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"Direct to Drug" screening as a precision medicine tool in multiple myeloma.
Blood Cancer J. 2020 May 11; 10(5):54.BC

Abstract

Seventy-six FDA-approved oncology drugs and emerging therapeutics were evaluated in 25 multiple myeloma (MM) and 15 non-Hodgkin's lymphoma cell lines and in 113 primary MM samples. Ex vivo drug sensitivities were mined for associations with clinical phenotype, cytogenetic, genetic mutation, and transcriptional profiles. In primary MM samples, proteasome inhibitors, dinaciclib, selinexor, venetoclax, auranofin, and histone deacetylating agents had the broadest cytotoxicity. Of interest, newly diagnosed patient samples were globally less sensitive especially to bromodomain inhibitors, inhibitors of receptor tyrosine kinases or non-receptor kinases, and DNA synthesis inhibitors. Clustering demonstrated six broad groupings of drug sensitivity linked with genomic biomarkers and clinical outcomes. For example, our findings mimic clinical observations of increased venetoclax responsiveness in t(11;14) patients but also identify an increased sensitivity profile in untreated patients, standard genetic risk, low plasma cell S-Phase, and in the absence of Gain(1q) and t(4;14). In contrast, increased ex vivo responsiveness to selinexor was associated with biomarkers of poor prognosis and later relapse patients. This "direct to drug" screening resource, paired with functional genomics, has the potential to successfully direct appropriate individualized therapeutic approaches in MM and to enrich clinical trials for likely responders.

Authors+Show Affiliations

Department of Hematology/Oncology, Mayo Clinic, Scottsdale, AZ, USA.Department of Hematology/Oncology, Mayo Clinic, Scottsdale, AZ, USA.Department of Hematology/Oncology, Mayo Clinic, Scottsdale, AZ, USA.Department of Hematology/Oncology, Mayo Clinic, Scottsdale, AZ, USA.Department of Hematology/Oncology, Mayo Clinic, Scottsdale, AZ, USA.Department of Department of Health Sciences Research, Mayo Clinic, Scottsdale, AZ, USA.Department of Hematology/Oncology, Mayo Clinic, Scottsdale, AZ, USA.Department of Department of Health Sciences Research, Mayo Clinic, Rochester, MN, USA.Department of Hematology/Oncology, Mayo Clinic, Scottsdale, AZ, USA.Department of Hematology/Oncology, Mayo Clinic, Scottsdale, AZ, USA.Department of Hematology/Oncology, Mayo Clinic, Scottsdale, AZ, USA.Department of Hematology/Oncology, Mayo Clinic, Rochester, MN, USA.Department of Department of Health Sciences Research, Mayo Clinic, Rochester, MN, USA.Department of Hematology/Oncology, Mayo Clinic, Scottsdale, AZ, USA.Department of Hematology/Oncology, Mayo Clinic, Scottsdale, AZ, USA.Department of Hematology/Oncology, Mayo Clinic, Scottsdale, AZ, USA.Department of Hematology/Oncology, Mayo Clinic, Scottsdale, AZ, USA.Department of Hematology/Oncology, Mayo Clinic, Rochester, MN, USA.Department of Hematology/Oncology, Mayo Clinic, Rochester, MN, USA.Department of Hematology/Oncology, Mayo Clinic, Rochester, MN, USA.Department of Hematology/Oncology, Mayo Clinic, Scottsdale, AZ, USA.Department of Hematology/Oncology, Mayo Clinic, Scottsdale, AZ, USA.Department of Hematology/Oncology, Mayo Clinic, Scottsdale, AZ, USA.Department of Hematology/Oncology, Mayo Clinic, Scottsdale, AZ, USA. stewart.keith@mayo.edu. Center for Individualized Medicine, Mayo Clinic, Rochester, MN, USA. stewart.keith@mayo.edu.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

