Several researchers from Jefferson’s Kimmel Cancer Center presented abstracts at the American Association for Cancer Research Annual Meeting 2012 in Chicago. Some of those findings include:
HuR and Ovarian Cancer
Silencing HuR may be a promising therapeutic approach for the treatment of ovarian cancer, according to an abstract presented at AACR by researchers from Thomas Jefferson University, Lankenau Institute for Medical Research, the Geisinger Clinic and the Massachusetts Institute of Technology.
HuR is a RNA-binding protein that post-transcriptionally regulates genes involved in the normal cellular response to cancer-associated stressors, like DNA damage, nutrient depletion and therapeutic agents. When triggered by stress, HuR translocates from the nucleus to the cytoplasm where it potently influences translation of key tumor promoting mRNAs by mRNA stabilization and direct facilitation of translation.
Previously, it has been shown that HuR expression is a prognostic marker in ovarian cancers. Thus, researchers tested the effects of manipulating HuR expression levels on ovarian tumor growth characteristics and tested the hypothesis that silencing HuR through delivery of an HuR siRNA would be effective in suppressing the growth of ovarian tumors.
Following treatment of ovarian cancer cells in culture with an adenovirus containing the HuR coding sequence, HuR expression was increased by about 40% above control cells.
In the patient cohort, researchers also detected HuR activation (i.e., cytoplasmic HuR positivity) in twenty-four of thirty four patients (71 percent), providing evidence that the majority of patients have activated HuR.
“These data provide evidence that silencing HuR, even as a monotherapeutic strategy, may be a promising therapeutic approach for the treatment of ovarian cancer,” wrote the authors.
Authors of the paper include Janet A. Sawicki and Yu-Hung Huang, of Lankenau Institute for Medical Research, Charles J. Yeo, Agnieszka K. Witkiewicz, Jonathan R. Brody, of Thomas Jefferson University, Radhika P. Gogoi, of Geisinger Clinic, Danville, Pa., and Kevin Love and Daniel G. Anderson, of Massachusetts Institute of Technology, Cambridge, Mass.
This work was supported by the Marsha Rivkin Center for Ovarian Cancer Research.
Radiotherapy and Glioblastoma
Radiotherapy’s effect on glioblastoma (GBM) is enhanced in the presence of a heat shock protein and a P13K inhibitor, researchers from the Department of Radiation Oncology reported at AACR.
Glioblastoma tumors frequently contain mutations in the tumor suppressor gene, PTEN, leading to loss of PTEN activity, which causes overactivation of the PI3K pathway, inducing inhibition of apoptosis and radioresistance.
Heat-shock protein 90 (HSP90) is a molecular chaperone that is over-expressed in GBM and that has among its client proteins, PI3K and Akt.
It was hypothesized that dual inhibition of HSP90 and PI3K signaling would additively or synergistically radiosensitize GBM through inhibition of radiation-induced PI3K/Akt signaling, leading to enhanced apoptosis.
Confirming their theory, the researchers found that the response of glioblastoma to radiotherapy was enhanced in the presence of BKM120 and HSP990. Enhanced apoptosis also contributed to the mechanism of cell death.
Authors of the study include Phyllis Rachelle Wachsberger, Yi Liu, Barbara Andersen, and Adam P. Dicker, of the Department of Radiation Oncology at Thomas Jefferson University Hospital and Richard Y. Lawrence, of Jefferson and the Sheba Medical Center, Tel Hashomer, Israel.
This work was supported by a grant from Novartis Pharmaceuticals.
Non-Small Lung Cancer and DACH1
Researchers from the Kimmel Cancer Center at Jefferson have identified a protein relationship that may be an ideal treatment target for non-small cell lung cancer (NSCLC). They presented their findings at AACR.
DACH1, a cell fate determination factor protein, appears to be a binding partner to p53, a known tumor suppressor, which inhibits NSCLC cellular proliferation.
As cancer develops and becomes more invasive, the expression of DACH1 decreases. Clinical studies have demonstrated a reduced expression of the DACH1 in breast, prostate and endometrial cancer.
In a previous study of more than 2,000 breast cancer patients, Jefferson researchers found that a lack of DACH1 expression was associated with a poor prognosis in breast cancer patients. Patients who did express DACH1 lived an average of 40 months longer.
Genetic studies have identified several oncogenes activated in lung cancer, including K-Ras and EGFR. Given the importance of the EGFR in human lung cancer, researchers examined the role of DACH1 in lung cancer cellular growth, migration and DNA damage response.
For this study, endogenous DACH1 was reduced in human NSCLC, with expression levels of DACH1 correlating inversely with clinical stage and pathological grade.
Re-expression of DACH1 also reduced lung cancer cell colony formation and cellular migration. Cell cycle analyses demonstrated that G2/M block by ectopic expression of DACH1 occurs synergistically with p53.
Fluorescent microscopy demonstrated co-localization of DACH1 with p53, and immunoprecipitation and western blot assay showed DACH1 association with p53.
“DACH1 enhanced the cytotoxcity of cisplatin and doxorubicin, two commonly used drugs for NSCLC,” the authors write in the abstract. “Together, our studies demonstrate that p53 is a DACH1 binding partner that inhibits NSCLC cellular proliferation.”
Authors of the study include Ke Chen, Kongming Wu, Wei Zhang, Jie Zhou, Timothy Stanek, Zhiping Li, Chenguang Wang, L. Andrew Shirley, Hallgeir Rui, Steven McMahon, Richard G. Pestell, of Thomas Jefferson University, Kimmel Cancer Center and Huazhong University of Science and Technology, Wuhan, China.