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Tobias Janowitz

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Tobias Janowitz and Hassal Lee. Photo by Caryn Koza

By Daniel Dunaief

Before treatments for any kind of health problem or disease receive approval, they go through a lengthy, multi-step process. This system should keep any drugs that might cause damage, have side effects or be less effective than hoped from reaching consumers.

In the world of cancer care, where patients and their families eagerly await solutions that extend the quality and quantity of life, these clinical trials don’t always include the range of patients who might receive treatments.

Hassal Lee. Photo by Caryn Koza

That’s according to a recent big-picture analysis in the lab of Cold Spring Harbor Laboratory Professor Tobias Janowitz. Led by clinical fellow Hassal Lee, these researchers compared where clinical trials occurred with the population near those centers.

Indeed, 94 percent of United States cancer trials involve 78 major trial centers, which were, on average, in socioeconomically more affluent areas with higher proportions of self-identified white populations compared with the national average.

“We should test drugs on a similar population on which we will be using the drugs,” said Lee. In addition to benefiting under represented groups of patients who might react differently to treatments, broadening the population engaged in clinical trials could offer key insights into cancer. Patient groups that respond more or less favorably to treatment could offer clues about the molecular biological pathways that facilitate or inhibit cancer.

Janowitz suggested that including a wider range of patients in trials could also help establish trust and a rapport among people who might otherwise feel had been excluded.

The research, which Lee, Janowitz and collaborators published recently as a brief in the journal JAMA Oncology, involved using census data to determine the socioeconomic and ethnic backgrounds of patient populations within one, two and three hour driving distances to clinical trials.

The scientists suggested researchers and drug companies could broaden the patient population in clinical trials by working with cancer centers to enlist trial participants in potential life-extending treatments through satellite hospitals.

Project origins

This analysis grew out of a study Janowitz conducted during the pandemic to test the effectiveness of the gerd-reducing over-the-counter drug famotidine on symptoms of Covid-19.

Janowitz generally studies the whole body’s reaction to disease, with a focus on cancer associated cachexia, where patients lose considerable weight and muscle mass. During the pandemic, however, Janowitz, who has an MD and PhD, used his scientific skills to understand a life-threatening disease. He designed a remote clinical trial study in which participants took famotidine and monitored their symptoms.

While the results suggested that the antacid shortened the severity and duration of symptoms for some people, it also offered a window into the way a remote study increased the diversity of participants. About 1/3 of the patients in that population were African American, while about 1/4 were Hispanic.

Lee joined Janowitz’s lab in early 2022, towards the end of the famotidine study. 

“The diverse patient population in the remote trial made us wonder if commuting and access by travel were important factors that could be quantified and investigated more closely,” Janowitz explained.

Lee and Janowitz zoomed out to check the general picture for cancer clinical trials.

To be sure, the analysis has limitations. For starters, the threshold values for travel time and diversity are proof of concept examples, the scientists explained in their paper. Satellite sites and weighted enrollment also were not included in their analysis. The cost other than time investment for potential clinical trial participants could present a barrier that the researchers didn’t quantify or simulate.

Nonetheless, the analysis suggests clinical trials for cancer care currently occur in locations that aren’t representative of the broader population.

The work “leveraged freely available data and it was [Lee’s] effort and dedication, supported by excellent collaborators that we had, that made the study possible,” Janowitz explained.

Since the paper was published, Cancer Center directors and epidemiologists have reached out to the CSHL scientists.

Searching for clinical research

After Lee, who was born in Seoul, South Korea and moved to London when she was five, completed her MD and PhD at the University of Cambridge, she wanted to apply the skills she’d learned to a real-world research questions.

She found what she was looking for in Janowitz’s lab, where she not only considered the bigger picture question of clinical trial participation, but also learned about coding, which is particularly helpful when analyzing large amounts of data.

Lee was particularly grateful for the help she received from Alexander Bates, who, while conducting his own research in a neighboring lab in the department of Neurobiology at the MRC Laboratory of Molecular Biology in Cambridge, offered coding coaching.

Lee described Bates as a “program whiz kid.”

A musician who enjoys playing classical and jazz on the piano, Lee regularly listened to music while she was in the lab. Those hours added up, with Spotify sending her an email indicating she was one of the top listeners in the United Kingdom. The music service invited her to an interview at their office to answer questions about the app, which she declined because she had moved to the United States by then.

The top medical student at Cambridge for three years, Lee said she enhanced her study habits when she felt unsure of herself as a college student.

She credits having great mentors and supportive friends for her dedication to work.

Lee found pharmacology one of the more challenging subjects in medical school, in part because of the need to remember a large number of drugs and how they work.

She organized her study habits, dividing the total number of drugs she needed to learn by the number of days, which helped her focus on studying a more manageable number each day.

Lee will be a resident at Mt. Sinai Hospital later this year and is eager to continue her American and New York journey.

As for the work she did with Janowitz, she hopes it “really helps people think about maintaining diversity in clinical trials using data that’s already available.”

