center, a treatment space for prostate, bladder, and related cancers at Memorial Sloan Kettering Cancer Center in New York City, where he works. In a windowless conference space, some fifteen doctors, researchers, and nurses sat around a U-shaped table in white coats, discussing the hospital's clinical drug trials. The meeting was a weekly status update for a drug called everolimus, which blocks a protein called mTOR that makes cells grow and divide. Forty-five bladder cancer patients had received everolimus. Nearly all of them—forty-three—had no response at all.
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> The doctors considered scrapping the drug entirely. But then Solit asked a critical question: What happened to the other two? One patient had had a partial response. But the other had gone into complete remission. She had remained cancer-free for two years. "I knew from that one patient that enough of the drug got into her tumor for it to work," Solit says. "For me, that meant it was a good drug. We just didn't know who to give it to."
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> The patient was exceptional, and Solit intended to find out why.
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> Cancer is not a single disease. In concept it is the growth of abnormal cells that spread around the body, overwhelming its systems like a weed in a garden. But what kind of weed it is and how fast it spreads are different in each case. Pancreatic cancer will kill you much faster, on average, than breast cancer. A type of lung cancer that is caused by a mutation in the gene for a protein called KRAS is far more lethal than the same type of lung cancer caused by a mutation in the gene for EGFR. What makes cancer so difficult to beat is that the mechanisms are unique to each person and, indeed, to each cancer. A drug that causes remission in one case may do nothing in another.
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> Because a tumor's genetic background can direct potential treatments, researchers have been keen to genetically map tumors since the technology became possible in 2000. If oncologists could map a tumor's entire genome, goes the theory, they could compare it with a reference sequence made up of normal DNA. Mismatches might explain what caused the tumor to grow. Correcting the mismatch could cure the cancer.
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> And so Solit will be the first to tell you that discovering the genetic target of the drug everolimus was partly due to luck. In 2010 whole-genome sequencing, the technique that would eventually allow Solit to sequence the tumor from the woman who had the exceptional response, was on the cusp of availability. At first he and more than a dozen of his colleagues tried to study the tumor "the old-fashioned way"—one gene at a time. Tumor cells have approximately twenty thousand genes, the same as in a normal human cell, which made this an inefficient, and not particularly promising, undertaking.
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> Then came the luck: Illumina, a San Diego–based biotech company, engineered a digital DNA sequencing machine, a sleek tabletop lab–computer complex that could analyze the sequence of bases—A, G, C, and T—in millions of fragments of DNA, then reconstruct the fragments to show a tumor's entire raw genetic code. The cost of the experiment Solit dreamed of doing, sequencing the full genome, dropped from millions of dollars to just $20,000. (As computer power accelerates, the cost continues to drop: The same experiment today would cost only $2,000.)
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> With the lower cost option available, the hospital contracted the sequencing out to Illumina, and, when the results returned, Solit and his colleagues began to sort through more than three billion base pairs' worth of data to figure out which one was relevant to the cancer. This is like trying to find a single misspelling in a book with six billion letters. It took six computational biologists five months to solve the puzzle. The exceptional patient had a mutation in two genes, called TSC1 and NF2. Through a complex metabolic pathway, the mutations allowed mTOR, the protein affected by everolimus, to run wild, creating new, malignant cells all over. There it was—sense made out of a blind mess of human suffering. A protein that told cells to grow and divide like crazy. The drug that shut it off.
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> "It was incredibly exciting," says Solit.
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> After undergoing the peer-review process, Solit's finding <http://news.sciencemag.org/health/2012/08/genome-sequencing-clears-cancer-medical-mystery> appeared in the journal Science in 2012. It wasn't exactly the cure for cancer, but it did point in the cure's direction, and other leaders in oncology noticed. At the National Cancer Institute, a part of the National Institutes of Health in Rockville, Maryland, oncologist and developmental therapeutics researcher Barbara Conley thought Solit's work could help her streamline testing for cancer drugs. In standard clinical trials for these types of drugs, patients are grouped according to the origin site of their cancer—prostate, breast, liver, brain. Then, depending on how the entire group responds during the test, a drug is either abandoned by the pharmaceutical company, or it's pursued through three phases of FDA trials until it is finally allowed on the market. Solit's work made Conley think patients could be grouped according to genetics instead.
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> More From Popular Mechanics
> "It would be nice if we could predict who will respond to which drugs," Conley says from her office on the fourth floor of the steel-and-granite National Institutes of Health building. She's in her early sixties, and has short hair and a warm smile. Her manner conveys a subdued enthusiasm—the cautious hope of a doctor acquainted with tragedy. Like Solit, she has suffered personal losses from cancer: Her father and all four grandparents died of it.
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> Soon after the Science article, Conley led the development of a new Exceptional Responders Initiative at the National Cancer Institute, which officially launched in September of last year. Today any oncologist anywhere in the country who has a patient who has responded positively to a cancer drug for at least six months can propose her case. The doctor sends an email without identifiers, but with enough details to assess whether the case is an exceptional responder, to a dedicated email address. Then a reviewing committee of doctors and scientists determines whether the patient is an exceptional responder, and the oncologist will call up one of those tissue banks and send in samples for genetic sequencing. Informaticists at the institute will comb through the data looking for mutations. Then the report will be given to researchers who assess whether the patient's drug response can be explained by his or her unique biochemistry.
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> Within two to five years the program's results may start to guide treatment decisions for the rest of us, eventually revolutionizing not only patient care but also the very nature of how drugs are tested. When you can determine what's causing a patient's cancer from the outset, the old standard of assigning patients to double-blind, randomized trials with a placebo arm and a treatment arm no longer makes sense. Trials will get smaller and more efficient, with drugs tested only in patients who have the right mutations and are most likely to benefit.
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> "You don't want to put extra people at risk," says Conley. "So we'll see smaller trials with higher response rates … that theoretically lead to faster approvals." To that end, the NCI is coordinating a new nationwide cancer drug trial that just started this summer. At up to twenty-four hundred centers across the country, cancer patients who have eligible mutations will be matched with one of more than forty targeted drugs. As doctors have long suspected, the cure for cancer will actually be cures for cancer. And we're about to find a lot more of them.
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> "I have a life again," she says. "It's a fun life now."
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> Back at Sloan Kettering the personalized approach to cancer treatment is already under way. In May of 2014 philanthropists Marie-Josée and Henry Kravis donated $100 million so the hospital could open a Center for Molecular Oncology under Solit's direction. By July the center had rolled out the cutting-edge MSK-IMPACT test, a screening tool that looks for mutations in 341 genes known to be associated with cancer. Since the IMPACT test was introduced, more than five thousand patients have been screened, at a rate of five hundred per month, which will increase to a thousand a month by the end of this year. If the test finds a known, treatable mutation, the patient is eligible for basket studies, new clinical trials in which patients are enrolled and treated based on their tumor's genetic profile rather than on where it is.
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> In Solit's windowed corner office overlooking East 69th Street, the doctor spins in his desk chair to face his computer, where he brings up two PET scans for a late-stage metastatic breast cancer patient who was treated in a basket trial after receiving the IMPACT test. "We've seen some dramatic responses," he says. He gestures to the first image, a pretreatment scan of the patient's body that looks like a target from a shooting range, lit up with between fifty and a hundred red dots, all of them tumors. The second scan shows the same patient after eight weeks in a trial for a drug that inhibits some of the functions of a protein that was malfunctioning to cause her cancer. The second scan is completely clear.
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Eric D. Schwerin
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