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MD Anderson Research Highlights for May 24, 2023

Featuring a new treatment for MCL plus insights into AML pathways, a rare kidney cancer, cell death and chemotherapy-induced chronic pain

( HOUSTON ― The University of Texas MD Anderson Cancer Center’s Research Highlights showcases the latest breakthroughs in cancer care, research and prevention. These advances are made possible through seamless collaboration between MD Anderson’s world-leading clinicians and scientists, bringing discoveries from the lab to the clinic and back.

Recent developments include a new treatment option for relapsed/refractory mantle cell lymphoma, a better understanding of protein variants that trigger tumor cell death and activate antitumor immunity, insights into the relationship between sickle cell trait and renal medullary carcinoma, clearer awareness of the clinical relevance of CD8 T cell state in acute myeloid leukemia, and an understanding of the distinct neuronal pathways triggered by chemotherapy and nerve injury.

Phase I/II trial shows safety and efficacy of pirtobrutinib in advanced MCL
Patients with relapsed/refractory (R/R) mantle cell lymphoma (MCL) – an aggressive subtype of B-cell non-Hodgkin lymphoma – initially respond well to covalent Bruton tyrosine kinase inhibitors (cBTKis) but eventually develop resistance, underscoring the need for more effective therapeutic strategies. Pirtobrutinib – a highly selective non-covalent BTKi – inhibits both normal and mutant BTK, providing a potential alternative. In a first-in-human Phase I/II clinical trial, researchers led by Michael Wang, M.D., examined the safety and efficacy of pirtobrutinib monotherapy in 90 patients with R/R MCL who previously received cBTKi treatment. The objective response rate was 57.8%, including 20% with complete responses, and the 12-month estimated duration of response rate was 57.1%. The most common side effects were fatigue, diarrhea and dyspnea. Grade 3 adverse events were infrequent and only 3% of patients discontinued treatment. The study demonstrated that pirtobrutinib was safe and showed durable efficacy in R/R MCL. Based on this data, the Food and Drug Administration granted accelerated approval for pirtobrutinib in R/R MCL in Jan. 2023. Learn more in the Journal of Clinical Oncology.

Specific protein variants trigger cancer cell death and improve antitumor response
The gasdermin B (GSDMB) protein can trigger cancer-associated pyroptosis – a form of programmed cell death that activates antitumor immune responses – but its exact role is controversial. The protein has multiple variants created from mRNA splicing, and these can have either anti- or pro-tumor functions. In this study, researchers led by Qing Kong, Ph.D., and Zhibin Zhang, Ph.D., examined six GSDMB splicing variants to provide insights into which are involved in pyroptosis. Relative to other variants, isoforms 3/4 were cytotoxic for tumor cells, triggering pyroptosis and resulting in better antitumor outcomes in bladder and cervical cancer models. The study suggests that tumors may be preferentially generating non-cytotoxic GSDMB variants in order to protect against pyroptosis. It also highlights the potential for therapeutic strategies that can increase production of cytotoxic GSDMB variants to improve antitumor immunity and enhance immunotherapy response. Learn more in Science Immunology. 

Link between sickle cell trait and SMARCB1 loss observed in renal medullary carcinoma
Renal medullary carcinoma (RMC) is a rare and aggressive form of kidney cancer that typically develops in young adults with sickle cell trait (SCT). Loss of the SMARCB1 tumor suppressor is a defining characteristic of RMC tumors. To better understand the mechanisms driving RMC and to improve treatment options, researchers led by Giannicola Genovese, M.D., Ph.D., Pavlos Msaouel M.D., Ph.D., and Melinda Soeung, Ph.D., investigated whether the loss of SMARCB1 provides a survival advantage in the presence of SCT. They demonstrated that a lack of oxygen induced by SCT leads to SMARCB1 degradation, protecting cells from hypoxic stress. The results suggest that SMARCB1 loss improves the survival of RMC cells under hypoxia, potentially explaining why SMARCB1-deficient tumors are resistant to therapeutic agents targeting hypoxia pathways. These insights may help researchers develop more effective treatments against RMC. Learn more in Proceedings of the National Academy of Sciences.

CD8 T Cells in AML display continuous differentiation and clonal hyperexpansion
Limited research is available on CD8 T cell exhaustion in hematologic cancers, specifically acute myeloid leukemia (AML). In a study led by Hussein Abbas, M.D, Ph.D., researchers characterized CD8 T cells from healthy donors as well as newly diagnosed (NewlyDx) and relapsed/refractory (R/R) AML patients. They discovered very few “exhausted” cells, with effector CD8 T cells from NewlyDx and R/R patients having different cytokine and metabolic profiles than the classic exhaustion signature seen in solid tumors. Researchers refined a 25-gene signature associated with poor outcomes in previously untreated AML patients, suggesting that the CD8 cell state may be clinically relevant. Analysis of T cell receptor sequencing data also revealed an increase in clonal hyperexpansion in R/R patient cells. The study highlights shared characteristics between CD8 cells in AML and those in solid cancer, suggesting that immune-based therapy in AML is likely to be most successful in earlier stages when CD8 T cells can afford plasticity. Learn more in Cancer Immunology Research.

