Only about 15% of advanced pancreatic patients are alive two years after their diagnosis. Margaret Schwarzhans has now made it 2 1/2 years – and not just survived, but thrived.
While it’s impossible to say why she’s been so fortunate, she partly credits her mental state. Schwarzhans, who turns 54 Friday, meditates daily, does yoga a few times a week, and takes regular walks. A former nurse, she’s decorated her house and car with inspirational quotes and draws empowering pictures. And she gets occasional home-cooked meals from one daughter who’s a chef.
That’s the high-touch part of her treatment. On good days, she said, she can just about forget she has cancer.
Then there’s the high-tech part. Using experimental protocols, some of Schwarzhans’ tumor cells are growing in lab dishes at Boston’s Beth Israel Deaconess Medical Center. Those avatars of her own tumor, tiny balls of cells called organoids, can be distributed among lab dishes and each dosed with a different drug. If the 3D mini-tumors in one treated dish die off, researchers have good reason to suspect that the drug added to that dish will kill off her cancer cells, too. If those in another dish continue to grow and thrive, the drug added to that dish probably won’t do much to her tumor, either.
Schwarzhans, who lives in Morris, N.Y., a tiny upstate town, is part of a clinical trial in which a patient’s own tumor cells are grown and tested this way in a first step toward personalized cancer treatment. This early-stage trial, the first where a report on the organoid drug response is generated and given to a doctor, isn’t yet aimed at guiding therapy; that will come in a Phase 2 trial. But the lead researcher is already using the results in treating patients including Schwarzhans, taking them into account when deciding which drug she should try after the most common therapy began failing her.
Dr. Joseph Grossman, who is leading the Harnessing Organoids for Personalized Therapy (or HOPE) study, has enrolled 76 patients so far, and grown tumor organoids suitable for drug testing from a dozen of them. With preliminary data from those dozen, supported by years of research in cells and mice, Grossman and others have found such personal organoids to be predictive. When the cells die in the dish, they generally die in the patient; when they continue to live, the patient sees no benefit, only side effects.
Grossman, also an instructor in medicine at Harvard Medical School, is quick to caution that none of his work has been validated, published, or peer-reviewed yet.
Schwarzhans’ treatment is part of the process of confirming this approach, making her among the first patients anywhere to have her therapy guided in part by what’s seen in these cells.
There’s a huge push across many cancers and other diseases to develop organoids to help guide treatment and develop new ones. The federal government is funding a national research effort to make, analyze, and distribute these.
In pancreatic cancer, the need remains particularly urgent because of the poor prognosis, limited treatment options, and the toxic side effects of many of the current therapies, said Dennis Plenker, a postdoctoral fellow at Cold Spring Harbor Laboratory, where he and colleagues have long been working to develop organoids for pancreatic and other cancers.
For some cancers, genetically sequencing the tumor is enough to guide treatment, directing patients to one targeted therapy or another. But “at the moment, sequencing for pancreatic cancer does not usually stratify patients towards a certain therapy,” Plenker said, in part because there aren’t enough drug options.
The long-term hope is that once enough organoids have been made, experimental drug compounds can be tested on them, and new therapies can be approved to treat pancreatic cancer, he said.
But there are still lots of challenges to making organoids.
One distinguishing feature of pancreatic cancer: Tumors include a lot of normal cells along with cancerous ones, Plenker said. Most of the time, researchers are lucky to find 20%-30% of cancer cells in a sample, while in other samples tumor cells are nearly undetectable. So researchers have had to figure out how to amplify the tumor cells — without changing them so much that they won’t be representative of the cancer anymore.
His lab and a few others have mastered it, Plenker said, noting that a major advance was learning how to grow cells in more realistic three dimensions, rather than on flat sheets, which did not accurately recapitulate tumor growth.
