Yale researchers design new cancer research model

October 25, 2016 2:20 am Leave a Comment

Yale researchers have designed the first mouse model that successfully mimics the growth of various stages of myeloma cancer in humans, opening a new door for myeloma research.

The researchers, led by School of Medicine professors Richard Flavell and Madhav Dhodapkar, developed a robust in-vivo model to grow and investigate individual myeloma tumors. According to the investigators, this model — which simulates the environment of the human bone marrow in which the cancer develops — is crucial, as it can now be used to screen potential myeloma treatments to develop more effective therapeutic approaches.

The study was published in the journal Nature Medicine on Oct. 10.

“Our results have opened up a plethora of questions needed to be addressed in the field of tumor diversity, biology and development, and our humanized model provides a convenient mode of addressing those questions and elucidating bone marrow niche interactions with individual tumors,” medical school postdoctoral research associate and co-first author Rituparna Das said.

As a malignancy of plasma cells — human cells that produce antibodies, which primarily reside in the bone marrow — myeloma is not easy to study, researchers explained. Myeloma resides in the bone marrow and grows until in a specific environment, Flavell said, adding that growth requirements include nourishing factors such as growth factors, cytokines and other molecules present in the bone marrow. This unique environment, known as a niche in the bone marrow, was first modeled by Flavell’s lab in 2014.

Flavell developed a sophisticated humanized mouse system that was able to replicate the unique niche found in human bone marrow. The system, which used a strain of mouse called MISTRG, contained the five essential cytokines of the bone marrow niche. In a Nature Biotechnology paper published in 2014, Flavell’s lab demonstrated the model’s usefulness in studying hematopoiesis, which refers to the process in which hematopoietic stem cells — undifferentiated human blood cells in the bone marrow — give rise to all types of blood cells.

What differentiates myeloma tumors’ growth microenvironment from the earlier mouse model is the requirement for the key human cytokine interleukin-6. Because myeloma is essentially a tumor of plasma cells, it retains the dependencies of plasma cells, including the cytokine IL-6.

“Researchers for decades have been trying to grow pre-neoplastic myeloma plasma cells in-vitro or in-vivo using mouse models, which remained a challenge. Unlike stem cells, [myeloma] are highly differentiated hematopoietic cells, which do not grow in vitro,” Rakesh Verma, a medical school postdoctoral associate and co-first author of the study, said.

To design an effective in-vivo model with the MISTRG mouse, the researchers incorporated an additional gene that had the ability to introduce human IL-6 into the microenvironment of MISTRG mice..

After introducing the IL-6, the investigators injected the INA-6 cell line with myeloma intrafemorally — into the bones of the mice. The cells grew in the bone of these MISTRG6 mice, but didn’t grow in MISTRG mice or other mouse strains. This supported the researchers’ hypothesis that introducing IL-6 in the model enables the growth of a myeloma tumor dependent on this cytokine.

Dhodapkar’s lab next injected primary tumor samples from human patients into the MISTRG6 mice, and the researchers similarly found a favorable environment in the bone marrow, restricting tumor development at the bone site, as in humans.

“On further growth of tumor, the cells circulated and engrafted other bone marrow sites, clearly reflecting the myeloma biology [in humans],” Das said.

Next, the Yale researchers injected the mice with a further stage of myeloma called plasma-cell leukemias, in which the disease spreads from the bone marrow throughout the whole body, Flavell said. Following this, the tumor spread everywhere.

“In other words, in the system that we studied, we had a very faithful replication in the mice of what you see in human patients,” Flavell said.

Verma also emphasized the importance of the mouse model’s ability to capture not only the cancer’s phenotype, but also the genetic complexity and evolution of the tumor.“This model can help move forward therapeutic platforms, including cellular, small molecular or monoclonal antibodies, from a pre-clinical stage to clinical stage of development,” he said.

More specifically, it can be used to screen myeloma immunotherapies, like CAR-T from Novartis, or small molecular antibody therapies, such as anti-CD38 from Johnson and Johnson, which have had successful preliminary results for myeloma patients.

Finally, the model could potentially assist in designing next-generation combination precision-medicine therapies, Verma said. Rather than waiting and using one line of therapy followed by another, Verma added, “we can bring in multiple targeted approaches in a very personalized way to the patient to get one step closer to the cure for myeloma.”

Correction, Oct. 25: An earlier version of this article misstated Rituparna Das’ role in the paper.

Sports Medicine

October 10, 2014 2:49 am Leave a Comment

Yale’s football team has 34 new freshman members this year, and most will toil in relative obscurity until they earn playing time as upperclassmen. But when Dante Chiappetta of North Haven joined the team, he got a press conference in a booth high above the Yale Bowl. While the cameras rolled, Chiappetta signed his name and committed himself to the team, then tossed a football to head coach Tony Reno in celebration. Those in attendance cheered.

