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an online version of the magazine Spring/Summer 2006
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Taming the Beast - Cancer patient Kim Lohr in the clinic with her oncologist Antonio Wolff. She makes monthly pilgrimages here for Herceptin treatments.
> Cancer patient Kim Lohr in the clinic with her oncologist Antonio Wolff. She makes monthly pilgrimages here for Herceptin treatments.
 
 
  Thirty-five years after declaring “war on cancer,” researchers still yearn for a magic bullet. But an interesting thing has happened during the slog through the battlefields: The monster is growing ever smaller. 
BY Randi henderson
 
 
 
 

Kim Lohr calls Friday, Nov. 13, 1998, the blackest day she’s ever known. As she sat in the driveway of her sons’ after-school daycare center late that afternoon, an ominous red light on her dashboard warned that her car had overheated. With steam puffing from under the hood, Lohr slumped forward and moaned. What else could go wrong? Already that morning, she had learned that at 32, she had breast cancer.

 

Lohr, an administrative assistant for the Army Corps of Engineers in Southern Maryland, was diagnosed with breast cancer at an uncommonly young age. That made her chances of recovering  more doubtful. Still, a week later, when her surgeon called to tell her the results of her lumpectomy, the two women shared hopeful tears. The tumor had been large—3.5 centimeters—but all 20 of the examined lymph nodes had been clear. Maybe she would live to see her children grow up.

For months after that, Lohr went  through chemotherapy, radiation and hormonal treatment with tamoxifen. Then, for a brief time, she relaxed a little. But in November 2000, she began experiencing nagging back pain, went for a series of PET scans and discovered the cancer had spread to her lungs and “my entire spine was doused with the cancer.” The hormonal treatments and chemo began again, coupled this time with therapy to strengthen her increasingly brittle bones.

Finally, late in 2003, Lohr decided to move her care to Johns Hopkins’ Sidney Kimmel Comprehensive Cancer Center. There, after studying her case, oncologist Antonio Wolff  met with her to lay out a treatment plan. Women in her situation, he told her gently, “did not tend to do well.” When Lohr’s cancer metastasized to her brain early in 2004, it seemed to confirm that prediction.

 

*****

 

The “war on cancer,” declared 35 years ago, has turned out to be a long one. And yet, throughout the 1990s and into the 21st century, death rates from cancer have continued to decline. With the right treatment and response, even patients in circumstances as dire as Kim Lohr’s have begun making it back from the brink.

“Simple things we’ve known about for years are getting applied,” says Martin Abeloff, director of the Kimmel Cancer Center. “And it’s not all razzle-dazzle science and technology. Refined chemotherapy cocktails are yielding better results with fewer side effects, hormonal therapies have become a mainstay for breast and prostate cancer; radiation today is more focused, and aggressive management of the disease is preventing recurrences.”

But what’s really exciting, Abeloff says, is that the current data on declining cancer death rates don’t even reflect the next wave in cancer treatment. Scientists now know that cancer occurs as a result of certain genetic mutations. The biology of this disease actually differs from person to person. That means a treatment that works for one doesn’t necessarily work for another. And with this understanding has come the development of novel, targeted chemotherpies and biologics.

Oncologists now are looking at a rapidly widening array of drugs that attack different parts of the cancer process. Instead of imperiling cancer cells with the macro assault of conventional chemotherapy, these cancer drugs do their work on a micro level. Generally taken orally with minimal side effects, they take direct aim at the genetic abnormalities that define the disease. As a class, they interfere with a specific pathway in the human body that is responsible for initiating or maintaining cancer.

Antonio Wolff, who took on Kim Lohr’s treatment early in 2004,  is reluctant to apply war analogies to the cancer fight. But he uses a military metaphor to describe what he sees happening: “We are moving away from carpet bombing to more smart bombing.” It was the earliest of these smart bombs that he counted on as he set out to try to help Lohr.

 

Trastuzumab neutralizes one specific protein in the body. A counter-attacking, laboratory-produced antibody, it was the first targeted biologic to come to market. Known commercially as Herceptin, this “monoclonal antibody” went through national patient studies all through the 1990s.

