All your environmental chemicals belong in the exposome

Emory researchers recently described a “contact tracing” system for environmental chemical exposures, published in Nature Communications. The apparent metabolic breakdown products of common drugs — antidepressants, blood thinners and beta-blockers – can be detected in clinical samples. Many of those breakdown products are uncharted territory, in terms of chemical analysis, and the Emory researchers’ system will help them map it.

But what about all the environmental chemicals that triggers the carbon offset level that are out there, such as PCBs (polychlorinated biphenyls), once widely used in electrical infrastructure, and pesticides such as DDT? PCB exposure has been connected with increased rates of cancer and harm to wildlife.

A companion paper from the same group, also in Nature Communications, focuses more on techniques for detecting those contaminants. It lays out a standard workflow for processing samples for large-scale studies of the human exposome – all the influences from the environment as well as foods, drugs and other domestic products.

“What we aimed for was a simple method that is affordable and can be adopted by any laboratory to study as many chemicals as possible,” says lead author Xin Hu, PhD, assistant professor of medicine at Emory University School of Medicine. “We know that most of the contaminants have a small effect size, which means large-scale studies on tens of thousands of people are needed to understand the health effect of those contaminants and their link to rare but devastating diseases, like cancer. A simple analytical method will allow us to combine efforts from different laboratories and studies, and eventually measure tens of thousands of chemicals on tens of thousands of people.”

Part of what the researchers needed to do is to test and optimize methods for studying each type of environmental chemical, using a technique called GC-HRMS (gas chromatography-high resolution mass spectrometry). Previous studies on PCBs and DDT use that technique, but the Emory team wanted to develop a standard low-volume approach that would avoid multiple processing steps, which can lead to loss of material, variable recovery, and the potential for contamination.

The researchers used their approach to analyze samples from human plasma, lung, thyroid and stool. They also showed that they could identify new chemicals in clinical samples. An advantage of the new method over traditional approaches is that the database retains information of unidentified chemicals that can be readily accessed for future characterization, Hu says.

Posted on October 6, 2021 by Quinn Eastman in Uncategorized Leave a comment

Precision medicine with multiple myeloma

“Precision medicine” is an anti-cancer treatment strategy in which doctors use genetic or other tests to identify vulnerabilities in an individual’s cancer subtype.

Winship Cancer Institute researchers have been figuring out how to apply this strategy to multiple myeloma, with respect to one promising drug called venetoclax, in a way that can benefit the most patients.

Known commercially as Venclexta, venetoclax is already FDA-approved for some forms of leukemia and lymphoma. Researchers had observed that multiple myeloma cells with one type of chromosomal DNA rearrangement tend to be sensitive to venetoclax. About 20 percent of multiple myelomas carry this rearrangement, called t(11;14).

“One of our main goals is to identify a better biomarker to predict patient response to venetoclax,” says Winship researcher Vikas Gupta, lead author of a paper published in Blood earlier this year.

Gupta works together with Winship hematologist Jonathan Kaufman and researcher Larry Boise, also associate director for education and training, to translate insights about myeloma cells into advances for patient care.

In a recent clinical trial led by Kaufman, a sizable fraction of people whose myelomas carried the t(11;14) rearrangement responded well to venetoclax, when their cancers were already refractory to other drugs. Another study that did not separate out myelomas with t(11;14) extended progression-free survival by almost a year.

However, venetoclax also was associated with increased mortality from infections, which led the FDA in 2019 to put the second study on hold temporarily. Other ongoing studies of venetoclax with multiple myeloma were affected. It highlights the need to predict which patients would benefit from venetoclax – and which would not be likely to, for whom the drug may pose more risk.

In their paper, Winship investigators discovered that a set of cell markers predicted sensitivity to venetoclax better than t(11;14). These were markers for B cells, a type of white blood cell related to both multiple myeloma and some of the other forms of leukemia and lymphoma venetoclax is used to treat.

Gupta says that it was already possible to obtain myeloma cells from patients and test whether they are sensitive to venetoclax directly in the laboratory. But this isn’t practical for most clinics in cancer centers elsewhere.