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Queen Elizabeth II. Pixabay photo

By Daniel Dunaief

Daniel Dunaief

During the Platinum Jubilee for Queen Elizabeth II to celebrate the monarch’s 70 years on the throne, Clary Evans, a radiation oncologist who works at Northwell Health, her husband Tobias Janowitz, a scientist at Cold Spring Harbor Laboratory, and their families got together with another English family to mark the occasion.

They made a cake and had tea, “aware that this was probably the last time” they would celebrate Queen Elizabeth’s lengthy legacy, Evans recalled in an email.

Residents of Suffolk, England, Evans’s parents Philip and Gillian shared memories and thoughts on Queen Elizabeth II, who died last week at the age of 96.

Before Elizabeth’s coronation at the age of 27, Philip Evans, who was a teenager, traveled with his brother Anthony to Trafalgar Square, where they camped out near the fountain.

After a night filled with an early June rain in 1953, Evans and his brother awaited the moment to see the queen, whose coronation occurred 16 months after she became queen.

Gillian and Philip Evans with their Patterdale terrier puppy in Mettingham, Suffolk, UK in August of this year. Photo from Clary Evans

The next morning, as crowds continued to grow, the police pushed the newer arrivals in front of the group, which meant Phillip was in the third tier of onlookers.

Through the crowd, he caught a glimpse of the young queen, offering a stiff wave to her subjects.

“It was a marvelous thing to do,” Evans said by phone from his home. The travel and waiting in the rain meant it “wasn’t easy.”

Gillian Evans, meanwhile, traveled with her family to visit her aunt, who, at the time, was the only one in her family who owned a television.

“It was lovely to see what a beautiful spectacle it was,” Gillian Evans said.

The queen executed her duties admirably under an intense spotlight that never dimmed during her over 70 years of service, she added.

“What a remarkable lady she had been,” Gillian Evans added. “She said she would give herself to the nation for as long as she lived, and she did. Right up to the very, very last, which is wonderful.”

While Gillian Evans thought such conditions were akin to being in  prison, with all the limitations and the constant responsibilities, she believed the queen “loved it. It showed in her face.” Being a part of a “love match” with her husband Prince Philip “must have helped enormously.”

The Evans matriarch, 83, who is a retired diagnostic radiographer, is amazed at the effect the queen’s death is having on residents.

Philip Evans, who said the queen did “jolly well,” recognized that the queen made mistakes, one of which arose during her muted reaction to the death of Princess Diana in a car crash in 1997.

“She had a really bad time when Princess Diana was killed,” said Philip Evans, who retired in 2000 as a general surgeon. “She was just pulled down by the power of the press. In legalese, ‘she was badly advised.’”

During a recent visit to the ophthalmologist, Evans chatted with three people about the queen and her son Charles, who has now become King Charles III.

People were saying “the queen had done a good job” and that they believed her son was “well suited” for his new role.

Philip Evans has noticed that the church bells ringing in the aftermath of her death don’t have their typical sound.

The sound alternates between loud and muted. The churches are using a so-called half-muffled peal, which creates a somber echo. The bells rang the same way last year after Prince Philip’s death.

“It’s very alarming and tells you that something is odd,” Evans said.

As the country prepares for the funeral of a queen born eight years after the Spanish Influenza pandemic of 1918 and who died two years after COVID-19, Clary Evans recognized that Queen Elizabeth II was a “link to those values of duty and service that were strong in those war and post-war years.”

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Members of the CanCan team, from left,Oliver Maddocks, David Lewis, Johan Vande Voorde, Bette Caan, Marcus Goncalves, Eileen White, Mariam Jamal-Hanjani, Tobias Janowitz, Karen Mustian, Janelle Ayres andToni Hui

By Daniel Dunaief

If a team Cold Spring Harbor Laboratory Assistant Professor Tobias Janowitz co-leads succeeds, researchers will know more about the end stage of numerous types of cancer that involves the loss of tissue and muscle mass.

Tobias Janowitz

Recently, lead scientists Janowitz; Eileen White, Rutgers Cancer Institute of New Jersey Deputy Director and Chief Scientific Officer; and Dr. Marcus DaSilva Goncalves, Assistant Professor of Medicine at Weill Cornell Medicine received $25 million in funding as a part of a Cancer Grand Challenge, which is a combined trans-Atlantic funding effort between Cancer Research UK and the National Cancer Institute in the United States.

The cachexia group was one of four teams to receive funding among 11 finalists.

Bruce Stillman, president of Cold Spring Harbor Laboratory, described cachexia as “one of the most difficult clinical problems with late stage cancer.”

Stillman added that the collaboration is promising because it brings together a group of “remarkable” scientists, including White, who was a postdoctoral fellow in Stillman’s lab. “It has great potential for making a difference in the lives of patients.”

Stillman believes Janowitz is an ideal co leader for this challenging project because he has an MD and a PhD and is clinically certified as an oncologist.

CanCan team

For his part, Janowitz is looking forward to the opportunity to team up with other ambitious research efforts to create a virtual institute.

Eileen White

“It’s incredibly exciting to get the chance to do something you think is higher risk with a large group of people who have come together around this problem,” said Janowitz. “We often talked about how it would be nice to bring team members from other disciplines into this area.”

