Cancer Research Scholars Program 2016-2017 Funded Collaborations

The Sheba group has been the co-discoverer of a subgroup of high risk acute lymphoblastic leukemias (ALL) characterized by aberrant expression of the receptor CRLF2 and activating mutations in CRLF21IL7R1JAK proteins. These CRLF2-ALLs are associated with poor outcome and no effective treatments.  The team will test the effect of inhibitors on CRLF2-ALL cell lines and patient derived xenografts in-vitro and in-vivo to evaluate their effect on anti-tumor immune activation. City of Hope is currently moving forward to clinically test CpG-STAT3siRNA in patients with B cell lymphoma as well as malignant glioma.  Positive findings from theses proposed studies have the potential to create effective new therapies to benefit ALL patients who fail current treatment.

The proposed study is designed to help understand the occurrence of breast cancer in very young women. About 5% of all breast cancers occur before the age of 35 years. Unfortunately we do not have means of prevention or early detection of breast cancer for this age group, as the dense breasts do not allow the use of most detection modalities. It is therefore of utmost importance to understand the genetic background of these women as well as the genetic characteristics of their tumors in order to develop proper control measures.  This study will investigate particularly events in genes that are known to be associated with the occurrence of breast cancer and other tumors, such as P53; but which are not routinely tested for. The team will study the role of these genes in breast cancer patients of Jewish and Arab origin, participants of a large population based study that collects big amounts of background information about the participant and her family and collects DNA and tissue samples to allow for studying possible etiologies and characteristics of this tumor type.

Triple-negative breast cancers [ER(-)/PR(-)/HER2wt (TNBC)] are highly aggressive breast cancers that frequently occur in BRCA1 mutation carriers. While Ashkenazi women with TNBC have a 48% incidence of germline BRCA1 mutations, over 50% of Ashkenazi women lack a BRCA1 mutation. The team discovered a novel tumor suppressor gene, WW domaincontaining oxidoreductase (WWOX) whose loss promotes progression and metastasis of TNBC. The preliminary data provide evidence that loss of WWOX activates glycolysis and glucose uptake. In this proposal, we aim to investigate the role of WWOX signaling in activating metabolism in TNBC. Aim 1 will test whether loss of WWOX in TNBC activate glycolysis by transcriptional activation of HIF1α. Aim 2 will investigate whether loss of WWOX expression predicts increased metabolism/glycolysis in TNBC and noncancerous mammary epithelial cells from high-risk women. These studies are directly relevant to cancer because they investigate a signaling pathway that promotes metastasis and aggressive biology of TNBC. The long-term goal of this project is to identify new targets for early detection and treatment of TNBC.