PDX models for functional precision oncology and discovery science
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Effective eradication of acute myeloid leukemia stem cells with FLT3-directed antibody-drug conjugates
Refractory disease and relapse are major challenges in acute myeloid leukemia (AML) therapy attributed to survival of leukemic stem cells (LSC). To target LSCs, antibody-drug conjugates (ADCs) provide an elegant solution, combining the specificity of antibodies with highly potent payloads. We aimed to investigate if FLT3-20D9h3-ADCs delivering either the DNA-alkylator duocarmycin (DUBA) or the microtubule-toxin monomethyl auristatin F (MMAF) can eradicate quiescent LSCs. We show here that DUBA more potently kills cell-cycle arrested AML cells compared to microtubule-targeting auristatins. Due to limited stability of 20D9h3-DUBA ADC in vivo, we analyzed both ADCs in advanced in vitro stem cell assays. 20D9h3-DUBA successfully eliminated leukemic progenitors in vitro in colony-forming unit and long-term culture initiating cell assays, both in patient cells and in patient-derived xenograft (PDX) cells. Further, it completely prevented engraftment of AML PDX leukemia-initiating cells in NSG mice. 20D9h3-MMAF had a similar effect in engraftment assays, but a less prominent effect in colony assays. Both ADCs did not affect healthy stem and progenitor cells at comparable doses providing the rationale for FLT3 as therapeutic LSC target. Collectively, we show that FLT3-directed ADCs with DUBA or MMAF have potent activity against AML LSCs and represent promising candidates for further clinical development.
Targeting LMO2-induced autocrine FLT3 signaling to overcome chemoresistance in early T-cell precursor acute lymphoblastic leukemia
Early T-cell Precursor Acute Lymphoblastic Leukemia (ETP-ALL) is an immature subtype of T-cell acute lymphoblastic leukemia (T-ALL) commonly show deregulation of the LMO2-LYL1 stem cell transcription factors, activating mutations of cytokine receptor signaling, and poor early response to intensive chemotherapy. Previously, studies of the Lmo2 transgenic mouse model of ETP-ALL identified a population of stem-like T-cell progenitors with long-term self-renewal capacity and intrinsic chemotherapy resistance linked to cellular quiescence. Here, analyses of Lmo2 transgenic mice, patient-derived xenografts, and single-cell RNA-sequencing data from primary ETP-ALL identified a rare subpopulation of leukemic stem cells expressing high levels of the cytokine receptor FLT3. Despite a highly proliferative state, these FLT3-overexpressing cells had long-term self-renewal capacity and almost complete resistance to chemotherapy. Chromatin immunoprecipitation and assay for transposase-accessible chromatin sequencing demonstrated FLT3 and its ligand may be direct targets of the LMO2 stem-cell complex. Media conditioned by Lmo2 transgenic thymocytes revealed an autocrine FLT3-dependent signaling loop that could be targeted by the FLT3 inhibitor gilteritinib. Consequently, gilteritinib impaired in vivo growth of ETP-ALL and improved the sensitivity to chemotherapy. Furthermore, gilteritinib enhanced response to the BCL2 inhibitor venetoclax, which may enable “chemo-free” treatment of ETP-ALL. Together, these data provide a cellular and molecular explanation for enhanced cytokine signaling in LMO2-driven ETP-ALL beyond activating mutations and a rationale for clinical trials of FLT3 inhibitors in ETP-ALL.
Early cardio-oncology intervention in thoracic radiotherapy: prospective single-arm pilot study
While there is increasing recognition of the morbidity of cardiovascular disease in cancer survivors, including accelerated atherosclerosis following thoracic radiotherapy, patients are frequently under-optimized for cardiovascular risk.
Semi-mechanistic efficacy model for PARP + ATR inhibitors—application to rucaparib and talazoparib in combination with gartisertib in breast cancer PDXs
Promising cancer treatments, such as DDR inhibitors, are often challenged by the heterogeneity of responses in clinical trials. The present work aimed to build a computational framework to address those challenges.
Trust in scientists and their role in society across 68 countries
Science is crucial for evidence-based decision-making. Public trust in scientists can help decision makers act on the basis of the best available evidence, especially during crises. However, in recent years the epistemic authority of science has been challenged, causing concerns about low public trust in scientists. We interrogated these concerns with a preregistered 68-country survey of 71,922 respondents and found that in most countries, most people trust scientists and agree that scientists should engage more in society and policymaking. We found variations between and within countries, which we explain with individual- and country-level variables, including political orientation. While there is no widespread lack of trust in scientists, we cannot discount the concern that lack of trust in scientists by even a small minority may affect considerations of scientific evidence in policymaking. These findings have implications for scientists and policymakers seeking to maintain and increase trust in scientists.
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