NIH Archives - Sanford Burnham Prebys
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AI-driven cancer prediction tool makes NIH director’s highlights for 2024

AuthorScott LaFee
Date

January 3, 2025

On April 18, 2024, first author Sanju Sinha, PhD, an assistant professor in the Cancer Molecular Therapeutics Program at Sanford Burnham Prebys, and colleagues published details about a new artificial intelligence-powered tool called PERCEPTION (PERsonalized Single-Cell Expression-Based Planning for Treatments In ONcology).

PERCEPTION was proof-of-concept that AI could be used to predict a cancer’s treatment responses from bulk RNA. Sinha and colleagues built AI models for 44 drugs approved by the FDA and found that their tool “predicted the success of targeted treatments against cell lines with a high degree of accuracy.”

The paper was among six specifically highlighted by Monica Bertagnolli, MD, in her blog as director of the National Institutes of Health.

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NIH director highlights Sanford Burnham Prebys and National Cancer Institute project to improve precision oncology

AuthorGreg Calhoun
Date

May 9, 2024

The NIH director’s blog features a recent publication detailing the study of a new AI tool that may be able to match cancer drugs more precisely to patients.

Monica M. Bertagnolli, MD, director of the National Institutes of Health (NIH), highlighted a collaboration between scientists at Sanford Burnham Prebys and the National Cancer Institute (NCI) on the NIH director’s blog. Bertagnoli noted advances that have been made in precision oncology approaches using a growing array of tests to uncover molecular or genetic profiles of tumors that can help guide treatments. She also recognizes that much more research is needed to realize the full potential of precision oncology.

The spotlighted Nature Cancer study demonstrates the potential to better predict how patients will respond to cancer drugs by using a new AI tool to analyze the sequences of the RNA within each cell of a tumor sample. Current precision oncology methods take an average of the DNA and RNA in all the cells in a tumor sample, which the research team hypothesized could hide certain subpopulations of cells—known as clones—that are more resistant to specific drugs.  

Bertagnoli said, “Interestingly, their research shows that having just one clone in a tumor that is resistant to a particular drug is enough to thwart a response to that drug. As a result, the clone with the worst response in a tumor will best explain a person’s overall treatment response.” 

More of Bertagnoli’s thoughts on this collaboration between scientists at Sanford Burnham Prebys and the NCI are available on the NIH director’s blog

Sanju Sinha, PhD, assistant professor in the Cancer Molecular Therapeutics Program at Sanford Burnham Prebys, is the first author on the featured study. 

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How cancer research silos perpetuate inequity in cancer outcomes: An interview with Svasti Haricharan

AuthorMiles Martin
Date

April 18, 2023

The National Institutes of Health recognizes National Minority Health Month each April. This is a time to raise awareness about the importance of reducing the health disparities faced by racial and ethnic minorities.

For our part, we spoke to Assistant Professor Svasti Haricharan, PhD, about her recently published review in Clinical Cancer Research. The paper describes some of the shortfalls of the current research focusing on cancer disparities. It also reveals what needs to happen to solve this problem. 

This paper describes “research silos” in cancer disparities, but what does this term mean?
The cancer research community has made a lot of progress recognizing that cancer research has a data diversity problem. We know that we need more researchers working on cancer disparities—for example, finding explanations as to why some racial and ethnic minorities have worse cancer survival rates than others. We also know that we need to generate more inclusive data in cancer research generally, which means building databases that include data from people of different backgrounds.

However, what we’re talking about in this new paper is a bit more subtle than that. It has more to do with which disparities researchers are studying and how they’re studying them. Cancer-disparities researchers tend to fall into two different categories with two very different approaches. One group focuses more on the societal problems driving disparities, and the other group is looking closely at the biology. But these two paths aren’t intersecting, which is preventing us from truly addressing racial disparities in cancer.

Can you tell us more about those two groups and how this division affects cancer research?
The first group includes researchers who study cancer disparities in the way most people understand them. They focus on social determinants of health, such as socioeconomic status and systemic bias in the healthcare system. The second group looks at the biology directly, focusing on how genetics impacts the molecular biology of cancer. These are both important research areas, and we’ve made a lot of progress independently with each of them.

