In:
Cancer Research, American Association for Cancer Research (AACR), Vol. 80, No. 16_Supplement ( 2020-08-15), p. LB-305-LB-305
Abstract:
Objectives: Personalized therapies target individual, tumor-specific alterations identified by descriptive genomics and transcriptomics. Selecting individual targets with high therapeutic potential remains a challenging task for Molecular Tumor Boards in today's clinical routine. Functional data, which help ranking alterations for their usefulness as therapeutic targets, are scarce, especially in individual tumors and in vivo. To bridge this gap, we invented a functional genomics in vivo approach which enables prioritizing alterations with high potential as therapeutic targets. Methods: Primary tumor cells from patients with acute leukemias (AL) were grown on immune compromised mice and patient derived xenografts (PDX) genetically modified using lentiviruses. For the first time, an inducible system was established in PDX-AL models, where knockdown was induced in vivo upon feeding mice with tamoxifen. In vivo assays were performed in a competitive way, with control and gene-of-interest cells in the same animal and monitored by recombinant fluorochromes. Results: MCL-1 is an anti-apoptotic protein frequently upregulated in tumors and inhibitors against MCL-1 are tested in clinical studies. We aimed at identifying AL patients who might profit from therapy targeting MCL-1. PDX cells were transplanted and grown in mice until tumors were established before MCL-1 knockdown was induced by feeding mice with tamoxifen. Established PDX AL revealed different intensities of growth disadvantages between individual samples, ranging from weak to strong phenotypes. In general, PDX models from patients with acute myeloid leukemia (AML) were more responsive than those from patients with acute lymphoblastic leukemia (ALL). MCL-1 played an essential role in vivo in several AML cells from patients with different cytogenetics and risk factors. In sensitive PDX samples, response to MCL-1 treatment was independent from disease stage as induction of MCL-1 knockdown severely reduced AML PDX fitness at all disease stages, from minimal to advanced disease. Inhibition of MCL-1 sensitized resistant AML cells towards different drugs. All in all, we show for the first time that PDX AML cells in vivo depend on MCL-1 and that MCL-1 represents an interesting therapeutic target for some, but not all AL samples. Conclusions: Taken together, we established a technique to identify and molecularly validate genes with an essential function in individual tumors in vivo. Our technique allows prioritizing alterations for their usefulness as therapeutic targets. Our approach will streamline clinical trials in personalized medicine in the future. Citation Format: Michela Carlet Polleux, Kerstin Völse, Jenny Vergalli, Marc Schmidt-Supprian, Irmela Jeremias. A novel in vivo technique to molecularly validate potential targets for personalized therapy [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr LB-305.
Type of Medium:
Online Resource
ISSN:
0008-5472
,
1538-7445
DOI:
10.1158/1538-7445.AM2020-LB-305
Language:
English
Publisher:
American Association for Cancer Research (AACR)
Publication Date:
2020
detail.hit.zdb_id:
2036785-5
detail.hit.zdb_id:
1432-1
detail.hit.zdb_id:
410466-3
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