But Dante’s addition to the Bulldogs’ roster was distinct in other ways as well. The most obvious is that he is only six years old.

Dante has cortical visual impairment and cerebral palsy, conditions that together nearly blinded him and have left him unable to walk without the assistance of leg braces. He attends physical, occupational and speech therapy daily, and can communicate only with basic words and sentences. His “draft” by the Bulldogs was arranged by Team IMPACT, a Boston non-profit that uses sports to improve the lives of children with chronic or life-threatening illnesses.

Only a few weeks later at Payne Whitney Gymnasium, the Yale men’s basketball team offered a similarly uplifting gesture to fourteen-year-old Riley Mack. A native of Florida who now lives in Trumbull, Connecticut, Riley was diagnosed at age three with a debilitating brain tumor that has sapped his energy and health. But now, thanks to the largesse of the Friends of Jaclyn Foundation — like Team IMPACT, a nonprofit pairing sick children with sports teams — Riley wears a No. 1 jersey while he looks on at Yale men’s basketball home games.

For kids and teams alike, the experience has been transformative. Dante’s and Riley’s parents say partnerships with the teams have given their kids energy and strength, while players say the kids’ presence helps power them through tough stretches. In an age of statistical analysis and sports by the numbers, some may be skeptical that such emotional gestures can have real returns. But if there are skeptics, those on the court or the field aren’t among them.

According to tight end Jackson Stallings ’17, “Dante is at the center of the growth of our team” — a team that is now 3–0 to start the season.

But the stories of Dante and Riley are more than just heartwarming. With professional sports constantly mired in scandal and players demanding multimillion-dollar salaries to play games designed to pass the time, their stories hint at questions of why we play sports in the first place.

* * *

Dante’s “draft” took place on Sept. 11, in the company of his father and mother, Joe and Jeanine, as well as his two brothers, Nate and London.

“The night of the draft, it was evident from the smile on his face, from ear to ear, that he loved being the center of attention,” said Joe Chiappetta, adding that Dante has taken to the team and will be dressing as a Yale football player on Halloween.

Stallings and defensive end Marty Moesta ’17 have been instrumental as liaisons between the football team and the Chiappetta family, but their job has been an easy one: Players say having Dante around has been completely natural.

When asked about his role in setting up the event for Dante, Stallings was quick to offer a correction.

“Well, it [wasn’t] really an event,” Stallings said. “We have a family-type relationship with the Chiappettas. They come to most practices and all of our home games. We have dinner together sometimes, and Dante is at the center of the growth of our team.”

The Bulldogs’ growth has been on full display this season as they currently boast a 3–0 record, highlighted by a remarkable 49–43 overtime victory against Army. And according to Stallings, Dante’s presence has played a vital role in the team’s success.

That sentiment — that the teams benefit just as much as the children they take in — is felt just as strongly up the street from the Yale Bowl, at Payne Whitney Gymnasium.

That was the venue where, just a few short weeks after the football team drafted Dante on Sept. 11, the Bulldogs’ basketball roster also grew by one, and point guard Javier Duren ’15 could not be more grateful for 14-year-old Riley Mack’s presence.

“He’s going to be able to impact us more than we can impact him,” Duren said in an interview for an article last week. “Whenever we’re feeling down, whether it’s because of practice or it’s because of games, we know that we can look at Riley for support and he’ll be there for us.”

After head coach James Jones presented Riley with a Yale jersey bearing the number one, the team welcomed the youngster with open arms and his very own stall in the locker room where he could hang up his new Nike top. Adorned with a nameplate, the stall will be Riley’s to call his own indefinitely.

“This relationship is for as long as Riley is alive. He’s going to have that locker in there and he’s going to be No. 1 at their games wearing their jersey,” said Denis Murphy, the founder of the Friends of Jaclyn Foundation. As Team IMPACT provided the platform for Dante to join Yale’s football team, Murphy’s foundation united Riley with the Elis’ basketball team.

If anyone understands what parents like Joe or Jeanine or Donna — Riley’s mother — are going through, it is Murphy.

The “Jaclyn” in “Friends of Jaclyn” is Jaclyn Murphy, Denis’s daughter. Her story inspired Riley’s.

* * *

Jaclyn was nine years old when, in 2004, she received news that would forever change her life as well as her family’s. Jaclyn was diagnosed with medulloblastoma, a malignant brain tumor.

But Jaclyn is now 20 years old, in remission and studying at Marist College. And neither she nor her family could have predicted that her diagnosis would change thousands of lives besides their own — and for the better.

The Friends of Jaclyn Foundation was the Murphy family’s response to a magical relationship Jaclyn had the fortune of experiencing. The year following the devastating news of her tumor, Jaclyn happened to become connected with the Northwestern University women’s lacrosse team.

