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 Read more

Promiscuous protein droplets regulate immune gene activity

Biochemists at Emory are achieving insights into how an important regulator of the immune system switches its function, based on its orientation and local environment. New research demonstrates that the glucocorticoid receptor (or GR) forms droplets or “condensates” that change form, depending on its available partners. The inside of a cell is like a crowded nightclub or party, with enzymes and other proteins searching out prospective partners. The GR is particularly well-connected and promiscuous, and Read more

Neutrophils flood lungs in severe COVID-19

In the lungs of severe COVID-19 patients, neutrophils camp out and release inflammatory cytokines and tissue-damaging Read more

pancreatic cancer

Fixing Humpty Dumpty in cancer cells

As Star Trek’s Spock once observed: “As a matter of cosmic history, it has always been easier to destroy than to create.”

The same is true inside human cells, explaining why Emory researchers’ recent accomplishment – finding a small-molecule compound that corrects a defective protein-protein interaction – is so significant for cancer research. It’s like putting Humpty Dumpty back together again.

Xiulei Mo, Haian Fu and colleagues have identified what they call a “mutation-directed molecular glue”. The glue restores a regulatory circuit that when defective, is responsible for acceleration of colorectal and pancreatic cancer. The results are reported in Cell Chemical Biology.

Restoring protein-protein interactions disrupted by an oncogenic mutation is like putting Humpty Dumpty back together again

“It is very exciting, because this is a clear example of a protein-protein interaction stabilizer that can reactivate the lost function and reestablish tumor-suppressive activity,” says Fu, who is chair of Emory’s Pharmacology and Chemical Biology department and leader of Winship Cancer Institute’s Discovery & Developmental Therapeutics program.

Scientists are very good at finding inhibitors for enzymes that are overactive. But they have meager results as far as strengthening interactions that are weak or absent. There are existing examples of drugs that stabilize protein-protein interactions (transplant drugs rapamycin and cyclosporine), but they inhibit the function of the proteins they target, as intended.

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Peeling away pancreatic cancers’ defenses

At Winship Cancer Institute, pancreatic cancer researcher Greg Lesinski and colleagues have a new paper in Molecular Cancer Therapeutics. It’s about a combination immunotherapy approach that gets through pancreatic cancers’ extra defenses, and it represents the preclinical counterpart to a clinical trial that is underway and almost finished at Winship, under the direction of GI oncologist Bassel El-Rayes.

Immunotherapies have transformed how other forms of cancer are treated, but for pancreatic cancers, an obstacle is getting through the dense layers of cellular shielding that the cancers build around themselves. Pancreatic cancers create “nests” of fibrotic stellate cells that pump out inflammatory cytokines such as IL-6.

Pancreatic cancer is anticipated to become the second deadliest cancer in the United States by 2030, surpassing breast and colon cancer. 

“Inflammation and a good immune response don’t always go hand in hand,” El-Rayes told us, for a 2018 Winship magazine article. “High IL-6 causes immune exhaustion, and keeps the good cells out of the tumor.”

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Update on pancreatic cancer: images and clinical trial

In 2018, Winship magazine had a feature story on pancreatic cancer. Our team developed an illustration that we hoped could convey the tumors’ complex structure, which contributes to making them difficult to treat. Oncologist Bassel El-Rayes described how the tumors recruit other cells to form a protective shell.

“If you look at a tumor from the pancreas, you will see small nests of cells embedded in scar tissue,” he says. “The cancer uses this scar tissue as a shield, to its own advantage.”

With El-Rayes and fellow oncologist Walid Shaib, Greg Lesinski’s lab recently published a paper in JCI Insight. The point of the paper was to look at how chemotherapy changes immune activity in the tumor microenvironment, but we also get vivid images giving us a glimpse of those nests. It helps to view these images as large as possible, so please check them out at the journal’s site, which has no paywall.

Regions stained green are tumor-rich; red regions are immune cell-rich, and blue regions are rich in stromal cells (stellate/fibroblast cells). The goal is to get immune cells to envelop the tumors more, like in square 8.

The 2018 magazine story also laid out some of Lesinski’s and El-Rayes’ ideas.

Based on his lab’s recent success in animal models, Lesinski thinks that combining an immunotherapy drug with agents that stop IL-6 could pry open pancreatic cancers’ protective shells. In those experiments, the combination resulted in fewer stellate cells and more T cells in the tumors. Fortunately, a couple of “off-the-shelf” options, drugs approved for rheumatoid arthritis, already exist for targeting IL-6, Lesinski says.

On that theme, we noticed that a clinical trial was posted on clinicaltrials.gov in December that implements those proposals: “Siltuximab and Spartalizumab in Patients With Metastatic Pancreatic Cancer”. El-Rayes is the principal investigator, and it is not yet recruiting. Siltuximab is an antibody against IL-6 and spartalizumab is a second generation PD-1 inhibitor.

