Q2FY24 Quarterly Report

SCIENCE AND MEDICINE NEWS

QUARTERLY

REPORT

Q2FY24 October–December 2023 PREPARED BY: Strategic Communication, Education and Outreach 1

CONTENTS 3

Introduction

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Select Scientific Discoveries

19 Announcements 22 Social Media 36 Earned Media

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The Strategic Communication, Education and Outreach team curates stories for press release using scientific impact and institutional strategic alignment as central criteria. The stories featured represent an esteemed fraction of discovery and accomplishment across the St. Jude research and clinical enterprise.

Additional media engagement is pursued for each release, accompanied by promotion across our channels and platforms.

Work published in Q2FY24 showcased thought leadership of St. Jude investigators in immunotherapy, computational biology, structural biology, and survivorship.

Featured in esteemed journals including Nature and Lancet Oncology, recent work revealed new insights into gene therapy for SCID-X1, mechanisms of neural communication, and novel druggable targets in pediatric cancers.

New institutional leadership was announced and celebrated, and the prestige of St. Jude science was recognized in national media.

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Q2 Press Releases and Announcements

+ 200

St. Jude employees contributed as authors in Q2 publications

30% of Q2 Publications appeared in Top 10 scientific journals

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Q2FY24: SELECT SCIENTIFIC DISCOVERIES

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Q 2 F Y 24 | S E L EC T S C I E N T I F I C D I S C O V E R I E S

Zhaoming Wang, PhD Deo Kumar Srivastava, PhD Les Robison, PhD

L A NCE T ONCOLO GY Genetics help explain childhood cancer survivors’ mortality risk from a second cancer •

Childhood cancer patients in the U.S. now have a greater than 85% survival rate five years after diagnosis, but survivors still experience excess mortality compared to their peers.

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A study from St. Jude found that inherited or germline changes in 60 genes are associated with a higher risk for survivors to develop second cancers.

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These genetic changes are detectable at the time of diagnosis, meaning patients and families can be armed with information. Survivors can take action by seeking genetic counseling, participating in genetic testing, and following personalized screening and prevention strategies.

https://www.stjude.org/media-resources/news-releases/2023-medicine-science-news/genetics-explain-childhoodcancer-survivors-mortality-risk-from-second-cancer.html

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Jiyang Yu, PhD Stephen Gottschalk, PhD

S C IENCE A DVA NCES 3D genome architecture influences SCID-X1 gene therapy success •

In 2019, St. Jude reported a cure for X-linked severe combined immunodeficiency disorder (SCID-X1) or “bubble boy disease” using lentiviral gene therapy.

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Scientists have since developed high-resolution methods to monitor the specifications and safety of this type of therapy.

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Lentiviral vectors carry gene editing machinery into cells. Research shows that these vectors integrate into parts of the genome that they encounter first upon entering a cell’s nucleus.

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Understanding this behavior, which is also observed in CAR T-cell-based therapies, creates a map to guide the future safe and effective implementation of lentiviral gene therapy.

https://www.stjude.org/media-resources/news-releases/2023-medicine-science-news/3d-genome-architectureinfluences-scid-x1-gene-therapy-success.html

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Chia-Hsueh Lee, PhD

N AT UR E Scientists reveal structures of neurotransmitter transporter •

Chemical compounds called monoamines are vital for communication between neurons. They are shuttled within cells by compartments called vesicles. Monoamines are loaded into these vesicles by proteins called vesicle monoamine transporters (VMATs) on the vesicle surface.

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Dysfunction in VMATs leads to hyperkinetic (excessive movement) disorders like Tourette Syndrome.

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Scientists at St. Jude have determined how a particular VMAT binds to its cargo and to small molecule drugs during different stages of its functional cycle (changes in physical conformation).

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Researchers can design more effective and safer therapies by understanding how various drugs target different protein conformations.

https://www.stjude.org/media-resources/news-releases/2023-medicine-science-news/scientists-reveal-structures-ofneurotransmitter-transporter.html

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Mark Hatley, MD, PhD Brian Abraham, PhD

N AT UR E COMMUNIC ATION S Fusion oncoprotein forces cell fates toward rhabdomyosarcoma •

Pediatric rhabdomyosarcoma is a cancer that forms in soft tissue, such as muscle. In some cases, rhabdomyosarcoma cells express a protein resulting from the fusion of two genes: PAX3 and FOXO1.

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Patients with this fusion-positive rhabdomyosarcoma have a dismal prognosis.

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St. Jude researchers found that expression of this fusion protein was enough to force muscle or endothelial cells to become identical tumors.

