Laura T Pierce

Publications (2)15.12 Total impact

• Article: Adenosine A2A and beta-2 adrenergic receptor agonists: novel selective and synergistic multiple myeloma targets discovered through systematic combination screening.

  Richard J Rickles, Winnie F Tam, Thomas P Giordano, Laura T Pierce, Melissa Farwell, Douglas W McMillin, Antoaneta Necheva, David Crowe, Mei Chen, William Avery, Vikram Kansra, Steffan T Nawrocki, Jennifer S Carew, Francis J Giles, Constantine S Mitsiades, Alexis A Borisy, Kenneth C Anderson, Margaret S Lee
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  ABSTRACT: The use of combination drug regimens has dramatically improved the clinical outcome for patients with multiple myeloma. However, to date, combination treatments have been limited to approved drugs and a small number of emerging agents. Using a systematic approach to identify synergistic drug combinations, combination high-throughput screening (cHTS) technology, adenosine A2A and β-2 adrenergic receptor (β2AR) agonists were shown to be highly synergistic, selective, and novel agents that enhance glucocorticoid activity in B-cell malignancies. Unexpectedly, A2A and β2AR agonists also synergize with melphalan, lenalidomide, bortezomib, and doxorubicin. An analysis of agonists, in combination with dexamethasone or melphalan in 83 cell lines, reveals substantial activity in multiple myeloma and diffuse large B-cell lymphoma cell lines. Combination effects are also observed with dexamethasone as well as bortezomib, using multiple myeloma patient samples and mouse multiple myeloma xenograft assays. Our results provide compelling evidence in support of development of A2A and β2AR agonists for use in multi-drug combination therapy for multiple myeloma. Furthermore, use of cHTS for the discovery and evaluation of new targets and combination therapies has the potential to improve cancer treatment paradigms and patient outcomes.
  Molecular Cancer Therapeutics 04/2012; 11(7):1432-42. · 5.23 Impact Factor
• Article: Adenosine A2A receptor agonists and PDE inhibitors: a synergistic multitarget mechanism discovered through systematic combination screening in B-cell malignancies.

  Richard J Rickles, Laura T Pierce, Thomas P Giordano, Winnie F Tam, Douglas W McMillin, Jake Delmore, Jacob P Laubach, Alexis A Borisy, Paul G Richardson, Margaret S Lee
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  ABSTRACT: Using a combination high-throughput screening technology, multiple classes of drugs and targeted agents were identified that synergize with dexamethasone (Dex) in multiple myeloma (MM) cells. Performing combination screening with these enhancers, we discovered an unexpected synergistic interaction between adenosine receptor agonists and phosphodiesterase (PDE) inhibitors that displays substantial activity in a panel of MM and diffuse large B-cell lymphoma (DLBCL) cell lines and tumor cells from MM patients. We have used selective adenosine receptor agonists, antagonists, and PDE inhibitors as well as small interfering RNAs targeting specific molecular isoforms of these proteins to dissect the molecular mechanism of this synergy. The adenosine A2A receptor and PDE2, 3, 4, and 7 are important for activity. Drug combinations induce cyclic AMP (cAMP) accumulation and up-regulate PDE4B. We also observe rigorous mathematical synergy in 3-way combinations containing A2A agonists, PDE inhibitors, and Dex at multiple concentrations and ratios. Taken together, these data suggest that A2A agonist/PDE inhibitor combinations may be attractive as an adjunctive to clinical glucocorticoid containing regiments for patients with MM or DLBCL and confer benefit in both glucocorticoid-sensitive and -resistant populations.
  Blood 04/2010; 116(4):593-602. · 9.90 Impact Factor