Chemotherapy and nerve injury induces chronic pain via different sensory neurons
Treatment with chemotherapy is necessary for many patients with cancer, but it can sometimes cause chronic pain similar to traumatic nerve injuries. Studies have shown chemotherapy-induced neuropathy augments glutamate NMDA receptor (NMDAR) activity in the spinal cord, but little is known about the pathways involved. Researchers led by Yuying Huang, Ph.D., Shao Rui-Chen, M.D., and Hui-Lin Pan, M.D., Ph.D., found that chemotherapy triggers NMDAR activity in specific excitatory neurons. Removing NMDAR from these primary sensory neurons diminished chemotherapy-induced pain in laboratory models. Alternatively, chronic pain from traumatic nerve injury mainly resulted from the NMDAR expressed in different spinal neurons. The results suggest that chronic pain following nerve injury and chemotherapy is triggered by the NMDAR in different neurons and pathways, highlighting potential cellular targets to help treat these separate conditions. Learn more in The Journal of Neuroscience. 

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New chemical compound demonstrates potential in nerve regeneration

Research led by UCL, in partnership with the MRC Laboratory of Molecular Biology (MRC LMB) and AstraZeneca, has identified a new compound that can stimulate nerve regeneration after injury, as well as protect cardiac tissue from the sort of damage seen in heart attack. The study, published in Nature, identified a chemical compound, named ‘1938’, that activates the PI3K signalling pathway, and is involved in cell growth. Results from this early research showed the compound increased neuron growth in nerve cells, and in animal models, it reduced heart tissue damage after major trauma and regenerated lost motor function in a model of nerve injury. Though further research is ...

New research finds dramatic increase in illegal ketamine seized by authorities, sparking concern about potential dangers of rising recreational use

A new analysis led by NYU Grossman School of Medicine and the National Drug Early Warning System (NDEWS) at the University of Florida found a 349 percent rise in seizures of illicit ketamine by drug enforcement throughout the United States from 2017 through 2022. The study findings suggest that rising use of ketamine, a short-acting dissociative anesthetic commonly prescribed off-label to treat chronic pain and depression, can increase the likelihood that people who use recreationally or who use inadvertently may encounter an adulterated and potentially harmful version of the drug. The study publishes online May 24 in JAMA Psychiatry. “This ...

COVID-19 and risk for mental disorders among adults in Denmark

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Association of community vulnerability and state gun laws with firearm deaths in children and adolescents

About The Study: In this study including 5,813 youths ages 10 to 19 who died of an assault-related firearm injury, socially vulnerable communities in the U.S. experienced a disproportionate number of assault-related firearm deaths among youths. Although stricter gun laws were associated with lower death rates in all communities, these gun laws did not equalize the consequences on a relative scale, and disadvantaged communities remained disproportionately impacted. While legislation is necessary, it may not be sufficient to solve the problem of assault-related firearm deaths among children and adolescents.  Authors: Deepika Nehra, M.D., of the University ...

Cannabis use disorder and subsequent risk of psychotic and nonpsychotic unipolar depression and bipolar disorder

About The Study: This study of 6.6 million individuals in Demark found that cannabis use disorder was associated with an increased risk of psychotic and nonpsychotic bipolar disorder and unipolar depression. These findings may inform policies regarding the legal status and control of cannabis use. Authors: Oskar Hougaard Jefsen, M.D., of Aarhus University Hospital–Psychiatry in Aarhus, Denmark, is the corresponding author. To access the embargoed study: Visit our For The Media website at this link (10.1001/jamapsychiatry.2023.1256) Editor’s ...

Quantum matter breakthrough: Tuning density waves

Quantum matter breakthrough: Tuning density waves
“Cold atomic gases were well known in the past for the ability to ‘program’ the interactions between atoms,” says Professor Jean-Philippe Brantut at EPFL. “Our experiment doubles this ability!” Working with the group of Professor Helmut Ritsch at the University of Innsbruck, they have made a breakthrough that can impact not only quantum research but quantum-based technologies in the future. Density waves Scientists have long been interested in understanding how materials self-organize into complex structures, such as crystals. In the often-arcane world of quantum physics, ...

Fewer suicides among boys in regions with more bipolar diagnoses

Bipolar disorder underlies roughly five percent of all suicides among young people. Previous studies also show that there is often a long delay between the onset of bipolarism and its correct diagnosis and treatment. Researchers at Karolinska Institutet now show that fewer boys commit suicide in Swedish regions where bipolar diagnoses are more common. The study, which is published in JAMA Psychiatry, could contribute to more proactive care for reducing the number of suicides. “Bipolar disorder is often more distressing for people who develop it early in life and is one of the psychiatric disorders most associated with suicide risk,” says ...

Scientists find first evidence for new superconducting state in Ising superconductor

Scientists find first evidence for new superconducting state in Ising superconductor
In a ground-breaking experiment, scientists from the University of Groningen, together with colleagues from the Dutch universities of Nijmegen and Twente and the Harbin Institute of Technology (China), have discovered the existence of a superconductive state that was first predicted in 2017. They present evidence for a special variant of the FFLO superconductive state on 24 May in the journal Nature. This discovery could have significant applications, particularly in the field of superconducting electronics. The lead author of the paper is Professor Justin Ye, who heads the Device Physics of Complex Materials group at the University of Groningen. Ye and his team have ...

Where do our limbs come from?

For Immediate Release Contact:  Mark Couch, 303-724-5377,   Where Do Our Limbs Come From?             AURORA, Colo. (May 24, 2023) – An international collaboration that includes scientists from the University of Colorado School of Medicine has uncovered new clues about the origin of paired appendages – a major evolutionary step that remains unresolved and highly debated. The researchers describe their study in an article published today in the journal Nature. “This has become ...


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[] MD Anderson Research Highlights for May 24, 2023
Featuring a new treatment for MCL plus insights into AML pathways, a rare kidney cancer, cell death and chemotherapy-induced chronic pain