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This work suggests why current therapeutic approaches might fail and creates new insights into the downstream effects of this fusion protein that might be targeted therapeutically.

https://www.stjude.org/media-resources/news-releases/2023-medicine-science-news/fusion-oncoprotein-forces-cellfates-toward-rhabdomyosarcoma.html

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Hongbo Chi, PhD

N AT UR E St. Jude scientists identify T-cell differentiation nodes to improve cancer-killing •

T cells are the component of the immune system most involved in directly killing cancer cells.

As a result, they are often leveraged in the development of immunotherapy.

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Tumor cells can produce signals that ‘shut down’ the function of these T cells, impairing their anti-cancer activity.

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St. Jude scientists mapped the gene regulatory networks that control the fate of T cells using CRISPRbased screening. Some of the genes they identified can modulate T-cell identity and increase tumorkilling ability.

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This network map provides a guide to future interventions that may improve immunotherapy.

https://www.stjude.org/media-resources/news-releases/2023-medicine-science-news/scientists-identify-t-celldifferentiation-nodes-to-improve-cancer-killing.html

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Daniel Savic, PhD

C ELL G E NO MIC S Robust chromatin map explains heterogeneity of pediatric acute lymphoblastic leukemia •

Acute lymphoblastic leukemia (ALL) is the most common childhood cancer and has many subtypes that vary in response to therapy.

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St. Jude scientists discovered that ALL subtypes differ in which regions of their DNA are accessible to proteins like transcription factors.

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They created a map of DNA accessibility, a ‘window to the genome’, that can accurately classify ALL subtypes and may help investigators develop new therapeutic approaches.

https://www.stjude.org/media-resources/news-releases/2023-medicine-science-news/robust-chromatin-map-explainsheterogeneity-of-pediatric-acute-lymphoblastic-leukemia.html

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Giedre Krenciute, PhD Paulina Velasquez, MD

C ELL REPO RTS MEDICINE Promising target for CAR T cells helps cancer trick the immune system •

Immunotherapy has greatly improved survival rates for patients with relapsed and recurrent pediatric leukemia and lymphomas, but not for those with brain or solid tumors.

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In immunotherapy, T cells are engineered to recognize proteins expressed on the surface of tumor cells and target them for destruction.

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Scientists at St. Jude identified that engineering T cells to target a particular protein (GRP78) expressed on the surface of tumor cells is effective in several preclinical models of brain and solid tumors.

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Additional work is underway to decipher the nuances of tumor and immune cell interaction revealed by the study.

https://www.stjude.org/media-resources/news-releases/2023-medicine-science-news/promising-target-for-car-t-cellshelps-cancer-trick-the-immune-system.html

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Chunliang Li, PhD

N AT UR E COMMUNIC ATION S St. Jude revealed functional targets of oncogenic HOXA9 in high-risk pediatric leukemia •

Though survival rates for patients with low- and medium-risk leukemias exceed 90%, some highrisk leukemias, particularly those that overexpress the protein HOXA9, require better targeted drug treatments.

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HOXA9 is a transcription factor that binds to DNA and regulates the expression of other genes.

It is difficult to study and is undruggable based on currently available techniques.

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St. Jude scientists created a system to map HOXA9 binding sites across the genome, representing a first step toward identifying novel drug targets downstream of HOXA9.

https://www.stjude.org/media-resources/news-releases/2023-medicine-science-news/functional-targets-of-oncogenichoxa9-in-high-risk-pediatric-leukemia.html

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Stephen Gottschalk, MD

N AT UR E BIO MEDIC A L EN G I N EER IN G Modular chimeric cytokine receptors improve CAR T-cell therapy for solid tumors •

Immunotherapy using engineered CAR T cells has greatly improved survival rates for pediatric patients with relapsed and recurrent leukemia.

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Solid tumors generate anti-immune signals that turn off T cell activity. As a result, infusion of CAR T cells is often accompanied by injection of cytokines to stimulate an immune response. This approach can have unintended toxicities in patients.

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Researchers at St. Jude developed a system that limits cytokine signals to the engineered CAR T cells, eliminating systemic toxicity.

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This work shows promise for improving CAR T-cell therapy for solid and brain tumors.

https://www.stjude.org/media-resources/news-releases/2023-medicine-science-news/modular-chimeric-cytokinereceptors-improve-car-t-cell-therapy-for-solid-tumors.html

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Andrew Murphy, MD Xiang Chen, PhD

N AT UR E C OMMUNIC ATION S Unraveling predisposition in bilateral Wilms tumor •

Children with bilateral Wilms tumor have tumors in each of their kidneys – a condition that suggests there is an underlying genetic driver of disease.

