The gift intensifies efforts to understand and combat rare cancers

Curing cancer has been the dream of countless doctors and researchers over the decades. Yet some types of cancer, either because they affect a relatively small number of people or lack influential advocates, pay less attention and resources than others.

Rare cancer cells known as blastic neoplasms of plasmacytoid dendritic cells, shown in purple and blue, appear among red blood cells. File: Clin Med Insights Case Rep 2013. doi: 10.4137 / CCRep.S12608, CC-BY-NC 3.0

A recent gift to Harvard Medical School intensifies efforts to understand and combat these understudied malignant tumors.

Founded in HMS by the Swiss Bertarelli Foundation based in Switzerland, the Bertarelli Rare Cancer Fund provides $ 15 million to support research projects and build a community around rare cancers.

The first round of grants has now been awarded, with more than $ 9 million divided by nine teams representing 19 leading and leading investigators across the HMS and its affiliated hospitals. The research began this winter.

“This exciting new program will enhance our ability to prevent, treat and cure rare cancers that, together, affect tens of thousands of patients and their loved ones in this country each year,” said HMS Dean George Q. Daley. “By building research capacity and inter-institutional collaboration, the fund helps us accomplish our mission of creating new biological insights and treatment strategies that improve health for all.”

Our common ambition is to conduct research and innovate for the benefit of society. Clearly, there is a need and opportunity to accelerate transformative research on rare cancers, and I hope the fund will create a community of researchers who, in collaboration with scientists from around the world, will transform the understanding, treatment and care of rare cancers. “

Dona Bertarelli, Co-Chair, Bertarelli Foundation

Although rare cancers by definition affect less than 40,000 Americans in a given year, together they make up about a quarter of all cancers and cancer deaths in this country, according to the National Cancer Institute.

It can be difficult to make progress in rare cancer research. For example, tissue samples are few, and pharmaceutical companies have less incentive to develop drugs for small patient markets. Academic institutions like the HMS can be especially helpful, Daley said.

With a fresh infusion from the Bertarelli Fund, HMS is able to build infrastructure, generate knowledge and strengthen research communities for rare cancers from which more common cancers benefit.

The gift “focuses on the needs of rare cancer research” and addresses some of them “by supporting promising new research, bringing researchers together and showing patients that progress can be made,” said fund director Ed Harlow of Virginia and DK Ludwig, professor of cancer research and teaching at the Blavatnik Institute in HMS.

The ultimate goal is to improve the detection, diagnosis, treatment, and prevention of rare cancers.

“We want to provide tangible progress that will lead to a reduction in the burden on patients and families,” Harlow said.

Findings from rare disease studies can transform science. William Kaelin, professor of medicine Sidney Farber at HMS and the Dana-Farber Cancer Institute, shared the 2019 Nobel Prize in Physiology or Medicine for studies of a rare tumor management disorder known as von Hippel-Lindau syndrome, which led to a fundamental insight in how cells feel oxygen, which in turn opened up new treatments for anemia and proved relevant to a number of more common cancers.

In addition to the importance of understanding the basics and developing treatments for rare cancers, Bertarelli said, “sometimes we find that what we think is a rare disease is not really that rare or that the biological mechanisms discovered in rare diseases are important for many other diseases. “

Divide and multiply

The first grants cover basic, translational and clinical sciences, while connecting lower and senior faculties in the HMS community. Multidisciplinary collaboration promises to approach problems from different perspectives and create a stronger science.

“A new look at any result can open up new angles, provide new insights, and reveal missing parts,” Harlow said. “We encourage everyone to share tips and information before posting as an important part of building a useful community.”

Grant recipients investigate a variety of individual rare cancers, as well as genetic and molecular mechanisms involving multiple rare cancers.

Nabeel Bardeesy, an associate professor of medicine at HMS and Massachusetts General Hospital, is studying a rare liver cancer in young adults known as fibrolamelar carcinoma. The fund enabled him to recruit experts from various fields into his team.

He is now investigating how the genetic change that defines this type of cancer affects tumor cells; using genetics and proteomics, a technique that measures the levels of each protein in a cell, to detect each gene and molecular cycle that drives tumor growth; and looking for vulnerabilities in cancer cells that researchers could use to design drugs for the attack.

