Cancer News and Discussions

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Research points to a strategy for overcoming colorectal cancers' immunotherapy resistance
https://medicalxpress.com/news/2021-10- ... tance.html
by Massachusetts General Hospital

Immune checkpoint inhibitors, which unleash the immune response against tumor cells, have revolutionized cancer treatment; however, the medications aren't effective in a large number of patients, including those with colorectal cancer. New research published in PNAS that was led by investigators at Massachusetts General Hospital (MGH) and the University of Geneva (UNIGE) provides insights on why some types of colorectal cancer don't respond to immune checkpoint inhibitors and offers a strategy to overcome their resistance.

"Colorectal cancer is the second leading cause of cancer-related death in the United States and worldwide," says senior and co–corresponding author Rakesh K. Jain, Ph.D., director of the E.L. Steele Laboratories for Tumor Biology at MGH and the Andrew Werk Cook Professor of Radiation Oncology at Harvard Medical School (HMS). "A major cause of mortality in patients with colorectal cancer is the development of liver metastases, which is the spread of cancer to the liver."
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Identifying a key gene responsible for cancer drug resistance

by University of Missouri
https://medicalxpress.com/news/2021-10- ... -drug.html
A researcher at the University of Missouri School of Medicine has discovered an enzyme that plays a key role in the ability of cancer cells to resist drug treatment.

Immunomodulatory drugs like thalidomide, lenalidomide and pomalidomide have improved the treatment of patients with multiple myeloma and other blood cancers. But almost all patients eventually develop resistance to these therapies.

Principal investigator Thang Van Nguyen, DVM, Ph.D., an assistant research professor in the Center for Precision Medicine, discovered that a protein called USP15 is highly expressed in cancer cells that become resistant to the standard immunomodulatory drugs.

"This USP15 protein protects the cancer cells from destruction by removing ubiquitin tags placed on the cells by the immunomodulatory drugs," Nguyen said. "Those tags initiate the cell degradation process. But if those tags are removed by USP15, the cancer cells will continue to grow and multiply."

Nguyen believes testing multiple myeloma patients for USP15 will help determine if a patient will be resistant to immunomodulatory drug therapy. That knowledge could lead to a more precise, customized treatment.
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New clues toward treating pediatric brain tumors harboring epigenetic mutation
https://medicalxpress.com/news/2021-10- ... oring.html
by University of Michigan
While substantial strides have been made against some types of childhood cancers, high-grade gliomas still lack effective treatments.

Thirty to 60% of these pediatric brain tumors bear mutations in the gene H3F3A. This gene contains the encoded blueprint for histone H3.3, which plays an important role in the structure of chromatin. One of these mutations is known to scientists as H3.3G34R/V—meaning the amino acid glycine that's normally found at position 34 has been replaced by either an arginine or a valine.

Now an international research team led by the University of Michigan Health Rogel Cancer Center has found a small-molecule inhibitor that was able to suppress tumor growth in animal models of this glioma—offering new hope toward developing therapies for pediatric patients. Their findings appear in Science Translational Medicine.

"These tumors tend to occur in slightly older children than some of the more well-known types of childhood glioma—usually between the ages of 10 and 18," said senior study author Sriram Venneti, M.D., Ph.D., the Al and Robert Glick Family Research Professor of Pediatrics in the Department of Pathology at Michigan Medicine. "And the prospects remain quite dismal due to a lack of effective treatments."
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Clinical trial demonstrates focused ultrasound can deliver antibody therapy to breast cancer metastases in the brain
https://medicalxpress.com/news/2021-10- ... ibody.html
by Focused Ultrasound Foundation
In a first-in-world clinical trial, researchers at Sunnybrook Health Sciences Centre in Toronto, Canada, have demonstrated that magnetic resonance (MR)-guided focused ultrasound can be used to safely deliver antibody therapy to breast cancer that has metastasized to the brain.

In this Phase I clinical trial for Her2-positive breast cancer patients, the Sunnybrook team captured images of the antibody therapy, trastuzumab (or Herceptin), precisely targeting tumors in the brain after using Insightec's Exablate Neuro focused ultrasound device to temporarily and non-invasively open the blood-brain barrier (BBB) and enable intravenous trastuzumab to more effectively access tumor sites.

