Paying it Forward

CINDY STOWELL’S LAST ACTS on this earth were aimed at helping others avoid her fate.

While in the final stages of metastatic colorectal cancer, the 41-year-old from Austin, Texas, fulfilled two dreams: to win $100,000 on the TV game show Jeopardy! and to donate those winnings to immunotherapy research.

“She couldn’t take the money with her, so she found something good to do with it,” her boyfriend, Jason Hess, said shortly after Stowell died in December 2016. “She was a scientist at heart. She had training in the sciences and really wanted it to go someplace that funded a lot of the basic research.”

Just over a year later, Stowell’s legacy is being carried forward by a researcher who shares her first name — and her passion.

Cindy Sears, M.D., and her colleagues are using Stowell’s winnings to research bacteria that live in the human gut, their role in the development of colorectal cancer and how they affect the disease’s responsiveness to treatment with immunotherapies. The work could uncover ways to prevent colorectal cancer and allow more of the people who develop it to benefit from immune-stimulating drugs.

Awarded in June 2017, the grant from the Cancer Research Institute (CRI) and Fight Colorecttal Cancer (CRC) will cover two years of study that will conclude in May 2019.

No matter how intently Sears focuses on the science involved in that project, she never forgets who made the effort possible. “It’s hard to be anything other than awestruck that someone would be so generous under difficult circumstances — that she cared enough to try to make it different for someone else,” says Sears, a professor of medicine at Johns Hopkins University School of Medicine in Baltimore. “In many ways, this is what we ask of every patient we try to enroll in a study, especially those with metastatic cancer. We’re always careful to say that ‘We can’t help you, probably, with this work, but we may be able to help others.’”

SECURING THE FUNDING

Funding for projects like theirs is precious because it can be especially difficult to secure, adds Sears’ colleague Franck Housseau, Ph.D., an assistant professor of oncology at Johns Hopkins. “This type of donation would be difficult to get through mainstream governmental funding because (the focus of the research is) very new,” he says. “It allows us to start some work that is provocative and innovative, and could (generate) data that (later) allow us access to a new avenue of funding by a more mainstream agency.”

The funding was awarded to the team as part of a $400,000 grant from CRI and Fight CRC, nonprofit groups that collaborated to find the best use for Stowell’s donation. CRI has spent 65 years funding cancer immunotherapy research. Fight CRC advocates for patients and funds studies aimed at curing colorectal cancer.

A portion of the funding came from outside donors inspired by Stowell’s generosity. “Cindy won approximately $100,000 and donated it to CRI. (After taxes,) we ended up with $70,000,” says Jill O’Donnell- Tormey, CRI’s chief executive officer and director of scientific affairs. “When all this was announced, a lot of people started contributing to us in Cindy’s memory — almost another $83,000. When Jeopardy!

did its Tournament of Champions this past fall, its producer, Quadra Productions, contributed $10,000, and other corporate donations came to $20,000. So, the total was $182,555.62.” O’Donnell-Tormey is excited about where those donations could lead. “If you fund really good people and give them the freedom to ask the questions they want to ask, amazing things come from it,” she says. “Cindy Stowell appreciated that, and we’re really honored that she trusted us to take her winnings and do something good with them.”

The rest of the funding — approximately $200,000 — came from Fight CRC, which had agreed, previous to Stowell’s donation, to work with CRI to fund colorectal cancer-focused immunotherapy research.

PURSUING THE SCIENCE

“It is always inspiring to witness fighters like Cindy Stowell, who selflessly take an opportunity like being on Jeopardy! to raise awareness and help others,” says Anjee Davis, president of Fight CRC. “Her life and her gift to research will continue to make a difference for others facing colorectal cancer. Cindy’s story and others like hers remind of us of the gravity of our mission to keep fighting.”

The scientific community’s understanding of immunotherapy’s potential to treat colorectal cancer is growing. As they prepared to award the grant money, CRI and Fight CRC experts were inspired by data showing that a small subset of cases responded to immunotherapies known as checkpoint inhibitors. These cancers are characterized as microsatellite instability-high (MSI-high), a mutation that causes them to have trouble repairing their own DNA, leaving them vulnerable to immunotherapies. The Food and Drug Administration recently approved two checkpoint inhibitors to treat colorectal cancers that express this mutation.