“In contrast, the B cell phenotype can easily be assessed by flow cytometry, a technique that is routinely performed in clinical labs,” Gupta says. “So we are attempting to refine and validate our panel of flow cytometry markers, so that it can be used to easily and accurately predict which patients are sensitive to venetoclax.”

Posted on July 23, 2021 by Quinn Eastman in Cancer Leave a comment

Engineered “stealth bomber” virus could be new weapon against metastatic cancer

People suffering from cancer want to do anything they can that is available to them as an option to try to overcome this ailment. Many opt for a holistic cancer treatment, as this type of treatment also takes into account their comfort and the fact that their body will be considerably affected by medications and chemotherapy. Others do both that and work with a naturopath to try to remain in the best physical health possible, specially with the unavoidable adverse effects of our current means of combating cancer. Scientists attempting to find a solution to this elusive and varied ailment are also trying to attack this problem from as many angles as possible and in doing so, have possibly found a somewhat out of the box solution that is currently still being developed and tested. Cancer researchers can claim to have devised “smart bombs.” What has been missing is the stealth bomber – a delivery system that can slip through the body’s radar defenses.

Oncolytic viruses, or viruses that preferentially kill cancer cells, have been discussed and tested for decades. An oncolytic virus against melanoma was approved by the FDA in 2015. But against metastatic cancers, they’ve always faced an overwhelming barrier: the human immune system, which quickly captures viruses injected into the blood and sends them to the liver, the body’s garbage disposal.

Researchers at Emory and Case Western Reserve have now circumvented that barrier. They’ve re-engineered human adenovirus, so that the virus is not easily caught by parts of the innate immune system.

The re-engineering makes it possible to inject the virus into the blood, without arousing a massive inflammatory reaction.

A cryo-electron microscopy structure of the virus and its ability to eliminate disseminated tumors in mice were reported on November 25 in Science Translational Medicine.

“The innate immune system is quite efficient at sending viruses to the liver when they are delivered intravenously,” says lead author Dmitry Shayakhmetov, PhD. “For this reason, most oncolytic viruses are delivered directly into the tumor, without affecting metastases. In contrast, we think it will be possible to deliver our modified virus systemically at doses high enough to suppress tumor growth — without triggering life-threatening systemic toxicities.”

Posted on November 30, 2020 by Quinn Eastman in Uncategorized Leave a comment

Marcus Lab researchers make key cancer discovery

A new discovery by Emory researchers in certain lung cancer patients could help improve patient outcomes before the cancer metastasizes.

The researchers in the renowned Marcus Laboratory identified that highly invasive leader cells have a specific cluster of mutations that are also found in non-small cell lung cancer patients. Leader cells play a dominant role in tumor progression, and the researchers discovered that patients with the mutations experienced poorer survival rates.

The findings mark the first leader cell mutation signature identified in patients and could prove key in teasing out high-risk patients, allowing oncologists to develop a treatment plan early on before the disease has progressed.

“It has been a lot of fun to see the research go from the basic science side inside the lab to hopefully having an actual clinical impact,” says Brian Pedro, an MD/PhD student in Emory’s Medical Scientist Training Program. “Our data suggest that if you have one or more of these mutations, then we could potentially intervene early and improve patient outcomes.”

Stopping leader cells before they metastasize has long been a goal of researchers at the Winship Cancer Institute. “That is what we strive for as researchers,” Pedro says. “We are optimistic that this could be a promising clinical tool.”

The findings were published in the American Cancer Society’s journal “Cancer.”

The researchers specifically found the novel mutation cluster on chromosome 16q and compared the survival rates of those who had the mutations with those who did not. The results showed the patients who had the mutations had poorer survival rates across all stages.

Pedro says more investigation is needed to figure out why the mutations lead to poorer outcomes. He adds that he hopes the mutation signature can prove useful for cancer types beyond lung cancer.

You can learn more from Pedro’s Tweetstorm.