“We’d learned by then that breast cancer is made up of an umbrella of diseases,” Wolff says. “They can look quite alike under the microscope, but they have very distinct molecular signatures and biologic behavior.”

As a key participant in the Herceptin trials, Hopkins watched with interest as a growing body of results confirmed that 25 percent of women with breast cancer—those with an aggressive tumor that proved positive for the surface protein HER2/neu receptor—lived longer when they received the drug. 

“Today, we know that Herceptin has resulted in an almost unheard of reduction in the recurrence of this cancer,” says Ross Donehower, director of medical oncology here.

Kim Lohr’s breast tumor proved positive for the HER2/neu receptor early on, so she’d already been through a course of Herceptin. And yet, even after neurosurgery and radiation had cleared her of all visible cancer in her brain, metastases continued to ripple through her body.

But Wolff was one of the specialists who had begun viewing Herceptin as the vanguard of a new generation of cancer treatments, and he thought the drug was worth another shot in this case.

And so, in the summer of 2004, Lohr walked into a treatment room at Johns Hopkins, took a deep breath and headed into her next round of cancer therapy. If anyone needed a new approach, she did. 

In the end, it was Wolff’s belief in Herceptin that gave Lohr her chance. By the time he took on her care, her breast cancer had spread to her bones, lungs and brain, but after he put her back on Herceptin in 2004, the cancer began disappearing.

Today, people who don’t know that Lohr makes monthly pilgrimages to Hopkins for Herceptin treatments take her for just one more mom who’s also holding down a full-time job. 

“I got all sorts of medications,” she says, “but Herceptin was the big kahuna.”

*****

 

Sarah Brady, gun control advocate: Her lung cancer had spread by the time it was discovered. Then, oncologist David Ettinger put Her on Iressa. Today, she is cured.  
sarah brady, gun control advocate: Her lung cancer had spread by the time it was discovered. Then, oncologist David Ettinger put Her on Iressa. Today, she is cured.

There are many who would also count Elizabeth Jaffee among cancer’s miracle workers. Jaffee, a Hopkins oncology researcher who holds an appointment in Cellular and Molecular Medicine, has spent the better part of a generation trying to find a workable treatment for the most deadly of all cancers—pancreatic.

Because pancreas cancer is notoriously chemo- and radiation-resistant, it has a dismal outlook. No one even talks about five-year survival rates. Less than 5 percent of patients live that long. In most cases, because the disease isn’t discovered until it is well advanced, death occurs within a year. 

Jaffee can pinpoint the event in her life that kindled her interest in this horrible disease. In 1987, when she was an intern, she received a call from her father telling her that her 51-year-old uncle had just been diagnosed with pancreas cancer. “Our families were very close to each other,” she says. “We lived just a few miles apart on Long Island, and we spent every weekend, vacation and holiday together. My cousins were still in high school when their father, my uncle, died just three months later. For me, it was devastating.”

Jaffee, who’d been fascinated with immunology since she was a teenager, began hypothesizing that she might be able to coax the immune system to mount a defense to an antigen in a cancer cell, much as it does to an infection. A fortifying response like that doesn’t occur naturally in cancer, because many of the over-expressed or altered proteins in the malignant cells grow relatively slowly. But Jaffe was convinced she could challenge the immune system to behave more aggressively. Her idea was to create a vaccine that incorporated some of the patient’s own tumor (inactivated with radiation) and then insert a gene that would trigger the immune system to respond to the cancer.

Through painstaking laboratory experiments, over time the young oncologist began achieving the response she was after. By 1997, Jaffee believed she had something in hand that could step up and suppress pancreas cancer in human patients.

At about that same time, 50-year-old Kathleen Dowell of Bowie, Md., walked through the doors of Johns Hopkins. Dowell had just been diagnosed with pancreas cancer and had come here so John Cameron, then chief of surgery, could do a Whipple procedure on her. Cameron is the worldwide master of this complicated operation—known technically as a pancreaticoduodenectomy—in which he removes most of the pancreas and parts of adjoining organs. When Cameron met with Dowell after he operated on her, his report was as bad as it could be. The cancer had spread beyond her pancreas, meaning her expected survival time was less than six months. Dowell prepared to go home to die, but then something unexpected happened: Oncologist Donehower stopped by to see her with a question: Would she consider becoming part of a trial for a new vaccine for pancreatic cancer?

