ACADEMIC COLLABORATIVE GRANTS
Heterogeneity in melanoma metastasis and resistance to immune checkpoint blockade
Targeting a novel proteasome-associated deubiquitinase for its therapeutic efficacy
USP9X is functionally associated with many cancers and neuro-disorders but its role is confusing since mis-regulation of USP9X expression has been reported either as an oncogene or as a tumour suppressor. We hypothesize that the dual role of USP9X in cancer may be modulated through its proteasomal association. We propose to combine structural insight, information on potential binding partners, and determinants of enzymatic characterization to gain mechanistic insight into USP9X dual activity that might be investigated for therapeutic interventions.
BRIDGING THE GAP IN CANCER (JOINT MICC-YEDA)
The goal of this program is to facilitate translation of academic research to clinical developments addressing unmet clinical needs with novel therapeutics as well as diagnostics and imaging tools, for the benefit of cancer patients.
The goal of this program is to facilitate translation of academic research to clinical developments addressing unmet clinical needs with novel therapeutics as well as diagnostics and imaging tools, for the benefit of cancer patients.
Targeting nucleotide metabolism to boost the immune response against cancer
NEXT-GEN ANTI-PD-L1 ANTIBODIES FOR CANCE IMMUNOTHERAPY
The goal of this study is to identify the optimal human IgG scaffold for therapeutic anti-PD-L1 Abs. To achieve this goal, we will mechanistically characterize the contribution of huFcgR pathways to the antitumor activity of FDA-approved PD-L1 Abs and will harness this new information to design optimal Fc variants as a framework for next-generation anti-PD-L1 Abs with improved activity.
Towards rational design of cancer vaccines, targeting tumors at various heterogeneity states using tumor single cells
Autologous cancer cell vaccines (AutoCCVs) represent a highly promising personalized cancer treatment. Yet, AutoCCVs were shown to have a significant clinical benefit only in a subset of cancer patients. It has been reported that intra-tumor heterogeneity (ITH), when causing NeoA heterogeneity, may negatively influence immune surveillance, and pan-cancer analyses show better survival for tumors with low ITH. Hence, generating single cell clones from a high ITH tumor and using the most immunogenic clones as an AutoCCV should improve vaccine efficiency. Consequently, we aim to develop a novel pipeline for AutoCCVs designed so as to further enhance the NeoA-targeted immunogenic response in a patient-specific manner.
PhD IN CANCER IMMUNOLOGY PROGRAM
The Moross Integrated Cancer Center has launched a new Ph.D. research program, aiming to promote basic research in cancer immunology. The program supports collaborative Ph.D. projects co-supervised by one PI from the Department of Immunology, and an additional scientist, from any other department, who is interested in cancer research.
Under the program, three PhD fellowships were awarded this year for the following projects.
The Moross Integrated Cancer Center has launched a new Ph.D. research program, aiming to promote basic research in cancer immunology. The program supports collaborative Ph.D. projects co-supervised by one PI from the Department of Immunology, and an additional scientist, from any other department, who is interested in cancer research.
Under the program, three PhD fellowships were awarded this year for the following projects.
Identifying Novel Regulators of T cell Exhaustion in Cancer Using Single-cell CRISPR Screening
Improved Antibody Design for Cancer Immunotherapy
PROOF OF CONCEPT
To support exciting, perhaps risky, innovative ideas in all areas of basic cancer research. The expectation is that this early-phase grant will enable the researcher to obtain enough preliminary results to apply for competitive external funding.
To support exciting, perhaps risky, innovative ideas in all areas of basic cancer research. The expectation is that this early-phase grant will enable the researcher to obtain enough preliminary results to apply for competitive external funding.
Detection of autoreactive T follicular helper cells in ovarian carcinoma patients
Redox Regulation of Tumor-Associated Sialyltransferases
Exploring a New Strategy for Anticancer Therapy: Could an Exceptionally Small, Multifunctional, and Multivalent Targeted Drug Delivery System be created from a Single, Unimolecular Component?
Mechanisms driving gene amplification in cancers with wild type p53
Targeting antigen specific CTLs to pulmonary metastatic lesions
The role of stromal heat shock factor 1 (HSF1) in exosome biogenesis and delivery in the tumor microenvironment
Studying Non-Canonical Expression of IGF2 and its Role in Tumorigenesis
DNA repair Biomarkers for Predicting Response of Lung Cancer Patients to Immunotherapy
Does the failure in innate immunity establish senescence? The c-Abl story
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.
High content CyTOF-based screening for discovery of novel immune-receptor inhibitors for lymphoma treatment (CyTOF-screen)
B cells and B cell lymphoma depend on BCR signaling for their survival. Removal or inhibition of the immune receptor signaling lead to elimination of the malignant cell. Thus, immune-receptor signaling pathways are an excellent target for cancer treatment. We aim to establish a large-scale screening method that generates numerous readouts in response to hundreds of perturbations by combing high throughput screening with CyTOF readouts. This would allow to define the effect of each treatment on immune cells and lymphoma cells from patients and examine multiple parameters readout by CyTOF.