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St. Jude scientists collected the largest reported cohort of Wilms tumor samples and conducted genomic analyses to unravel mechanisms of disease.

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They found that inherited changes in particular genes, detected in blood samples, contributed to increased chances of developing Wilms tumor.

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This work has the potential to impact genetic counseling for patient families, treatment decisions, and design of future clinical trials.

https://www.stjude.org/media-resources/news-releases/2023-medicine-science-news/unraveling-predisposition-inbilateral-wilms-tumor.html

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Stephanie Dixon, MD, MPH

JOUR NAL OF CL INIC A L ON COLOG Y Prediabetes treatment may reduce heart and kidney risks in childhood cancer survivors •

Childhood cancer survivors experience chronic conditions such as diabetes at relatively young ages.

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Work from St. Jude showed that survivors have nearly twice the prevalence of prediabetes that similarly aged control individuals, and this diagnosis is associated with a significant increase in life-threatening kidney and heart diseases.

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Since prediabetes is treatable with lifestyle interventions and medicine, this work may help improve clinical care in childhood cancer survivors.

https://www.stjude.org/media-resources/news-releases/2023-medicine-science-news/prediabetes-treatment-mayreduce-heart-kidney-risks-in-childhood-cancer-survivors.html

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Madan Babu, PhD

S CIENCE GPCR structure: Research reveals molecular origins of function for a key drug target •

G protein-coupled receptors (GPCRs) are the target of one-third of all FDA-approved drugs.

To understand how drugs affect GPCRs, scientists are working to decipher the structure of these receptors at the atomic level.

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St. Jude investigators uncovered the network of effects that drug binding has on a particular GPCR, defining the individual impact of each amino acid, or receptor building block.

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This work opens new avenues for drug design and establishes a framework that can be used to interrogate any receptor in exquisite detail.

https://www.stjude.org/media-resources/news-releases/2023-medicine-science-news/gpcr-structure-research-revealsmolecular-origins-of-function-for-key-drug-target.html

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Ji Sun, PhD

S CIENCE Structure of Parkinson’s disease-linked proteins offer a framework for understanding how they work together •

Parkinson’s disease is the second-most common neurodegenerative disease, affecting 1-2% of the population over 65 years of age.

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One of the leading causes of Parkinson’s disease is a mutation in a specific protein: the leucine-rich repeat kinase 2 (LRRK2).

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Scientists at St. Jude used cryo-electron microscopy to define, for the first time, the structure of the active form of LRRK2 and its binding partner.

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This work suggests a mechanism of action for the protein and underlies future drug discovery efforts.

https://www.stjude.org/media-resources/news-releases/2023-medicine-science-news/structuresparkinsons-disease-linked-proteins-offer-framework.html

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Q2FY24: ANNOUNCEMENTS

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Q 2 F Y 24 | A N N O U N C E M E N T S

St. Jude Children’s Research Hospital, ALSAC announce new board leaders St. Jude Children’s Research Hospital and ALSAC, its fundraising and awareness organization, announced new leaders of the St. Jude Board of Governors and ALSAC Board of Directors today. The announcement comes at a time when St. Jude is advancing the largest strategic investment in its 61-year history, designed to profoundly impact children around the world who face cancer and other life-threatening diseases. Those elected to lead the Boards include St. Jude Chair Judy A. Habib, St. Jude Vice Chair Gabriel G. Haddad, MD, ALSAC Chair Frederick M. Azar, MD, and ALSAC Vice Chair Sharon L. McCollam.

Giles Robinson, MD, named director of the Neuro-Oncology Division at St. Jude Children’s Research Hospital Giles Robinson, MD, has assumed the role of director for the Department of Oncology’s Division of NeuroOncology. He has also become co-leader of the Neurobiology and Brain Tumor Program within the St. Jude Comprehensive Cancer Center. These combined units comprise one of the largest clinical brain tumor programs in North America.

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‘Highly cited’ St. Jude scientists named to annual list

Twelve scientists from St. Jude Children’s Research Hospital are among the investigators named to the 2023 list of Highly Cited Researchers. The annual list selects individuals who have demonstrated significant and broad influence in their research fields. Each researcher on the list has authored multiple scientific papers that rank in the top 1% by citations for their fields in the year the work was published.