After building a most unlikely friendship, the team adopted Jaclyn as an honorary member. Even more unlikely, the team that had been established just three years prior went on to capture Northwestern’s first NCAA national championship in any sport in 64 years.

Inspired by Jaclyn, the team went on a run for the ages. One title would certainly have been enough for everyone to walk away happy and thankful to have witnessed such a feat.

Instead, the team went on to win the next six national championships.

The Murphys hoped to replicate the unique bond that only sports can produce, and in the nine years since FOJ was founded, over 500 children have been adopted by collegiate athletic programs across the country — Riley was the 520th. But Murphy says the experience will never grow old.

“It’s hard because we’ve lost 103 children. I’m around death. People see me and they run,” Murphy said in an Oct. 1 interview for an earlier article in the News. “You don’t know how long a child’s journey is going to be, whether it’s a day or a week or a year — that’s how insidious this disease is. But one day at a time, that’s why we live in the moment and play in the moment.”

For FOJ and Team IMPACT, the missions are one and the same: to improve the quality of life for children who have been fighting uphill battles for the majority of their lives.

It’s hardly a surprise that sports are a key ingredient. Murphy fondly recalled the memories of his family attending practice at Northwestern, and the wondrous sensation of immersing themselves in the midst of that team’s storybook run to the title.

For a couple of hours at a time, sports enabled Jaclyn and her family a release from the immense pressures and stresses of real life.

Eleven years later, sports are doing the same for Riley.

According to Murphy, Riley suffers from chronic fatigue that makes completing his physical therapy near impossible. Nevertheless, Riley played for over an hour on the court at Payne Whitney, dribbling and shooting with his new teammates with energy his mother hadn’t seen in some time.

Though Riley’s turnaround on that day may seem inexplicable, Duren, the point guard — who has experienced the adrenaline rush of sports many a time — offered as straightforward an explanation as possible.

“Sports can change lives, man,” he said.

* * *

Murphy declined to accept praise for what he has created with FOJ, noting that he’s “nothing but a brain tumor dad” trying to make Jaclyn’s vision come to life.

Like Duren or Stallings, he doesn’t see what he’s doing as one-sided charity. Teams give something to the kids they adopt and the kids give something back, whether they realize it or not.

All the same, Murphy acknowledged that what he does can be difficult, as is inevitable when in such an emotional and potentially heartbreaking line of work. But if you ask the players who have gotten to know Riley and Dante, the strength that such difficulty requires is what makes the relationship special.

For Children, Kesem Brings Magic

September 5, 2014 2:26 am Leave a Comment

I’ve never heard someone tease out a single week and identify it as the most meaningful week of their life. So this week, when not one but four people told me unanimously that working at Camp Kesem was the most special, most fulfilling week they had ever lived, I began to discover that this camp is, well — more than a camp.

Jayne Flynn ’15 waves her arms and raises her eyebrows up and down as she enthusiastically tells me about working at Kesem. “It consumes my life now and makes me happier than anything in the world,” Flynn says.

Camp Kesem was founded in 2000 at Stanford University to give kids who have a parent who either has, is in remission from or has been killed by cancer the opportunity to “just be kids,” explains Cortney Lebeda, Camp Kesem Program Director for Yale.

Over 3 million children in America have a parent who has struggled or is still struggling with cancer, and, according to Lebeda, Kesem has expanded into 63 chapters since its founding. In the past summer, over 4,000 kids attended various branches of Camp Kesem throughout the country.

Flynn initially developed an interest in Kesem after her sister worked at the Stanford branch of the camp as an undergraduate. When Flynn contacted the Camp Kesem national office her sophomore year, she was surprised to learn that two Yale seniors, Amanda Murray ’14 and Danna Moustafa ’14 had already begun applying for funding to start a Camp Kesem at Yale. By spring of 2013, Flynn, Murray, and Moustafa had gotten the organization approved, sent out applications to create a board and received a Livestrong grant to start funding. This summer, Yale hosted its first camp.

Kesem means magic in Hebrew, explains Flynn. “The whole point of the week for us is to make magic. To kind of forget your reality at home and go into this camp reality where you’re singing and dancing and laughing the whole entire time. We never explicitly say the word ‘cancer’ at camp.”

* * *

Flynn, Murray and Moustafa, started recruiting board members and counselors in the spring of 2013. They ended up recruiting 22 counselors — whom Flynn describes as people who would never be friends with each other in Yale culture otherwise — from varsity baseball players to members of children’s theater. “We are all each other’s best friends at this point,” Flynn gushes. “The 22 of us had the best time with each other and with these 40 kids.”