IgG Fc glycome as a checkpoint for antitumor immunity
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.
Growing to Die – Diverting Cell Size Regulation Mechanisms to Death Pathways in Cancer Cells
We hypothesize that mechanisms underlying cell size regulation in normal cells are diverted to survival/death pathways in cancer cells, raising the prospect of selectively targeting such mechanisms as a therapeutic strategy. Identifying key hubs in intracellular networks that may shift a size-sensing mechanism to control of proliferation or survival is likely to open new avenues for therapeutic development in the future.
Developing an approach for precision treatment of uveal and thyroid cancers
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.
Boosting anti-cancer immunotherapy using pH-switchable reagents
Cancer cells tend to acidify their immediate microenvironment due to increased consumption of glucose at limiting oxygen conditions. These unique biophysical properties could be utilized to achieve differential recognition of antigens using the same therapeutic mAbs. Thus, incorporating pH-switchable recognition elements into therapeutic antibodies could result with the desired differential recognition. This would allow increasing the dose of the mAbs to maximize the therapeutic effect while reducing the severity of, or completely eliminate the off-target side effects.
Intercellular mRNA transfer and the tumor microenvironment
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.
Real time microscopy of the lung vasculature for dissecting the role of the nuclear lamina in tumor cell extravasation and metastasis
Multiple types of circulating tumor cells (CTCs) metastasize into the lung parenchyma by extravasating the pulmonary vasculature. The space between the alveolus and the capillary (approximately 2 um) imposes a significant mechanical barrier on extravasating CTCs that need to squeeze their bulky and stiff nuclei through it with minimal nuclear damage. Using live imaging of the lung parenchyma with 2-photon microscopy set-up integrated with a thoracic window apparatus we will dissect the mechanisms by which cells transiently reduces their nucleus stiffening enabling extravasation. Genetic manipulations of several breast cancer cell lines by transient and permanent lamin A/C silencing and by CRISPR technology to eliminate a key laminin serine phosphorylation site will be utilized to unravel molecular players involved.
Finding the Achilles heel(s) of triple negative breast cancer
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.
Tumor infiltrating B lymphocytes: tumor suppressors or just bystanders?
The importance of T cells in antitumor responses is currently well recognized; however, the role of B cells in cancer immunology is only scantly probed and studied. This is presumably due to the lack of reliable models for functional analysis of distinct B cell subsets in the tumor microenvironment and their contribution to both pro- as well as antitumor immune responses. Focusing on pancreatic cancer, we wish to characterize the potential contribution of B-cells in the microenvironment to cancer control, management and therapy. Specifically, we propose to utilize novel intravital imaging modalities integrated with lineage specific B cell reporter mice to study tumor-infiltrating lymphocytes (TIL) B cells in the tumor microenvironment in both mouse and human pancreatic tumors.
STUDENT AND POST-DOC CANCER RESEARCH INNOVATION AWARDS COMPETITION
The MICC 1st Student and Post-doc Cancer Research Innovation Awards Competition was held on November 29, 2018. The aim of the competition was to stimulate creative thinking among students and post-docs, and to inspire collaborations among students and post-docs from different research groups and/or disciplines.
During the event, applicants who submitted proposals presented their projects and all the participants voted for their favorites.
The following project proposals, which received the highest number of votes, were awarded research funding of $10,000 apiece
The MICC 1st Student and Post-doc Cancer Research Innovation Awards Competition was held on November 29, 2018. The aim of the competition was to stimulate creative thinking among students and post-docs, and to inspire collaborations among students and post-docs from different research groups and/or disciplines.
During the event, applicants who submitted proposals presented their projects and all the participants voted for their favorites.
The following project proposals, which received the highest number of votes, were awarded research funding of $10,000 apiece
The Intrinsic and Extrinsic Mechanism of Therapy-Induced Senescence Escape
Submitted by Lior Roitman (Krizhanovsky lab) and Adi Jacob Berger (Straussman lab)
Discovery of Antibody Binding Targets in Ovarian Cancer
Submitted by Dr. Roei Mazor (Shulman and Sagi labs), Ran Salomon (Dahan lab) & Dr. Merav Shmueli (Merbl lab)
Being at the right time in the right cell: Following the dynamics of gefitinib resistance in lung cancer cells
Submitted by Tom Kaufman (Straussman & Rotter labs) & Michal Shreberk-Shaked (Oren lab)
MOROSS INTERDISCIPLINARY CANCER RESEARCH GRANT PROGRAM
The grant aims to support innovative approaches to important challenges in contemporary cancer research, using the combined expertise of at least two scientific fields. The proposals were submitted jointly by a team of at least two scientists, one of whom being a member of the Life Sciences faculties (Biology, Biochemistry) and one being a member of another faculty.
The grant aims to support innovative approaches to important challenges in contemporary cancer research, using the combined expertise of at least two scientific fields. The proposals were submitted jointly by a team of at least two scientists, one of whom being a member of the Life Sciences faculties (Biology, Biochemistry) and one being a member of another faculty.
