MOROSS INTEGRATED CANCER CENTER GRANTS

DNA damage response determines cell fate. A classical view is that under DNA damage cells either die or survive while maintaining a certain degree of genome instability and rearrangements. A significant number of these surviving cells harbor MNi. MNi has lately been reported to activate the cGAS-STING innate immunity pathway. Remarkably, the same cGAS-STING pathway plays a role in inducing senescence Our preliminary data suggest that under c-Abl inhibition/knockout the IFN-I pathway is compromised whereas the senescence program is activated. We will investigate the possibility that failure to activate innate immunity (IFN-I) facilitates senescence.

Anti-tumor antibodies are being produced in patients with different cancer types. Yet, they fail to mediate effective clearance of the tumor cells and to engage efficient anti-tumor immune response. We hypothesize that the Fc-glycan repertoire is a key determinant that regulate the anti-tumor antibody response. Here, we propose to develop mass-spectrometry based assay to characterize the IgG Fc-glycome in patients and mouse models of different cancer types.

Somatic mutations in eIF1A, especially in the N-terminal tail (NTT), were recently found to be associated with uveal, thyroid and ovarian cancers. Presently very little is known about the biological function of eIF1A in mammalian cells and how perturbations of its function by the mutations contribute to cancer development. We seek to develop pharmacological tools to selectively interfere with the scanning promoting activity of eIF1A, as a novel personalized therapeutic approach against uveal and thyroid cancers bearing the aforementioned gain-of-function mutations in eIF1A.

The tumor microenvironment affects the survival, development, and progression of cancer. Particularly, it is thought that the transfer of full length mRNA molecules between cancer and normal cells might profoundly affect the local microenvironment. We recently discovered a phenomenon by which full-length mRNAs can be transferred between cells. In this project we will explore this process in relation to the tumor microenvironment and cell physiology by determining the biological consequences of the transfer of oncogenic or tumor suppressive mRNAs on the phenotype of downstream acceptor cells and determine whether mRNA transfer occurs in vivo employing human tumor xenografts. Lastly, we will use biochemical/genetic approaches to screen for genes involved in mRNA transfer.

Breast cancer is the most prevalent and lethal cancer in women. 15% of breast cancers do not overexpress the estrogen, progesterone or HER2 receptors also known as Triple Negative Breast Cancers (TNBC). This type of cancers is more aggressive, has poor prognosis, and lack any targeted therapy. This stems partly from our lack of understanding of driver events in TNBC and for lack of validated targets for its pathogenicity. We propose to identify new molecular drivers of TNBC and their respective pathways via covalent fragment phenotypic screening, utilizing an innovative electrophilic fragment library. We have assembled a collection of 993 electrophilic fragments for cellular phenotypic screening that will be used to discover proteins that selectively contribute to TNBC viability, validate them orthogonally via knockdowns and explore their biological roles in TNBC pathogenicity. We will harness the covalent nature of these compounds to pull down their target proteins and characterize them via proteomics. This library can offer an unprecedented window to the working of TNBCs.

Omental spread is common in gastric adenocarcinoma, representing an advanced stage that harbors poor prognosis mostly due to resistance to systemic therapy. We have shown previously that factors secreted by fresh human omental-fat specimens induce chemoresistance of gastric cancer cells. In this project, we will further characterize the effects that omental-fat secreted factors have on the chemoresistance of gastric cancer. In vitro co-culture system will be used to systematically assay the effect of the different omental-fat secreted factors on chemoresistance. In addition, FPLC/MS and secretome library screening will be used to find relevant factors that can confer resistance. Next, we will explore omentum-mediated resistance mechanisms with in vitro and vivo studies. Finally, the clinical implications of blocking selected secreted factors on drug treatment efficacy will be tested using PDX mice models.

The tumor suppressor p53 is commonly mutated in glioblastoma, conferring it with aggressive oncogenic features. Consequently, we aimed to develop a new therapy approach for glioblastoma in which anti- mutant p53 drugs will be packaged into exosomes which then be delivered to patients for treatment. Previously, we were able to show that gliomas readily take up MSCs-derived exosomes and by that we were able to specifically change the gene expression and influence the biological behavior of glioma cells. Our results suggest that various cells may be used as natural bio-factories for the ex vivo production of nanoscale-sized exosomes containing mutant p53-targeting drugs. We showed that these exosomes can be delivered to targeted cells and to reduce mutant p53 expression. This study provides a proof-of-concept that exosomes loaded with anti-mutant p53 drug might be considered as an efficient novel strategy for human glioblastoma therapy.