Indeed, the cachexia team, which White named CanCan for Cancer Cachexia Action Network believes cachexia is a tumor-driven metabolic imbalance. The group is pursuing different areas of research, including metabolism, neuroendocrinology, clinical research, and immunology, among others, to define clinical subtypes with the hopes of creating individualized therapies.

While the effort brings together a range of scientists with different expertise and technological skills, researchers don’t expect an immediate therapeutic solution within that time frame. Rather, they anticipate that their experiments and clinical data will help inform future approaches that could enhance efforts to prevent and treat a wasting disease that causes severe declines in a patient’s quality of life.

“What we would deem as a success is, if in five years time, we have maybe one to three strong lead hypotheses that comes out of our shared work on how we can either prevent or treat cachexia as it emerges,” Janowitz said.

The complexity of cachexia

Dr. Marcus DaSilva Goncalves

As a complex process that involves an understanding of numerous interconnected dynamics, cachexia has been a challenging field for researchers and a difficult one for funding agencies looking for discrete problems with definable results and solutions.

Cachexia research had “never reached this critical mass that people were seeing where we can say, ‘Okay, there’s enough work going on to really unravel this,’” Janowitz said.

The CanCan team has several scientific themes. Janowitz will be involved with metabolic dysregulation. He would like to understand the behavioral changes around appetite and food intake.

Additionally, the group will explore the interaction of normal cells and cancer cells by looking at the tumor micro environment. This research will explore how cancer cells can reprogram healthy host cells.

“We’ve got a really exciting axis of research” within the network, Janowitz said.

Searching for signaling molecules

Janowitz said Norbert Perrimon, James Stillman Professor of Developmental Biology at Harvard Medical School is one of the leading experts in fly genetics and fly biology. Perrimon has created a model of cachexia in the fruit fly. While that sounds far from patients, Perrimon can use single molecule resolution of the entire organism to get an insight and understanding of candidate molecules.

“We are hoping to search for new signaling molecules that might get involved” in cachexia, Janowitz said. Once the research finds new candidates, he and others can validate whether they also work in mouse models of cancer and cancer cachexia.

With numerous clinical groups, Janowitz hopes to contribute to the design and execution of experimental medicine studies.

The Cancer Grand Challenge will distribute the funds based on what members need. Janowitz described the allocation of funds as “roughly equitable.” He will use that funding to support a postdoctoral researcher, a PhD student and a technician, who can help with specific projects he’s merging in his lab to combine with the team effort.

The funds will also support his salary so he can supervise the work in his lab and help with the coordination of this effort.

The funding agencies have an additional budget to organize conferences and meetings, where researchers can discuss ideas in person and can ensure that any clinical and laboratory work is standardized and reproducible in different facilities.

Cold Spring Harbor Laboratory will host the first full gathering of the cachexia team in November.

Challenging beginnings

When he was a doctor in the United Kingdom, Janowitz was fascinated and confounded by cachexia. In the early years of his training, he saw patients who had a small tumor burden, but were so sick that they died. Those experiences made “such a strong imprint” that he wanted to help unravel this process as a junior oncologist, he said.

Getting funding was challenging because cachexia was complex and didn’t involve a finely defined project that linked a receptor protein to a cell type that led to a diseased condition.

Janowitz, among others in this field, felt passionate enough about this area to continue to search for information about cachexia. After he restructured his research into a narrower focus, he secured more funding.

An unsolved mystery

With enough researchers continuing along this path, Janowitz said the group developed an awareness that this is “one of the big, unsolved mysteries of cancer progression.”

Janowitz appreciates the opportunity to work with a team that has accomplished researchers who work in fields that are related or synergistic, but aren’t necessarily considered part of the cachexia field.

The significant funding comes with expectations.

“The grant is both a great joy, but also, essentially, a mandate of duty,” he said. “Now, you have to utilize this grant to make significant contributions to understand and hopefully treat this debilitating condition.”

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Famotidine molecule Image courtesy of Wikipedia

By Daniel Dunaief

An over-the-counter stomach-soothing medication may also relieve some of the symptoms of mild to moderate COVID-19.

Tobias Janowitz Photo courtesy of CSHL

In a study recently published in the journal Gut, Cold Spring Harbor Laboratory Assistant Professor Tobias Janowitz and a team of collaborators at CSHL and The Feinstein Institutes for Medical Research at Northwell Health demonstrated that Famotidine, the active ingredient in Pepcid, shortened the duration of symptoms for a diverse patient group of adults soon after developing COVID-19 symptoms.

In a placebo-controlled study, people taking 80 milligrams of Famotidine three times a day reported that symptoms such as headaches declined after 8.2 days, compared with 11.4 days for patients who were taking the placebo.

“We think that the results are preliminary, but encouraging,” Janowitz explained in an email. 

The research, which included 55 volunteers, may offer health care providers another tool to help treat mild to moderate cases of COVID-19. In the clinical study, the use of Famotidine helped reduce a potentially overactive inflammatory response without suppressing the immune system’s efforts to ward off the virus.