“What do I have to lose?” Dowell asked herself.

Kathleen Dowell became patient No. 8 in the trial of GVAX, the first vaccine that Liz Jaffee created with her clinical partner Daniel Laheru. The protocol called for her to receive four doses of the vaccine one to two months apart and a booster shot six months after the fourth dose. Each dose would be a whopper. An intradermal injection of 0.3 cubic centimeters is generally considered the top comfortable volume for a vaccine, but these patients would receive vaccine doses of 0.7 cc’s in each shot. To lessen the effects of the injections, they would be pretreated with an anesthetic cream called EMLA before each cycle of shots—one in each arm and one in each upper thigh. Meanwhile, along with the vaccine, they would receive chemotherapy.

Dowell had her first injection in the spring of 1997. The shots stung and burned her, but her response to the chemotherapy was much more distressing. She suffered seizures and then a stroke that temporarily paralyzed her right arm and leg. She became so seriously ill that physicians halted her vaccine injections after only two doses.

 

Liz JaffeE: “With the results we’re getting, We’ll be able to think about making pancreas cancer a chronic disease rather than a death sentence.”  
Liz JaffeE: “With the results we’re getting, We’ll be able to think about making pancreas cancer a chronic disease rather than a death sentence.”

But that isn’t the end of the story. Dowell’s immune response to two doses of Jaffee’s cancer vaccine turned out to be stronger than what Jaffee had expected from the full course of treatment. In fact, the vaccine prompted Dowell’s immune system to mount such a powerful T cell response to a tumor-associated molecule called mesothelin on the vaccine cells that today, eight years later, she remains cancer-free—a phenomenon in the world of pancreas cancer. Dowell is one of three long-term survivors of pancreas cancer from Jaffee’s first trial. Annual CT scans and marker tests continue to show that each of these surviving patients had similarly strong T cell responses.

Since then, Jaffee and Laheru have tested further renditions of their vaccine. Today, more than two years after their last trial, 78 percent of the patients who took part have survived at least two years. In contrast, statistics on pancreas cancer show that 90 percent of patients whose disease has spread are dead within a year.

Jaffee is now modulating her vaccine to enhance its effects and beginning to plan for a large multicenter trial. “We’re still not hitting home runs,” she says. “But the results we’re getting make us think that at some point we’re going to be able to think about making pancreas cancer a chronic disease rather than a death sentence.”

 

*****

 

Medical oncologist David Ettinger uses almost the same words as Jaffee when he talks about late-stage lung cancer. “The goal,” he says, “is to make this a chronic disease and focus on good quality of life for the longest period of time. And yes, I am talking about advanced disease.”

Maybe that’s what’s changed most about cancer treatment: the fact that today, a top specialist like Ettinger can hold out hope for anyone with advanced disease—and mean it. For the doubters, Ettinger points to patient after patient he’s treated successfully with the new therapies.

Sarah Brady is one of them. Six years ago, when she was 58, the national crusader for gun control was living quietly on the Delaware shore with her husband, Jim  (who took a bullet during the 1981 assassination attempt on Ronald Reagan) when she was diagnosed with stage III lung cancer. A lifelong smoker whose father had died of lung cancer, Brady knew her chances of surviving for five years were less than 30 percent.

“This is it, then? My life is over?” she mused. When exploratory surgery found the cancer had spread to her lymph nodes, death seemed a certainty. But Brady has practice in beating the odds. She headed immediately into an intense regimen of radiation and chemo drugs—taxol, carboplatin, cisplatin and Navelbene. When she was referred to Hopkins for a PET scan to evaluate some suspicious shadows, she met Ettinger. Won over from the start by the oncologist’s brusque compassion, she asked him, “What do you have for me?”

In early 2001, Ettinger put Brady on a trial for a drug that he thought looked hopeful for lung cancer—Iressa, one of the new targeted therapies. Brady knew she was getting Iressa, but she didn’t know how much. Today, five years later, she’s still on the drug. But she is cancer-free.

