Standard anticancer treatments, such as chemotherapy, target rapidly dividing cells by damaging their DNA. A newer strategy is to undercut cancer cells’ ability to repair DNA damage.
Radiation oncologist David Yu, MD, PhD
Winship Cancer Institute investigators led by David Yu, MD, PhD have identified a distinct function in DNA double strand break repair for an enzyme called SAMHD1. Depleting or inhibiting SAMHD1 could augment anticancer treatments that induce DNA double-strand breaks, such as ionizing radiation or PARP inhibitor drugs, they suggest. Ionizing radiation is a mainstay of cancer treatment and PARP inhibitors are being developed for several cancer types.
The findings were published this week in Cell Reports (open access).
SAMHD1 was known for its ability to chop up the building blocks of DNA, and had come to the attention of virologists because it limits the ability of retroviruses such as HIV to infect some cell types. The first author of the paper, postdoc Waaqo Daddacha, PhD, previously studied SAMHD1 with virologist Baek Kim, PhD, professor of pediatrics.
Cancer researchers had already sought to harness a retroviral protein called Vpx, which viruses evolved to disable SAMHD1. Acute myeloid leukemia cells use SAMHD1 to get rid of the drug cytarabine, so Vpx can sensitize AML to that drug. The Cell Reports paper shows that virus-like particles carrying Vpx could be deployed against other types of cancer, in combination with agents that induce DNA double-strand breaks. Read more
This monthâ€™s intriguing images come from radiation oncologist Ian Crocker and colleagues. Each one shows a patient with a glioblastoma, an aggressive brain tumor. The patientâ€™s brain was scanned in two ways: on the left, MRI (magnetic resonance imaging) and on the right, PET (positron emission tomography), using a probe developed at Emory. We can see that the tumorâ€™s PET signal is more distinct than the tumorâ€™s appearance on MRI.
Since the 1990s, Mark Goodman, John Votaw and colleagues at Emoryâ€™s Center for Systems Imaging have been developing the probe FACBC (fluoro-1-amino-3-cyclobutyl carboxylic acid) as a probe for the detection of tumors.
Cells sometimes â€œfixâ€ DNA the wrong way, creating an extra mutation, Emory scientists have revealed.
Biologist Gray Crouse, PhD, and radiation oncologist Yoke Wah Kow, PhD, recently published a paper in Proceedings of the National Academy of Sciences that shows how mismatch repair can introduce mutations in nondividing cells. Their paper was recognized by the National Institute of Environmental Health Sciences as an extramural paper of the month. The first author is lead research specialist Gina Rodriguez.
In DNA, a mismatch is when the bases on the two DNA strands do not conform to Watson-Crick rules, such as G with T or A with C. Mismatches can be introduced into DNA through copying errors as well as some kinds of DNA damage.
If the cell â€œfixesâ€ the wrong side, that will introduce a mutation (see diagram). So how does the cell know which side of the mismatch needs to be repaired? Usually mismatch repair is tied to DNA replication. Replication enzymes appear to somehow mark the recently copied strand as being the one to replace — exactly how cells accomplish this is an active area of research.
In some situations, mismatch repair could introduce mutations into DNA.
Overall, mismatch repair is a good thing, from the point of view of preventing cancer. Inherited deficiencies in mismatch repair enzymes lead to an accumulation of mutations and an increased risk of colon cancer and other types of cancer.
But many of the cells in our bodies, such as muscle cells and neurons, have stopped dividing more or less permanently (in contrast with the colon). That means they no longer need to replicate their DNA. Other cells, such as resting white blood cells, have stopped dividing temporarily. Mutations in nondividing cells may have implications for aging and cancer formation in some tissues.
Through clever experimental design, Crouseâ€™s team was able to isolate examples of when mismatch repair occurred in the absence of DNA replication.
