MD Anderson Research Highlights for November 16, 2022

Featuring a new combination therapy for advanced AML, a link between the microbiome and treatment-related fever, and a therapeutic target for immunotherapy-related colitis

The University of Texas MD Anderson Cancer Center’s Research Highlights provides a glimpse into recent basic, translational and clinical cancer research from MD Anderson experts. Current advances include a promising targeted therapy combination for patients with relapsed/refractory acute myeloid leukemia (AML), a link between the gut microbiome and therapy-related neutropenic fever, a novel therapeutic target for immunotherapy-related colitis, a telementoring model for training providers on cervical cancer prevention in limited-resource areas, a new understanding of the prognostic value of RUNX1 mutations in AML, and insights into the effects of opioid use on the pain sensitivity pathway.

Combination targeted therapy is promising for patients with relapsed/refractory AML
Effective therapies for patients with relapsed/refractory (R/R) acute myeloid leukemia (AML) remain limited, especially for those ineligible for cytotoxic chemotherapy. In a Phase Ib trial led by Naval Daver, M.D. and Michael Andreeff, M.D., Ph.D., researchers evaluated the combination of venetoclax and idasanutlin in 56 patients with R/R AML unfit for chemotherapy. The trial used a two-dimensional dose-escalation design, translating a preclinical concept developed by Andreeff. Patients received venetoclax daily with idasanutlin on the first five days of a 28-day cycle, followed by a dosing schedule optimization to evaluate reduced venetoclax schedules. IDH1/2 and RUNX1 mutations were associated with higher composite complete remission (CRc) rates of 50% and 45%, respectively, and were linked to therapy sensitivity. Conversely, the CRc rate was 20% in patients with TP53 mutations, with responses noted among those with co-occurring IDH and RUNX1 mutations. The combination had a manageable safety profile with common side effects, including diarrhea and nausea. Based on these encouraging results, studies are ongoing to evaluate BCL-2/MDM2 inhibitor combinations in both front-line and R/R AML. Learn more in Blood.

Study identifies link between gut microbiome and neutropenic fever after cancer therapy
A common complication of cancer therapy is neutropenia, a reduction in white blood cells, which can lead to infections and high fever. Previous studies suggested that patients with acute myeloid leukemia and neutropenic fever also had changes in their gut microbiome. To offer insights into how the gut microbiome may influence febrile neutropenia after cancer treatment, Jennifer Karmouch, Ph.D., Mohamed Jamal, Ph.D., Robert Jenq, M.D., and colleagues studied both clinical samples and laboratory models. They demonstrated that higher levels of a specific mucin-degrading bacteria were associated with a higher incidence of febrile neutropenia and that treatment with antibiotics helped restore those levels to normal. Additionally, the researchers found that dietary supplementation with propionate, a metabolic end product, also suppressed these bacteria and improved outcomes. This study highlights the link between diet, the gut microbiome and febrile neutropenia, suggesting possible strategies to reduce or prevent this treatment side effect. Learn more in Science Translational Medicine.

Laboratory models uncover therapeutic target for immunotherapy-related colitis
Immune checkpoint inhibitors (ICIs) improve patient outcomes in many cancers, but they also are associated with an increased risk of serious immune-related adverse events (irAEs), such as colitis. To understand the underlying mechanisms behind colitis following ICI treatment and to identify potential therapeutic targets, researchers led by Yifan Zhou, Ph.D., and Stephanie Watowich, Ph.D., developed laboratory models predisposed to intestinal inflammation and evaluated the effects of anti-CTLA 4 therapy, including immune signatures. The team discovered these inflammation-prone models developed neutrophil accumulation in the colon and systemic interleukin-6 (IL-6) release. Using IL-6 blockade with antibiotic treatment reduced intestinal damage and improved outcomes. Additionally, these signatures were confirmed to be present among biopsies from patients with ICI-related colitis, further validating their potential utility. Going forward, these novel preclinical models will allow for further investigation into the mechanisms of intestinal irAEs. Learn more in the Journal of Experimental Medicine.

Cervical cancer prevention telementoring program increases provider knowledge and evidence-based practices in Cameroon
Despite ongoing global efforts to reduce the burden of cervical cancer, this preventable disease remains a major public health issue in limited-resource settings such as sub-Saharan Africa, where human papillomavirus (HPV) vaccination and screening coverage are among the lowest worldwide. To help train local providers, an MD Anderson team led by Joel Fokom Domgue, M.D., adapted, implemented and evaluated the Cameroon Cervical Cancer Prevention Project ECHO. The telementoring program helped providers in Cameroon develop skills for diagnosis and treatment of pre-invasive disease. In this study, Fokom Domgue, Sanjay Shete, Ph.D., and colleagues report that 53.8% of prior ECHO attendees achieved a satisfactory knowledge score, compared to 4.5% of newcomers. Additionally, 68.8% of ECHO participants reported adopting best practice care or applying knowledge learned to their practice, demonstrating Project ECHO is an effective model for training African providers in cervical cancer prevention and early detection. Learn more in JAMA Network Open.

Prognostic value of RUNX1 mutations is treatment-dependent in acute myeloid leukemia
Patients with RUNX1-mutated (mRUNX1) acute myeloid leukemia (AML) have poor outcomes with intensive chemotherapy, but the prognostic value of this gene has not been investigated in the context of newer, lower-intensity treatments. Researchers led by Nicholas Short, M.D., retrospectively analyzed the genes of 907 patients with newly diagnosed AML who received various front-line treatments, including intensive chemotherapy and low-intensity chemotherapy with or without venetoclax, to see if RUNX1 mutation status impacted clinical outcomes. Contrary to previous findings, patients with mRUNX1 treated with venetoclax trended toward better overall survival, although the difference did not reach statistical significance. This is consistent with recent preclinical work by other MD Anderson researchers suggesting that mRUNX1 AML may be particularly sensitive to venetoclax. This study suggests that the prognostic value of RUNX1 mutations in AML may be treatment-dependent and stresses the importance of factoring in both molecular features and treatment type when developing prognostic models. Learn more in The American Journal of Hematology.

Study uncovers underlying pain sensitivity pathway affected by analgesic opioid use
Opioids commonly are used as an analgesic for pain treatment in cancer and following surgery, but they can cause pain hypersensitivity and loss of efficacy, leading to dependence, addiction and potentially fatal overdoses. This highlights a critical need to understand the effects of opioid use on the pain signaling pathway in order to improve patient outcomes. Researchers led by Shao-Rui Chen, M.D., and Hui Lin Pan, M.D., Ph.D., used in vitro spinal cord models to study the underlying cellular and molecular mechanisms affected by opioid exposure. They showed opioid exposure affects long-term activation of excitatory neurons and increases activity in ion channel NMDA receptors, offsetting the initial pain-relieving effect and amplifying pain sensitivity over time. The study suggests opioid use during anesthesia should be reconsidered and minimized, if possible, and offers potential targets to prevent or reduce this increased pain sensitivity and opioid tolerance. Learn more in the Journal of Neuroscience.

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