 

*****

 

Steve Baylin describes what’s happening in the world of cancer therapy this way: “To conquer a disease, we first have to understand it. We have to know why it occurs, how it develops and how it functions. And gradually, that’s what we’re doing.”

Baylin, who is chief of cancer biology here, acknowledges this basic-science detective work has proven especially daunting with cancer “because these cells are the most complex things you have ever seen.” But he himself is an expert in one of the most complex areas of all: DNA methylation.

Researchers have known for awhile that understanding the methylation process—in which small carbon groups from nearby molecules attach to the DNA—would be vital to understanding cancer. Distorted patterns of methylation have been found in all types of human cancer cells.

Several years ago, Baylin, along with his longtime colleague James Herman, set out to  analyze how this distortion is able to occur in a way that disrupts normal gene functioning. Over time, the two researchers discovered that as the cancer cells become hypermethylated at the “start sites” of particular genes, those genes just stop functioning.

 

Steve Baylin: “To conquer a disease. We have to know why it occurs.”  
Steve Baylin: “To conquer a disease, We have to know why it occurs.”

 “The good news,” Baylin says, “was that unlike mutations, abnormal methylation is reversible in the test tube. And we now have drugs like 5-aza-cytidine that can reduce the number of methyl groups attached to a patient’s DNA and restore the gene’s functioning.”

But Baylin and Herman quickly realized that the drug needs assistance because as the abnormal DNA methylation occurs, a group of enzymes known as histone deacetylases, or H-DAC’s, introduces changes in proteins that collaborate with the methylation to diminish gene function. And, inhibiting the H-DAC turns out not to be effective unless 5-aza-cytidine is started first. Once they’d figured that out, the two researchers realized that opportunities for novel cancer drugs had suddenly opened up. By using the two inhibitors in combination, it would be possible to delay or even reverse the progress of the disease.

 

*****

 

For John Kepics, the breakthrough couldn’t have come at a better time. A pharmaceutical representative from Harrisburg, Pa., Kepics developed leukemia in 2004 when he was 39. Stricken with a variety of debilitating symptoms, including cellulitis and lung infection, he was going downhill fast when he met medical oncologist Steven Gore, who had been studying how Baylin’s breakthrough could help patients. “He was on the brink,” Gore says.

Kepics became the first patient in a clinical trial combining the demethylation agent aza-cytidine with an H-DAC inhibitor. He began treatment on Nov. 8, 2004, the day the trial was activated, and received two shots a day of aza-cytidine for 10 days, followed by the H-DAC inhibitor. Gore had told him that the new inhibitor treatment would take three to six months to work, but as Kepics waited for signs of improvement, he went through pure hell from the effects of his disease. An agonizing infection of his esophagus put him in and out of the hospital and left him unable to eat except intravenously.

As January turned into February, Kepics had lost 50 pounds and felt worse than he’d ever felt in his life. But he was hanging on. Then, around Valentine’s Day 2005, he started feeling better and his blood counts began to come up. By April he was back at work.

Today, Kepics is in full-blown remission from his disease. He continues to take the drugs, but “I live a normal life,” he says. “It’s like I never was sick.”

“Patients have shown dramatic responses,” Baylin says of the demethylation therapy. “We’ve had two trials, with some 40 patients on the drugs. In the first group, we got up to 50 percent response; in the second, up to 70 percent. In several people, all symptoms of the disease disappeared. They remain cancer-free.”

Donehower sums it all up this way: “There is no single panacea for cancer, not targeted therapy, not vaccine, not hormonal treatment, not bone marrow transplant, not one but all, and each when appropriate and tailored to the individual patient.”

By changing to this kind of wide-angle perception, physician/ scientists are achieving successes with once-intractable malignancies. And sometimes they are even working miracles.

 
 
 
 
Features
 Taming the Beast
 Anatomy of a Surgical Dilemma
 
Departments
 Circling the Dome
 Medical Rounds
 Annals of Hopkins
 
Class Notes
 Match Day 2006
 Rounding Through the Ages
 Lock Conley Looks Back and Blushes
 
Opinions
 Post-Op
 
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