“These results were just coming out when we were convening our working group,” O’Donnell-Tormey says. “We were trying to focus on what is different (about MSI-high colorectal cancers) and, in the vast majority of patients with colorectal cancer who don’t have that mutation, how to make them more responsive to checkpoints.”

Leaders of the two nonprofit organizations decided that the grant including Stowell’s donation should focus on those questions, and they agreed with Sears that considering the microbiome would be a good place to start. “If we understood it better,” O’Donnell-Tormey says, “maybe people could take probiotics to change the (gut) flora, and it would make a difference in how they respond to an immunotherapy.”

As they began their project, Sears and her colleagues were hot off the heels of another; that study’s findings were recently published in the journal Science. By examining tissue removed from patients with a hereditary condition that predisposed them to developing colorectal cancer, the researchers discovered that two particular communicable bacteria, living in the colon, may cause the disease.

“This is really a surprise finding, and now we need to back up and figure out how often we can find those organisms in people, and then how often both are acting on the cells that line the colon,” Sears says. “We’re discussing ways to interfere with the activity of the toxins (released by these bacteria). The most commonly used in infectious disease would be a (preventive) vaccine of some sort.”

Stowell’s donation is funding different but related work. Sears and her team will now seek to show how oncogenic bacteria can change the microenvironment around a cancer and the immune system’s likelihood of attacking the disease.

DEVELOPING A VISION

“The CRI grant will allow us, at basic levels, to understand how these communities (of bacteria and their diversity are) linked to tumors affecting the immune system, and whether the immune system can be assisted by checkpoint inhibitor therapy,” Sears says. “Then, we can learn how to apply this to understand which bacteria are bad and which may be better. That would lead directly to trying to figure out ways for a patient to have the best microbiome possible to allow the immunotherapy to work.”

Stowell, who held a doctorate in chemical engineering and worked as a science content developer, never tried immunotherapy. Due to ulcerative colitis, Hess says, she underwent regular screenings for colorectal cancer. But in March 2015, abdominal pain between screenings led to a colonoscopy, which detected an intestinal blockage. It was stage 3b colorectal cancer.

Stowell was treated with surgery followed by FOLFOX combination chemotherapy. But in November 2015, Hess says, the cancer recurred on one of her ovaries, so she underwent an oophorectomy and a second-line chemotherapy regimen. Two months later, cancer developed again at the same site, and Stowell agreed to undergo more surgery, followed immediately by hyperthermic intraperitoneal chemotherapy — heated treatment in her abdominal cavity. Unfortunately, complications led to sepsis and a prolonged recovery.

“By the time she recovered from the complications from that surgery, the cancer had spread,” Hess recalls. “(In July 2016,) a PET scan found new spots on her lungs and liver. Once it metastasizes, they classify it as terminal, and she was given a three- to six-month prognosis. It was a really hard last couple of years. She tried everything she could, but it just wasn’t meant to be.”

A week after learning that she had run out of medical options, Stowell — who had auditioned for Jeopardy! three years earlier — was invited to audition again. When she explained her health status, show staff members expedited her chance to compete.

Although she was sick and sometimes feverish during taping in August 2016, and host Alex Trebek knew she had cancer, her fellow contestants were not told.

Stowell won six games and just over the amount she had set as her goal: $103,801. Stowell died on Dec. 5, eight days before her first appearance aired. Her friends and relatives watched the first three episodes of her winning streak at her funeral. “A couple of people said they secretly hoped she’d never stop winning, because it would let them have one more day with her,” Hess recalls.

Stowell’s legacy includes not only the research project but also a continuing role in Fight CRC’s efforts to raise awareness about the increasing number of younger adults getting colorectal cancer.

“Cindy’s story is definitely one of many highlighting the rise in early-onset cases,” Davis says. “Recent studies are underscoring a rise in diagnosis of colorectal cancer for those under 50 years of age, and we don’t fully understand why. “Cindy’s story is one we can point to when training advocates and working with lawmakers to reinforce the need for more research funding,” Davis continues. “As Cindy showed by her donation, research will lead to these answers, and we continue sharing her story.”