MD Anderson Research Highlights for October 2, 2024

Featuring insights into metastases, novel targets for nerve pain, overcoming treatment resistance in CRC, and a link between the gut microbiome and lung cancer

MD Anderson News Release October 02, 2024

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.

Study offers insights into molecular drivers of brain metastases from breast cancer cells
Brain metastases from breast cancer patients have elevated levels of Cdk5, which is typically found in neurons and is associated with poor outcomes. Researchers led by Dihua Yu, M.D., Ph.D., and Arseniy Yuzhalin, DPhil, examined how breast cancer cells spread to the brain and evade the immune system to develop. The researchers discovered that astrocytes, a type of cell in the brain, trigger the overproduction of Cdk5 in breast cancer cells metastasized to the brain, which reduces the expression of MHC-I, a critical signal for immune system recognition. Inhibiting Cdk5, either genetically or pharmacologically with roscovitine, restored normal MHC-I levels and reduced the survival and outgrowth of cancer cells in the brain. Further, blocking Cdk5 enhanced responses to immunotherapy by increasing the presence of immune cells in brain metastasis tumors in vivo. The study highlights Cdk5 as a viable therapeutic target for patients with brain metastases from advanced breast cancer. Learn more in Nature Cell Biology.

BEACON trial analysis provides insights into BRAF-V600E-mutated colorectal cancer
Patients with metastatic colorectal cancer harboring BRAF-V600E mutations have poor prognoses, highlighting a need to identify biomarkers that can optimize treatment. The recent BEACON trial showed that the combination of encorafenib (BRAF inhibitor) and cetuximab (anti-EGFR antibody), with or without binimetinib (MEK inhibitor), improved overall survival, objective response rates and progression-free survival in pretreated patients compared to those receiving cetuximab with chemotherapy. In a follow-up analysis, researchers led by Scott Kopetz, M.D., Ph.D., performed genomic and transcriptional profiling on tumor tissue and plasma samples from patients treated with either combination to examine how the molecular environment changes following treatment. Patients who had tumors with a stronger immune signature showed an increased benefit from the triplet combination than with cetuximab and chemotherapy. The analysis also highlighted potential targets for overcoming treatment resistance. Learn more in Nature Medicine.

Novel therapeutic target may improve pain oversensitivity after nerve injury
Neuropathic pain, a chronic condition resulting from injury or damage to the nervous system, can in some cases lead to allodynia – a condition in which nerves are overly sensitive and cause pain from stimuli that normally wouldn’t hurt. Previous studies have shown that allodynia caused by peripheral nerve injury is associated with an increase in B cells, but their role is poorly understood. To provide insights, researchers led by Peter Grace, Ph.D., investigated the role of B cells in the development of allodynia pain after nerve injury. They found that B cells produce immunoglobulin G (IgG) antibodies that interact with specific nerve cell receptors to trigger pain signals. Removing B cells or blocking their activity by removing the corresponding receptors led to a decrease of pain behavior in vivo. These findings highlight the critical role of B cells and their immune cell interactions in driving allodynia, suggesting that targeting this signaling pathway could lead to the development of treatments for chronic neuropathic pain. Learn more in Science Translational Medicine.

First-in-human study of novel inhibitor shows promise in MTAP-deleted solid tumors 
The PRMT5 enzyme plays a vital role in cellular processes, including gene expression. The enzyme’s dysregulation promotes tumor growth by affecting expression of both oncogenes and tumor suppressor genes, suggesting its potential as a therapeutic target. PRMT5 inhibitors have shown antitumor effects in preclinical tumor models, especially those harboring MTAP deletions, which make up 10 to 15% of all solid tumors. However, the first generation of these inhibitors caused severe blood-related toxicities. A first-in-human trial of the novel PRMT5 inhibitor AMG 193 – which targets a vulnerability in MTAP-deleted tumors – led by Jordi Rodon, M.D., Ph.D., demonstrated a manageable safety profile and no significant blood-related toxicities. The most common side effects were nausea, fatigue and vomiting. AMG 193 also showed antitumor responses in eight different tumor types, supporting its continued exploration as a monotherapy or in combination with other therapies. Learn more in Annals of Oncology.

Gut microbiome changes are drivers of inflammation and lung cancer development
Changes to the diversity and composition of the gut microbiome as well as elevated expression of the antimicrobial protein Lcn2 are associated with the development of lung adenocarcinoma, a type of non-small cell lung cancer, in preclinical models. To provide further insights, researchers led by Zahraa Rahal, M.D., Yuejiang Liu and Humam Kadara, Ph.D., examined the relationship between the microbiome and lung tumor immune environment following transplantation of fecal microbiota from Lcn2-deficient lab models. These models had increased gut inflammation and a reduced response to immunotherapy in the lung tumor microenvironment, specifically due to an increase in certain microbes and via the interleukin-6 pathway, which regulates immune responses. Analysis of samples from patients with lung adenocarcinoma were consistent with these findings. The study shows that gut microbiome imbalances affect inflammation, which leads to immunosuppression in lung tumors, highlighting novel therapeutic targets for this patient population. Learn more in Cancer Immunology Research.

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Immunofluorescence image of dorsal root ganglia from the peripheral nervous system showing co-localization of immunoglobulin G (magenta), neurons (yellow) and a pain-related marker (white). Image courtesy of Peter Grace, Ph.D.