The problem is that focusing on one or the other ignores something critical that has gained attention in recent years: lifestyle factors have a direct impact on the molecular biology of cancer. Our lived experiences leave a unique footprint in our cells on top of what’s already there because of what we inherited at birth. By keeping these two types of cancer research trapped in silos, we’re missing synergistic leaps that could truly transform our understanding of cancer outcome inequity. Breaking down these silos is the only way to keep moving this type of research forward.

How can we break down these silos? 
Looking at it broadly, funding bodies need to invest more in research that develops datasets using biological samples from underrepresented groups. This will help us learn more about how societal factors can have a different impact on the biology of cancer—depending on the person with the disease. Here in the lab, we need to create experimental systems that better represent the biology of people from racial and ethnic minorities. This could also help us solve an even bigger problem.

Therapeutic strategies for cancer that we find in the lab don’t often make it to the clinic. Improving the diversity of our cancer data will improve this success-to-failure ratio. It will help us identify treatments that work better in some people than in others and choose the best treatments for each patient. In other words, it will help us work toward truly individualized medicine. Ultimately, we can only develop good precision medicine for cancer when we start looking at all patient demographics more equitably.

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Cosimo Commisso explains cancer metabolism on NIH website

AuthorJessica Moore
Date

June 7, 2016

The most deadly of all cancers are driven by mutations in a family of genes known as RAS. In a new article on the website for the National Cancer Institute’s RAS Initiative, Cosimo Commisso, PhD, assistant professor in SBP’s NCI-designated Cancer Center, discusses how the metabolism of cancer cells might be different in different parts of solid tumors.

The RAS Initiative is a collaborative effort to explore innovative approaches for attacking the proteins encoded by mutant forms of RAS genes, which drive 30% of human cancers.

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SBP researcher receives NIH Outstanding Investigator Award to study deadly pathogens

AuthorSusan Gammon
Date

June 7, 2016

Francesca Marassi, PhD, professor in SBP’s NCI-designated Cancer Center, has been awarded an Outstanding Investigator Award from the National Institute of General Medical Sciences (NIGMS). The $4 million grant is to study how proteins on the surface of pathogens promote virulence by mediating the first-line interactions with human host cells. The project has important implications for biology and medicine.

“Our initial focus is on a protein called Ail (attachment invasion locus) that is expressed on the outer membrane of Yersinia pestis, the causative agent of plague,” said Marassi. “The Y. pestis bacterium is highly pathogenic, spreads rapidly and causes an extremely high rate of mortality. Ail is critical for suppressing the human immune defenses and for promoting bacterial invasion”

Although it is sensitive to some antibiotics, the potential use of Y. pestis as a biological weapon has led to its classification as a Tier 1 Biothreat Agent – a designation used by the U.S. Department of Health and Human Services to identify pathogens and toxins that can be misused to threaten public health or national security.

“The emerging threat of bacterial drug resistance makes our work particularly important,” added Marassi. “We will be using a technology called NMR (nuclear magnetic resonance) to determine the three-dimensional structure of Ail and examine how it associates with its human protein partners. Visualizing these biomolecular complexes helps us understand how pathogens engage their human host, and advances our ability to design effective drugs and vaccines for bacteria and viruses,” added Marassi.

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Will you be part of the largest-ever clinical research study?

Authorjmoore
Date

March 23, 2016

It’s called the Precision Medicine Initiative (PMI) Cohort Program, and it was just announced in February by President Obama. If you join the cohort (group of subjects tracked over a long period of time), you can help researchers improve precision medicine, in which doctors select the treatments and preventive strategies that will work best for each patient. This program is just one component of the larger Precision Medicine Initiative announced during last year’s State of the Union address.

What’s the goal? According to NIH Director Francis Collins, the cohort program “seeks to extend precision medicine to all diseases by building a national research cohort of one million or more U.S. participants,” all enrolled by 2019.

Why recruit so many people? Since the program is intended to benefit people affected by many diseases and conditions, it must include large, representative samples of people with each type. Large samples increase the likelihood that studies using these data will find new associations and interactions among genes, environmental factors, and disease risk.

What will participants do? Volunteers will share their health records, complete surveys on lifestyle and environmental exposures, undergo a physical, and provide a biological sample (e.g. blood) for genetic testing.

