Publications by authors named "Mark A Murakami"

10 Publications

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Signalling input from divergent pathways subverts B cell transformation.

Nature 2020 07 22;583(7818):845-851. Epub 2020 Jul 22.

Department of Systems Biology, City of Hope Comprehensive Cancer Center, Monrovia, CA, USA.

Malignant transformation of cells typically involves several genetic lesions, whose combined activity gives rise to cancer. Here we analyse 1,148 patient-derived B-cell leukaemia (B-ALL) samples, and find that individual mutations do not promote leukaemogenesis unless they converge on one single oncogenic pathway that is characteristic of the differentiation stage of transformed B cells. Mutations that are not aligned with this central oncogenic driver activate divergent pathways and subvert transformation. Oncogenic lesions in B-ALL frequently mimic signalling through cytokine receptors at the pro-B-cell stage (via activation of the signal-transduction protein STAT5) or pre-B-cell receptors in more mature cells (via activation of the protein kinase ERK). STAT5- and ERK-activating lesions are found frequently, but occur together in only around 3% of cases (P = 2.2 × 10). Single-cell mutation and phospho-protein analyses reveal the segregation of oncogenic STAT5 and ERK activation to competing clones. STAT5 and ERK engage opposing biochemical and transcriptional programs that are orchestrated by the transcription factors MYC and BCL6, respectively. Genetic reactivation of the divergent (suppressed) pathway comes at the expense of the principal oncogenic driver and reverses transformation. Conversely, deletion of divergent pathway components accelerates leukaemogenesis. Thus, persistence of divergent signalling pathways represents a powerful barrier to transformation, while convergence on one principal driver defines a central event in leukaemia initiation. Pharmacological reactivation of suppressed divergent circuits synergizes strongly with inhibition of the principal oncogenic driver. Hence, reactivation of divergent pathways can be leveraged as a previously unrecognized strategy to enhance treatment responses.
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http://dx.doi.org/10.1038/s41586-020-2513-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7394729PMC
July 2020

Pan-SRC kinase inhibition blocks B-cell receptor oncogenic signaling in non-Hodgkin lymphoma.

Blood 2018 05 22;131(21):2345-2356. Epub 2018 Mar 22.

Swiss Institute for Experimental Cancer Research, School of Life Sciences, École Polytechnique Fédérale de Lausanne, Lausanne, Switzerland.

In diffuse large B-cell lymphoma (DLBCL), activation of the B-cell receptor (BCR) promotes multiple oncogenic signals, which are essential for tumor proliferation. Inhibition of the Bruton's tyrosine kinase (BTK), a BCR downstream target, is therapeutically effective only in a subgroup of patients with DLBCL. Here, we used lymphoma cells isolated from patients with DLBCL to measure the effects of targeted therapies on BCR signaling and to anticipate response. In lymphomas resistant to BTK inhibition, we show that blocking BTK activity enhanced tumor dependencies from alternative oncogenic signals downstream of the BCR, converging on MYC upregulation. To completely ablate the activity of the BCR, we genetically and pharmacologically repressed the activity of the SRC kinases LYN, FYN, and BLK, which are responsible for the propagation of the BCR signal. Inhibition of these kinases strongly reduced tumor growth in xenografts and cell lines derived from patients with DLBCL independent of their molecular subtype, advancing the possibility to be relevant therapeutic targets in broad and diverse groups of DLBCL patients.
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http://dx.doi.org/10.1182/blood-2017-10-809210DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5969377PMC
May 2018

Targeting minimal residual disease: a path to cure?

Nat Rev Cancer 2018 04 29;18(4):255-263. Epub 2018 Jan 29.

Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, USA, and at the Broad Institute of the Massachusetts Institute of Technology and Harvard University, Cambridge, Massachusetts 02142, USA.

Therapeutics that block kinases, transcriptional modifiers, immune checkpoints and other biological vulnerabilities are transforming cancer treatment. As a result, many patients achieve dramatic responses, including complete radiographical or pathological remission, yet retain minimal residual disease (MRD), which results in relapse. New functional approaches can characterize clonal heterogeneity and predict therapeutic sensitivity of MRD at a single-cell level. Preliminary evidence suggests that iterative detection, profiling and targeting of MRD would meaningfully improve outcomes and may even lead to cure.
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http://dx.doi.org/10.1038/nrc.2017.125DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6398166PMC
April 2018

PDX-MI: Minimal Information for Patient-Derived Tumor Xenograft Models.

Cancer Res 2017 11;77(21):e62-e66

Greehey Children's Cancer Research Institute, University of Texas Health Science Center at San Antonio, San Antonio, Texas.

Patient-derived tumor xenograft (PDX) mouse models have emerged as an important oncology research platform to study tumor evolution, mechanisms of drug response and resistance, and tailoring chemotherapeutic approaches for individual patients. The lack of robust standards for reporting on PDX models has hampered the ability of researchers to find relevant PDX models and associated data. Here we present the PDX models minimal information standard (PDX-MI) for reporting on the generation, quality assurance, and use of PDX models. PDX-MI defines the minimal information for describing the clinical attributes of a patient's tumor, the processes of implantation and passaging of tumors in a host mouse strain, quality assurance methods, and the use of PDX models in cancer research. Adherence to PDX-MI standards will facilitate accurate search results for oncology models and their associated data across distributed repository databases and promote reproducibility in research studies using these models. .
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http://dx.doi.org/10.1158/0008-5472.CAN-17-0582DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5738926PMC
November 2017

Cancer models: The next best thing.