In fact, there were so many applications to be counselors that some had to be turned away, and there has been even more interest expressed this year. Flynn says that she’s already had juniors and seniors coming up to her with news that they’ve heard of Kesem and want to know if there’s any way they can get involved.

But while enthusiasm has spread, some of the group’s older members started working for Kesem for personal reasons.

I sit on the lawn of cross campus with Erin Alexander ’15 and Duane Bean ’17, the public relations and marketing coordinators for Kesem at Yale. Bean and Alexander also served as counselors this summer — Alexander for 13-16 year old girls, and Bean for 6-8 year old boys. I ask if either of them has had experience with cancer in their family. There’s a moment’s pause.

“My mom has cancer,” Alexander answers, breaking the silence.

“My dad had cancer when I was 10,” says Bean.

Bean says that experience was the real reason he joined Kesem: He would have loved to have something like the camp around at that age. Bean and Alexander say that they had not even known how some of their peer’s lives had been affected by cancer until the “empowerment” ceremony, which took place on the Wednesday night of camp. Empowerment is the only time during the week where cancer is deliberately brought up — a night where campers pass around a ball of yarn, and, as it unravels, each has the opportunity to share their story.

“It was an emotionally moving experience, but it was something that I’ll take away with me — hearing all the counselors’ stories, the kids’ stories, being supported by everyone around you — it was one of the greatest feelings I’ve ever experienced,” Alexander said.

Although Alexander initially thought that the kids would be reluctant to open up, she says reckons around three quarters of them shared their stories that night.

Laura Brink ’15, co-director of the camp with Flynn, said she was surprised how much the children were able to share, despite some of them being of a young age — Kesem’s youngest campers are six years old. She describes being taken aback by one preteen boy — a kid who was always running around and cracking jokes — who showed a deeply reflective side at the ceremony as he spoke about dealing with his father’s cancer.

“This boy was 10 times more mature than I’ll ever be,” said Brink.

* * *

Flynn stresses that the main focus of the camp is not necessarily “helping” kids but rather providing them companionship and a loving support network. Besides the Wednesday empowerment ceremony, the atmosphere resembles any other camp, with singing, dancing, laughing and games. In the mornings, campers choose between a shifting schedule of dance and drama, sports, arts and crafts, and outdoor activities. In the afternoon, there are camp-wide events like a carnival, a lake day, and slip and slide. At night, people gather for a campfire or talent show.

Each camper — and counselor — chooses a “camp name” to further facilitate the “escape from their home reality,” as Flynn describes it. Flynn’s own camp name is “Trex” — a name she received due to her brother’s comments that she runs in the fashion of a T. rex. The counselors and campers go by the imagined names throughout the week, ranging from “Spike” and “Attack” to “Airplane” and “Little Rascal.” In fact, Yale students involved with Camp Kesem use the camp names throughout the year — when I told Flynn that I was interviewing Alexander and Bean later in the day, she asked me if I meant to say Cedar and Jade.

Brink says that Yale’s Camp Kesem has no problem finding counselors or campers — there were 10 kids on the wait-list this past summer who weren’t able to attend — the real problem is finding funding. The camp is offered free of cost to every child, but, as a result, there are around $40,000 in operating expenses that the student-organizers have to cover. The national organization does not provide any funding, so other than the original Livestrong grant, the students are left to fundraise on their own. Efforts have included letter-writing drives, donations from local businesses and even jars set outside of Family Weekend a capella concerts. Flynn says she hopes that they will be able to solicit more funding now that they have established themselves with a successful summer.

But that funding is also important for Yale’s program to establish itself among those at other colleges. Flynn pointed out that other schools that organize Kesem branches — such as MIT and Duke — have so many campers that they have two sessions of per summer. At Stanford, there are over 120 campers who regularly attend.

Yale’s members aren’t yet aiming for that number — they only planned host to 40 kids this year — but their current goal for the next year is to double the number of campers. Flynn has dreams for many more.

“To only be one year new and already have the campus presence that we do is so exciting for us and hopefully makes our reach more widespread and more influential. We want as many people who want to get involved. It’s amazing. and I can’t wait to see how this year goes.”

* * *

At 4:00 a.m. on Wednesday, the loud peal of a telephone ring awakened Brink. She was told that the guardians of one of the eight-year-old girls would be coming to pick her up and bring her to the hospital — the girl’s mother was in critical condition.

“Her mom died that afternoon,” Brink said.

Later in the day, Brink received yet another phone call — the girl was coming back to camp.

“We were all at dinner. We put her stuff away, I’m walking her into dinner, and one of the counselors comes up and picks her up and gives her a huge hug, her whole table comes up and gives her a huge hug, and she’s just happy, happy, happy, a huge smile on her face.”

Brink said she thinks it’s the biggest testament to what Kesem does — that the girl wanted to come back to camp.

Yale Daily News

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