How will people benefit? Participants will be considered partners in research—they’ll have access to their genetic data and, where possible, how their genes, surroundings, and habits affect their health. They’ll also have a say in how the research is conducted and what questions it should address.

Who’s running it? The NIH is overseeing the whole program, but it will be directly run from multiple institutions (which are currently being selected). The pilot phase will be led by Vanderbilt University and Verily (formerly Google Life Sciences).

What’s the cost? $130 million has been allotted in this fiscal year, but more money will be needed to keep the program going.

Should I be excited about it? Maybe. Some leaders in the health field have criticized the program for throwing money at the latest big thing instead of more low-tech problems like unequal access to healthcare, but such a huge data resource is bound to lead to answers to many important questions. 

What are the challenges for the PMI?

  • Scale—The program will generate one of the largest clinical databases yet, and it’s not clear how difficult it will be to make systems that can store and analyze it.
  • Privacy—Data will be anonymized, but keeping the health information of a million people in one place might represent a target for hackers sophisticated enough to figure out participants’ identities.
  • Interoperability—Health record systems are notoriously incompatible with one another. Though the PMI also has provisions to correct this, it likely won’t be a quick fix.

How can I sign up? Enrollment has not yet begun, but the NIH will announce when the public can get involved. So stay tuned…

 

Institute News

Rare Disease Day symposium brings together experts on disorders of glycosylation

Authorjmoore
Date

March 2, 2016

The Rare Disease Day symposium on February 26-27 featured many fascinating talks from experts on numerous aspects of congenital disorders of glycosylation (CDGs), from fundamental work on glycosylation pathways to animal models to diagnosis in the clinic. Following are summaries of each presentation:

Lawrence Tabak, D.D.S, PhD, deputy director of the NIH—After presenting his research on glycosylating enzymes in the 1980s, which helped lay the foundation for understanding the processes that are impaired in CDGs, Tabak discussed several initiatives by the NIH, including the Precision Medicine Initiative and efforts to increase reproducibility.

William Gahl, MD, PhD, director of the National Human Genome Research Institute (NHGRI)—Gahl highlighted several successes of the Undiagnosed Diseases Program. Most relevant to the field of CDGs was the discovery of the gene underlying a new type of CDG, in which an enzyme responsible for generating a necessary precursor for protein glycosylation (uridine diphosphate) is inactivated. This work also found that supplementation with uridine was an effective therapy.

Shengfang Jin, PhD, scientist at Agios Pharmaceuticals Inc.Jin presented her work on a mouse model of PMM2-CDG, which is caused by mutations in the gene for phosphomannomutase 2. Her research has identified a promising biomarker for PMM2-CDG, which is one of the more common types of CDG.

Richard Steet, PhD, associate professor at the University of Georgia—Steet’s lab is developing a new method of identifying which proteins are glycosylated by particular enzymes, which is important for understanding how each CDG-associated mutation leads to disease.

Reid Gilmore, PhD, professor at University of Massachusetts Medical School—Gilmore gave a detailed view of how two CDG-associated mutations, in isoforms of the same component (STT3A and STT3B) of a major glycosylating enzyme, oligosaccharyltransferase, impair protein glycosylation.

Robert Haltiwanger, PhD, professor at the University of Georgia—In another presentation on fundamental glycobiology, Haltiwanger described the function of two enzymes in the same pathway (fucosylation) inactivated in certain CDGs. Mutations in these enzymes underlie Peters plus syndrome and a single case of an unnamed severe CDG, respectively.

Marjan Huizing, PhD, staff scientist at the NHGRI—Using a mouse model of GNE myopathy, a progressive muscle disease caused by mutations in an enzyme required for protein sialylation, Huizing’s lab identified a therapy, supplementation with the sugar ManNAc, which is now in phase 2 trials, and identified a key biomarker. The mouse model also suggested that sialylation problems may be associated with certain kidney diseases, which is now under investigation.

Raymond Wang, MD, clinical geneticist at CHOC Children’s Clinic—Wang told the story of how he and scientific collaborators diagnosed an unusual case that initially appeared to be a CDG because of abnormal glycosylation. The disease-causing mutation was finally identified to be in mitochondrial translation, highlighting the similarities between CDGs and mitochondrial diseases.

