Dissecting the biology and exploiting the dependency of myeloma cells on P300/CBP
Ricky Johnstone
PhDThe University of Melbourne
Project Term: July 1, 2022 - June 30, 2025
In recent work of our collaborating labs, the protein acetyltransferases P300 and CBP emerged as potent and preferential dependencies for multiple myeloma (MM) based on genetic depletion, catalytic inhibition or chemical degradation studies. Our current project will define distinct vs. redundant molecular and biological functions of P300/CBP in MM, identify the mechanisms of resistance to their inhibition/degradation and exploit these findings to develop new therapeutic modalities to treat MM.
Multiple myeloma (MM) is a presently incurable malignancy of plasma cells that develops within the bone marrow and represents the second most frequent form of blood cancers. This project involves collaboration of three labs from the Peter MacCallum Cancer Centre in Melbourne, Australia (Johnstone Laboratory), Dana Farber Cancer Institute (Mitsiades Laboratory, Boston, USA) and Massachusetts General Hospital Cancer Centre (Ott Laboratory, Boston USA). Recent studies of the collaborating labs converged to the same fundamental observation, i.e. that MM cells are exquisitely dependent on the function of two molecules called P300 and CBP. Using a variety of experimental approaches to knockout the genes that produce these proteins, block their function or force MM cells to rapidly breakdown these proteins, the collaborating labs determined that MM cells are on average significantly more dependent on either of these molecules than malignant cells from other blood cancers or solid tumors. The investigators of this proposal also confirmed that the treatment with first-generation inhibitors against these proteins prolongs the survival of mice with disseminated MM tumors. It is also notable that extensive studies supporting this project document that inhibition of P300 and CBP disrupts the biology of MM cells in a previously unanticipated manner which sets these molecules apart from other similarly promising therapeutic targets for MM. For instance, the specific biological roles of P300 and CBP in regulating gene expression in MM cells create distinct opportunities for combined or sequential use of inhibitors of these molecules with other established or investigational therapies for MM. To facilitate the translation of this new knowledge into future clinical applications for MM, the collaborating investigators will further examine how P300 and CBP control, separately vs. in combined manner, the growth and survival of MM cells and define pre-emptively, using preclinical models that faithfully simulate the biology of MM in the bone marrow of patients, how MM cells may potentially develop resistance to agents that inhibit or degrade P300 and CBP. We will use this information to derive new therapeutic regimens that will be tested in pre-clinical models of MM. Taken together these studies will provide novel insight into the biological roles of P300 and CBP and provide a platform for the development of new therapeutic options from MM.