Excited to share our new paper, published online today @JournalCancer (https://t.co/Mo0VlAsjJY). Briefly, we found that mutations identified from invasive leader cells correlate with poor survival in non-small cell #lungcancer patients. For those interested, here’s a #tweetorial:

— Brian Pedro (@brian_pedro) April 22, 2020

Posted on April 28, 2020 by Wayne Drash in Cancer, Uncategorized Leave a comment

To fight cancer, mix harmless reovirus with ‘red devil’

A recent paper in Journal of Virology mixes tried-and-true cancer-fighting tactics with the exotic. Sort of a peanut-butter-and-chocolate story, but definitely not tasty!

The tried and true is doxorubicin (Adriamycin), the notorious ‘red devil’ chemotherapy drug, which has been around for decades. On the exotic side, we have oncolytic viruses – viruses retuned to attack cancer cells more than healthy cells. This idea finally made it to FDA approval in 2015 in the form of a re-engineered herpes virus directed against melanoma.

Bernardo Mainou’s lab in the Department of Pediatrics is combining both of these approaches together. He and his team are looking to supercharge reoviruses, a mostly harmless type of virus that has been adapted into an anticancer agent. A Canadian company has brought its reovirus forward into several cancer clinical trials, but its product has not gotten to the finish line.

In the JVI paper, graduate students Roxana Rodriguez-Stewart, Jameson Berry and their colleagues infected triple-negative breast cancer cells with a variety of reoviruses, in an effort to select for those that replicate better in those cells. They also looked for drugs that enhance viral infection of those cells, and landed on doxorubicin and related drugs. Doxorubicin is part of a class of anticancer drugs that inhibit topoisomerases, enzymes that unwind DNA as part of the process of replication.

Yesterday at the GDBBS graduate research symposium, Berry gave a talk about the next step: attaching the souped-up reovirus to doxorubicin.

Three varieties of reovirus were grown together in breast cancer cells to select for efficient replication.

Posted on January 29, 2020 by Quinn Eastman in Cancer Leave a comment

Nox-ious link to cancer Warburg effect

At Emory, Kathy Griendling’s group is well known for studying NADPH oxidases (also known as Nox), enzymes which generate reactive oxygen species. In 2009, they published a paper on a regulator of Nox enzymes called Poldip2. Griendling’s former postdoc, now assistant professor, Alejandra San Martin has taken up Poldip2.

Griendling first came to Nox enzymes from a cardiology/vascular biology perspective, but they have links to cancer. Nox enzymes are multifarious and it appears that Poldip2 is too. As its full name suggests, Poldip2 (polymerase delta interacting protein 2) was first identified as interacting with DNA replication enzymes. Poldip2 also appears in mitochondria, indirectly regulating the process of lipoylation — attachment of a fatty acid to proteins anchoring them in membranes. That’s where a recent PNAS paper from San Martin, Griendling and colleagues comes in. It identifies Poldip2 as playing a role in hypoxia and cancer cell metabolic adaptation.

Part of the PNAS paper focuses on Poldip2 in triple-negative breast cancer, more difficult to treat. In TNBC cells, Poldip2’s absence appears to be part of the warped cancer cell metabolism known as the Warburg effect. Lab Land has explored the Warburg effect with Winship’s Jing Chen.

Posted on February 15, 2018 by Quinn Eastman in Cancer, Heart Leave a comment

Cancer drug discovery: targeting DNA repair

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

Posted on August 23, 2017 by Quinn Eastman in Cancer Leave a comment

To explain cancer biology, use metaphors

Using metaphors to explain biomedical concepts is our bread and butter. That’s why we were tickled to see a recent paper from Winship Cancer Institute bioethicist Rebecca Pentz and colleagues, titled:

Using Metaphors to Explain Molecular Testing to Cancer Patients

Pentz’s team systematically evaluated something that science writers and journalists try to do all the time (and not always well). And they did so with actual conversations between doctors and patients at Winship. The first author of the paper, published in The Oncologist, was medical student Ana Pinheiro.

The researchers studied 66 conversations with nine oncologists. In 25 of those conversations, patients reported that they were able to hear a metaphor. Here’s one example:

“We try to figure out what food makes this kind of cancer grow. For this cancer, the food was estrogen and progesterone. So we’re going to focus on blocking the hormones, because that way we starve the cancer of its food.”

