MD Anderson Research Highlights for February 7, 2024

Featuring a novel method to mechanically destroy cancer cells; combination treatments for AML, MDS and CMML; and new targets for breast and brain cancers

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 a combination treatment for patients with acute myeloid leukemia (AML), the discovery of a molecular driver in metastatic breast cancer, an oral combination therapy for high-risk myelodysplastic syndromes (MDS) and chronic myelomonocytic leukemia (CMML), a novel method to mechanically destroy cancer cells, targeting innate immunity to treat a subset of brain tumors, an improved method to stratify patients for a subset of lung cancer, insights into the clinical significance of specific KRAS mutations in pancreatic cancer, and a new model of patient competence to aid long-term self-care behaviors.  

Triple combination yields promising survival rates in AML patients with FLT3 mutations
Patients with newly diagnosed FLT3-mutated acute myeloid leukemia (AML) who are ineligible for intensive chemotherapy often experience resistance to the current standard-of-care treatment, azacitidine plus venetoclax. In a Phase II trial led by Nicholas Short, M.D., the addition of gilteritinib, an oral FLT3 inhibitor, to the standard regimen resulted in high complete remission rates, deep FLT3 molecular responses and encouraging survival in trial participants. The trial enrolled 30 patients with newly diagnosed FLT3-mutated AML, who received 80 milligrams of gilteritinib once daily in combination with azacitidine and venetoclax. All patients responded to the regimen, and the relapse-free survival and overall survival rates at 18 months were 71% and 72%, respectively. These results compare favorably to historical expectations with the current standard of care, highlighting the combination’s therapeutic potential in this population. Learn more in the Journal of Clinical Oncology.

SMYD2 methyltransferase identified as driver of breast cancer metastasis
The majority of breast cancer deaths are linked to its metastatic spread to distant organs, but therapeutic options remain limited for certain types of aggressive breast cancer that frequently metastasize. A new study led by Pawel Mazur, Ph.D., identified the lysine methyltransferase SMYD2 as a critical regular of breast cancer metastasis. The SMYD2 enzyme acts by modifying other proteins that can induce changes in the cellular cytoskeleton. In preclinical models, inhibiting SMYD2 activity increased overall survival by blocking the primary tumor cell’s ability to metastasize. This makes SMYD2 a promising target for novel therapeutics to prevent the metastatic progression of malignant breast cancer. Learn more in Cell Discovery

Novel oral combination therapy yields promising response rates in patients with higher-risk MDS or CMML
The standard of care for most patients with myelodysplastic syndromes (MDS) is a hypomethylating agent, such as azacitidine or decitabine, which requires either intravenous or subcutaneous administration for several days a month in each cycle. In a Phase 1/2 trial led by Guillermo Garcia-Manero, M.D., and Alex Bataller, M.D., researchers investigated an all-oral combination of decitabine/cedazuridine and the oral BCL-2 inhibitor venetoclax in patients with higher-risk MDS and chronic myelomonocytic leukemia (CMML). This combination achieved an overall response rate over 95% and an acceptable toxicity profile. In addition, a significant fraction of patients was able to undergo stem cell transplantation. At the time of this report, the median survival of these patients had not been reached. These results are the first example of a completely oral therapy approach for patients with MDS and CMML. Learn more in The Lancet Haematology.

‘Molecular jackhammers’ demonstrate ability to destroy cancer cells
A team of scientists including Jeffrey Myers, M.D., Ph.D., demonstrated a new method for using molecular vibrations to mechanically damage cell membranes, leading to cancer cell death. The study used molecules known as aminocyanines, which attach to the cell membranes of cancer cells. When activated by near-infrared light, the electrons in these molecules vibrate rapidly, destroying the cell membrane beyond repair. The researchers named these molecules ‘molecular jackhammers’ for their ability to mechanically destroy their targets, a method that has the added advantage of cells being unlikely to develop resistance. Using this method, the scientists completely destroyed human melanoma cells in vitro and achieved 50% tumor-free efficacy in vivo, highlighting the therapeutic potential of this approach for targeting cancer cells. Learn more in Nature Chemistry.

