Pharmacogenomics and Experimental Therapeutics
Members in the Pharmacogenomics and Experimental Therapeutics Program aim to improve cancer therapies by focusing on several research themes including the development of novel cancer therapeutics, pharmacogenomics of cancer therapeutics, and the interaction of chemotherapy and radiation.
In 2012, Program members produced nearly 130 peer-reviewed publications, many in high-impact journals. The high number of intraprogrammatic (30%) and interprogrammatic (38%) papers highlight the extent to which Program members interact with other UCCCC investigators. Selected research findings are summarized below. These papers were selected to illustrate high-profile, collaborative research, and to emphasize translational initiatives and the growing pediatric oncology activities.
Gene signature predicts poor survival outcome in a subtype of glioblastoma
Ralph Weichselbaum, MD, and his colleagues isolated 8 genes related to the interferon/STAT1 pathway and found that overexpression of these genes predicted poor survival outcome in patients with glioblastoma multiforme (GBM), an aggressive brain cancer with typically poor prognosis. Genes in this signaling pathway have previously been associated with resistance to radiation therapy in head and neck and breast cancer. The gene signature was found to be dependent on the cancer subtype and has implications for understanding the molecular mechanisms responsible for tumor progression and response to therapy. (Duarte et al., PLoS ONE 7:e29653, 2012)
This work was supported by grants T32-Hl007457, CA097247, K01 DK080188 and CA071933 from the National Institutes of Health, and grant S08-221ST TO4 from the Science Applications International Corporation.
Ganitumab combination therapy shows benefit in metastatic pancreatic cancer
An investigational drug combined with gemcitabine, commonly used to treat patients with metastatic disease, improves the survival rate of patients with metastatic pancreatic cancer. Hedy Kindler, MD, led a phase II trial to evaluate the safety and efficacy of ganitumab, an antagonist of insulin-like growth factor 1 receptor, and conatumumab, an agonist of a human cell death receptor, combined with gemcitabine in patients with previously untreated metastatic pancreatic cancer. Patients who received the ganitumab combination therapy experienced tolerable toxicity and showed a trend toward improved 6-month and overall survival rates, whereas patients who received the conatumumab combination therapy showed no improvement in overall survival compared to gemcitabine alone. A phase III study is ongoing to provide additional information on the efficacy of ganitumab combination therapy in metastatic pancreatic cancer. (Kindler et al., Ann Oncol 23:2834-42, 2012)
Database catalogs intrinsic growth rates of cells
M. Eileen Dolan, PhD, along with colleagues Drs. R. Stephanie Huang and Nancy Cox (Cancer Prevention and Control Program), developed a novel method to calculate the growth rate of cell lines from the International HapMap Project, which are used in genetic studies of disease risk and drug response. They found that more than 30% of the nearly 11,000 genes examined were associated with growth rate, and that specific genetic variants influenced growth. Results from this comprehensive analysis were deposited into the PACdb database and made widely available to the research community to support pharmacogenomics research. (Im et al., PLoS Genet 8:e1002525, 2012)
This work was supported by grant UO1GM61393 from the National Institutes of Health (NIH), by the University of Chicago Breast Cancer SPORE Grant (P50 CA125183) from the National Cancer Institute (NCI), by NIH/NCI RO1 CA136765, by the University of Chicago Cancer Center Grant (P30 CA014599-36) from the NCI, and by a Specialized Center of Research Grant from the Leukemia and Lymphoma Society.
Genomic markers predict sensitivity to common chemotherapy drug
A team of UCCCC investigators identified new genetic variants and genes associated with sensitivity to capecitabine, an oral chemotherapy drug widely used to treat breast, colorectal, and gastric cancers. The researchers conducted a genome-wide association study to identify underlying genetic factors that influence the response to capecitabine treatment. They examined genetic information in cell lines derived from over 500 individuals across world populations and found a new genetic variant near the 5-methyltetrahydorfolate-homocysteine mehtyltransferase reductase (MTTR) gene, as well as a genetic variant of the DNA regulating SMARCAD1 gene, associated with drug sensitivity. Results from this study may help physicians personalize cancer therapy by selecting patients who would most likely respond to treatment. M. Eileen Dolan, PhD, Peter O’Donnell, MD, Nancy Cox, PhD, (Cancer Prevention and Control Program) and R. Stephanie Huang, PhD, were among the study authors. The group is also evaluating top genetic variants from the preclinical study in a clinical trial of capecitabine initiated by Dr. O'Donnell with the Translational Breast Cancer Research Consortium. (O’Donnell et al., Cancer 118:4063-73, 2012)
This study was supported by The University of Chicago Breast Cancer Specialized Program of Research Excellence (SPORE) grant P50 CA125183, by National Institutes of Health (NIH)/National Institute of General Medical Sciences (NIGMS) grant UO1 GM61393 to the Pharmacogenomics of Anticancer Agents Research Group, by NIH/National Cancer Institute grant F32 CA136123, by NIH grant TL1 RR25001, and by NIH/NIGMS grant K08 GM089941.
Grapefruit juice enhances effect of anti-cancer drug
Results from a clinical trial demonstrate that drinking eight ounces a day of grapefruit juice allows patients with advanced cancer to derive the same benefits from rapamycin as they would from more than three times as much of the drug itself. Rapamycin is an inhibitor of the mTOR signaling pathway that shows efficacy in preclinical models. Ezra Cohen, MD, and colleagues Drs. Mark Ratain, Thomas Gajewski, (Immunology and Cancer Program) Gini Fleming, and Michael Maitland, observed that rapamycin can be feasibly administered orally once weekly with a similar toxicity profile as other mTOR inhibitors. In combination with grapefruit juice, a potent inhibitor of cytochrome P450 enzymes which metabolize drugs, rapamycin blood levels increased by 350%. These results warrant further evaluation of rapamycin in comparative studies with other approved rapamycin analogs. (Cohen et al., Clin Cancer Res 18:4785-93, 2012)