MSK Research Highlights, March 9, 2023

(Press-News.org) New research from Memorial Sloan Kettering Cancer Center (MSK) and the Sloan Kettering Institute — a hub for basic science and translational research within MSK — offers new proof-of-concept compounds against acute myeloid leukemia; reports results from a phase 1 clinical trial appraising two drugs against low-grade glioma; examines MSK’s first-in-the-nation program integrating herbal medicine into oncology care; and identifies how high-grade histologic patterns in lymph node metastases could better predict lung cancer outcomes.

New degraders offer proof-of-concept approach against AML Acute myeloid leukemia (AML) is a blood cancer characterized by uncontrolled proliferation of immature myeloid cells. A new collaboration between researchers at the Sloan Kettering Institute and Harvard University developed small-molecule degraders of two proteins that are critical for the development of AML: IKZF2, a transcription factor specific to blood formation, and casein kinase 1 alpha (CK1α), a serine/threonine kinase. Degradation of IKZF2 and CK1α blocked cell growth and induced myeloid cells to differentiate into healthy mature cells, delaying leukemia progression in mouse models of AML. While these “tool compounds” aren’t ready to be given to people, they provide a proof of concept, demonstrating that simultaneously degrading IKZF2 and CK1α is a viable therapeutic strategy, note the study authors, who were led by first authors Sun-Mi Park, PhD, a postdoctoral researcher in the lab of senior study author Michael Kharas, PhD, at MSK, and David Miyamoto, a graduate student in the lab of senior study author Christina Woo, PhD, at Harvard. The findings also provide a framework for developing degraders against other types of cancer, or which could be used in combination with immunotherapies. in Cancer Cell.

Treatment for low-grade glioma advances to phase 3 clinical trial Most low-grade gliomas in adults harbor mutations in the genes encoding IDH1 or IDH2. A phase 1 trial for patients undergoing surgery for recurrent IDH1-mutant gliomas compared two different IDH inhibitors (vorasidenib and ivosidenib) to determine which drug was more effective at penetrating the brain and at suppressing 2-HG — the metabolic product of mutated IDH. The randomized, multisite trial enrolled 49 patients between April 2019 and April 2020. Both vorasidenib and ivosidenib reduced concentrations of 2-HG by more than 90%, were well-tolerated, and showed encouraging tumor responses, according to findings from a research team led by study first-author Ingo Mellinghoff, MD, Chair of MSK’s Department of Neurology. Vorasidenib showed greater brain penetration than ivosidenib. Reduction of 2-HG was associated with a decrease in tumor cell proliferation and with a reversal of gene expression programs typically associated with IDH mutations, documenting an active role of the mutant IDH enzyme in tumor maintenance. Based on the phase 1 trial results, vorasidenib was advanced to a phase 3 trial. in Nature Medicine.

Study examines novel MSK program integrating herbal medicine into oncology care Nearly 60% of patients with cancer self-prescribe herbal supplements during and after cancer treatment, often without consulting their doctors. Some supplements, however, like antioxidants, can interfere with chemotherapy and radiation treatment. MSK launched its Herbal Oncology Program in 2019 — the first such program in the nation — to help patients get relief for symptoms like constipation, fatigue, insomnia, and pain while improving patient-provider communication about the risks and benefits of supplements. A new study from MSK’s Jun Mao, MD, MSCE, Chief of MSK’s Integrative Medicine Service, and colleagues examines the implementation of the herbal medicine program within the context of a large academic cancer center and its impact on patient well-being. In the program’s first couple of years, 1,500 traditional Chinese medicine herbal prescriptions were written for more than 850 patients. Herbal supplements were most commonly prescribed to address gastrointestinal symptoms (37%); pain (28%); and treatment-related fatigue, sleep, and mood disorders (27%). More than 100 patients responded to a survey about their experiences, with more than 70% reporting they were satisfied with the effectiveness of the herbs, and less than 7% reporting having experienced mild adverse events that went away after discontinuing the herbs. “The study’s findings support the feasibility of integrating herbal medicine into an academic oncology setting,” the authors conclude, adding that the observed patterns of herbal prescriptions also point toward future areas of research to strengthen evidence around safe and effective supplement use. in Supportive Care in Cancer.

High-grade histologic patterns in lymph node metastases could better predict lung cancer outcomes The presence of high-grade tumor cells in the lymph nodes of stage 2 and stage 3 lung cancer patients can predict poor outcomes, according to a new study from MSK researchers. These predictions might be used to better identify patients who are at higher risk for worse outcomes than the current staging system used to determine treatment, which relies on the location of the lymph nodes to which lung cancer has spread and the number of lymph nodes involved, the authors found. The study by senior author Prasad Adusumilli, MD, and colleagues analyzed overall survival, recurrence, and lung cancer-related death in 360 patients who underwent lobectomy for stage 2 or stage 3 lung adenocarcinoma, with a median follow-up time of 6.8 years. Both micropapillary and solid histologic patterns in lymph node metastases were associated with poor outcomes. The findings suggest that not all stage 2 and 3 patients are alike and there is potential value in using the histologic patterns in the lymph nodes to guide decision-making in clinical practice and clinical trials, the authors note. in the Journal of Thoracic Oncology.

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