Project Details
Projekt
Exploiting metabolic vulnerability of triple negative breast cancer based on shifts in the expression of metabolic enzyme isoforms
Applicant
Dr. Marie-Kristin von Wahlde
Subject Area
Gynaecology and Obstetrics
Term
from 2014 to 2016
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 262993625
Approximately 20% of all breast cancers lack the expression of the estrogen (ER) and progesterone (PR) receptors and have normal copy numbers for the human epidermal growth factor receptor 2 (HER2) and referred to as triple negative breast cancers (TNBC). For currently unknown reasons, TNBC is more common in African American women, in younger women and among carriers of BRCA1 mutation. The only treatment options for these patients are chemotherapy. Approximately one third of these cancers are highly chemotherapy sensitive based on preoperative chemotherapy studies in stage I-III breast cancers, the rest have poor prognosis. No major therapeutic advances occurred for these cancers since the introduction of taxanes over 15 years ago. High throughput genomic analytical technologies including DNA sequencing and gene expression profiling provide an opportunity to identify potential new therapeutic targets through the molecular analysis of human cancer samples. These methods revealed significant differences in gene expression, DNA copy number and mutation distribution between TNBC and other subtypes of breast cancer. However, there are no recurrent, high frequency mutations or copy umber abnormalities in TNBC other than mutations in p53, and less commonly in PI3K mutations. On the other hand, there are a large number of genes that are consistently overexpressed in TNBC relative to other breast cancer subtypes or compared to normal breast tissues and form the basis of a robust molecular classification. Some of these aberrantly expressed genes may represent novel, breast cancer subtype-specific therapeutic targets. The goal of my postdoctoral research fellowship at the Pusztai laboratory in Yale Cancer Center is to discover novel triple negative breast cancer-specific therapeutic targets from human breast cancer genomic data and credential these potential targets in the laboratory. Our ultimate goal is to pursue the most promising lead target and develop new drugs for this form of breast cancer. Hypothesis Metabolic enzymes have multiple different isoforms that share similar catalytic activities and most cells simultaneously express several different isoforms. We assume that this multiplicity of isoenzymes represent functional redundancy. Our hypothesis is that iosenzyme expression changes occur during neoplastic transformation, or in response to environmental pressure in cancer cells, and loss of isoenzyme diversity, may render cancer cells more vulnerable to metabolism targeted therapies. Our goal is to identify isoenzyme expression shifts in human triple negative breast cancer compared to normal breast tissue and identify metabolic processes that rely on the expression of only one or a few enzyme isoforms due to loss of isoenzyme diversity in the TNBC cells.
DFG Programme
Research Fellowships
International Connection
USA
