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1447 Targeted Protein Degradation for c-MYC Overcomes Therapy Resistance in T-Cell Acute Lymphoblastic Leukemias

Program: Oral and Poster Abstracts
Session: 605. Molecular Pharmacology and Drug Resistance: Lymphoid Neoplasms: Poster I
Hematology Disease Topics & Pathways:
Research, Lymphoid Leukemias, ALL, Acute Myeloid Malignancies, AML, apoptosis, Translational Research, genomics, drug development, Diseases, Therapies, Lymphoid Malignancies, Myeloid Malignancies, Biological Processes, molecular biology, Technology and Procedures, profiling
Saturday, December 9, 2023, 5:30 PM-7:30 PM

Faryal Munir, MD, MBBS1,2, Shayaun Khazaei, BS1*, Phoebe H. Calkins1*, Darah Scruggs, MS1*, Hideaki Mizuno, MD, PhD1*, Lauren B. Ostermann, BSc1*, Branko Cuglievan3, Miriam B. Garcia, DO2*, Dong Chen, PhD4*, Youzhi Tong, PhD4*, Zhihua Ren, PhD4*, Michael Andreeff, MD PhD5 and Yuki Nishida, MD, PhD1

1Section of Molecular Hematology and Therapy, Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX
2Division of Pediatrics, The University of Texas MD Anderson Cancer Center, Houston, TX
3The University of Texas MD Anderson Cancer Center, Houston, TX
4Kintor Pharmaceutical Ltd, Suzhou, China
5Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX

T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematological malignancy characterized by diffuse infiltration of the bone marrow by immature lymphoblasts of thymic origin expressing T-cell surface markers. Early T cell precursor (ETP)-ALL is a distinct subtype of T-ALL characterized by a lack of CD1a and CD8; low expression of CD5 and the presence of myeloid or stem cell markers, and recent studies have shown resistance to conventional chemotherapies and poor outcome in ETP-ALL compared to thymic or mature T-ALL. A recent study revealed distinct gene expression profiles in adult compared to pediatric-adolescent ETP-ALL, representing higher expression levels of BCL2 and CD34 (Dai et al. Proc Natl Acad Sci 2022), however, detailed proteomic profiling in ETA-ALL has yet to be determined.

Amplification of overexpression of MYC oncogene or stabilization of c-MYC protein occurs up to 70% in human cancers. Multifaceted activities of MYC include rapid proliferation of malignant cells supported by increased mitochondrial and ribosome biogenesis, dysregulated protein translation, and altered metabolism. NOTCH1-MYC signaling axis activation is one of the hallmarks that drives T-ALL leukemogenesis (Weng et al, Science 2004; Sanchez-Martin and Ferrando, Blood 2017). We have reported that targeting of BRD4 proteins induces suppression of leukemia initiating cells (LICs) in T-ALL by inhibiting the NOTCH1-MYC-CD44 axis, providing rationale to target MYC in therapy-resistant T-ALL (Piya et al. Leukemia 2022). We recently reported targeted protein degradation of c-MYC utilizing GT19715, the first-in-class cereblon modulator (CELMoD) for c-MYC exhibited promising anti-leukemia efficacy in acute myeloid leukemias (Nishida et al. ASH 2022). Here we employ GT19715 to investigate efficacy of targeting protein degradation of c-MYC in T-ALL.

GT19715 induced dose-dependent apoptosis and cytoreduction in T-ALL cell lines with IC50 values below 10 nM except HPB-ALL cells. We found substantial decrease of c-MYC protein levels in sensitive but not in resistant cells (HPB-ALL). GT19715 induced apoptosis and ³ 90% cytoreduction at nanomolar concentrations in primary, therapy-resistant T-ALL. GT19715 also enhanced cell death induced by dexamethasone. In a xenograft model of CCRF-CEM cells carrying NOTCH1, PTEN, FBXW7, KRAS and TP53 mutations, GT19715 (3 mg/kg, three IP injections per week, two weeks on and one week off) reduced > 99% circulating human CD45+ leukemia cells compared to vehicle on day 16 after engraftment (Fig. A), suggesting promising anti-leukemia efficacy in T-ALL in vivo.

ETP-ALL cells from an adult patient exhibited distinct clustering compared to those from an adolescent patient as determined by single-cell mass cytometry (CyTOF) (N = 2). Adult ETP-ALL cells were characterized by increased protein levels of BCL2, CD34, CD44 and p-S6 compared to adolescent ETP-ALL cells, suggesting more stem-like properties. On the other hand, adolescent ETP-ALL cells showed higher CD7, CD33 and CD38 levels compared to the adult sample (Fig. B). Interestingly, GT19715 treatment predominantly reduced p-S6high clusters in adult ETP-ALL cells, potentially suggesting c-MYC degradation-induced suppression of the AKT-mTOR pathway.

Conclusion: Targeted protein degradation of c-MYC induces promising anti-leukemia efficacy in T-ALL cells in vitro and in vivo. Further mechanistic and in vivo studies are ongoing.

Disclosures: Chen: Kintor Pharmaceutical: Current Employment. Tong: Kintor Pharmaceutical Ltd: Current Employment, Current equity holder in publicly-traded company. Ren: Kintor Pharmaceutical Ltd: Current Employment, Current equity holder in publicly-traded company. Andreeff: PMV: Research Funding; Kintor Pharmaceutical: Research Funding. Nishida: Kintor Pharmaceutical: Research Funding.

*signifies non-member of ASH