Participants in the study received Famotidine or placebo pills along with a host of instruments they could use at home to gather clinical data about themselves, including a cellular activated Apple iPad, a scale, thermometer, fitness tracker, spirometer to measure air flow in and out of the lungs and a pulse oximeter, which measured oxygen levels by taking a reading over a person’s fingernails.

The protocol for the study allowed volunteers to stay home, where they gathered results from the instruments and reported on their health and any symptoms they felt. Technicians came to the home of each volunteer on the first, seventh, 15th, and 28th days after entering the clinical trial.

Researchers and doctors involved in the analysis of the effectiveness of COVID believe this remote approach to participating in clinical trials could prove a safe and effective way to conduct research for other diseases.

“In today’s virtual world, our clinical trial strategy has significant implications for how to study new drugs in patients at home,” Dr. Kevin Tracey, president and CEO of the Feinstein Institutes, explained in a Cold Spring Harbor Laboratory news brief.

Janowitz added that other studies could also use testing protocols at home, including for other diseases. “We are looking forward to employing it to help develop better treatments for people with cancer,” which is the disease at the center of his research, he explained.

The CSHL Assistant Professor focuses on the whole body response to cancer, although many of the biological considerations are transferable to other diseases.

Pivot to COVID

According to Janowitz, “It was relatively easy for us to pivot to COVID research when it was a global area of unmet need.” 

The researchers chose Famotidine because of encouraging studies and from a case series, Janowitz explained. They also found a potential mechanism of action where Famotidine blocked the H2 receptor, which encouraged them to move to a phase 2 randomized clinical trial.

The researchers were pleased that the participants in this small trial included people from a range of ages and ethnic groups. Nearly two thirds of patients, who were 18 years and older, were from black, mixed-race or Hispanic communities.

“Patients with different ancestry may have different responses to this disease,” Janowitz explained. “It helps to learn about the generalizability of the results.”

In a CSHL news brief, Nicole Jordan-Martin, executive director for New York City Health + Hospitals, added that “accessible, safe and low-cost outpatient treatment options are a priority in our global efforts to combat COVID-19.” Northwell and New York City Health + Hospitals provided care for the communities most in need of support for New York City, she added.

The collaborators were also encouraged by their teamwork.

“Our institutions worked extremely well together to face challenges the pandemic posed, like offering digital solutions and reaching populations who struggled for access to care,” Dr. Christina Brennan, vice president of clinical research at the Feinstein Institute and co-investigator of the trial, said in the news brief. 

“From screening patients to organizing home delivery of the equipment and medication, this sets a new model for future trials and convenience for participants.”

Janowitz described the safety profile of Famotidine as “excellent” and said it “appears to have few interactions with other drugs and very few side effects in general.”

To be sure, Janowitz cautioned doctors and patients not to stock up on Famotidine before researchers conduct additional studies.

“Our trial is not conclusive and an early phase clinical trial (phase 1 or 2) is not sufficient to inform clinical practice,” he wrote.

Additionally without further study, researchers don’t know the best potential dose and dosing interval for this possible treatment. At this point, they know how long the drug stays in the blood and the strength of its binding to its receptor.

A dose of 20 milligrams per day or less may be too little to achieve an effect, but “we do not know this for certain,” Janowitz explained.

While researchers agreed that further studies were necessary to answer key questions, they believed that the results from this research could provide fodder for studies outside of the COVID world.

“It is possible that sustained inflammation contributes to illness in other contexts and changing this inflammation would be beneficial,” Janowitz wrote. “This will have to be explored separately. Importantly, the methods used in this trial are also transferrable, so we have learned a lot of important information” from this research.

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Feinstein Institutes’ Drs. Kevin Tracey and Christina Brennan break down the current COVID-19 clinical trials and treatments. Photo courtesy of The Feinstein Institutes for Medical Research

By Daniel Dunaief

In a collaboration between Cold Spring Harbor Laboratory and Northwell Health’s Feinstein Institutes for Medical Research, doctors and researchers are seeking patients with mild to moderate symptoms of COVID-19 for an at-home, over-the-counter treatment.

The two-week trial, which will include 84 people who are 18 years old and older, will use a high, but safe dose of Famotidine, or PEPCID, in a double-blind study. That means that some of the participants will receive a placebo while others will get the Famotidine.

Volunteers will receive the dosage of the medicine or the placebo at home and will also get equipment such as pulse oximeters, which measure the oxygen in their blood, and spirometers, which measure the amount of air in their lungs. They will also receive a scale, a thermometer, a fitness tracker and an iPad.

Dr. Christina Brennan. Photo courtesy of The Feinstein Institutes for Medical Research

Northwell Health will send a certified phlebotomist — someone licensed to draw blood — to the participants’ homes to collect blood samples on the first, 7th, 14th, and 28th day of the study.

The study is the first time CSHL and Northwell Health have designed a virtual clinical trial that connects these two institutions.

“What is very powerful with our work with Cold Spring Harbor Laboratory is the ability to do a virtual trial and utilize patient-recorded outcome measures,” said Christina Brennan, a co-investigator on the study and Vice President for Clinical Research for Northwell Health. “I’m thrilled that we’re doing this type of virtual trial. It’s very patient-centric.”