David Beeson, PhD, professor at the University of Oxford—Beeson described a subset of congenital myasthenias caused by mutations in glycosylating enzymes, which have distinct symptoms from other myasthenias. These mutations likely cause this disorder by selectively impairing processing of the receptor by which muscle cells receive signals from nerves—the nicotinic acetylcholine receptor.

Lance Wells, PhD, professor at the University of Georgia— Wells summarized his work on the molecular basis of dystroglycanopathies, a subgroup of muscular dystrophies that arise from defects in O-mannosylation enzymes. Most recently, his lab resolved the puzzle of how mutations in an enzyme involved in a different form of glycosylation could cause this disease—they showed that the enzyme’s function had been incorrectly assigned.

Taroh Kinoshita, PhD, professor at Osaka University—Kinoshita is an expert on the addition of sugar-based anchors to lipids (GPI anchors), which link many proteins to the cell surface. He presented some of the extensive work from his team on how mutations in GPI-synthesizing enzymes cause disease, including identification of a therapy, vitamin B6, for seizures in GPI deficiencies.

Eva Morava, MD, PhD, professor at Tulane University Medical Center and the University of Leuven—Morava described preliminary results of a clinical trial of galactose supplementation to treat PGM1-CDG, in which patients are deficient in phosphoglucomutase-1 (this also impairs glucose metabolism). In these patients, galactose improves liver function and endocrine abnormalities and normalizes clotting factors.

Lynne Wolfe, MS, C.N.R.P. clinical research coordinator at the NHGRI—Wolfe discussed the CDG natural history study underway at the NIH—its goals and progress so far. The findings of this study will serve as a resource both for future diagnoses and for researchers in the field to correlate pathways with symptoms.

Tadashi Suzuki, D.Sci., team leader at the RIKEN Global Research Cluster—NGLY1 is different from other CDG-associated genes—it encodes a deglycosylating enzyme, which helps degrade glycosylated proteins that aren’t properly folded. Suzuki’s team has shown that inhibiting another deglycosylating enzyme, ENGase, prevents the formation of aggregates of misfolded proteins, suggesting that it could be a therapeutic target.

Hamed Jafar-Nejad, MD, associate professor at Baylor College of Medicine—Using fruit flies as a model, Jafar-Nejad’s lab is investigating how NGLY1 deficiency affects development. These flies replicate many of the features of human disease, including growth delay and impaired movement, so they could yield important insights into pathogenesis.

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21st Century Cures Act will benefit SBP in Lake Nona, according to Orlando Medical News

Authorjmoore
Date

January 27, 2016

A recent article highlighted how the federal 21st Century Cures Act will benefit Orlando-area research institutes, including SBP. The legislation, which was passed by the House of Representatives in July, would promote medical research and accelerate the translation of discoveries into new drugs and medical devices by increasing funding for the National Institute of Health (NIH) and making research and healthcare policy changes.

The 21st Century Cures Act, which remains to be passed by the Senate, calls for annual increases in the stagnating budget for the NIH amounting to about 3% per year for 3 years when adjusted for inflation, as well as an additional $2 billion per year for 5 years to create an “NIH Innovation Fund.” NIH funding was recently increased by $2 billion (6.7%) in December as part of the 2016 budget.

The article quotes Stephen Gardell, PhD, senior director of Scientific Resources at SBP, on the importance of NIH funding: “The NIH is making an investment in the work of researchers and looking for a return on that investment—discoveries that will provide the foundation for new therapies and new devices that will improve human health and combat disease.”

Gardell’s research focus involves the profiling of metabolites in blood, urine and tissues to discover novel biomarkers. Large-scale profiling of metabolites enabled by remarkable advances in mass spectrometry has created a new area of research called metabolomics. Hundreds of different metabolites (“biomarker candidates”) can now be measured in a single drop of blood. The metabolite profile provides a signature of health, disease and drug action that can help to recognize a disease early and guide the care provider to select the right drug.

Gardell also emphasized that SBP is well equipped to carry out the translation of discoveries from bench to bedside that the act is intended to promote. He described the SBP drug discovery program as “a very capable and powerful resource that is modeled after the infrastructure in the world-leading pharmaceutical companies.”

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NIH funding gets biggest increase in 12 years

Authorsgammon
Date

December 28, 2015

The National Institute of Health is getting a $2 billion funding increase, giving biomedical research institutions a good reason to celebrate the new year. The increase represents a big turnaround for the agency that has been working with a stagnant budget since 2003. The funding boost promises to ignite the science—and the scientists—that rely on government funding to find new ways to prevent disease and improve health.

