2018-2019 Funded Collaborations

2018-2019 FUNDED COLLABORATIONS

International Collaborative Grants

Markus Müschen, M.D., Ph.D., Systems Biology, City of Hope
 
 
Funded Collaborations - Shai Izraeli
Shai Izraeli, MD, Hematology Oncology, Schneider Children’s Medical Center of Israel
Oncogenic Feedback Signaling in “Ph-like” ALL: Mechanisms and Therapeutic Opportunities

Constitutive activation of JAK-STAT pathway characterizes a subgroup of poor prognosis B cell precursor acute lymphoblasic leukemia (BCP-ALL) named also “Ph-like” because of the similarity of their gene expression signature to ALL carrying the Philadelphia (Ph) chromosome. We and others discovered that “Ph-like” ALL is most commonly caused by activation of CRLF2/IL7R/TSLPR/ pathway. While targeted therapy by a JAK1/2 inhibitor (Ruxolitinib) is being tested in clinical trials, only modest responses have been observed in preclinical experiments. The Izraeli (ISR) and the Müschen (COH) groups have independently discovered the ubiquitous induction of negative feedback regulators of JAK-STAT signaling in Ph-like ALLs. We hypothesize that this “buffering” of JAK-STAT signaling is essential for leukemic cell survival since hyperactivation of oncogenic signaling pathways may kill the B lineage leukemic cells by activating the autoimmunity checkpoint (AIC). Here we propose to study this hypothesis using in-vitro and in-vivo models of primary lymphoid and leukemic cells. Specifically we will test the innovative hypothesis that despite oncogenic transformation, B cell tumors are fully sensitive to AIC-activation. Applying selective pressures from opposite directions may compromise Darwinian selection for drug-resistant mutants.
 
Dan Raz, MD, Surgery, City of Hope
 
Ravid Straussman, MD, PhD, Molecular Cell Biology, Weizmann Institute of Science The Effect of Intra-Tumor Bacteria on the Sensitivity of NSCLC to EGFR and ALK Inhibitors

Drug resistance remains the “final common pathway” in the treatment of many advanced cancer patients. Many new and promising targeted therapies are being developed, and although many patients initially respond to therapy, a complete response is rarely observed. The tumor microenvironment has been shown to have major influences on response to drug treatment and its effects are continuously being elucidated. In our previous joint collaboration we have analyzed the NSCLC microbiome and found bacteria in many of the tumors. We have characterized the lung tumor microbiome and showed that bacteria can be specifically present in lung samples. Moreover, we were able to show that bacteria can affect the response of lung cancer cells to EGFR and ALK targeting therapies in vitro. The effect of bacteria on the responses of lung tumors to targeted therapies (EGFR and ALK inhibition) and the mechanisms they use to interfere with treatment remains largely unexplored. In this study we intend to fill this gap by further examining the effect of more bacteria on targeted treatments in vitro and uncover the various mechanisms that are used by the bacteria to interfere with treatment. We will also examine the effect of these bacteria on treatment of tumors in vivo in mice models. Functional studies will be carried out with the mice in order to find strategies to abolish the interference of bacteria on treatment. We expect that our new findings may open novel strategies towards the design of better treatment options for patients with lung cancer.
 
Jeffrey Weitzel, MD, Population Sciences/Clinical Cancer Genetics, City of Hope
 
Gad Rennert, MD, PhD, Carmel Medical Center, Community Medicine and Epidemiology, Clalit National Cancer Control Center
Cancer Susceptibility Mutations in Young Israeli Breast Cancer (BC) Patients
 
We propose to conduct high-throughput genomic profiling on existing biospecimens for breast cancer cases who are at high risk/high probability of genetic predisposition and had an uninformative clinical gene testing (14 founder mutations in BRCA1 and BRCA2) to evaluate the role of variants in a large spectrum of genes, formerly shown to be involved in solid tumors, in young breast cancer causation. Study participants will come from the Breast Cancer in Northern Israel Study (BCINIS) which is a population-based, case–control study of incident female breast cancer in Northern Israel with recruitment starting at January 1, 2000. They are all consented participants in the BCINIS who were diagnosed with invasive BC at age < 50 years old, and have an available DNA sample; 3605 women currently fulfill these criteria (of them 297 were tested in a former study year). DNA will be extracted and shipped to COH for analysis on multi-gene cancer exome panel which includes hematologic malignancy related genes and at a second phase a selected sub group of cases without identified mutations will be studied, given availability of FFPE block, for somatic mutations and microsattelite instability and further studied for the competence of their immune system with a tailored multigene gene-expression panel. When mutations are detected (or have been detected in a former phase of the study) we will invite family members to test and if necessary will provide clinical counselling for prevention and early detection.
 
Victoria Seewaldt, MD, Population Sciences, City of Hope
 
Rami Aqeilan, PhD, Lautenberg Center for Immunology and Cancer Research , Hebrew University/Hadassah Medical School
WWOX Loss Activities Aerobic Glycolysis in TNBC

Triple-negative breast cancers [ER(-)/PR(-)/HER2wt (TNBC)] are highly aggressive breast cancers. We discovered a novel tumor suppressor gene, WWOX that is lost in 88% of TNBC we tested. We have shown recently that WWOX deficiency activates glycolysis and glucose uptake. In this proposal, we aim to mechanistically investigate the role of WWOX signaling in activating glycolysis and glucose uptake in TNBC. Our long-term goal to test whether WWOX and downstream activation of glycolysis can be targeted to prevent metastasis of TNBC.
Studies that were initiated by Dr. Aqeilan at Hebrew University and Dr. Seewaldt at City of Hope provide preliminary evidence that loss of WWOX expression activates metabolism. We further aim to investigate the molecular mechanism by which loss of WWOX may increase glycolysis. Our studies will span from basic mechanistic studies in transgenic models to validation in live and fixed clinical samples from City of Hope patients.
Together our Hebrew University-City of Hope Partnership will test from bench to the clinic the hypothesis that loss of the tumor suppressor WWOX activates glycolysis in TNBC via transcriptional activation of HIF1alpha. The study draws on the expertise of both partners: Dr. Aqeilan's expertise in tumor suppressor signaling and Dr. Seewaldt's expertise in translational research and biomarker signaling This project could not be accomplished by one investigator alone and requires the synergy created by this Hebrew University - City of Hope team.

About the Israel Cancer Research Fund
Israel Cancer Research Fund, a 501(c)(3) organization, is the largest nationwide charitable organization in North America solely devoted to supporting cancer research in Israel. Since its establishment in 1975, ICRF has provided more than 2,200 grants to outstanding cancer researchers whose laboratories are located in all of the leading research institutions, universities and hospitals across Israel. For more information, visit www.icrfonline.org.