Molecularly targeted drug combinations demonstrate selective effectiveness for myeloid- and lymphoid-derived hematologic malignancies

Stephen E. Kurtz, Christopher A. Eide, Andy Kaempf, Vishesh Khanna, Samantha L. Savage, Angela Rofelty, Isabel English, Hibery Ho, Ravi Pandya, William J. Bolosky, Hoifung Poon, Michael W. Deininger, Robert Collins, Ronan T. Swords, Justin Watts, Daniel A. Pollyea, Bruno C. Medeiros, Elie Traer, Cristina E. Tognon, Motomi (Tomi) MoriBrian Druker, Jeffrey Tyner

Research output: Contribution to journalArticle

32 Citations (Scopus)

Abstract

Translating the genetic and epigenetic heterogeneity underlying human cancers into therapeutic strategies is an ongoing challenge. Large-scale sequencing efforts have uncovered a spectrum of mutations in many hematologic malignancies, including acute myeloid leukemia (AML), suggesting that combinations of agents will be required to treat these diseases effectively. Combinatorial approaches will also be critical for combating the emergence of genetically heterogeneous subclones, rescue signals in the microenvironment, and tumor-intrinsic feedback pathways that all contribute to disease relapse. To identify novel and effective drug combinations, we performed ex vivo sensitivity profiling of 122 primary patient samples from a variety of hematologic malignancies against a panel of 48 drug combinations. The combinations were designed as drug pairs that target nonoverlapping biological pathways and comprise drugs from different classes, preferably with Food and Drug Administration approval. A combination ratio (CR) was derived for each drug pair, and CRs were evaluated with respect to diagnostic categories as well as against genetic, cytogenetic, and cellular phenotypes of specimens from the two largest disease categories: AML and chronic lymphocytic leukemia (CLL). Nearly all tested combinations involving a BCL2 inhibitor showed additional benefit in patients with myeloid malignancies, whereas select combinations involving PI3K, CSF1R, or bromodomain inhibitors showed preferential benefit in lymphoid malignancies. Expanded analyses of patients with AML and CLL revealed specific patterns of ex vivo drug combination efficacy that were associated with select genetic, cytogenetic, and phenotypic disease subsets, warranting further evaluation. These findings highlight the heuristic value of an integrated functional genomic approach to the identification of novel treatment strategies for hematologic malignancies.

Original languageEnglish (US)
Pages (from-to)E7554-E7563
JournalProceedings of the National Academy of Sciences of the United States of America
Volume114
Issue number36
DOIs
StatePublished - Sep 5 2017

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Hematologic Neoplasms
Drug Combinations
Acute Myeloid Leukemia
B-Cell Chronic Lymphocytic Leukemia
Cytogenetics
Pharmaceutical Preparations
Drug Approval
Neoplasms
Tumor Microenvironment
Genetic Heterogeneity
United States Food and Drug Administration
Phosphatidylinositol 3-Kinases
Epigenomics
Phenotype
Recurrence
Mutation
Therapeutics

Keywords

  • Drug combinations
  • Ex vivo assay
  • Hematologic malignancies
  • Targeted therapies

ASJC Scopus subject areas

  • General

Cite this

Molecularly targeted drug combinations demonstrate selective effectiveness for myeloid- and lymphoid-derived hematologic malignancies. / Kurtz, Stephen E.; Eide, Christopher A.; Kaempf, Andy; Khanna, Vishesh; Savage, Samantha L.; Rofelty, Angela; English, Isabel; Ho, Hibery; Pandya, Ravi; Bolosky, William J.; Poon, Hoifung; Deininger, Michael W.; Collins, Robert; Swords, Ronan T.; Watts, Justin; Pollyea, Daniel A.; Medeiros, Bruno C.; Traer, Elie; Tognon, Cristina E.; Mori, Motomi (Tomi); Druker, Brian; Tyner, Jeffrey.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 114, No. 36, 05.09.2017, p. E7554-E7563.

Research output: Contribution to journalArticle

Kurtz, SE, Eide, CA, Kaempf, A, Khanna, V, Savage, SL, Rofelty, A, English, I, Ho, H, Pandya, R, Bolosky, WJ, Poon, H, Deininger, MW, Collins, R, Swords, RT, Watts, J, Pollyea, DA, Medeiros, BC, Traer, E, Tognon, CE, Mori, MT, Druker, B & Tyner, J 2017, 'Molecularly targeted drug combinations demonstrate selective effectiveness for myeloid- and lymphoid-derived hematologic malignancies', Proceedings of the National Academy of Sciences of the United States of America, vol. 114, no. 36, pp. E7554-E7563. https://doi.org/10.1073/pnas.1703094114
Kurtz, Stephen E. ; Eide, Christopher A. ; Kaempf, Andy ; Khanna, Vishesh ; Savage, Samantha L. ; Rofelty, Angela ; English, Isabel ; Ho, Hibery ; Pandya, Ravi ; Bolosky, William J. ; Poon, Hoifung ; Deininger, Michael W. ; Collins, Robert ; Swords, Ronan T. ; Watts, Justin ; Pollyea, Daniel A. ; Medeiros, Bruno C. ; Traer, Elie ; Tognon, Cristina E. ; Mori, Motomi (Tomi) ; Druker, Brian ; Tyner, Jeffrey. / Molecularly targeted drug combinations demonstrate selective effectiveness for myeloid- and lymphoid-derived hematologic malignancies. In: Proceedings of the National Academy of Sciences of the United States of America. 2017 ; Vol. 114, No. 36. pp. E7554-E7563.
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