MS in Biomedical Engineering (M.S.B.E.)
Degree Granting Department
Ariosto Silva, Ph.D.
Robert Frisina, Jr., Ph.D.
William Lee III, Ph.D.
cancer, decision support system, drug sensitivity, personalized therapy, precision medicine
Multiple Myeloma (MM) is a treatable, yet incurable, malignancy of bone marrow
plasma cells. This cancer affects many patients and many succumb to relapse of tumor burden
despite a large number of available chemotherapeutic agents developed for therapy. This is
because MM tumors are heterogeneous and receive protection from therapeutic agents by the
microenvironment and other mechanisms including homologous MM-MM aggregation.
Therefore, therapy failure and frequent patient relapse is due to the evolution of drug resistance,
not a lack of available drugs. To analyze and understand this problem, the evolution of drug
resistance has been explored and presented herein. We seek to describe the methods through
which MM cells become resistant to therapy, and how this resistance evolves throughout a
patient’s treatment history. We achieve this in five steps.
First we review the patient’s clinical history, including treatments and changes in
tumor burden. Second, we trace the evolutionary tree of sub-clones within the tumor
burden using standard of care fluorescence in situ hybridization (FISH). Thirdly,
immunohistochemistry slides are stained and aligned to quantify the level of environmental
protection received by surrounding cells and plasma in the bone marrow microenvironment
(coined environment mediated drug resistance score [EMDR]). The fourth analysis type is
produced through a novel 384-well plate ex vivo chemosensitivity assay to quantify sensitivity of
primary MM cells to chemotherapeutic agents and extrapolate these findings to 90-day clinical
response predictions. In addition to direct clinical application in the choice of best treatment, this
tool was also used to study changes in sensitivity of patient tumors to other drugs, and it was
observed that, upon relapse, in addition to developing resistance to the current line of therapy,
tumors become cross-resistant to agents that they were never exposed to. Finally, MM-MM
homologous aggregation is quantified to assess the level of drug resistance contributed by
clustering of patient tumor cells, which causes upregulation of Bcl-2 expression and other
The findings of such experimentation improve comprehension of the driving factors that
contribute to drug resistance evolution on a personalized treatment basis. The aforementioned
factors all contribute in varying degrees for unique patient cases, seven of which are presented in
depth for this project. In summary: Environmental protection plays a critical initial role in drug
resistance, which is followed by increase in tumor genetic heterogeneity as a result of mutations
and drug-induced Darwinian selection. Eventually, environment-independent drug resistant subpopulations
emerge, allowing the tumor to spread to unexplored areas of the bone marrow while
maintaining inherited drug resistant phenotype2. It is our hope that these findings will help in
shifting perspective regarding optimal management of MM by finding new therapeutic
procedures that address all aspects of drug resistance to minimize chance of relapse and improve
quality of life for patients.
Scholar Commons Citation
Jacobson, Timothy, "A Trans-Dimensional View of Drug Resistance Evolution in Multiple Myeloma Patients" (2016). Graduate Theses and Dissertations.