James R. Downing, MD, recognized as one of Modern Healthcare’s 100 Most Influential People for the second consecutive year James R. Downing, MD, president and CEO of St. Jude, has been recognized by Modern Healthcare as one of the 100 Most Influential People in Healthcare of 2023. This prestigious recognition program acknowledges and honors individuals deemed by their peers and the senior editors of the influential healthcare industry trade publication to be the most influential figures in the industry in terms of leadership and impact.

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Q 2 F Y 24 | S O C I A L M E D I A

How St. Jude advanced influenza research in 2023

2023 RESEARCH WRAP-UP

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Immune cells present long before infection predict flu symptoms St. Jude researchers discovered distinct populations of immune cells are associated with protection from flu symptoms. This understanding may allow scientists to design vaccines to bolster those cells that offer improved flu defense.

Nature Immunology IMMUNOLOGY / HOST-MICROBE INTERACTIONS Paul Thomas and Richard Webby Labs

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Genetic changes increased bird flu severity during US spread St. Jude scientists discovered how the current H5N1 avian influenza virus (bird flu) gained new genes and greater virulence as it spread west. Their work is central to assessing the continually evolving risk to both humans and birds.

Nature Communications INFECTIOUS DISEASES Richard Webby Lab

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Mutation accessibility fuels influenza evolution

Researchers at St. Jude established a mathematical model to predict genetic mutations during the evolution of viruses. Their “survival of the accessible” concept suggests more accessible mutations, regardless of fitness, are likely to predominate in a population.

Science Advances STRUCTURAL BIOLOGY M. Madan Babu Lab

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Method for improving seasonal flu vaccines also aids pandemic prediction during US spread St. Jude researchers discovered that flu strains with unstable viral proteins compromise the efficacy of the seasonal flu vaccine. By conducting a simple experiment testing protein stability, scientists can better assess the potential pandemic risk of novel influenza viruses.

Science Advances INFECTIOUS DISEASES Charles Russell and Richard Webby Labs

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Nickhill Bhakta, MD, MPH, says collaboration is the secret sauce behind the work of St. Jude Global to build international coalitions to treat childhood cancer.

Nickhill Bhakta, MD, MPH, and Manoo Bhakta, MD

“Every day offers an opportunity to learn something different, and as someone who is passionate about learning new things, I can’t think of a better job or field to be in.”

Shendgar Tsai, PhD

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Recently, the FDA approved two gene therapies for adults that target sickle cell disease, one of which is the first commercially available treatment in the United States based on geneediting technology.

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1. “We are thrilled 2 new curative options are now available for sickle cell disease patients over the age of 12,” says Mitchell Weiss, MD, PhD, Hematology Department Chair. “We are optimistic these therapies will prove suitable for younger patients in the future.”

4. One of the ways investigators use

2. St. Jude scientists are advancing our understanding of, and ability to modify, genetic mutations that cause catastrophic pediatric diseases including bone marrow failure disorders.

5. The capacity to produce therapeutic tools in-house accelerates the creation of genome editing medicines for sickle cell disease, bone marrow failures and other blood diseases.

3. Investigators at St. Jude have engineered high-throughput methods to assess safety of editing tools and developed novel human cell-based systems to evaluate genome editors.

6. Molecular diagnostics bring treatment opportunities to infants with brain tumors

These capabilities position St. Jude at the forefront of therapeutic development.

genome editing technologies to advance personalized genomic medicines by using facilities, like a state-of-the-art Good Manufacturing Practices (GMP) facility, where St. Jude manufactures biological and cellular products for clinical trials.

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Investigators at St. Jude are integrating multiplediagnostic methods for more accurate brain tumor diagnoses.

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How St. Jude advanced therapeutics and clinical care research in 2023

2023 RESEARCH WRAP-UP

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Pharmacotyping of childhood leukemia provides a blueprint for ‘true precision medicine’

The Yang Lab performed the largest study yet examining drug sensitivity in childhood acute lymphoblastic leukemia across genomic subtypes and associations with treatment response.

Nature Medicine PHARMACY AND PHARMACEUTICAL SCIENCES Jun J. Yang Lab

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St. Jude scientists create more efficient CAR immunotherapies using a molecular anchor

By adding a molecular anchor to chimeric antigen receptors (CARs), scientists have increased the anti-cancer activity of cellular immunotherapies in multiple cancer models.

