What factors contribute to immunomodulatory drug resistance in myeloma and other diseases?

We have studied the clinical and non-clinical pharmacology of the immunomodulatory drugs (IMiDs) for more than a decade. The IMiDs include thalidomide, lenalidomide and pomalidomide, and while they have very similar chemical structures, physicochemical properties, chemical stability, and aqueous solubility, and they all target the cereblon (CRBN) protein, they have significantly different pharmacokinetics and biodistribution properties. We have explored the potential for transporter-mediated drug-drug interactions and tumor resistance mechanisms with these agents. Our current funding has focused on the ability of AR-42 (REC-2282), a histone deacetylase inhibitor, to modulate IMiD resistance in myeloma through downregulation of the hyularonan receptor, CD44.

Publications related to this project:

  1. Thangavadivel S, Zhao Q, Epperla N, Rike L, Mo X, Badawi M, Bystry DM, Phelps MA, Andritsos LA, Rogers KA, Jones J, Woyach JA, Byrd JC, Awan FT. Early Intervention with Lenalidomide in Patients with High-risk Chronic Lymphocytic Leukemia. Clin Cancer Res. 2020 Dec 1;26(23):6187-6195. doi: 10.1158/1078-0432.CCR-20-1280. Epub 2020 Sep 21. PubMed PMID: 32958702.
  2. Saygin C, Larkin K, Blachly JS, Orwick S, Ngankeu A, Gregory CT, Phelps MA, Mani S, Walker A, Garzon R, Vasu S, Walsh KJ, Bhatnagar B, Klisovic RB, Grever MR, Marcucci G, Byrd JC, Blum W, Mims AS. A phase I study of lenalidomide plus chemotherapy with idarubicin and cytarabine in patients with relapsed or refractory acute myeloid leukemia and high-risk myelodysplastic syndrome. Am J Hematol. 2020 Aug 10. PMID: 32777116. PMCID: PMC7821016 DOI: 10.1002/ajh.25958
  3. Hughes JH, Upton RN, Reuter SE, Rozewski DM, Phelps MA, Foster DJR. Development of a physiologically based pharmacokinetic model for intravenous lenalidomide in mice. Cancer Chemother Pharmacol. 2019 Nov;84(5):1073-1087. Epub 2019 Sep 6. PMID: 31493176 PMCID: PMC7375688 DOI: 10.1007/s00280-019-03941-z
  4. Hughes JH, Phelps MA, Upton RN, Reuter SE, Gao Y, Byrd JC, Grever MR, Hofmeister CC, Marcucci G, Blum W, Blum KA, Foster DJR. Population pharmacokinetics of lenalidomide in patients with B-cell malignancies. Br J Clin Pharmacol. 2019 May;85(5):924-934. Epub 2019 Feb 27. doi: 10.1111/bcp.13873; PMID: 30672004; PMCID: PMC6475687.
  5. Sborov DW, Canella A, Hade EM, Mo X, Khountham S, Wang J, Ni W, Poi M, Coss C, Liu Z, Phelps MA, Mortazavi A, Andritsos L, Baiocchi RA, Christian BA, Benson DM, Flynn J, Porcu P, Byrd JC, Pichiorri F, Hofmeister CC. A phase 1 trial of the HDAC inhibitor AR-42 in patients with multiple myeloma and T- and B-cell lymphomas. Leuk Lymphoma. 2017 Oct;58(10):2310-2318. Epub 2017 Mar 7. doi: 10.1080/10428194.2017.1298751. PMID: 28270022. PMCID: PMC5489371.
  6. Maly JJ, Christian BA, Zhu X, Wei L, Sexton JL, Jaglowski SM, Devine SM, Fehniger TA, Wagner-Johnston ND, Phelps MA, Bartlett NL, Blum KA. A Phase I/II Trial of Panobinostat in Combination with Lenalidomide in Patients with Relapsed or Refractory Hodgkin Lymphoma. Clin Lymphoma Myeloma Leuk. 2017 Jun;17(6):347-353. Epub 2017 May 22. doi: 10.1016/j.clml.2017.05.008. PMID: 28622959. PMCID: PMC6033275.
  7. Harshman SW, Canella A, Ciarlariello PD, Agarwal K, Branson OE, Rocci A, Cordero H, Phelps MA, Hade EM, Dubovsky JA, Palumbo A, Rosko A, Byrd JC, Hofmeister CC, Benson DM Jr, Paulaitis ME, Freitas MA, Pichiorri F. Proteomic characterization of circulating extracellular vesicles identifies novel serum myeloma associated markers. J Proteomics. 2016 Mar 16;136:89-98. Epub 2016 Jan 13. doi: 10.1016/j.jprot.2015.12.016. PMID: 26775013. PMCID: PMC4783258.
  8. Cheng H, Xie Z, Jones WP, Wei XT, Liu Z, Wang D, Kulp SK, Wang J, Coss CC, Chen CS, Marcucci G, Garzon R, Covey JM, Phelps MA, Chan KK. Preclinical Pharmacokinetics Study of R- and S-Enantiomers of the Histone Deacetylase Inhibitor, AR-42 (NSC 731438), in Rodents. AAPS J. 2016 May;18(3):737-45. Epub 2016 Mar 4. doi: 10.1208/s12248-016-9876-3. PMID: 26943915. PMCID: PMC5256597.