While reports about the potential benefits of Famotidine have circulated around the country over the last year, this study will provide a data-driven analysis.

“If we study this in the outpatient population, then we might have an opportunity to see if [Famotidine] really does play a role in the reduction of the immune overreaction,” Brennan said.

At this point, researchers believe the drug may help reduce the so-called cytokine storm, in which the immune system becomes so active that it starts attacking healthy cells, potentially causing damage to organs and systems.

In an email, Principal Investigator Tobias Janowitz, Assistant Professor and Cancer Center Member at Cold Spring Harbor Laboratory, wrote that “there are some retrospective cohort studies” that suggest this treatment might work, although “not all studies agree on this point.”

In the event that a trial participant developed more severe symptoms, Janowitz said the collaborators would escalate the care plan appropriately, which could include interrupting the use of the medication.

In addition to Janowitz, the medical team includes Sandeep Nadella, gastroenterologist at Northwell, and Joseph Conigliaro, Professor of the Feinstein Institutes for Medical Research.

Janowitz said he does not know how any changes in the virus could affect the response to famotidine.

In the trial, volunteers will receive 80 milligrams of famotidine three times a day.

The dosage of famotidine that people typically take for gastric difficulties is about 20 milligrams. The larger amount per day meant that the researchers had to get Food and Drug Administration approval for an Investigational New Drug.

“This has gone through the eyes of the highest regulatory review,” Brennan said. “We were given the green light to begin recruitment, which we did on January 13th.”

Volunteers are eligible to join the study if they have symptoms for one to seven days prior to entering the trial and have tested positive for the virus within 72 hours.

Potential volunteers will not be allowed in the trial if they have had other medications targeting COVID-19, if they have already used Famotidine in the past 30 days for any reason, if they have severe COVID that requires hospitalization, have a history of Stage 3 severe chronic disease, or if they are immunocompromised by the treatment of other conditions.

Brennan said Northwell has been actively engaged in treatment trials since the surge of thousands of patients throughout 2020.

Northwell participated in trials for remdesivir and also provided the steroid dexamethasone to some of its patients. The hospital system transfused over 650 patients with convalescent plasma. Northwell is also infusing up to 80 patients a day with monoclonal antibodies. The hospital system has an outpatient remdesivir trial.

“Based on all our experience we’ve had for almost a year, we are continuously meeting and deciding what’s the best treatment we have available today for patients,” Brennan said.

Janowitz hopes this trial serves as a model for other virtual clinical trials and is already exploring several potential follow up studies.

Brennan said the best way to recruit patients is to have the support of local physicians and providers. 

People interested in participating in the trial can send an email to [email protected] or call 516-881-7067.

When the study concludes, the researchers will analyze the data and are “aware that information on potential treatments for COVID-19, no matter if the data show that a drug works or does not work, should be made available to the community swiftly,” Janowitz wrote in an email.

The decision to test this medicine as a potential treatment for COVID-19 arose out of a conversation between Director of the Cold Spring Harbor Laboratory Cancer Center Dave Tuveson and CEO of the Feinstein Institute Kevin Tracey.

“I got involved because I proposed and developed the quantitative symptom tracking,” Janowitz explained.

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From left, Research Assistant Onur Eskiocak, CSHL Fellow Semir Beyaz and graduate student Ilgin Ergin. Photo by Gina Motisi, 2019/CSHL.

By Daniel Dunaief

It’s a catch-22: some promising scientific projects can’t get national funding without enough data, but the projects can’t get data without funding.

That’s where private efforts like The Mark Foundation for Cancer Research come in, providing coveted funding for promising high-risk, high-reward ideas. Founded and funded by Pamplona Capital Management CEO Alex Knaster in 2017, the Foundation has provided over $117 million in grants for various cancer research efforts.

Tobias Janowitz

This year, The Mark Foundation, which was named after Knaster’s father Mark who died in 2014 after contracting kidney cancer, has provided inaugural multi-million dollar grants through the Endeavor Awards, which were granted to three institutions that bring scientists with different backgrounds together to address questions in cancer research. 

In addition to teams from the University of California at San Francisco and a multi-lab effort from Columbia University, Memorial Sloan Kettering Cancer Center and Johns Hopkins University School of Medicine, Cold Spring Harbor Laboratory scientists Tobias Janowitz and Semir Beyaz received this award.

“We are absolutely delighted,” Janowitz wrote in an email. “It is a great honor and we are excited about the work.” He also indicated that the tandem has started the first set of experiments, which have produced “interesting results.”

The award provides $2.5 million for three years and, according to Janowitz, the researchers would use the funds to hire staff and to pay for their experimental work.

Having earned an MD and a PhD, Janowitz takes a whole body approach to cancer. He would like to address how the body’s response to a tumor can be used to improve treatment for patients. He explores such issues as how tumors interact with the biology of the host.

Semir Beyaz

Semir Beyaz, who explores how environmental factors like nutrients affect gene expression, metabolic programs and immune responses to cancer, was grateful for the support of the Mark Foundation.