Update: The XL888 + pembrolizumab study mentioned in the article is also moving along, presented by Mehmet Akce at the Gastrointestinal Cancers Symposium.

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Genomics plus human intelligence

Emory geneticists Hong Li and Michael Gambello recently identified the first pediatric case of a rare inherited metabolic disorder: glucagon receptor deficiency. Their findings, published in Molecular Genetics and Metabolic Reports, show the power of gene sequencing to solve puzzles – when combined with human intelligence. Although the diagnosis did not resolve all the issues faced by the patient, it allowed doctors to advise the family about diet and possible pancreatic tumor risk.

The family of a now 9-year-old girl came to Li when the girl was 4 years old. Based on newborn screening, the girl had been diagnosed with a known disorder called arginase deficiency. Arginase breaks down the amino acid arginine; if it is deficient, arginine and toxic ammonia tend to accumulate. At birth, the girl had high arginine levels – hence the initial diagnosis.

The girl had a history of low body weight, anorexia and intermittent vomiting, which led doctors to place a feeding tube through the abdominal wall into her stomach. For several years, she was given a special low-protein liquid diet and supplements, aimed at heading off nutritional imbalance and tissue breakdown. However, she did not have intellectual disability or neurological symptoms, which are often seen with arginase deficiency.

In fact, her blood amino acids, including arginine, were fully normalized, and a genetic test for arginase deficiency was normal as well.  These results were perplexing. By reviewing all the clinical, biochemical and molecular data, Li concluded the girl did not have arginase deficiency, and began looking for an alternative diagnosis. Read more

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Pilot human trial for image-guided cancer surgery tool

The Spectropen, a hand-held device developed by Emory and Georgia Tech scientists, was designed to help surgeons see the margins of tumors during surgery.

Some of the first results from procedures undertaken with the aid of the Spectropen in human cancer patients were recently published by the journal PLOS One. A related paper discussing image-guided removal of pulmonary nodules was just published in Annals of Thoracic Surgery.

To test the Spectropen, biomedical engineer Shuming Nie and his colleagues have been collaborating with thoracic surgeon Sunil Singhal at the University of Pennsylvania.

As described in the PLOS One paper, five patients with cancer in their lungs or chest participated in a pilot study at Penn. They received an injection of the fluorescent dye indocyanine green (ICG) before surgery.

ICG is already FDA-approved for in vivo diagnostics and now used to assess cardiac and liver function. ICG accumulates in tumors more than normal tissue because tumors have leaky blood vessels and membranes. The Spectropen shines light close to the infrared range on the tumor, causing it to glow because of the fluorescent dye.

[This technique resembles the 5-aminolevulinic acid imaging technique for brain tumor surgery being tested by Costas Hadjipanayis, described in Emory Medicine.]

In one case from the PLOS One article, the imaging procedure had some tangible benefits, allowing the surgeons to detect the spread of cancerous cells when other modes of imaging did not. Read more

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Pancreatic cancer: Front and center

With the sad news today of the death of actor Patrick Swayze, the public is again focused on pancreatic cancer and searching for more information on this aggressive cancer.

Recently, David Kooby, MD, Emory Winship Cancer Institute, and an assistant professor, Department of Surgical Oncology, authored a blog for the Atlanta Journal-Constitution’s “Doctor Is In” on this topic.

Emory Winship Cancer Institute

Emory Winship Cancer Institute

The following is an excerpt from the blog:

Pancreatic cancer is an aggressive malignancy that begins in the cells of the duct (or tube) running along the length of the pancreas. Each year about 42,000 new cases of pancreatic cancer are diagnosed and more than 35,000 people die from this cancer. A diagnosis of pancreatic cancer is usually made after discovery of a mass or a dilated duct in the pancreas.

Pancreatic cancer can be difficult to diagnose. Patients often come in for a doctor’s visit with non-specific symptoms such as abdominal or back pain or weight loss. Some patients will develop jaundice (yellowing of the skin) as a result of the tumor blocking the duct draining bile from the liver

No one knows the exact causes of pancreatic cancer, although some risk factors are known through research that has been done.

According to the National Cancer Institute, the following are risk factors for development of pancreatic cancer:

  • Age — The likelihood of developing pancreatic cancer increases with age. Most pancreatic cancers occur in people over the age of 60.
  • Smoking — Cigarette smokers are two or three times more likely than nonsmokers to develop pancreatic cancer.
  • Diabetes mellitus — Pancreatic cancer occurs more often in people who have diabetes than in people who do not.
  • Being male — More men than women are diagnosed with pancreatic cancer.
  • Being African-American — African-Americans are more likely than Asians, Hispanics or whites to get pancreatic cancer.
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