Antibody therapies can help the immune system fight cancer cells, and they are often used in combination with radiation and chemotherapy. However, the BBB presents a challenge when attempting to target sites in the brain. The BBB is a layer of cells lining blood vessels that protects the brain from viruses, bacteria, and other toxins—but it can also prevent therapeutics, such as trastuzumab, from reaching the brain in high enough concentrations to be effective.

"This is the first visual confirmation that focused ultrasound can improve the delivery of targeted antibody therapy across the BBB," says Dr. Nir Lipsman, the study's principal investigator and director of the Harquail Centre for Neuromodulation at Sunnybrook. "These are preliminary, but very promising results, that with continued research, have implications well beyond brain cancer for other neurological conditions, including Parkinson's disease and Alzheimer's, where the blood-brain barrier poses a challenge to drug delivery."
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Uncovering key vulnerability of aggressive lymphomas
https://medicalxpress.com/news/2021-10- ... homas.html
by Jim Schnabel, Cornell University
Lymphomas can turbo-charge their ability to proliferate by crowding growth-supporting enzymes into highly concentrated compartments within tumor cells, according to a study led by researchers at Weill Cornell Medicine.

The preclinical study, published Sept. 3 in Cancer Research, demonstrated that certain aggressive B-cell lymphomas use a protein-shepherding molecule called HSP90 to form and maintain these densely packed metabolic compartments, which are full of enzymes that synthesize amino acids and other cellular building blocks.

The researchers found that they could use an existing experimental drug that inhibits HSP90 to break up these metabolic compartments and slow lymphoma metabolism in lab-dish and animal studies.

"This strategy looks very promising as a way to treat aggressive lymphomas and also sensitize them to other therapies—we're hoping to test it soon in lymphoma patients," said senior author Dr. Leandro Cerchietti, associate professor of medicine in the Division of Hematology and Medical Oncology and a member of the Sandra and Edward Meyer Cancer Center at Weill Cornell Medicine.
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Novel computational pipeline could help repurpose cancer drugs for rare diseases
https://medicalxpress.com/news/2021-10- ... -rare.html
by University of Pittsburgh

By combining computational and experimental approaches, University of Pittsburgh School of Medicine and Prairie View A&M University researchers identified cancer drugs that show promise for treating pulmonary hypertension, or PH, a rare and incurable lung disease.

Published today in Science Advances, the study used a new algorithm to identify candidate cancer drugs for PH. Two of these compounds improved markers of the disease in human cells and rodents. The findings support broader use of this drug-repurposing platform for other non-cancerous conditions that don't yet have effective treatments.

"Repurposing drugs can cut down the time and cost of developing treatments for rare diseases, which historically don't receive much investment into research and drug development," said senior author Stephen Chan, M.D., Ph.D., professor of medicine and director of the Vascular Medicine Institute at Pitt and UPMC. "Pulmonary hypertension is an example of a rare disease where there is an unmet need for new treatments, given its devastating consequences. We developed this pipeline to rapidly predict which drugs are effective for PH and get these treatments to patients faster."

Pulmonary hypertension is a type of high blood pressure that occurs in the vessels that transport blood from the heart to the lungs. As the disease progresses and the heart must strain harder against these high pressures, it can lead to heart failure, multi-organ dysfunction and death. PH affects people of all ages but hits young women more often than men.

One of these young women is Allison Dsouza, a 24-year-old nurse who not only lives with the condition herself but also treats PH patients in the UPMC Lung Transplant Program. She was diagnosed with PH as a high school senior after she started having trouble walking to her car and doing hobbies like horseback riding. According to Dsouza, she was the sickest patient with the highest lung pressures that her doctors had seen.
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Study shows new strategy to boost immune system to fight melanoma
https://medicalxpress.com/news/2021-10- ... anoma.html
by Yale Cancer Center
A new study led by Yale Cancer Center researchers shows that the enzyme KDM5B suppresses anti-melanoma immunity. These findings could help develop a new treatment strategy to benefit patients with melanoma and other cancers, especially those who do not respond to current therapies. The research is published online today in the journal Nature.