Beyaz initially spoke with the foundation about potential funding several months before Janowitz arrived at Cold Spring Harbor Laboratory. When the researchers, whose labs are next door to each other, teamed up, they put together a multi-disciplinary proposal.

“If the risks [of the proposals] can be mitigated by the innovation, it may yield important resources or new paradigms that can be incorporated into research proposals that can be funded by the [National Institutes of Health] and other government agencies,” Beyaz said.

Janowitz wrote that he had a lunch together in a small group with Knaster, who highlighted the importance of “high-quality data and high-quality data analysis to advance care for patients with cancer.”

Michele Cleary, the CEO of The Mark Foundation, explained that the first year of the Endeavor program didn’t involve the typical competitive process, but, rather came from the Foundation’s knowledge of the research efforts at the award-winning institutions.

“We wanted to fund this concept of not just studying cancer at the level of the tumor or tumor cells themselves, but also studying the interaction of the host or patient and their [interactions] with cancer,” Cleary said. “We thought this was a fantastic project.”

With five people on the Scientific Advisory Committee who have PhDs at the Foundation, the group felt confident in its ability to assess the value of each scientific plan.

Scientists around the world have taken an effective reductionistic approach to cancer, exploring metabolism, neuroendocrinology and the microbiome. The appeal of the CSHL effort came from its effort to explore how having cancer changes the status of bacteria in the gut, as well as the interplay between cancer and the host that affects the course of the disease.

From left, Becky Bish, Senior Scientific Director, Ryan Schoenfeld, Chief Scientific Officer and Michele Cleary, CEO of The Mark Foundation at a workshop held at the Banbury Center at Cold Spring Harbor Laboratory in September 2019. Photo by Constance Brukin.

These are “reasonable concepts to pursue, [but] someone has to start somewhere,” Cleary said. “Getting funding to dive in, and launch into it, is hard to do if you can’t tell a story that’s based on a mountain of preliminary data.”

Beyaz said pulling together all the information from different fields requires coordinating with computational scientists at CSHL and other institutions to develop the necessary analytical frameworks and models. This includes Cold Spring Harbor Laboratory Fellow Hannah Meyer and Associate Professor Jesse Gillis.

“This is not a simple task,” Beyaz said. The researchers will “collaborate with computational scientists to engage currently available state-of-the-art tools to perform data integration and analysis and develop models [and] come up with new ways of handling this multi-dimensional data.”

Cleary is confident Janowitz and Beyaz will develop novel and unexpected insights about the science. “We’ll allow these researchers to take what they learn in the lab and go into the human system and explore it,” she said.

The researchers will start with animal models of the disease and will progress into studies of patients with cancer. The ongoing collaboration between CSHL and Northwell Health gives the scientists access to samples from patients.

With the Endeavor award, smaller teams of scientists can graduate to become Mark Foundation Centers in the future. The goal for the research the Foundation funds is to move towards the clinic. “We are trying to join some dots between seemingly distinct, but heavily interconnected, fields,” Beyaz said.

Beyaz has research experience with several cancers, including colorectal cancer, while Janowitz has studied colorectal and pancreatic cancer. The tandem will start with those cancers, but they anticipate that they will “apply similar kinds of experimental pipelines” to other cancer types, such as renal, liver and endometrial, to define the shared mechanisms of cancer and how it reprograms and takes hostage the whole body, Beyaz said. 

“It’s important to understand what are the common denominators of cancer, so you might hopefully find the Achilles Heel of that process.”

While Cleary takes personal satisfaction at seeing some of the funding go to CSHL, where she and Mark Foundation Senior Scientific Director Becky Bish conducted their graduate research, she said she and the scientific team at the foundation were passionate to support projects that investigated the science of the patient.

“No one has tried to see what is the cross-talk between the disease and the host and how does that actually play out in looking at cancer,” said Cleary, who earned her PhD from Stony Brook University. “It’s a bonus that an institution that [she has] the utmost respect for was doing something in the same space we cared” to support.

The CSHL research will contribute to an understanding of cachexia, when people with cancer lose muscle mass, weight, and their appetite. Introducing additional nutrition to people with this condition doesn’t help them gain weight or restore their appetite.

Janowitz and Beyaz will explore what happens to the body physiologically when the patient has cachexia, which can “help us understand where we can intervene before it’s too late,” Cleary said.

The CSHL scientists will also study the interaction between the tumor and the immune system. Initially, the immune system recognizes the tumor as foreign. Over time, however, the immune system becomes exhausted.

Researchers believe there might be a “tipping point” in which the immune system transitions from being active to becoming overwhelmed, Cleary said. People “don’t understand where [the tipping point] occurs, but if we can figure it out, we can figure out where to intervene.”

Scientists interested in applying for the award for next year can find information at the web site: https://themarkfoundation.org/endeavor/. Researchers can receive up to $1 million per year for three years. The Mark Foundation is currently considering launching an Endeavor call for proposals every other year.

 

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Tobias Janowitz. Photo from CSHL

By Daniel Dunaief

The body’s savior in its battle against disease, immune cells respond to a collection of signals which tell them to dial up or down their patrolling efforts.