The paper lists all 17 (bus driver, boss, switch, battery, circuit, broken light switch, gas pedal, key turning off an engine, key opening a lock, food for growth, satellite and antenna, interstate, alternate circuit, traffic jam, blueprint, room names, Florida citrus) and how they were used to explain eight cancer-related molecular testing terms.

When patients were asked about the helpfulness of a metaphor that was used, 85 percent of the time they demonstrated understanding and said it was helpful. So let the metaphors fly!

Posted on March 23, 2017 by Quinn Eastman in Heart Leave a comment

Bad neighbors cause bad blood -> cancer

Certain DNA mutations in bone cells that support blood development can drive leukemia formation in nearby blood stem cells, cancer researchers have found.

Many cancer-driving mutations are “cell-autonomous,” meaning the change in a cell’s DNA makes that same cell grow more rapidly. In contrast, an indirect neighbor cell effect was observed in a mouse model of Noonan syndrome, an inherited disorder that increases the risk of developing leukemia.

In mouse bone marrow, mesenchymal stem cells (red), which normally nurture blood stem cells, produce a signal that is attractive for monocytes. The monocytes (green) prod nearby blood stem cells to proliferate, leading to leukemia. From Dong et al Nature (2016).

The findings were published Wednesday, October 26 in Nature.

The neighbor cell effect could be frustrating efforts to treat leukemias in patients with Noonan syndrome and a related condition, juvenile myelomonocytic leukemia (JMML). That’s because bone marrow transplant may remove the cancerous cells, but not the cause of the problem, leading to disease recurrence. However, the researchers show that a class of drugs can dampen the cancer-driving neighbor effect in mice. One of the drugs, maraviroc, is already FDA-approved against HIV infection.

“Our research highlights the importance of the bone marrow microenvironment,” says Cheng-Kui Qu, MD, PhD, professor of pediatrics at Emory University School of Medicine, Winship Cancer Institute and Aflac Cancer and Blood Disorders Center, Children’s Healthcare of Atlanta. “We found that a disease-associated mutation, which disturbs the niches where blood stem cell development occurs, can lead to leukemia formation.”

Editorial note: This Nature News + Views, aptly titled “Bad neighbors cause bad blood,” explains JMML, and how the relapse rate after bone marrow transplant is high (about 50 percent). It also notes that a variety of genetic alterations provoke leukemia when engineered into bone marrow stromal cells in mice (like this), but Qu and his colleagues described one that is associated with a known human disease.

Noonan syndrome often involves short stature, distinctive facial features, congenital heart defects and bleeding problems. It occurs in between one in 1000 to one in 2500 people, and can be caused by mutations in several genes. The most common cause is mutations in the gene PTPN11. Children with Noonan syndrome are estimated to have a risk of developing leukemia or other cancers that is eight times higher than their peers.
Read more

Posted on November 8, 2016 by Quinn Eastman in Cancer, Immunology Leave a comment

Anticancer strategy: expanding what is druggable

Scientists at Winship Cancer Institute, Emory University have identified compounds that stop two elusive anticancer targets from working together. In addition to striking two birds with one stone, this research could expand the envelope of what is considered “druggable.”

Many of the proteins and genes that have critical roles in cancer cell growth and survival have been conventionally thought of as undruggable. That’s because they’re inside the cell and aren’t enzymes, for which chemists have well-developed sabotage strategies.

In a twist, the potential anticancer drugs described in Cancer Cell disable an interaction between a notorious cancer-driving protein, MDM2, and a RNA encoding a radiation-resistance factor, XIAP.

The compounds could be effective against several types of cancer, says senior author Muxiang Zhou, MD, professor of pediatrics (hematology/oncology) at Emory University School of Medicine and Aflac Cancer and Blood Disorders Center.

In the paper, the compounds show activity against leukemia and neuroblastoma cells in culture and in mice, but a fraction of many other cancers, such as breast cancers (15 percent) and sarcoma (20 percent), show high levels of MDM2 and should be susceptible to them.

Posted on September 22, 2016 by Quinn Eastman in Cancer 1 Comment

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