Do you work at the Brigham? Having trouble with something and not sure who to ask?
Since 2012, we have awarded ten research projects with $100,000 BRIght Futures Prizes, supported by the philanthropic contributions to the BRIght Futures Fund. These are just some of the exciting ideas and projects that have been transformed in large part due to donor support.
As part of the 2022 Cambridge Science Festival, Brigham & Women’s Hospital (BWH) will showcase interactions between local middle schoolers and the finalists of our 10th BWH BRIght Futures Prize competition. Join us for this lively event which will kick off with videos of kids posing questions to BWH scientists about their BRIght Futures research projects and how they can impact human health. You will have a chance to ask your own questions as well as to vote for the winning project which will get a $100,000 award!
Dr. Elzoghby is our 10th BRIght Futures Prize winner. Watch the recap of all three projects below.
Precision Medicine to Treat a Bone Marrow Failure and Pre-leukemic Disorder
Myelodysplastic syndrome (MDS) is a pre-leukemic blood cancer. Patients with MDS don’t make enough blood cells, and their disease can progress towards acute leukemia, a type of deadly blood cancer.
MDS is most common in the elderly, with more than 10,000 new cases per year in the U.S. As the population ages, MDS takes an increasingly heavier toll on limiting life expectancy and quality of life. Many patients with MDS are treated with a type of drug called hypomethylating agents, or HMA.
About half of the patients respond to HMA treatment, which means their blood counts get better. However, the other half of the patients don’t respond to HMA, and they die within six months from worsening disease or transformation to acute leukemia.
Currently, there is no treatment available to improve overall survival after HMA failure and no way to predict who will get better and live longer from the treatment, and who will not.
We need predictive tests that can guide a clinician to better manage the care of patients with MDS and use HMA treatment for the right patients. We also need molecular biomarkers that can help guide new therapies for patients on HMA drugs at an individual level.
By completing our proposed studies, we can better understand how current therapies help or harm patients with MDS.
We can also pursue new therapeutic approaches based on what we learn and provide clinical, personalized treatment for patients with MDS on HMA therapy.
SALL4 is a gene that is turned on in the embryo and disappears in most adult normal tissues. Importantly, SALL4 is switched back on in various cancers, including high-risk MDS and leukemia. SALL4 is considered a cancer gene that drives tumor development, and abnormally expressed SALL4 can cause MDS.
We recently published in the New England Journal of Medicine about our observation that, in some patients, HMA treatment may reawaken this “sleeping” cancer gene, and that these patients had poor outcomes.
To better help patients with MDS, we propose to develop a diagnostic test focused on this gene, study how its activation leads to a poor prognosis and pursue alternative treatments that capitalize on SALL4’s abundance. Our goal is to predict prognosis of patients with MDS on HMA treatment and offer them personalized care.
With funding from the BRIght Futures Prize, we hope to take the first step in creating and validating an ultrasensitive test for SALL4.
We will use the single molecular array (Simoa) platform which was developed by our collaborator David Walt who is affiliated with both the Brigham and the Wyss Institute in Cambridge, MA.
We will look for SALL4 in patients’ blood samples to help develop a minimally invasive method to monitor for the gene. Simultaneously, the grant will allow us to continue our preclinical work on SALL4-targeting treatment.
Nano-Engineering Turns Cancer Cell Friends into Foes
Pancreatic ductal adenocarcinoma (PDA) is one of the most aggressive and deadliest forms of cancer. Although immunotherapy — drug treatments that enhance the immune system’s ability to detect and fight cancer — has been successfully used to treat many types of solid tumors, challenges limit their success in PDA.
In PDA, we see a lot of one kind of cell, known as fibroblasts, around the site of the tumor. These cancer-associated fibroblasts (CAFs) may act like a shield, protecting pancreatic cancer cells in the tumor core from the effects of immunotherapy. We think CAFs play a major role in PDA resistance to immunotherapy.
First, CAFs secrete substances that suppress the activity of immune cells that could otherwise hunt and destroy cancer cells. Second, this shield prevents immune cells from infiltrating the tumor core. Third, CAFs wrap around blood vessels, preventing nanomedicines from reaching their cancer cell targets.