Scientists and doctors are constantly trying to determine what combination of beneficial or detrimental signals can lead to different outcomes.

Recently, Assistant Professor Tobias Janowitz and Professor Douglas Fearon of Cold Spring Harbor Laboratory, working with Duncan Jodrell at the University of Cambridge Cancer Research Institute, used an inhibitor developed and tested for the treatment of the human immunodeficiency virus (HIV), the virus that causes AIDS, in patients with colorectal and pancreatic cancer for a week.

Douglas Fearon. Photo from CSHL

The study was done on 24 patients and is a phase 0 effort, in which scientists and doctors test the pharmacokinetics and pharmacodynamics of the treatment.

In the study, which was published in the prestigious journal Proceedings of the National Academy of Sciences of the United States of America, the researchers showed that the treatment got into the blood, that the patients tolerated it, and that it enabled immune treatments to reach the tumors.

While this is an encouraging step, Janowitz cautioned that any such studies are far from a potentially viable treatment for either type of cancer. Indeed, the Food and Drug Administration requires a lengthy and rigorous scientific process for any possible therapy, in part because numerous promising efforts haven’t led to viable therapies for a host of reasons.

Still, this study offers a promising beginning for a potential approach to treating various forms of cancer.

Janowitz said patients “tolerated the treatment by and large very well,” and that “no new toxicities were observed compared to the ones that were known.” Some people developed slight disturbances in their sleep, which were immediately resolved after they discontinued using the treatment.

The history of the possible treatment for HIV showed similar side effects years ago. “We anticipated it would have a favorable toxicity profile,” said Janowitz.

The link between this early candidate for HIV treatment and cancer came from an analysis of the receptor that is expressed on immune cells, called CXCR4.

This receptor is targeted by the drug plerixafor. Most of the work linking the inhibited receptor to potential cancer treatment came from Fearon’s lab, Janowitz explained.

Fearon found that blocking the receptor enabled immune cells to migrate to cancer in a mouse study. Along with Janowitz and CSHL Cancer Director David Tuveson, he published a paper on the preclinical study in a mouse model in PNAS in 2013.

This inhibitor also has been used to release stem cells from bone marrow that can be used in a hematological context for treatment and transplantation. During their cancer study, the scientists found these stem cells circulating in the blood. It’s unclear from this first study how the combination of cancer therapy and releasing stem cells from bone marrow affects patients.

“We are not able to say that that has a relevancy to the cancer patient,” Janowitz said.

While some drug treatments work for a period of time until a cancer returns, immunotherapy may have a longer term benefit than chemotherapeutics, as some studies suggest.

“By giving this drug, our hope is that we enable an influx of immune cells into the tumor and have an across the board integrated immune response,” Janowitz said.

Down the road, Janowitz said the group hopes that this treatment will be a part of a combination of treatments that treat cancer.

By enabling immune cells to access cancer where the mutation rate is lower, these treatments could provide a sustained treatment.

The researchers chose pancreatic and colorectal cancer because those cancers don’t respond to current immunotherapy. “It’s really important to uncover why that is,” said Janowitz. The scientists had evidence from pre-clinical models that the pathway and the biochemistry that this drug activates can be effective.

In his lab, Janowitz performed some of the mechanistic work to understand why this drug might function. A medical doctor who is awaiting his license to practice in New York, Janowitz was also involved in the trial management group and in analyzing the multiplicity of data that came together.

The researchers in this study came from fields including bioinformatics, clinical medicine, pharmacology, and immunology. Fearon explained in an email that Jodrell wrote the grant to Stand Up to Cancer, or SU2C, in 2014 to obtain funding for the trial. Jodrell oversaw the clinical trial and Fearon directed the evaluation of the immunology findings.

Janowitz had a “major role in putting together the clinical data for the write-up,” and Daniele Biasci, a computational biologist at Cambridge, developed the analysis of the transcriptional data of the tumor biopsies, said Fearon.

As for the next stages in this work, physicians at Johns Hopkins Medicine International and Dana Farber Cancer Institute will soon start a phase 2 trial that is already registered and that combines this inhibitor with anti-PD-1.

Fearon said his continued pre-clinical research has shown that this immune suppressive pathway may be relevant to multiple human carcinomas, and has identified new potential targets for more effective immunotherapy.

Janowitz, meanwhile, will explore the systemic immune competence of the body as he continues to take a top down, broad-based approach to cancer.

He would like to know the degree to which the body can mount an effective immune response, while also exploring the factors that diminish that ability.

Separately, with three young children at home, Janowitz and his wife Clary, who is a radiation oncologist, have been balancing between their busy careers and the demands of parenting during the pandemic. Their extended families are both in Europe.

“We can’t visit them and they can’t visit us,” he said adding that he appreciated the way CSHL has offered day care to young children on campus.

As for this study, Janowitz said he’s encouraged by the early results.

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Tobias Janowitz with research technician Ya Gao at Cold Spring Harbor Lab Photo by ©Gina Motisi, 2019/CSHL

By Daniel Dunaief

It’s a low-tech setting with high stakes. Scientists present their findings, often without slides and pictures, to future colleagues and collaborators in a chalk talk, hoping faculty at other institutions see the potential benefit of offering them an employment opportunity.

