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precision oncology

Working Toward Greater Precision in Childhood Cancers

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Pediatric Cancer

Credit: National Cancer Institute, NIH

Each year, more than 15,000 American children and teenagers will be diagnosed with cancer. While great progress has been made in treating many types of childhood cancer, it remains the leading cause of disease-related death among kids who make it past infancy in the United States [1]. One reason for that sobering reality is our relatively limited knowledge about the precise biological mechanisms responsible for childhood cancers—information vital for designing targeted therapies to fight the disease in all its varied forms.

Now, two complementary studies have brought into clearer focus the genomic landscapes of many types of childhood cancer [2, 3]. The studies, which analyzed DNA data representing tumor and normal tissue from more than 2,600 young people with cancer, uncovered thousands of genomic alterations in about 200 different genes that appear to drive childhood cancers. These so-called “driver genes” included many that were different than those found in similar studies of adult cancers, as well as a considerable number of mutations that appear amenable to targeting with precision therapies already available or under development.


KRAS Targeted Cancer Strategy Shows Early Promise

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KRAS in active and inactive states

Caption: Mutant KRAS protein (white) keeps switch (red/pink) open in active state for GTP (arrow). After treatment with ARS-1620 (blue), switch is trapped in inactive GDP-bound state.
Credit: Adapted from Cell. 2018 Jan 25;172(3):578-589.

Of the more than 1.7 million Americans expected to be diagnosed with cancer this year, nearly one-third will have tumors that contain at least one mutation in the RAS family of genes [1]. That includes 95 percent of pancreatic cancers and 45 percent of colon cancers. These mutations result in the production of defective proteins that can drive cancer’s uncontrolled growth, as well as make cancers resistant to therapies. As you might expect, RAS has emerged as a major potential target for fighting cancer. Unfortunately, it is a target that’s proven very difficult to “hit” despite nearly three decades of work by researchers in both the private and public sectors, leading NIH’s National Cancer Institute to begin The RAS Initiative in 2013. This important effort has made advances with RAS that have translational potential.

Recently, I was excited to hear of progress in targeting a specific mutant form of KRAS, which is a protein encoded by a RAS gene involved in many lung cancers and some pancreatic and colorectal cancers. The new study, carried out by a pharmaceutical research team in mouse models of human cancer, is the first to show that it is possible to shrink a tumor in a living creature by directly inhibiting mutant KRAS protein [2].


Precision Oncology: Gene Changes Predict Immunotherapy Response

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Cancer Immunotherapy

Caption: Adapted from scanning electron micrograph of cytotoxic T cells (red) attacking a cancer cell (white).
Credits: Rita Elena Serda, Baylor College of Medicine; Jill George, NIH

There’s been tremendous excitement in the cancer community recently about the life-saving potential of immunotherapy. In this treatment strategy, a patient’s own immune system is enlisted to control and, in some cases, even cure the cancer. But despite many dramatic stories of response, immunotherapy doesn’t work for everyone. A major challenge has been figuring out how to identify with greater precision which patients are most likely to benefit from this new approach, and how to use that information to develop strategies to expand immunotherapy’s potential.

A couple of years ago, I wrote about early progress on this front, highlighting a small study in which NIH-funded researchers were able to predict which people with colorectal and other types of cancer would benefit from an immunotherapy drug called pembrolizumab (Keytruda®). The key seemed to be that tumors with defects affecting the “mismatch repair” pathway were more likely to benefit. Mismatch repair is involved in fixing small glitches that occur when DNA is copied during cell division. If a tumor is deficient in mismatch repair, it contains many more DNA mutations than other tumors—and, as it turns out, immunotherapy appears to be most effective against tumors with many mutations.

Now, I’m pleased to report more promising news from that clinical trial of pembrolizumab, which was expanded to include 86 adults with 12 different types of mismatch repair-deficient cancers that had been previously treated with at least one type of standard therapy [1]. After a year of biweekly infusions, more than half of the patients had their tumors shrink by at least 30 percent—and, even better, 18 had their tumors completely disappear!


Precision Oncology: Epigenetic Patterns Predict Glioblastoma Outcomes

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Brain scan analysis

Caption: Oncologists review a close-up image of a brain tumor (green dot).
Credit: National Cancer Institute

Scientists have spent much time and energy mapping the many DNA misspellings that can transform healthy cells into cancerous ones. But recently it has become increasingly clear that changes to the DNA sequence itself are not the only culprits. Cancer can also be driven by epigenetic changes to DNA—modifications to chemical marks on the genome don’t alter the sequence of the DNA molecule, but act to influence gene activity. A prime example of this can been seen in glioblastoma, a rare and deadly form of brain cancer that strikes about 12,000 Americans each year.

In fact, an NIH-funded research team recently published in Nature Communications the most complete portrait to date of the epigenetic patterns characteristic of the glioblastoma genome [1]. Among their findings were patterns associated with how long patients survived after the cancer was detected. While far more research is needed, the findings highlight the potential of epigenetic information to help doctors devise more precise ways of diagnosing, treating, and perhaps even preventing glioblastoma and many other forms of cancer.


Precision Oncology: Nanoparticles Target Bone Cancers in Dogs

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Timothy Fan and his dog Ember

Caption: Veterinary researcher Timothy Fan with his healthy family pet Ember.
Credit: L. Brian Stauffer

Many people share their homes with their pet dogs. Spending years under the same roof with the same environmental exposures, people and dogs have something else in common that sometimes gets overlooked. They can share some of the same diseases, such as diabetes and cancer. By studying these diseases in dogs, researchers can learn not only to improve care for people but for their canine friends as well.

As a case in point, an NIH-funded team of researchers recently tested a new method of delivering chemotherapy drugs for osteosarcoma, a bone cancer that affects dogs and people, typically teenagers and older adults. Their studies in dogs undergoing treatment for osteosarcoma suggest that specially engineered, bone-seeking nanoparticles might safely deliver anti-cancer drugs precisely to the places where they are most needed. These early findings come as encouraging news for the targeted treatment of inoperable bone cancers and other malignancies that spread to bone.


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