Design and development of novel nanosensors for real time monitoring of tumor proteolytic activity using MRI
Cancer progression and growth are intimately correlated with proteolytic activity of the tumor microenvironment. The latter is mediated by increased matrix metalloproteinases (MMPs) expression and activity found in most types of cancers. Therefore, monitoring and/or controlling MMPs dysregulated proteolytic activity in vivo is an emerging need in the field of cancer diagnosis and therapy. The project aims to develop a transformative robust imaging platform for monitoring MMPs activity allowing earlier and better diagnostics of tumor onset and progression.
In vivo metabolic imaging of the cancerous pH gradient for diagnostic and therapeutic implications
Tumors hijack physiological chemical reactions, including those that maintain the pH for their own benefit in order to grow and metastasize. While all cells maintain a highly regulated “physiological pH” to enable a normal biochemical function, cancerous cells remodel chemical reactions to maintain this optimal pH internally, while creating an acidic pH outside the tumor that kills the surrounding healthy cells and allows the tumor to propagate. Cancer cells are also known to generate high amounts of lactic acid, a compound that then needs to be disposed to maintain intracellular pH values within physiological limits. Based on recent studies that we have carried out we proposed a hypothesis, according to which, the acidity created by lactate inside cancerous cells in addition to being extruded, is also neutralized by a cascade of new reactions that increase certain chemicals. Using cancer cell lines and other models we have confirmed that an increase in key anti-acidic metabolites –glutamine and ammonia– occurs inside the cells. These findings could potentially suggest new ways of treating cancers by devising scavengers that defeat this cancerous cells survival strategy. In order to develop this hypothesis further we propose to couple treatments that manipulate ammonia and glutamine intracellular concentrations, with emerging magnetic resonance (MR) techniques in 1H and hyperpolarized 13C MRI. This will enable real-time characterization of intra- and extra-cellular pH changes upon manipulating these anti-acidic agents in vitro and in animal models of various cancers. If proven correct, this strategy could be translated to the cancer patients as a novel approach to monitor and treat cancer progression.
CLINICAL COLLABORATIVE GRANTS
The objective of this funding program is to promote both basic and translational biomedical research, by bringing together scientists and physicians. The expectation is that this program will facilitate the incorporation of novel approaches from the bench to clinical applications.
The objective of this funding program is to promote both basic and translational biomedical research, by bringing together scientists and physicians. The expectation is that this program will facilitate the incorporation of novel approaches from the bench to clinical applications.
Tumor microbiome and Glioblastoma: Characterization, effects and translational opportunities
DNA repair Biomarkers for Predicting Response to Immunotherapy of Lung Cancer Patients
Omental fat-mediated chemoresistance to gastric cancer originating metastases
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.
EPCR and TM Guide Hematopoetic Stem Cell Homing to the Bone Marrow without Niche Clearance
Bone marrow (BM) recognition, homing and lodgment of long term repopulating hematopoietic stem cells (LT HSCs) are essential first steps for durable blood cell production during embryonic development and in clinical stem cell transplantation. Rare, BM retained LT HSCs endowed with the highest repopulation potential highly express EPCR (endothelial protein c receptor) and PAR1, which control LT HSC retention and chemotherapy resistance by limiting nitric oxide levels. We found that transplanted EPCR+ LT HSCs preferentially home to the BM, in contrast to immature progenitors. Intriguingly, EPCR+ LT HSCs can engraft the BM of non-irradiated recipients, while remaining quiescent, without giving rise to differentiated progeny. Strikingly, the quiescent homed EPCR+ LT HSCs were awakened by treating engrafted hosts with nitric oxide donor or with low dose chemotherapy, revealing that preconditioning and clearance of occupied HSC niches are not required.Importantly, we have treated human cord blood CD34+ stem and progenitor cells with a PAR1 mimicking peptide in vitro for 2 hours which reduced their nitric oxide levels and doubled their homing to the bone marrow of transplanted immune deficient mice. Our study provides mechanistic insights concerning LT HSC homing, which may lead to improved BM transplantation protocols and be applied to prevent chemotherapy resistance of EPCR-expressing cancer stem cell
Targeting mutant p53 in glioblastoma by an exosome-based therapy
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.
Identifying microbial determinants of response and resistance to targeted therapy in melanoma
Mutations in the BRAF gene occur in over half of melanoma tumors and result in constitutive signaling of the mitogen activated protein kinase (MAPK) pathway leading to enhanced cellular proliferation and survival. Treatment with MAPK pathway inhibitors targeting this genetic abnormality is associated with clinical benefit in the majority of patients with BRAF-mutant melanoma. However, relapse is almost universal. We focused on one aspect of the tumor microenvironment that remains largely unstudied in the context of acquired resistance to BRAF/MAPK pathway inhibitors, namely, the role of the host microbiome. We hypothesized that bacteria present in the tumor and gut of patients may differentially modulate responses to targeted therapy, and that through targeting these bacteria, therapeutic responses might be enhanced. We have located a small number of bacterial species that are highly enriched in the group of melanoma patients that responded to BRAF/MEK inhibitors. We are now developing a syngeneic model of tumors that can be infected with bacteria for the identification of strategies to overcome microbial-mediated resistance to targeted therapy in-vivo.