Time filter

Source Type

New Philadelphia, PA, United States

Leone R.D.,University of Pennsylvania | Amaravadi R.K.,Abramson Cancer Center
Trends in Endocrinology and Metabolism | Year: 2013

Cancer cells display several features of aberrant cellular metabolism. Two consequences of this dysregulated metabolism are rapid depletion of intracellular nutrients and a buildup of aggregated proteins and damaged organelles. Autophagy provides a mechanism for recycling proteins, lipids, and organelles. In cancer cells, oncogenes and conditions of severe stress drive profound upregulation of autophagy. In this setting, autophagy ameliorates the ill effects of dysregulated cellular metabolism, allowing a steady supply of nutrients and removal of damaged organelles. Although therapeutic strategies targeting cancer cell metabolism and autophagy are already entering clinical trials, further study of the precise mechanisms of interplay between oncogenic signaling, cellular metabolism, and autophagy will provide more effective strategies in the future. © 2013 Elsevier Ltd.

Ward P.S.,Abramson Cancer Center | Patel J.,Sloan Kettering Cancer Center | Wise D.R.,Abramson Cancer Center | Abdel-Wahab O.,Sloan Kettering Cancer Center | And 12 more authors.
Cancer Cell | Year: 2010

The somatic mutations in cytosolic isocitrate dehydrogenase 1 (IDH1) observed in gliomas can lead to the production of 2-hydroxyglutarate (2HG). Here, we report that tumor 2HG is elevated in a high percentage of patients with cytogenetically normal acute myeloid leukemia (AML). Surprisingly, less than half of cases with elevated 2HG possessed IDH1 mutations. The remaining cases with elevated 2HG had mutations in IDH2, the mitochondrial homolog of IDH1. These data demonstrate that a shared feature of all cancer-associated IDH mutations is production of the oncometabolite 2HG. Furthermore, AML patients with IDH mutations display a significantly reduced number of other well characterized AML-associated mutations and/or associated chromosomal abnormalities, potentially implicating IDH mutation in a distinct mechanism of AML pathogenesis. © 2010 Elsevier Inc. All rights reserved.

Take triple-negative breast cancer (TNBC), an aggressive subtype with poor clinical outcome, for example. Genomic studies of TNBC to crack its tough-to-treat status have mainly focused on protein-coding genes and the function of non-coding genes is still largely unknown. Using a clinically guided genetic screening approach, researchers from the Perelman School of Medicine at the University of Pennsylvania identified LINP1, a lncRNA. This lncRNA is overexpressed in triple-negative breast cancer cells and regulated by the tumor suppressor p53 and the activated cell surface protein, EGFR. LINP1 enhances the repair of DNA breaks by serving as a scaffold that links two other proteins in the repair machinery. A BRCA1 mutation is associated with a higher risk for TNBC, which represents about 10 to 20 percent of all breast cancer cases. TNBC test negative for both the estrogen and progesterone receptors and the cell surface receptor Her2, hence its name. Since hormones are not supporting growth, the cancer is unlikely to respond to hormonal therapies and medications that target HER2. Because of these limited therapeutic targets, many cancers, including TNBCs, are typically treated with surgery and a combination of radiation and chemotherapy that induce various types of DNA damage. However, many TNBC patients are resistant to these combination therapies. With support from the Basser Center for BRCA at Penn, the team was led by senior authors Lin Zhang, MD, the Harry Fields Associate Professor of Obstetrics and Gynecology, Chi V. Dang, MD, PhD, director of the Abramson Cancer Center, and first author Youyou Zhang, MD, PhD, a postdoctoral fellow in the department of Obstetric and Gynecology. They published their findings this week in Nature Structural & Molecular Biology. Recent studies, including publications from the Penn group, have identified lncRNAs with tumor suppressive and oncogenic activities in cancers. The two repair scaffold proteins, Ku80 and DNA-PKcs, that LINP1 links coordinate the non-homologous end-joining (NHEJ) repair molecules that fix double-strand breaks in DNA. Importantly, the team found that blocking LINP1 significantly increases sensitivity by the tumor cells to radiation therapy. The NHEJ pathway, which repairs double-strand breaks in DNA, is one of the major pathways in tumor cells that respond to radiation treatment and chemotherapeutic agents. Inhibition of the NHEJ pathway has been proposed by oncology researchers to synergize DNA-damaging therapies for better treatment outcomes for TNBCs. "Given the important role of LINP1 in the NHEJ pathway, our study indicates that this new class of cancer-driver gene—the lncRNAs—may serve as unique therapeutic targets and novel biomarkers in cancer," Zhang said. "Collectively, our study provides new insight into the DNA damage repair pathway, long non-coding RNAs, and triple-negative breast cancer." More information: Youyou Zhang et al, Long noncoding RNA LINP1 regulates repair of DNA double-strand breaks in triple-negative breast cancer, Nature Structural & Molecular Biology (2016). DOI: 10.1038/nsmb.3211

Beatty G.L.,Abramson Cancer Center | Moon E.K.,University of Pennsylvania
OncoImmunology | Year: 2014

Chimeric antigen receptor (CAR) modified T cells have shown early promise in hematological malignancies. However, in solid malignancies CAR T cells must overcome a distinct immunosuppressive microenvironment which may compromise their capacity to mediate antitumor activity. © 2014 Taylor & Francis Group, LLC.

Amaravadi R.K.,Abramson Cancer Center
Journal of Investigative Dermatology | Year: 2013

Chloroquine (CQ) can induce cell death in a subset of cancer cell lines, and some melanoma cell lines are quite susceptible. Although it is well known that CQ impairs lysosomal function and can serve as an autophagy inhibitor, the molecular target of CQ and the subsequent cascade of events that lead to cell death are not fully understood. Recent evidence indicates that in melanoma cell lines, CQ induces apoptosis by preventing degradation of the pro-apoptotic BH3-only protein p53-upregulated modulator of apoptosis. This finding adds to the unfolding story of CQ's mechanism of action as a cancer therapeutic agent. © 2013 The Society for Investigative Dermatology.

Discover hidden collaborations