Finally, CAFs secrete exosomes, or “tiny packets of materials,” that internalize easily into the neighboring cancer cells to help them grow and thrive. Given all the advantages that CAFs may provide for cancer cells, we urgently need a way to target CAFs and reprogram the protective shield before we go after cancer cells.
More than 62,000 people are expected to be diagnosed with pancreatic cancer in the United States in 2022 according to the American Cancer Society’s statistics, and more than 49,000 people will die of pancreatic cancer.
Based on our preliminary results, we anticipate that our strategy can prolong the survival and reduce the incidence of therapy resistance for patients with pancreatic cancer.
This will improve the lives of cancer patients and will help lower the expenses of cancer therapy. We would also like to further develop our therapeutic technology to treat other types of solid tumors such as colorectal and lung cancers.
We want to exploit CAFs, transforming them into factories that will produce cancer killing machinery.
We’re drawing inspiration from the unique location of fibroblasts between blood vessels and cancer cells. This gives us a critical advantage and a chance to use nanoparticles to reprogram CAFs to produce tiny, deadly packets known as cytotoxic exosomes for killing pancreatic cancer cells.
To do this, we will design lipid nanoparticles — similar to the lipid shells that are used in mRNA vaccines — loaded with DNA that can target and genetically reprogram CAFs to change the cargo/content of their exosomes. In this way, we are going to trick the cancer cells.
CAFs will begin churning out cytotoxic exosomes, which will be specifically internalized into cancer cells, resulting in death of cancer cells instead of helping their growth.
We will use the BRIght Futures Prize to take the first steps in making this idea a reality. The prize will allow us to engineer the nanomedicine and test its safety and effectiveness in a preclinical model of pancreatic cancer. This will help us attract the next round of funding to further perfect this technology before we reach patients.
A Blood Test to Help Black Breast Cancer Patients
Black breast cancer patients are disproportionately dying in the United States and we do not know why. Black patients are also at a higher risk of developing the most aggressive type of breast cancer.
Some have blamed this imbalance on a lack of access to early detection and timely treatment. However, we found that those factors can only explain a small portion of the increased risk of death faced by Black breast cancer patients. We propose a new idea. Our idea is based on the fact that a healthy immune system is required for the body to fight the abnormal cells that cause breast cancer.
We think that constant exposure to racial stresses faced by many Black people in society — prejudice, social alienation, economic exclusion, and discrimination — cause a decline in immune health. We call that stress-induced decline “immune weathering.” We think immune weathering is bad for two reasons.
First, it increases a person’s risk of developing breast cancer. Second, current breast cancer medicines are designed to trigger the immune system to attack cancer cells, but immune weathering may make those medicines less effective.
The ability to detect signs of immune weathering in the blood would provide a new, inexpensive, and widely accessible way to assess the risk of breast cancer.
Detecting immune weathering in the blood would point us to new medicines designed to boost immune health and help patients fight disease.
Our BRIght Futures project will enable us to gather insights that will save lives. And while our passion and focus is breast cancer, we think that “immune weathering” could contribute to other cancers or medical conditions that are more commonly seen in Black patients.
The problem is that we do not know why Black people are at increased risk of breast cancer. Immune system health is currently not being measured or considered as part of breast cancer patient care.
Our solution is derived from discoveries made in Dr. McAllister’s research laboratory and Dr. Mittendorf’s breast cancer clinic at the Dana-Farber/Brigham Cancer Center. Together, we developed a new laboratory test using cutting-edge technology that enables us to detect changes in immune cells that circulate in the blood.
We plan to use our new test to look for signs of immune weathering in the blood. Specifically, we think that the constant stress faced by Black patients changes their immune cells in a way that is detectable by our new technology. The BRIght Futures Prize will allow us to develop and refine a simple blood test to detect immune weathering.
Dr. Elizabeth Mittendorf is my co-investigator. Our affiliations include:
After you’ve learned a bit about each project, we welcome you to cast your vote for the project you think should receive the $100,000 Bright Futures Prize this year.
We will be announcing the winner at a Bright Futures Prize Event as part of the Cambridge Science Festival this year and encourage you to register for that event as well as check out all of the activities that are part of the Cambridge Science Festival.
Voting will be open from September 21st until the event at the Cambridge Science Festival on October 7th.