"These results are exciting as we discovered fundamental roles of some poorly studied genetic elements in immune responses and identified a new way to stimulate the ability of our immune system to fight cancer," said Qin Yan, Ph.D., Associate Professor of Pathology and Director of the Epigenetics Program in the Department of Pathology and a member of Yale Cancer Center. "In addition, we showed that this method can be used to overcome the resistance to current cancer immunotherapies."

In the study, researchers show depletion of the protein KDM5B, which is critical for melanoma maintenance and drug resistance, induces robust adaptive immune responses, and enhances responses to immune checkpoint blockade. KDM5B partners with SETDB1, a protein coding gene, to repress the expression of certain genetic elements such as MMVL30. Expression of these genetic elements stimulates RNA and DNA sensing pathways and subsequent interferon responses, leading to tumor rejection and immune memory.

Yan and his team have been working on the roles of KDM5 proteins in development and cancer for many years. These studies began when researchers sought to understand the roles of KDM5B in melanoma in close collaboration with the lab of fellow Yale researcher Marcus Bosenberg, MD, Ph.D., a co-corresponding author of the study. Resources and expertise provided by the Yale Center for Immuno-Oncology and the Yale SPORE in Skin Cancer were critical for this research.
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New molecule targets, images and treats lung cancer tumors in mice
https://phys.org/news/2021-10-molecule- ... umors.html
by Liz Ahlberg Touchstone, University of Illinois at Urbana-Champaign

Lung cancer can be elusive to spot and difficult to treat because the markers for it are found in other tissues, too. Now, University of Illinois Urbana-Champaign researchers have developed a finely tuned molecular agent that can target lung and other cancer cells for imaging and treatment.

In a paper published in the journal Nature Chemistry, the researchers described the molecule's ability to target lung cancer cells, image them and deliver targeted treatment in cultures of human cancer cell lines as well as in live mice.

The researchers picked a surprising biomarker to target: glutathione, a molecule naturally produced in tissues throughout the body but expressed in greater quantities in lung cancer. Because of its ubiquity, they said, it has not been a good target for treatments such as chemotherapy.

"One of the biggest issues with developing diagnostic tools or targeted drugs is off-target effects," said Illinois chemistry professor Jefferson Chan, who conducted the study with graduate student Melissa Lucero. "When you give a patient a chemotherapeutic, it's kind of an arms race: You're killing the cancer cells, but you're also killing the rest of the body because so many things are similar. We used a unique chemistry approach to tune the reactivity of our molecule, so that we're targeting what would typically be considered a bad biomarker."
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Two reasons why cancers thrive in chromosomal chaos
https://medicalxpress.com/news/2021-10- ... chaos.html
by Scott Lafee, University of California - San Diego

Writing in EMBO reports, researchers at University of California San Diego School of Medicine and Moores Cancer Center at UC San Diego Health describe how a pair of fundamental genetic and cellular processes are exploited by cancer cells to promote tumor survival and growth.

The findings appear in the October 26, 2021 issue of the journal, a publication of the European Molecular Biology Organization.

Cancer is driven by multiple types of genetic alterations, including DNA mutations and copy number alterations ranging in scale from small insertions and deletions to whole genome duplication events.

Collectively, somatic copy number alterations in tumors frequently result in an abnormal number of chromosomes, termed aneuploidy, which has been shown to promote tumor development by increasing genetic diversity, instability and evolution. Approximately 90 percent of solid tumors and half of blood cancers present some form of aneuploidy, which is associated with tumor progression and poor prognoses.

In recent years, it has become apparent that cells cohabiting within a tumor microenvironment are subject not only to external stressors (mainly of metabolic origin, such as lack of nutrients), but also to the internal stressor aneuploidy. Both activate a stress response mechanism called the unfolded protein response (UPR), which leads to an accumulation of misfolded proteins in the endoplasmic reticulum (ER) of cells—an organelle that synthesizes proteins and transports them outside the cell.
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