DS-5272 / Daiichi Sankyo - LARVOL DELTA

CRISPR/Cas9 Library Screens Identified Atp2a2 As an In Vivo Specific Tumor Suppressor in Myeloid Neoplasms (ASH 2024) - "We then examined the effect of Atp2a2 depletion in MA9 cells on responses to cytotoxic drugs, cytarabine and a p53 activating agent, DS-5272. Deletion of Atp2a2 alters Ca2+ signaling, increases ER stress and confers resistance to cytotoxic drugs in myeloid tumors. Our data also suggest that SOCE is a synthetic lethal target for myeloid tumors with low ATP2A2 activity."

Preclinical • Hematological Malignancies • Leukemia • Oncology • Solid Tumor • ASXL1 • CD8 • SETBP1 • STIM1

Machine Learning-Based Predictive Modeling Maximizes the Efficacy of mTOR/TP53 Co-Targeting Therapy Against Acute Myeloid Leukemia (ASH 2024) - "We then assessed the combined effect of rapamycin and a TP53-activating drug, DS-5272, in human AML cell lines with wild-type TP53 : MOLM13, MV4-11, and OCI-AML3...In summary, we showed that mTOR/TP53 co-targeting therapy has a curative effect on monocytic AMLs with wild-type TP53 and low Rapa-11 score. The machine learning-based predictive approach has the potential to be applied to other drugs and tumors to develop optimally tailored treatments for individual patients."

Clinical • Machine learning • Predictive model • Acute Myelogenous Leukemia • Hematological Malignancies • Inflammatory Arthritis • Leukemia • Oncology • ASXL1 • MCL1 • MYC • RUNX1 • SETBP1 • TP53

Machine Learning-Based Predictive Modeling Maximizes the Efficacy of mTOR/p53 Co-Targeting Therapy Against AML. (PubMed, Cancer Sci) - "Co-treatment with rapamycin and DS-5272 had a dramatic in vivo effect on MLL-AF9-driven AML, curing 85% of the leukemic mice. Thus, machine learning-based predictive approaches identified monocytic AML with wild-type TP53 and low Rapa-11 score as a rapamycin-sensitive AML subtype and an ideal target for mTOR/p53 co-targeting therapy."

Journal • Acute Myelogenous Leukemia • Hematological Malignancies • Leukemia • Oncology • ASXL1 • MCL1 • MIR34A • MYC • RUNX1 • SETBP1

Synergistic Activity of Combined FLT3-ITD and MDM2 Inhibition With Quizartinib and Milademetan in FLT3-ITD Mutant/TP53 Wild Type Acute Myeloid Leukemias. (PubMed, Clin Cancer Res) - P1 | "Preclinical and mechanistic rationale and preliminary clinical data support the future development of MDM2/FLT3 targeting strategies for FLT3-mutant AML."

Journal • Acute Myelogenous Leukemia • Hematological Disorders • Hematological Malignancies • Leukemia • Oncology • CD34 • FLT3 • TP53 • YTHDF2

Mdm2/p53 levels in bone marrow mesenchymal stromal cells are essential for maintaining the hematopoietic niche in response to DNA damage. (PubMed, Cell Death Dis) - "In a syngeneic mouse model of acute myeloid leukemia (AML), Trp53 deletion in BM-MSCs improved survival, and protected BM against hematopoietic toxicity from a murine Mdm2i, DS-5272. The transcriptional changes were associated with dysregulation of glycolysis, gluconeogenesis, and Hif-1α in BM-MSCs. Our results reveal a physiologic function of Mdm2 in BM-MSC, identify a previously unknown role of p53 pathway in BM-MSC-mediated support in AML and expand our understanding of the mechanism of hematopoietic toxicity of MDM2is."

Journal • Stroma • Acute Myelogenous Leukemia • Hematological Disorders • Hematological Malignancies • Leukemia • Oncology • Thrombocytopenia • HIF1A • MDM2 • TP53

MDM2 antagonist improves therapeutic activity of azacitidine in myelodysplastic syndromes and chronic myelomonocytic leukemia. (PubMed, Leuk Lymphoma) - "We investigated the combination of the HMA azacitidine (AZA) with DS-3032b and DS-5272, novel antagonists of the TP53 negative regulator MDM2, in cellular and animal models of MDS and CMML. RNA-Seq analysis in mouse bone marrow hematopoietic stem and progenitors indicated that DS-5272 and AZA combination caused down-regulation of leukemia stem cell marker genes and activation of pathways of TP53 function and stability. These findings demonstrate that combining an MDM2 antagonist with AZA has potential to improve AZA treatment in TP53 wildtype MDS and CMML."