  9. Maddocks K, Wei L, Rozewski D, Jiang Y, Zhao Y, Adusumilli M, Pierceall WE, Doykan C, Cardone MH, Jones JA, Flynn J, Andritsos LA, Grever MR, Byrd JC, Johnson AJ, Phelps MA, Blum KA. Reduced occurrence of tumor flare with flavopiridol followed by combined flavopiridol and lenalidomide in patients with relapsed chronic lymphocytic leukemia (CLL). Am J Hematol. 2015 Apr;90(4):327-33. Epub 2015 Feb 25. doi: 10.1002/ajh.23946. PMID: 25639448. PMCID: PMC4552311.
  10. Maddocks K, Ruppert AS, Browning R, Jones J, Flynn J, Kefauver C, Gao Y, Jiang Y, Rozewski DM, Poi M, Phelps MA, Harper E, Johnson AJ, Byrd JC, Andritsos LA. A dose escalation feasibility study of lenalidomide for treatment of symptomatic, relapsed chronic lymphocytic leukemia. Leuk Res. 2014 Sep;38(9):1025-9. Epub 2014 May 29. doi: 10.1016/j.leukres.2014.05.011. PMID: 25082342. PMCID: PMC4312491.
  11. Jiang Y, Wang J, Rozewski DM, Kolli S, Wu CH, Chen CS, Yang X, Hofmeister CC, Byrd JC, Johnson AJ, Phelps MA. Sensitive liquid chromatography/mass spectrometry methods for quantification of pomalidomide in mouse plasma and brain tissue. J Pharm Biomed Anal. 2014 Jan;88:262-8. Epub 2013 Sep 2. doi: 10.1016/j.jpba.2013.08.036. PMID: 24095801. PMCID: PMC3860284.
  12. Rozewski DM, Herman SE, Towns WH 2nd, Mahoney E, Stefanovski MR, Shin JD, Yang X, Gao Y, Li X, Jarjoura D, Byrd JC, Johnson AJ, Phelps MA. Pharmacokinetics and tissue disposition of lenalidomide in mice. AAPS J. 2012 Dec;14(4):872-82. Epub 2012 Sep 7. doi: 10.1208/s12248-012-9401-2. PMID: 22956478. PMCID: PMC3475844.
  13. Hofmeister CC, Yang X, Pichiorri F, Chen P, Rozewski DM, Johnson AJ, Lee S, Liu Z, Garr CL, Hade EM, Ji J, Schaaf LJ, Benson DM Jr, Kraut EH, Hicks WJ, Chan KK, Chen C-S, Farag SS, Grever MR, Byrd JC, Phelps MA. Phase I trial of lenalidomide and CCI‐779 in patients with relapsed multiple myeloma: evidence for lenalidomide-CCI-779 interaction via P-glycoprotein. J Clin Oncol. 2011 Sept 1;29(25):3427-34. Epub 2011 Aug 8. doi: 10.1200/JCO.2010.32.4962. PMID: 21825263. PMCID: PMC3164245.
  14. Blum W, Klisovic RB, Becker H, Yang X, Rozewski DM, Phelps MA, Garzon R, Walker A, Chandler JC, Whitman SP, Curfman J, Liu S, Schaaf L, Mickle J, Kefauver C, Devine SM, Grever MR, Marcucci G, Byrd JC. Dose escalation of lenalidomide in relapsed or refractory acute leukemias. J of Clin Oncol. 2010 Nov 20;28(33):4919-25. Epub 2010 Oct 18. doi: 10.1200/JCO.2010.30.3339. PMID: 20956622. PMCID: PMC3020696.
  15. Liu Q, Farley KL, Johnson AJ, Muthusamy N, Hofmeister CC, Blum KA, Schaaf LJ, Grever MR, Byrd JC, Dalton JT, Phelps MA*. Development and validation of a highly sensitive liquid chromatography/mass spectrometry method for simultaneous quantification of lenalidomide and flavopiridol in human plasma. Ther Drug Monit. 2008 Oct;30(5):620-7. doi: 10.1097/FTD.0b013e318185813d. PMID: 18708993. PMCID: PMC3740534.

Current and Past Funding for This Project:

  1. 08/01/2016 – 07/31/2021. Overcoming IMiD resistance in Myeloma. National Cancer Institute/National Institute of Health. R01CA201382. Role: MPI (MPIs: Phelps, Hofmeister, Pichiorri). Goal: This project evaluates the mechanisms of IMiD resistance in multiple myeloma and evaluate the ability of AR-42 to overcome resistance in a phase 1/2 clinical trial.
  2. 08/01/2019 – 07/31/2021. Diversity Supplement–A. Castillo: Overcoming IMiD resistance in myeloma. National Cancer Institute. R01CA201382 (Supplement) Role: MPI (Pichiorri/Hofmeister/Phelps). Goal: The proposed studies will investigate the mechanisms of IMID-induced resistance by assessing: (a) the functional role of CD44 in IMiD cellular uptake; (b) the role of small-non-coding-RNA (miRNA) in regulating CRBN and IRF4 and their significance in IMiD treatment; (c) if resistance can be overcome by combining AR-42 with an IMiD in a Phase 1 clinical trial.

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