Targeting innate immune system may be therapeutic strategy for subset of brain tumors
Patients with diffuse gliomas – aggressive brain tumors – usually have disease recurrence after treatment, partially due to an immunosuppressive microenvironment. Over 80% of IDH1-mutant astrocytomas, a type of glioma, also have inactivation of the chromatin remodeling gene ATRX, yet the reason for this co-occurrence and how it affects the immune system is unknown. Therefore, researchers led by Jason Huse, M.D., Ph.D., generated ATRX-deficient glioma models with and without IDH1. They found that ATRX-deficient glioma cells are sensitized to innate immune activation and infiltration in vitro, leading to impaired glioma growth and prolonged survival in vivo. Interestingly, IDH1 mutations mask these effects, suppressing key immune genes and increasing tumor aggressiveness. Using an IDH1-mutant inhibitor reversed this suppression, suggesting that innate immunity is a potential therapeutic strategy in developing treatments for certain patients with gliomas. Learn more in Nature Communications.

Immune environment associated with treatment response in squamous cell lung cancer
Determining optimal immune checkpoint inhibitor treatments for metastatic squamous non-small cell lung cancer (SqNSCLC) has remained a consistent challenge. To address this, researchers including Jianjun Zhang M.D., Ph.D., Cara Haymaker, Ph.D., and Edwin Roger Parra, M.D., Ph.D., analyzed samples from patients with advanced SqNSCLC in a Phase III trial evaluating nivolumab alone compared with nivolumab plus ipilimumab. Higher immune scores and spatial immune cell distribution correlated with better responses and improved survival. Regulatory T cells were linked to poorer overall survival in specific combinations, while an active immune response was associated with better survival. Tumors with a higher burden of copy number variations were associated with a less active immune response and shorter survival. Blood tests measuring immune proteins could potentially predict progression long before actual progression on CT scans. The study highlights the importance of considering immune cell environments and genetic factors to identify SqNSCLC patients who would benefit the most from immunotherapy. Learn more in Clinical Cancer Research.

KRAS mutations are clinically prognostic in pancreatic cancer
KRAS mutations are found in nearly 90% of patients with pancreatic cancer, but their clinical impact remains understudied. To provide insights into specific KRAS mutations and how they influence clinical outcomes, researchers led by Abdelrahman Yousef, M.D., and Dan Zhao, M.D., Ph.D., analyzed data from 803 pancreatic adenocarcinoma patients. They discovered that patients with KRAS wildtype and KRAS G12R mutations had better survival than those with KRAS G12D or KRAS Q61 mutations; a pattern that was consistently validated in an external cohort. KRAS G12D mutations were correlated with metastatic disease, while KRAS G12R mutations were common in well- to moderately-differentiated tumors. Co-mutations, especially involving the ARID1A gene, also influenced outcomes; patients with ARID1A-mutated tumors had worse overall survival. These findings underscore the need for tailored therapeutic strategies based on specific KRAS mutation and co-mutation profiles, providing valuable insights for targeting KRAS in pancreatic cancer treatment. Learn more in NPJ Precision Oncology.

New model of patient competence necessary to aid nurses in caring for patients living with cancer and diabetes
Cancer and type 2 diabetes mellitus often appear together due to shared risk factors like smoking, obesity and a sedentary lifestyle. Successfully managing these conditions requires self-care practices such as blood glucose monitoring, dietary modifications or decreasing alcohol intake. The complexity of these behaviors assumes a certain level of patient competence, but this concept has not been fully developed. In a study led by Vivian Crowder and Meagan Whisenant, Ph.D., researchers redefined patient competence as the ability of patients living with chronic illness to reach skill mastery, acquire knowledge, maintain a positive attitude, trust themselves and their health care professional, and actively engage in self-care behaviors. This new definition enables researchers to develop tools that can help health care professionals better assess patient competence and improve long-term self-care behaviors. Learn more in the Journal of Clinical Nursing.

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