Journal • Chronic Myelomonocytic Leukemia • Hematological Malignancies • Leukemia • Myelodysplastic Syndrome • Oncology • TET2 • TP53

Inhibition of MDM2 Improves the Therapeutic Effect of Hypomethylating Agents in Myelodysplastic Syndromes (MDS) and Chronic Myelomonocytic Leukemia (CMML) (ASH 2021) - "To test this hypothesis, we evaluated in vitro the effects of the combination of the MDM2 inhibitor DS-3032b and azacytidine (AZA)...DS-5272 and AZA were administered to mice sequentially: DS-5272 (50 mg/kg) was administered orally for 5 days, followed by daily AZA (2.5 mg/kg, i.p.) for a 7 days...In conclusion, our work provides proof-of-concept evidence that combining an MDM2 inhibitor with AZA can improve the therapeutic efficacy of AZA in MDS and CMML, through mechanisms including synergistic activation of TP53 in BM HSPCs and inhibition of LT BM repopulating activity. This concept should be further evaluated through pre-clinical studies and clinical trials."

Acute Myelogenous Leukemia • Chronic Myelomonocytic Leukemia • Hematological Malignancies • Leukemia • Myelodysplastic Syndrome • Oncology • Transplantation • CDKN1A • MDM2 • PTPRC • TET2

Effect of MDM2 inhibitors in preclinical models of advanced clear cell carcinomas originating from ovaries and kidneys. (PubMed, Cancer Sci) - "Herein, we characterized the anti-angiogenic and antitumor effects of the Murine double-minute 2 inhibitors, DS-3032b and DS-5272, in six clear cell ovarian carcinoma cell lines and two clear cell renal carcinoma cell lines, as well as in clear cell ovarian carcinomas subcutaneous xenograft and ID8 (murine ovarian cancer cells with wild-type TP53) cancer peritonitis mouse models. Meanwhile, combined therapy with MDM2 inhibitors and everolimus showed synergistic, and dose-reduction potential, for clear cell carcinoma treatment. Our findings suggest that Murine double-minute 2 inhibitors represent promising molecular targeted therapy for clear cell carcinomas, thereby warranting further studies to evaluate the efficacy and safety of dual Murine double-minute 2/mammalian target of rapamycin inhibitors in clear cell carcinoma patients."

Journal • Preclinical • Gynecologic Cancers • Oncology • Ovarian Cancer • Renal Cell Carcinoma • Solid Tumor • CD31 • mTOR

Antitumor immunity augments the therapeutic effects of p53 activation on acute myeloid leukemia. (PubMed, Nat Commun) - "Here we show that an orally active inhibitor of p53-MDM2 interaction, DS-5272, causes dramatic tumor regressions of MLL-AF9-driven AML in vivo with a tolerable toxicity...We also found that NK cells are important mediators of antileukemia immunity. Our study showed the potent activity of a p53-activating drug against AML, which is further augmented by antitumor immunity."

Journal

p53 Mediated Bone Marrow Mesenchymal Stem Cell Expansion Supports Acute Myeloid Leukemia Development (ASH 2019) - "We further evaluated the effect of a Mdm2 inhibitor, DS-5272, on BM-MSCs in our traceable mouse models...In conclusion, we identified p53 activation as a novel mechanism by which BM-MSCs regulate proliferation and apoptosis of hematopoietic cells. This knowledge highlights a new mechanism of hematopoietic failure after AML therapy and informs new therapeutic strategies to eliminate AML."

CCL4 • IL1B • IL6 • TP53

Combined inhibition of MDM2 and Bcr-Abl tyrosine kinase targets chronic myeloid leukemia stem/progenitor cells in a murine model. (PubMed, Haematologica) - "Combined inhibition of BCR-ABL1 with imatinib and MDM2 with DS-5272 increased NOXA level, markedly reduced leukemic linage-SCA-1+C-KIT+ cells and hematopoiesis, decreased leukemia burden, significantly prolonged the survival of mice engrafted with bone marrow cells from Scl-tTa-BCR-ABL1 mice, and significantly decreased chronic myeloid leukemia stem cell frequency in secondary transplantations. Our results suggest that chronic myeloid leukemia stem/progenitor cells have increased p53 signaling and a propensity for apoptosis. Combined MDM2 and BCR-ABL1 inhibition targets chronic myeloid leukemia stem/progenitor cells and has the potential to improve cure rates for chronic myeloid leukemia."

IO Biomarker • Journal • Preclinical