Thalidomide (Thal) and its derivatives, Lenalidomide (Len) and Pomalidomide (POM), are immune modulatory drugs (IMiDs) used in the treatment of multiple myeloma (MM) and few other hematological malignancies. Although they represent the backbone treatment for both newly diagnosed and relapse/refractory MM patients, their clinical use remains mostly empirical because of lack of suitable in vivo model systems to study their complex mechanisms of action. Murine cells are intrinsically resistant to IMiDs because of different amino acid sequence in the IMiD binding domain of cereblon (CRBN). By building upon our extensively validated Vk*MYC transgenic mouse model of MM, we have generated a novel transgenic mouse, Vk*MYChCRBN, expressing the full human CRBN (hCRBN) gene under the control of its endogenous regulatory elements, rendering it IMiD sensitive. As previously done for the Vk*MYC model, we will extensively characterize the new Vk*MYChCRBN model and will use it to understand the IMiD effects on the tumor and the immune system with the ultimate goal to inform clinical practice.

Public Health Relevance

Thalidomide and related drugs Lenalidomide and Pomalidomide (IMiDs) are very active in the treatment of multiple myeloma, but their clinical use remains mostly empirical because of lack of proper model systems that allow studying their complex effects on the tumor and on the immune system. To overcome this translational need we have generated a novel transgenic mouse model expressing the cellular receptor for these drugs and propose to validate it its use for understanding how IMiDs work in human with the ultimate goal to inform clinical practice.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA234181-03
Application #
10053331
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Watson, Joanna M
Project Start
2018-12-07
Project End
2023-11-30
Budget Start
2020-12-01
Budget End
2021-11-30
Support Year
3
Fiscal Year
2021
Total Cost
Indirect Cost
Name
Mayo Clinic, Arizona
Department
Type
DUNS #
153665211
City
Scottsdale
State
AZ
Country
United States
Zip Code
85259