Nature 2017 09 30;549(7670):39-41. Epub 2017 Aug 30.

Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, USA.

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http://dx.doi.org/10.1038/nature23545DOI Listing
September 2017

Drug sensitivity of single cancer cells is predicted by changes in mass accumulation rate.

Nat Biotechnol 2016 Nov 10;34(11):1161-1167. Epub 2016 Oct 10.

Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.

Assays that can determine the response of tumor cells to cancer therapeutics could greatly aid the selection of drug regimens for individual patients. However, the utility of current functional assays is limited, and predictive genetic biomarkers are available for only a small fraction of cancer therapies. We found that the single-cell mass accumulation rate (MAR), profiled over many hours with a suspended microchannel resonator, accurately defined the drug sensitivity or resistance of glioblastoma and B-cell acute lymphocytic leukemia cells. MAR revealed heterogeneity in drug sensitivity not only between different tumors, but also within individual tumors and tumor-derived cell lines. MAR measurement predicted drug response using samples as small as 25 μl of peripheral blood while maintaining cell viability and compatibility with downstream characterization. MAR measurement is a promising approach for directly assaying single-cell therapeutic responses and for identifying cellular subpopulations with phenotypic resistance in heterogeneous tumors.
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http://dx.doi.org/10.1038/nbt.3697DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5142231PMC
November 2016

High-throughput measurement of single-cell growth rates using serial microfluidic mass sensor arrays.

Nat Biotechnol 2016 Oct 5;34(10):1052-1059. Epub 2016 Sep 5.

Program in Computational and Systems Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.

Methods to rapidly assess cell growth would be useful for many applications, including drug susceptibility testing, but current technologies have limited sensitivity or throughput. Here we present an approach to precisely and rapidly measure growth rates of many individual cells simultaneously. We flow cells in suspension through a microfluidic channel with 10-12 resonant mass sensors distributed along its length, weighing each cell repeatedly over the 4-20 min it spends in the channel. Because multiple cells traverse the channel at the same time, we obtain growth rates for >60 cells/h with a resolution of 0.2 pg/h for mammalian cells and 0.02 pg/h for bacteria. We measure the growth of single lymphocytic cells, mouse and human T cells, primary human leukemia cells, yeast, Escherichia coli and Enterococcus faecalis. Our system reveals subpopulations of cells with divergent growth kinetics and enables assessment of cellular responses to antibiotics and antimicrobial peptides within minutes.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5064867PMC
http://dx.doi.org/10.1038/nbt.3666DOI Listing
October 2016

An ED pilot intervention to facilitate outpatient acute care for cancer patients.

Am J Emerg Med 2016 Oct 24;34(10):1934-1938. Epub 2016 Jun 24.

Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215; Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115.

Introduction: Unplanned hospitalizations are common in patients with cancer, and most hospitalizations originate in the emergency department (ED).

Methods: We implemented an ED-based pilot intervention designed to reduce hospitalizations among patients with solid tumors. The intervention, piloted at a single academic medical center, involved a medical oncologist embedded in the ED during evening hours. We used a quasiexperimental preimplementation/postimplementation study design to evaluate the proportion of ED visits that resulted in inpatient hospital admission, before and after pilot implementation. General estimating equations were used to evaluate the association between the intervention and hospital admission.

Results: There were 390 ED visits by eligible cancer patients in the preintervention period and 418 visits in the intervention period. During the intervention period, 158 (38%) of 418 ED visits were identified by the embedded oncologist during the evening intervention shift. The proportion of ED visits leading to hospitalization was 70% vs 69% in the preintervention and intervention periods (odds ratio, 0.93 [95% confidence interval, 0.69-1.24]; P= .62). There were no differences between periods in ED length of stay or subsequent use of acute care. Among patients with initial ED presentation during the operating hours of the intervention, the proportion of ED visits leading to hospitalization was 77% vs 67% in the preintervention and intervention periods (odds ratio, 0.62 [0.36-1.08]; P= .08).

Conclusion: Embedding an oncologist in the ED of an academic medical center did not significantly reduce hospital admissions. Novel approaches are needed to strengthen outpatient acute care for patients with cancer.
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http://dx.doi.org/10.1016/j.ajem.2016.06.076DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8048096PMC
October 2016

The Public Repository of Xenografts Enables Discovery and Randomized Phase II-like Trials in Mice.

Cancer Cell 2016 04;29(4):574-586

Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, 450 Brookline Avenue, Dana 510B, MA 02215, USA.

More than 90% of drugs with preclinical activity fail in human trials, largely due to insufficient efficacy. We hypothesized that adequately powered trials of patient-derived xenografts (PDX) in mice could efficiently define therapeutic activity across heterogeneous tumors. To address this hypothesis, we established a large, publicly available repository of well-characterized leukemia and lymphoma PDXs that undergo orthotopic engraftment, called the Public Repository of Xenografts (PRoXe). PRoXe includes all de-identified information relevant to the primary specimens and the PDXs derived from them. Using this repository, we demonstrate that large studies of acute leukemia PDXs that mimic human randomized clinical trials can characterize drug efficacy and generate transcriptional, functional, and proteomic biomarkers in both treatment-naive and relapsed/refractory disease.
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http://dx.doi.org/10.1016/j.ccell.2016.03.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5177991PMC
April 2016