MD Anderson Research Highlights for August 7, 2024

Featuring cell biology insights, new targets to prevent dysphagia, improved treatments for advanced cancers and ALL, and liquid biopsies for early pancreatic cancer detection

MD Anderson News Release August 07, 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.

Recent developments at MD Anderson include insights into evolutionary cellular adaptations to environmental stressors, potential targets to overcome trouble swallowing in head and neck cancer patients treated with radiation therapy, a promising chemotherapy-free combination treatment for patients with a subset of acute lymphocytic leukemia, a single-cell atlas for stomach cancer metastasis, encouraging results of a PARP inhibitor on patients with advanced cancers and specific DNA damage repair mutations, and a liquid biopsy signature that could improve early pancreatic cancer detection.

Rapid adaptation to environmental change in yeast is driven by hidden genetic variation
Heat shock protein 90 (Hsp90) is an essential protein folding machine within our cells, with crucial roles in environmental stress response and cell signaling. However, we do not fully understand how Hsp90 influences a population’s ability to adapt to environmental stressors. To provide insights into this critical area of evolutionary biology, researchers led by Georgios Karras, Ph.D., explored how domesticated yeast manage environmental stress on Hsp90 from ethanol, which is a product of the fermentation process in beer and bread making. They demonstrated that domesticated yeasts evolved with extra copies of genes that make the metabolism of relevant sugars like maltose more robust to ethanol stress, improving their ability to survive under industrial fermentation conditions. This study uncovers Hsp90 as a vulnerability to environmental exposure and shows how hidden Hsp90-dependent genetic variation has fueled adaptive evolution in a real-life setting. These results have potential implications for human health and biotechnology. Learn more in Science.  

Specific nerves are associated with poorer outcomes in oral cancer treated with radiation
Patients with human papillomavirus (HPV)-mediated head and neck cancers have a favorable prognosis, but radiation therapy can often lead to dysphagia, or trouble swallowing. Cancer cells are known to change nerve signals in the tumor microenvironment, but how these nerve changes affect swallowing is poorly understood. Therefore, researchers led by Moran Amit, M.D., Ph.D., Katherine Hutcheson, Ph.D., and Shajedul Islam, Ph.D., examined samples from patients with head and neck cancers treated with radiation to compare tumor-associated neuronal changes in correlation with patient outcomes. Tumors enriched with specific nerve types were linked to poorer swallowing outcomes, and follow-up in vivo testing of this mechanism confirmed these results. The preclinical study shows that certain neuronal signaling pathways directly affect swallowing function after treatment and may serve as biomarkers for patient risk assessment. The authors suggest future studies should investigate blocking these target signals by repurposing existing neurological drugs to potentially preserve swallowing function and improve patient outcomes. Learn more in Science Translational Medicine.

Chemotherapy-free combination therapy shows promise for Ph-positive ALL
Patients with newly diagnosed Philadelphia chromosome (Ph)-positive acute lymphocytic leukemia (ALL) have limited treatment options and end up needing intensive chemotherapy or stem cell transplants. To investigate alternative treatments, researchers led by Hagop Kantarjian, M.D., and Elias Jabbour, M.D., evaluated the chemotherapy-free combination therapy of blinatumomab and ponatinib in 60 patients with Ph-positive ALL. In updated results with a median follow-up of 24 months, the combination achieved a complete response rate of 83% and a negative measurable residual disease in 98% of patients. The estimated three-year overall survival rate and event-free survival rate were 91% and 77%, respectively. Only two patients required hematopoietic stem cell transplants, and side effects were manageable. The study highlights the potential of this chemotherapy-free combination therapy to reduce the need for stem cell transplants and improve outcomes for patients with Ph-positive ALL. Learn more in the Journal of Clinical Oncology.

Atlas of metastatic progression of stomach cancer suggests potential therapeutic target
Research on the metastatic progression of gastric adenocarcinoma (GAC), an aggressive type of stomach cancer with a poor patient prognosis, is limited. To provide further insights, researchers led by Pawel Mazur, Ph.D., Jaffer Ajani, M.D., and Linghua Wang, M.D., Ph.D., performed single-cell transcriptome and immune profiling of 68 paired treatment-naïve and primary metastatic tumors to observe changes in the tumor microenvironment (TME) during metastatic progression. The results showed that cancer cells in liver and peritoneal metastases avoid ferroptosis, or cell death, by upregulating a specific enzyme, GPX4. Inhibiting GPX4 reduced tumor growth and enhanced the efficacy of chimeric antigen receptor (CAR) T cell therapy. The study provides the largest single-cell atlas of metastatic GAC and suggests that cancer cells co-evolve with their TME at metastatic sites, highlighting the therapeutic potential of combining ferroptosis-targeting treatments with CAR T cell therapy to improve outcomes for patients with metastatic GAC. Learn more in Gastroenterology.

PARP inhibitor shows promise for advanced cancers with BRCA1/2 mutations
Talazoparib is a PARP inhibitor that blocks DNA damage repair (DDR), leading to cancer cell death. It is used for treating certain types of breast and ovarian cancers with BRCA1/2 mutations, but its effects on other cancers with BRCA1/2 mutations or other DDR deficiencies are unknown. In a Phase II study, researchers led by Sarina Piha-Paul, M.D., and Funda Meric-Bernstam, M.D., tested the efficacy of talazoparib in 79 patients with metastatic or inoperable advanced cancers with somatic or germline BRCA1/2 mutations as well as patients with PTEN tumor suppressor or other DDR pathway mutations. Talazoparib was effective for patients with somatic and germline BRCA1/2 mutations, with a clinical benefit rate of 32.5% and 30.6%, respectively. PTEN mutations were associated with limited clinical benefit, reduced survival and shorter time to progression with talazoparib, highlighting a need to further investigate whether PTEN can be a prognostic or predictive biomarker of treatment response. Learn more in NPJ Precision Oncology. 

Blood-based miRNA signature improves early-stage pancreatic cancer detection
Pancreatic cancer has poor survival outcomes in part due to late diagnosis in asymptomatic patients. The CA19-9 biomarker has limited sensitivity for early-stage cancer, leading researchers Subrata Sen, Ph.D., Warapen Treekitkarnmongkol, Ph.D., and Jianliang Dai, Ph.D., to investigate new early detection approaches. The researchers examined 2,083 plasma micro-RNAs (miRNAs) from 203 age-matched samples. Focusing on cancer-associated pathways, they developed a three-miRNA signature that improved early detection when combined with CA19-9 compared to CA19-9 alone. For stage I and II cases, the sensitivities of the combination were 92% and 40% in discriminating from healthy and pancreatitis controls, respectively, compared to 60% and 11% for CA19-9 alone. Validation studies revealed an increase in diagnostic performance of the signature with early detection of up to 12 months before diagnosis. This miRNA signature merits further investigation with larger cohorts in different pancreatic cancer subtypes. Learn more in Gastro Hep Advances.

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Immunofluorescence image of the tumor neural microenvironment in a radiation-treated patient with dysphagia showing enrichment of certain nerves (red and green). Image courtesy of the Amit lab.