As the NIEHS Newsletter notes:
â€œThe researchers introduced specific mispairs into the DNA of yeast cells in a way that let them observe the very rare event of non-strand dependent DNA repair. They found that mispairs, not repaired during replication, sometimes underwent mismatch repair later when the cells were no longer dividing. This repair was not strand dependent and sometimes introduced mutations into the DNA sequence that allowed cells to resume growth. In one case, they observed such mutations arising in cells that had been in a non-dividing state for several days.â€
Although the Emory teamâ€™s research was performed on yeast, the mechanisms of mismatch repair are highly conserved in mammalian cells. Their results could also shed light on a process that takes place in the immune system called somatic hypermutation, in which mutations fine-tune antibody genes to make the most potent antibodies.
Emory Healthcare is a key player in plans to bring the worldâ€™s most advanced radiation treatment for cancer patients to Georgia.Â Emory Healthcare has signed a letter of intent with Advanced Particle Therapy, LLC, of Minden, Nevada, opening the door to a final exploratory phase for development of The Georgia Proton Treatment Center – Georgiaâ€™s first proton therapy facility.
For certain cancers, proton therapy offers a more precise and aggressive approach to destroying cancerous and non-cancerous tumors, as compared to conventional X-ray radiation. Proton therapy involves the use of a controlled beam of protons to target tumors with precision unavailable in other radiation therapies. According to The National Association for Proton Therapy, the precise delivery of proton energy may limit damage to healthy surrounding tissue, potentially resulting in lower side effects to the patient. This precision also allows for a more effective dose of radiation to be used.
Proton therapy is frequently used in the care of children diagnosed with cancer, as well as in adults who have small, well-defined tumors in organs such as the prostate, brain, head, neck, bladder, lungs, or the spine.Â And research is continuing into its efficacy in other cancers.
The gantry, or supporting structure, of a proton therapy machine.
The closest proton therapy facility to Georgia is the University of Florida Proton Therapy Institute in Jacksonville.Â Currently there are only nine proton therapy centers in the United States, including centers at Massachusetts General Hospital, MD Anderson Cancer Center in Houston and the University of Pennsylvania.
This is an exciting development in our ability to offer not only patients throughout Georgia and the Southeast the widest possible array of treatment options but patients from around the world who can come to Atlanta via the world’s busiest airport, Hartsfield-Jackson International. In addition, we will work to expand its utility and access for patients through collaborative research projects with Georgia Tech and other institutions. Winship physicians will also be able to reach out to their international colleagues and provide direction in how best to study and implement this technology in the care of cancer patients.
Under the letter of intent, Emory Healthcare faculty and staff will provide physician services, medical direction, and other administrative services to the center. Advanced Particle Therapy, through a Special Purpose Company, Georgia Proton Treatment Center, LLC, (GPTC) will design, build, equip and own the center.Â The facility, which will be funded by GPTC, will be approximately 100,000 square feet and is expected to cost approximately $200 million.Â Site selection for the facility is underway, and pending various approvals, groundbreaking is expected in the Spring of 2012.
The follow video presents a 3D simulation of proton therapy technology.
This title for a 2008 paper in Journal of Immunology, from pathologist Andrew Gewirtz’s laboratory, is astounding. Flagellin can protect against all those things (in mice, of course)? What about bullets or heartbreak? What is flagellin?
Flagellin is a structural feature many bacteria have in common — courtesy of iGEM via Creative Commons
Flagellin is the main structural component of flagella, the miniature whips bacteria use to propel themselves.Â Several Emory scientists are investigating how flagellin could be used as a protective agent to strengthen the body’s innate defenses and also as a vaccine component.
When Cynthia Anderson, MD, prepares her patients for stereotactic radiosurgery she emphasizes three things: the surgery is fast, friendly and focused. Initially used to treat the part of the brain associated with brain tumors, stereotactic radiosurgery has gained currency as a treatment for various types of cancer. This type of surgery uses x-ray beams instead of scalpels to eliminate tumors of the liver, lung and spine.
“It’s fast because the actual radiation treatment itself is very short,” says Anderson, a radiation oncologist at the Winship Cancer Institute of Emory University. “It’s friendly because it’s all done as an outpatient. And it’s focused because these targeted radiation beams get the maximum dose of radiation to a tumor and give the most minimal dose of radiation to the critical organs that surround the tumor.”