“NIH funding fuels some of the most important, influential research that expands our understanding of diseases, and funds new approaches to prevent, diagnose, treat, and in some cases even cure illnesses that impact world health,” said Kristiina Vuori, MD, PhD, president of SBP. “This increase in NIH funding will help SBP—and similar biomedical medical research institutions—to continue to make groundbreaking scientific discoveries and translate our findings into applied medicine for the benefit of patients.  We couldn’t be more pleased.”

SBP, which ranks in the top four of NIH awards to independent research organizations, has a big reason to celebrate.  Almost 50% of the funding for our primary research areas—cancer, neuroscience, immunity, and disorders of the metabolism—comes from NIH grants. Moreover, the money helps support the more than 800 scientific staff at SBP that are directly making and advancing our discoveries.

Included in the $2 billion are $200 million for precision medicine, an additional $350 million for Alzheimer’s disease research, and $85 million for the BRAIN Initiative—the project to map the human brain.

The approval of the spending bill is a significant bipartisan achievement by a Congress that became convinced that investing in medical science is a good use of taxpayer money.

Congratulations to all involved, especially NIH Director Francis Collin for his ongoing efforts to bring this to a successful outcome.

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‘Big Data’ used to identify new cancer driver genes

Authorsgammon
Date

October 20, 2015

In a collaborative study led by Sanford Burnham Prebys Medical Discovery Institute (SBP), researchers have combined two publicly available ‘omics’ databases to create a new catalogue of ‘cancer drivers’. Cancer drivers are genes that when altered, are responsible for cancer progression. The researchers used cancer mutation and protein structure databases to identify mutations in patient tumors that alter normal protein-protein interaction (PPI) interfaces. The study, published today in PLoS Computational Biology, identified more than 100 novel cancer driver genes and helps explain how tumors driven by the same gene may lead to different patient outcomes.

“This is the first time that three-dimensional protein features, such as PPIs, have been used to identify driver genes across large cancer datasets,” said lead author Eduard Porta-Pardo, PhD, a postdoctoral fellow at SBP. “We found 71 interfaces in proteins previously unrecognized as cancer drivers, representing potential new cancer predictive markers and/or drug targets. Our analysis also identified several driver interfaces in known cancer genes, such as TP53, HRAS, PI3KCA and EGFR, proving that our method can find relevant cancer driver genes and that alterations in protein interfaces are a common pathogenic mechanism of cancer.”

Cancer is caused by the accumulation of mutations to DNA. Until now, scientists have focused on finding alterations in individual genes and cell pathways that can lead to cancer. But the recent push by the National Institutes of Health (NIH) to encourage data sharing has led to an era of unprecedented ability to systematically analyze large scale genomic, clinical, and molecular data to better explain and predict patient outcomes, as well as finding new drug targets to prevent, treat, and potentially cure cancer.

“For this study we used an extended version of e-Driver, our proprietary computational method of identifying protein regions that drive cancer. We integrated tumor data from almost 6,000 patients in The Cancer Genome Atlas (TCGA) with more than 18,000 three-dimensional protein structures from the Protein Data Bank (PDB),” said Adam Godzik, PhD, director of the Bioinformatics and Structural Biology Program at SBP. “The algorithm analyzes whether structural alterations of PPI interfaces are enriched in cancer mutations, and can therefore identify candidate driver genes.”

“Genes are not monolithic black boxes. They have different regions that code for distinct protein domains that are usually responsible for different functions. It’s possible that a given protein only acts as a cancer driver when a specific region of the protein is mutated,” Godzik explained. “Our method helps identify novel cancer driver genes and propose molecular hypotheses to explain how tumors apparently driven by the same gene have different behaviors, including patient outcomes.”

“Interestingly, we identified some potential cancer drivers that are involved in the immune system. With the growing appreciation of the importance of the immune system in cancer progression, the immunity genes we identified in this study provide new insight regarding which interactions may be most affected,” Godzik added.

The study was performed in collaboration with the European Bioinformatics Institute (UK), Centro de Investigación Principe Felipe (Spain), and CIBER de Enfermedades Raras (Spain).