“There was no critical mass of people studying fibrolamelar carcinoma, nor a good tool for experimental model systems for biology research,” Bardeesy said. “The gift allows us to make progress by addressing some of the biggest issues on the ground, finding new approaches and strengthening the foundation for drug development, which would have an impact on patient care.”

Vamsi Mootha, a professor of systems biology at the Blavatnik Institute at HMS and a professor of medicine at Mass General, uses a recently discovered class of genes that trigger cancer to better understand and fight Hürthle cell carcinoma, a rare thyroid cancer.

Christopher French, associate professor of pathology at HMS and Brigham and Women’s Hospital, focuses on the molecular interactions that drive NUT cancer, an aggressive cancer most commonly found in the head, neck and lungs, while Andrew Lane, associate professor of medicine at HMS -u and Dana-Farber, aim to detect essential proteins that trigger uncontrolled cell division in blast plasmacytoid neoplasm of dendritic cells, blood cancer, bone marrow and other tissues.

Stephen Elledge, Gregor Mendel, professor of genetics and medicine at HMS and Brigham and Women, takes a broader approach. His team wants to develop a collection of all abnormally fused genes known to play a role in rare cancers.

“These fusion oncogenes have been less studied than other cancer-causing genes,” Elledge said. “They are often found in rarer cancers, although some common cancers, such as prostate cancer, have these fusion oncogenes in over 50 percent of tumors.”

Researchers can then use any or all of the genes in the Elledge collection to study specific cancers or more universal cancer management processes. The website will monitor the links between fusion oncogenes and the proteins that drive fusion and incorporate new findings as soon as they are discovered.

Denting the tooth into a problem

Several funded projects focus on clear cell cancer, especially the understudied type of rare cancer.

John Hanna, assistant professor of pathology at HMS and Brigham and Women, performs DNA and RNA sequencing of clear tumor cell samples. Although many clear cell carcinomas look similar under a microscope, genetic analyzes should allow for a more nuanced classification, which in turn helps doctors and researchers improve patients’ diagnosis and prognosis and develop more accurate treatments.

We identify completely new types of bistrocellular tumors and other rare tumors that were not previously recognized or were incorrectly associated with other tumor types due to a similar appearance. Understanding specific molecular and genetic changes in tumors will have a major impact on our ability to care for patients. “

John Hanna, Assistant Professor of Pathology, HMS and Brigham and Women

Two projects – one led by Miguel Rivera, associate professor of pathology at HMS and Mass General, and the other by Kimberly Stegmaier, professor of pediatrics at HMS and Dana-Farber – investigate EWS fusion oncoproteins: abnormally fused proteins first discovered in Ewing sarcoma. The researchers plan to shed light on how these fusion proteins work and test new methods to combat them.

“These cancers lack effective targeted therapies because fusion proteins are so difficult to achieve,” Stegmaier said. “Our multidisciplinary team of Ewing’s sarcoma and fusion oncoprotein experts, chemists and structural biologists are incredibly excited to work together to address this problem using new chemical approaches that use a mechanism to deposit natural proteins in the cell.”

Stegmaier hopes the model of the system her team is building to study EWS fusion proteins will help the wider research community study other fusion-induced cancers.

Meanwhile, a team led by John Iafrate, Austin L. Vickery, a junior professor of pathology at HMS and Mass General, is trying to identify biomarkers that help detect and treat clear-cell odontogenic carcinoma, carcinoma of the teeth, jaw and related tissues, and use them to develop a blood test to monitor cancer during and after treatment.

Fund administrators plan to support additional projects that build biological tools to study clear cell cancers, including cell lines, xenografts (tumor samples from patients studied in mice), mouse models, and three-dimensional tissue structures known as organoids.

Harlow and team are seeking additional funding to expand the program and gain even more momentum in the community in rare cancer studies.

The Bertarelli Fund for Rare Cancers complements Bertarelli’s program in translational neuroscience and neuroengineering by supporting bench-to-bed research at HMS.

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