Research
Dr. Weinshilboum's research program focuses on pharmacogenomics, which is the study of the role of inheritance in variations in drug response phenotypes. These phenotypes can vary from severe life-threatening adverse drug reactions to the lack of the desired therapeutic drug effect.
Over the years, pharmacogenetics has evolved into pharmacogenomics. Recently, it has evolved further into pharmaco-omics with the integration of genomics with transcriptomics, proteomics and metabolomics. Each of these studies can involve millions or even billions of data points requiring significant computational analysis.
Dr. Weinshilboum's lab pursues pharmacogenomic studies related to drug therapies for:
- Cancers, including childhood leukemia and breast cancer.
- Psychiatric diseases, including major depressive disorder, also known as depression, which is the most common of all psychiatric diseases, and alcohol use disorder.
These projects combine drug therapy, genomics and molecular biology. For analyses, these projects use machine learning and artificial intelligence.
Cancer pharmacogenomics
Acute lymphoblastic leukemia is the most common cancer in children. It is now possible to cure over 90% of children with this cancer through drug therapy. One of the key drugs used to treat childhood acute lymphoblastic leukemia is mercaptopurine. But this important drug will occasionally destroy a child's bone marrow, resulting in a life-threatening adverse drug reaction.
Dr. Weinshilboum's lab discovered that this severe drug reaction is due to genetic variations in a gene encoding the enzyme thiopurine methyltransferase (TPMT), which the body uses to inactivate mercaptopurine. That discovery made TPMT genetic polymorphisms one of the earliest and most widely used clinical pharmacogenomic biomarkers. This made it possible to avoid an adverse drug reaction.
Dr. Weinshilboum's program has applied a similar approach to drugs used to treat breast cancer. He seeks to understand both drug response and underlying mechanisms responsible for variations in the efficacy of antineoplastic drugs.
Major depressive disorder pharmacogenomics
Major depressive disorder is a major cause of medical disability worldwide. Because of the risk of suicide, it also is a major cause of mortality. Selective serotonin reuptake inhibitors (SSRIs) are the standard of care for the drug therapy of major depressive disorder. However, SSRI therapy does not adequately relieve symptoms for one-third to one-half of patients with major depressive disorder.
Dr. Weinshilboum's research program has used genome-wide association studies to scan the genome and identify genes associated with variations in SSRI clinical response. In addition, by employing pharmaco-omics, he has used metabolomics data to inform genome-wide association studies to make it possible to identify novel genes associated with variations in SSRI clinical response, genes such as ERICH3 and TSPAN5. Then using single nucleotide polymorphisms in those genes — combined with clinical data and machine learning techniques — he has developed algorithms to predict who will respond to SSRI therapy.
Dr. Weinshilboum is taking a similar approach to study variations in response to drugs used to treat patients who have alcohol use disorder.
Conclusion
The pharmacogenomics research program of Dr. Weinshilboum's lab uses genomics, transcriptomics, proteomics and metabolomics to identify genes associated with variations in response to drugs used to treat cancer and neuropsychiatric disease. The lab pursues the underlying biological mechanisms responsible for those variations to design better drugs and more accurately predict variations in drug response.