32393731

Citation

Bonolo de Campos, Cecilia, et al. ""Direct to Drug" Screening as a Precision Medicine Tool in Multiple Myeloma." Blood Cancer Journal, vol. 10, no. 5, 2020, p. 54.
Bonolo de Campos C, Meurice N, Petit JL, et al. "Direct to Drug" screening as a precision medicine tool in multiple myeloma. Blood Cancer J. 2020;10(5):54.
Bonolo de Campos, C., Meurice, N., Petit, J. L., Polito, A. N., Zhu, Y. X., Wang, P., Bruins, L. A., Wang, X., Lopez Armenta, I. D., Darvish, S. A., Ahmann, G. J., Henderson, K. J., Tian, S., Kruse, J. J., Stewart, W. M., Larsen, J. T., Reeder, C. B., Dingli, D., Kapoor, P., ... Stewart, A. K. (2020). "Direct to Drug" screening as a precision medicine tool in multiple myeloma. Blood Cancer Journal, 10(5), 54. https://doi.org/10.1038/s41408-020-0320-7
Bonolo de Campos C, et al. "Direct to Drug" Screening as a Precision Medicine Tool in Multiple Myeloma. Blood Cancer J. 2020 May 11;10(5):54. PubMed PMID: 32393731.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - "Direct to Drug" screening as a precision medicine tool in multiple myeloma. AU - Bonolo de Campos,Cecilia, AU - Meurice,Nathalie, AU - Petit,Joachim L, AU - Polito,Alysia N, AU - Zhu,Yuan Xiao, AU - Wang,Panwen, AU - Bruins,Laura A, AU - Wang,Xuewei, AU - Lopez Armenta,Ilsel D, AU - Darvish,Susie A, AU - Ahmann,Greg J, AU - Henderson,Kimberly J, AU - Tian,Shulan, AU - Kruse,Jonas J, AU - Stewart,William M, AU - Larsen,Jeremy T, AU - Reeder,Craig B, AU - Dingli,David, AU - Kapoor,Prashant, AU - Kumar,Shaji K, AU - Fonseca,Rafael, AU - Bergsagel,P Leif, AU - Braggio,Esteban, AU - Stewart,A Keith, Y1 - 2020/05/11/ PY - 2019/12/31/received PY - 2020/04/20/accepted PY - 2020/04/03/revised PY - 2020/5/13/entrez PY - 2020/5/13/pubmed PY - 2020/5/13/medline SP - 54 EP - 54 JF - Blood cancer journal JO - Blood Cancer J VL - 10 IS - 5 N2 - Seventy-six FDA-approved oncology drugs and emerging therapeutics were evaluated in 25 multiple myeloma (MM) and 15 non-Hodgkin's lymphoma cell lines and in 113 primary MM samples. Ex vivo drug sensitivities were mined for associations with clinical phenotype, cytogenetic, genetic mutation, and transcriptional profiles. In primary MM samples, proteasome inhibitors, dinaciclib, selinexor, venetoclax, auranofin, and histone deacetylating agents had the broadest cytotoxicity. Of interest, newly diagnosed patient samples were globally less sensitive especially to bromodomain inhibitors, inhibitors of receptor tyrosine kinases or non-receptor kinases, and DNA synthesis inhibitors. Clustering demonstrated six broad groupings of drug sensitivity linked with genomic biomarkers and clinical outcomes. For example, our findings mimic clinical observations of increased venetoclax responsiveness in t(11;14) patients but also identify an increased sensitivity profile in untreated patients, standard genetic risk, low plasma cell S-Phase, and in the absence of Gain(1q) and t(4;14). In contrast, increased ex vivo responsiveness to selinexor was associated with biomarkers of poor prognosis and later relapse patients. This "direct to drug" screening resource, paired with functional genomics, has the potential to successfully direct appropriate individualized therapeutic approaches in MM and to enrich clinical trials for likely responders. SN - 2044-5385 UR - https://www.unboundmedicine.com/medline/citation/32393731/"Direct_to_Drug"_screening_as_a_precision_medicine_tool_in_multiple_myeloma L2 - http://dx.doi.org/10.1038/s41408-020-0320-7 DB - PRIME DP - Unbound Medicine ER -
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