MD Anderson Research Highlights for June 29, 2022
Featuring targeted therapy advances, CRISPR screens to identify tumor suppressors, and insights into anti-tumor immune response in brain metastases
MD Anderson News Release June 29, 2022
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 lower-intensity therapy for acute myeloid leukemia, a new target for treating chronic myelomonocytic leukemia, real-world synthetic controls for clinical trials in rare cancers, a potential biomarker to predict endocrine therapy response in breast cancer, integrated CRISPR screens to identify novel tumor suppressors, and a deeper knowledge of the immune tumor microenvironment in melanoma-derived brain metastases.
Venetoclax combined with cladribine/LDAC shows high responses in older patients with AML
Adding venetoclax to 5-azacitidine (5-AZA) improves remission rates and survival compared with 5-AZA alone in patients with newly diagnosed acute myeloid leukemia (AML) who are 75 or older or are otherwise unfit for intensive chemotherapy. Tapan Kadia, M.D., and colleagues led a trial to investigate whether adding this combination to low-intensity chemotherapy could further improve outcomes for older patients. The Phase II study evaluated venetoclax combined with cladribine (CLAD)/low-dose cytarabine (LDAC) alternating with venetoclax and 5-AZA for patients ≥ 60 years with newly diagnosed AML. Out of 60 patients, 56 (93%) experienced a composite complete response and out of 51 responding patients, 43 (84%) had undetectable minimal residual disease (MRD). The median overall survival was not yet reached after 22.1 months of follow-up. The high MRD-negative rates were similar to what has been reported with more intensive therapies, but this approach had less toxicity. Overall, the trial suggests that venetoclax added to CLAD/LDAC alternating with venetoclax and 5-AZA is safe and establishes its efficacy as a novel lower-intensity therapy in this patient population. Learn more in the Journal of Clinical Oncology.
Dual alterations drive chronic myelomonocytic leukemia, revealing new treatment target
TET2 gene mutations belong to the most important somatic lesions linked with increased risk of developing myeloid disorders, such as chronic myelomonocytic leukemia (CMML), during ageing. In TET2-deficient models, inflammatory signaling pathways help maintain survival of bone marrow hematopoietic stem and progenitor cells (BM HSPCs) and clonal expansion. One mediator of these pathways, KDM6B, is overexpressed in BM HSPCs of CMML. To further explore the relationship between TET2 and KDM6B, researchers led by Yue Wei, Ph.D. and Guillermo Garcia-Manero, M.D., analyzed the genomes of 28 patients with CMML and discovered that 18% had both TET2 mutations and KDM6B overexpression. The researchers developed a model with both genetic abnormalities and observed more pronounced CMML features, such as monocytosis, anemia, enlarged spleen and an increase in BM HSPCs, compared to either alteration alone. The dual abnormalities activated inflammatory pathways and suppressed pathways important to genomic stability. These are features associated with “inflammaging,” a chronic inflammatory condition that accelerates many age-related diseases. Treatment with a KDM6B inhibitor reduced the tumor burden in patient-derived xenograft models, providing a possible therapy target for CMML. Learn more in Leukemia.
Real-world synthetic controls may be useful to evaluate therapies against rare mutations
With more targeted therapy options emerging for treating non-small cell lung cancer (NSCLC), clinical trials are increasingly focused on smaller groups of patients with specific alterations. This can benefit patients with rare mutations, but it also makes it more challenging to lead statistically informative randomized trials. In a new study, Vivek Subbiah, M.D., and colleagues explored the use of real-world data as synthetic controls, using the single-arm Phase I/II ARROW trial as an example. The trial evaluated the RET inhibitor pralsetinib in patients with RET fusion-positive NSCLC – an alteration present in just 1%-2% of cases. Comparing trial data to multiple cohorts of real-world data, the researchers demonstrated that pralsetinib offered a survival benefit over standard immunotherapy and chemo-immunotherapy. Because non-randomized treatment comparisons can be biased, they also performed a quantitative analysis to identify sources of selection bias from this approach. The study suggests real-world data may be feasible for synthetic controls in rare oncogene-driven cancers and highlights sources of bias to guide future studies. Learn more in Nature Communications.
Sensitivity to endocrine therapy index associated with tumor response in breast cancer
Neoadjuvant endocrine therapy (NeoET) trials provide patients with stage II-III breast cancer an opportunity to begin treatment with endocrine therapy and possibly avoid chemotherapy, but there is a need for biomarkers to predict those likely to benefit from NeoET. In a study led by Fraser Symmans, M.D., researchers analyzed the sensitivity to endocrine therapy index (SET2,3) to evaluate prediction of response and event-free survival (EFS) following NeoET in the Alliance Z1031 trial. Patients with high SET2,3 had a higher rate of pharmacodynamic response (88.2%) than patients with low SET2,3 (56.9%). Patients with high SET2,3 also had longer EFS than patients with low SET2,3. These results indicate the potential for SET2,3 as an important pre-treatment biomarker to identify patients with endocrine-sensitive breast cancer who should consider NeoET. Learn more in Clinical Cancer Research.
Integrated screen approach identifies novel tumor suppressor and treatment target
The Hippo signaling pathway is involved in tumor suppression, so identifying cell surface proteins involved in this pathway could provide potential therapeutic targets. In a study led by Chao Wang, Ph.D., Xu Feng, Ph.D., Dan Su, Ph.D., and Junjie Chen, Ph.D., researchers used a computational approach to create a screening library of over 1,100 known cell surface proteins and evaluated their impact on tumor growth using an in vivo CRISPR-based gene editing model. They identified the cell adhesion molecule KIRREL as a novel tumor suppressor, showing that KIRREL loss inactivated Hippo signaling and increased tumor growth. KIRREL operates through another regulatory protein, SAV1, to activate the Hippo pathway, highlighting its therapeutic potential and supporting the use of CRISPR-based screens as a useful approach in identifying future treatment targets. Learn more in Proceedings of the National Academy of Sciences.
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