Grossman and his colleagues have worked extensively on the medium in which the organoids are grown. Senthil Muthuswamy, director of the Cell Biology Program at the Cancer Center at Beth Israel Deaconess and Harvard Medical School, said he has spent six-plus years refining conditions that support the growth of organoids from both normal and cancer cells of multiple organs.
Muthuswamy compares what he’s trying to do to what doctors do when figuring out which antibiotic to give a sick patient. They grow out the cells and see which drug works best. “It’s been robustly powerful all these decades,” he said. “Why shouldn’t we do it with this cancer?”
Dr. Manuel Hidalgo, chief of hematology/oncology at Weill Cornell Medicine, who designed the HOPE trial, said the two biggest challenges of this approach are “racing against time” to get the organoid ready fast enough to benefit the patient, and better drugs and combinations to offer patients. “Very few drugs work and we don’t know who to treat with those drugs,” he said. “In some patients we test 10-20 drugs and none of them work. It’s horrible.”
Growing organoids remains experimental for now, he said.
Another challenge to organoid-directed therapy may be the tumor itself. Tumors change over time, and in an ideal world, a doctor would derive multiple organoids as the cancer evolved.
But Hidalgo thinks some findings will be generalizable across a single patient’s experience and from one patient to another. The hope is that once enough organoids have been generated, researchers will find markers in those lab dishes that will help them predict how other patients will fare on specific drug regimens – without the need to make organoids from them.
In late 2018, Schwarzhans was still being cared for (and cared for well, by her estimation) at Massachusetts General Hospital. She had been receiving a three-drug regimen typically used to treat pancreatic cancer. It was holding her cancer at bay, but its side effects — including nausea, vomiting, diarrhea, extreme fatigue, and neuropathy in her hands and feet — were increasing, so she had taken a break from it.
She allowed Grossman, who was providing a second opinion on her care, to take some of her lymph node biopsy tissue, and he grew organoids from the tissue. Earlier this year, he began treating her, in part guided by the results of the organoid drug screening.
He put her on a new two-drug combination guided by her genetics and organoids. Markers of tumor growth went down for a short time, and then climbed, but her disease looked stable. So he put her back on two of the three traditional drugs, skipping one which, based on the organoid results, seemed to have no effect on the tumor cells but which were causing some of her serious side effects.
This again helped for a while, but then tumor markers climbed. He switched to another standard drug guided in part by the organoid testing and during these nine months, she had few side effects from treatment and no evidence of progressive disease on imaging, Grossman said.
Schwarzhans, Grossman, and others on her medical team said her results could just be luck. About 4% of advanced pancreatic cancer patients typically survive as long as she has.
But both suspect it’s the combination of approaches that have made the difference.
In a presentation before the hospital’s grand rounds on Tuesday and in a follow-up phone call, Schwarzhans said she feels that the two approaches have helped each other. The cutting-edge therapy provides her the best possible treatment for her “rogue” cancer cells, and the mind-body therapies boost her immune system and keep her feeling strong.
“I have the best of both worlds,” Schwarzhans said. She bristles at the description of some of her therapies as “alternative.” “That implies giving up one for the other,” she said. “For me, it’s a complementary thing. They’re both very good for me.”
When she was first offered these complementary therapies at Mass. General, including acupuncture and yoga, she figured at least they wouldn’t do any harm, and “something that is thousands of years old, it seems logical to me that there must be some value to it,” she said.
Dr. Aditi Nerurkar, the internist who manages Schwarzhans’ care at the Cheng-Tsui Integrated Health Center at Beth Israel Deaconess, said she focuses on the idea of healing rather than cure. She tries to promote resiliency in her patients, to help them achieve what they want, and to find meaning in their difficult journey with cancer.
Overall, Schwarzhans said, the dual approaches help her keep cancer in perspective and keep her quality of life high.
“I could curl up on the couch and sob for the rest of my life — but I’m going to miss out on the rest of my life whatever that is, or I can try to focus on the positive, try to keep things in perspective, live in the moment and make memories.”