Nature Biotechnology BONE MARROW TRANSPLANTATION & CELLULAR THERAPY Stephen Gottschalk Lab

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St. Jude refines definition and hones treatment of hyperdiploid leukemia

Hyperdiploidy, a genetic condition observed in cancer cells and characterized by an increased number of chromosomes, is prevalent in patients with B-cell acute lymphoblastic leukemia. Researchers are working to better understand this type of ALL to more accurately predict outcomes

Journal of Clinical Oncology PHARMACY AND PHARMACEUTICAL SCIENCES / ONCOLOGY Jun J. Yang Lab / Ching-Hon Pui, MD, Clinical Research

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Base editing shows potential superiority for curing sickle cell disease

Gene therapy that targets hemoglobin genes may cure blood diseases that afflict millions of individuals. In collaboration with the Broad Institute, St. Jude researchers used base editing technology to restart fetal hemoglobin production in patient cells.

Nature Genetics HEMATOLOGY Mitchell Weiss Lab

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Q2FY24: EARNED MEDIA

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Q 2 F Y 24 | E A R N E D M E D I A

10/17/23, 10:38 AM

Campbell Clinic's chief of staff to lead ALSAC board - Memphis Local, Sports, Business & Food News | Daily Memphian

HEALTH CARE

Campbell Clinic’s chief of staff to lead ALSAC board

By Aisling Mäki, Daily Memphian Published: October 16, 2023 8:04 PM CT

Dr. Frederick Azar, Campbell Clinic’s chief of staff, has been elected to lead the board of directors at ALSAC, the fundraising and awareness arm of St. Jude Children’s Research Hospital.

On Monday, Oct. 16, St. Jude announced new leaders to both St. Jude’s board of governors and ALSAC’s board of directors.

Dr. Frederick Azar examines an X-ray of a patient’s right leg at Campbell Clinic Orthopaedics. Azar has been elected to lead the board of directors at ALSAC. (Patrick Lantrip/The Daily Memphian file)

Dr. Frederick Azar, Campbell Clinic’s chief of staff, has been elected to lead the board of directors at ALSAC, the fundraising and awareness arm of St. Jude Children’s Research Hospital.

On Monday, Oct. 16, St. Jude announced new leaders to both St. Jude’s board of governors and ALSAC’s board of directors.

St. Jude files permits for new high-rise towers https://dailymemphian.com/section/business/article/39232/campbell-clinics-frederick-azar-to-lead-alsac-board-st-jude

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Judy Habib and Paul Ayoub both raised money doorto-door as kids in West Roxbury for St. Jude. Now the two Boston businesspeople lead the hospital’s national board of governors.

Two Boston businesspeople, Judy Habib, left, a co-founder of KHJ Brand Activation, and Paul Ayoub, right, the chair of the law firm Nutter, are new vice chair and chair of St. Jude Children’s Research Hospital. Marlo Thomas, the daughter of late St. Jude founder Danny Thomas, poses with them.

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A new study highlights both the promise and the limitations of gene editing, as a highly lethal form of avian influenza continues to spread around the world.

Marissa Gonzalez survived a rare and aggressive cancer, retinoblastoma, that almost only affects children.

We asked experts why we cough and sniffle more when we head to bed, and what to do for better sleep.

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Through their tireless efforts, the eight Breakthroughs honorees have improved the lives of countless people around the world. These individuals and organizations are true architects of progress, fully aware that success doesn’t arrive swiftly or easily.

From discoveries that paved the way for mRNA COVID-19 vaccines to pursuing cures for rare genetic conditions, these honorees are harnessing the power of science, technology and unyielding determination to make breakthroughs that have propelled us into a new era of possibility.

(MEMPHIS, Tenn. – December 13, 2023) A study from St. Jude Children’s Research Hospital sheds light on the incidence of prediabetes and diabetes in childhood cancer survivors for better prevention and treatment.

At a younger age, childhood cancer survivors can experience chronic conditions such as diabetes, typically associated with older individuals.

NEW YORK – Drugmakers and researchers at the American Society of Hematology’s annual meeting in San Diego reported data on gene therapies for various genetic blood disorders. Below are brief reports on data readouts from the conference.

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SAN DIEGO — Researchers on Saturday presented an unusual case of a T cell lymphoma marked with a CAR, the key synthetic protein in CAR-T therapy, in an online abstract for the American Society of Hematology annual meeting.

The Food and Drug Administration on Friday approved the world’s first medicine based on CRISPR gene-editing technology, a groundbreaking treatment for sickle cell disease that delivers a potential cure for people born with the chronic and life-shortening blood disorder.

SAN DIEGO — News of the Food and Drug Administration’s historic approval of the first gene therapies for sickle cell disease sparked discussion, debate, and, above all, measured optimism at this year’s meeting of the American Society of Hematology.

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