For Tobias Janowitz, this discussion convinced him that Cold Spring Harbor Laboratory was worth uprooting his wife and three young children from across the Atlantic Ocean to join.

Chalk talks in most places encourage people to “defend their thinking. Here, it was completely different. They moved on from my chalk talk quickly,” said Janowitz in a recent interview.

Research technician Ya Gao and Tobias Janowitz at Cold Spring Harbor Lab. Photo by ©Gina Motisi, 2019/CSHL

Janowitz recalled how CSHL CEO Bruce Stillman asked him “what else will you do that’s important and high risk. He moved me on from that discussion within five minutes and essentially skipped a step I’d usually spend at another institution. It’s a very special place.”

Janowitz, who earned a medical degree and a doctorate from the University of Cambridge, came to the lab to work in a field where he’s distinguished himself with cancer research that points to the role of a glycoprotein called interleukin 6, or IL-6, in a specific step in the progression of the disease, and as a medical oncologist. He will work as a clinician scientist, dedicated to research and discovery and advancing clinical care, rather than delivering standard care.

As CSHL continues to develop its ongoing relationship with Northwell Health, Janowitz said he expects to be “one of the intellectual bridges between the two institutions.”

In his research, the scientist specializes in understanding the reciprocal interaction between a tumor and the body. Rather than focusing on one type of cancer, he explores the insidious steps that affect an organ or system and then wants to understand the progression of signals and interactions that lead to conditions like cachexia, in which a person with cancer loses weight and his or her appetite declines, depriving the body of necessary nutrition.

CSHL Cancer Center Director David Tuveson appreciates Janowitz’s approach to cancer.

“Few scientists are ready to embrace the macro scale of cancer, the multiple organ systems and body functions which are impaired,” Tuveson said. Janowitz is “trying to understand the essential details [of cachexia and other cancer conditions] so he can interrupt parts of it and give patients a better chance to go on clinical trials that would fight their cancer cells.”

A successful and driven scientist and medical doctor, Janowitz “is very talented and could be anywhere,” Tuveson said, and was pleased his new colleague decided to join CSHL.

Janowitz suggested that the combination of weight loss and loss of appetite in advancing cancer is “paradoxical. Why would you not be ravenously hungry if you’re losing weight? What is going on that drives this biologically seemingly paradoxical phenomenon? Is it reversible or modifiable?”

At this point, his research has shown that tumors can reprogram the host metabolism in a way that it “profoundly affects immunity and can affect therapy.” Reversing cachexia may require an anti-IL-6 treatment, with nutritional support.

As he looks for clinical cases that could reveal the role of this protein in cachexia, Janowitz has seen that patients with IL-6-producing tumors may have a worse outcome, a finding he is now seeking to validate.

At this point, treatment for other conditions with anti-IL-6 drugs has produced few side effects, although patients with advanced cancer haven’t received such treatment. Researchers know how to dose antibodies to IL-6 in the human body and treatment intervals would last for a few weeks.

Scientists have long thought of cancer as being like a wound that doesn’t heal. IL-6 is important in infections and inflammation.

Ultimately, Janowitz hopes to extend his research findings to other diseases and conditions. To do that, he would need to take small steps with one disease before expanding an effective approach to other conditions. “Are disease processes enacting parts of the biological response that are interchangeable?” he asked. “I think that’s the case.”

Eventually, Janowitz hopes to engage in patient care, but he first needs to obtain a license to practice medicine in the United States. He hopes to take the steps to achieve certification in the next year.

He plans to gather samples from patients on Long Island to study cancer and its metabolic consequences, including cachexia.

Several years down the road, the scientist hopes the collaborations he has with neuroscientists can reveal basic properties of cancer.

Tuveson believes Janowitz has “the potential of having a big impact individually as well as on everyone around him,” at Cold Spring Harbor Laboratory. “We are lucky to recruit him and want him to succeed and solve vexing problems so patients get better.”

Janowitz lives in Cold Spring Harbor Laboratory housing with his wife Clary and their three children, Viola, 6, Arthur, 4, and Albert, 2.

Clary is a radiation oncologist who hopes to start working soon at Northwell Health.

The Janowitz family has found Long Island “very welcoming” and appreciates the area’s “openness and willingness to support people who have come here,” he said. The family enjoys exploring nature.

The couple met at a production of “A Midsummer Night’s Dream,” which was performed by a traveling cast of the Globe in Emmanuel College Gardens in Cambridge, England.

As with many others, Janowitz has had family members who are living with cancer, including both of his parents. His mother has had cancer for more than a decade and struggles with loss of appetite and weight. He has met many patients and their relatives over the years who struggle with these phenomena, which is part of the motivation for his dedication to this work.

Most cancer patients, Janowitz said, are “remarkable individuals. They adjust the way that they interact with the world and themselves when they get life changing diagnoses.” Patients have a “very reflected and engaged attitude” with the disease, which makes looking after them “incredibly rewarding.”

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