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For over 35 years, the Forbeck Foundation has helped transform the way researchers communicate in order to accelerate progress in cancer treatments

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“The only barrier for us to cure all of these various cancers is people working together and pushing forward new therapies. The technology is here. We’re very capable of curing all of these cancers.”

Oren Becher, MD, Northwestern University

Collaborative Papers from Past Meetings

Vertical suppression of the EGFR pathway prevents onset of resistance in colorectal cancers
September 22, 2015
AUTHORS

Sandra Misale, Ivana Bozic, Jingshan Tong, Ashley Peraza-Penton, Alice Lallo, Federica Baldi, Kevin H. Lin, Mauro Truini, Livio Trusolino, Andrea Bertotti, Federica Di Nicolantonio, Martin A. Nowak, Lin Zhang, Kris C. Wood, Alberto Bardelli

ABSTRACT

Molecular targeted drugs are clinically effective anti-cancer therapies. However, tumours treated with single agents usually develop resistance. Here we use colorectal cancer (CRC) as a model to study how the acquisition of resistance to EGFR-targeted therapies can be restrained. Pathway-oriented genetic screens reveal that CRC cells escape from EGFR blockade by downstream activation of RAS-MEK signalling. Following treatment of CRC cells with anti-EGFR, anti-MEK or the combination of the two drugs, we find that EGFR blockade alone triggers acquired resistance in weeks, while combinatorial treatment does not induce resistance. In patient-derived xenografts, EGFR-MEK combination prevents the development of resistance. We employ mathematical modelling to provide a quantitative understanding of the dynamics of response and resistance to these single and combination therapies. Mechanistically, we find that the EGFR-MEK Combo blockade triggers Bcl-2 and Mcl-1 downregulation and initiates apoptosis. These results provide the rationale for clinical trials aimed at preventing rather than intercepting resistance.

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Von Hippel-Lindau status influences phenotype of liver cancers arising from PTEN loss
February 1, 2015
AUTHORS

Adam B Sendor, Kathryn E Hacker, Shufen Chen, Armando L Corona, Oishee Sen, Derek Y Chiang, Anna Snavely, Arlin B Rogers, Stephanie A Montgomery, W Kimryn Rathmell, Autumn J McRee

ABSTRACT

PTEN loss contributes to the development of liver diseases including hepatic steatosis and both hepatocellular carcinoma (HCC) and cholangiocarcinoma (CC). The factors that influence the penetrance of these conditions are unclear. We explored the influence of sustained hypoxia signaling through co-deletion of Pten and Vhl in a murine model.

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RAS signaling promotes resistance to JAK inhibitors by suppressing BAD-mediated apoptosis
December 23, 2014
AUTHORS

Peter S. Winter, Kristopher A. Sarosiek, Kevin H. Lin, Manja Meggendorfer, Susanne Schnittger, Anthony Letai, Kris C. Wood

ABSTRACT

Myeloproliferative neoplasms (MPNs) frequently have an activating mutation in the gene encoding Janus kinase 2 (JAK2). Thus, targeting the pathway mediated by JAK and its downstream substrate, signal transducer and activator of transcription (STAT), may yield clinical benefit for patients with MPNs containing the JAK2(V617F) mutation. Although JAK inhibitor therapy reduces splenomegaly and improves systemic symptoms in patients, this treatment does not appreciably reduce the number of neoplastic cells. To identify potential mechanisms underlying this inherent resistance phenomenon, we performed pathway-centric, gain-of-function screens in JAK2(V617F) hematopoietic cells and found that the activation of the guanosine triphosphatase (GTPase) RAS or its effector pathways [mediated by the kinases AKT and ERK (extracellular signal-regulated kinase)] renders cells insensitive to JAK inhibition. Resistant MPN cells became sensitized to JAK inhibitors when also exposed to inhibitors of the AKT or ERK pathways. Mechanistically, in JAK2(V617F) cells, a JAK2-mediated inactivating phosphorylation of the proapoptotic protein BAD [B cell lymphoma 2 (BCL-2)-associated death promoter] promoted cell survival. In sensitive cells, exposure to a JAK inhibitor resulted in dephosphorylation of BAD, enabling BAD to bind and sequester the prosurvival protein BCL-XL (BCL-2-like 1), thereby triggering apoptosis. In resistant cells, RAS effector pathways maintained BAD phosphorylation in the presence of JAK inhibitors, yielding a specific dependence on BCL-XL for survival. In patients with MPNs, activating mutations in RAS co-occur with the JAK2(V617F) mutation in the malignant cells, suggesting that RAS effector pathways likely play an important role in clinically observed resistance.

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Monitoring Tumorigenesis and Senescence In Vivo with a p16INK4a-Luciferase Model
January 17, 2013
AUTHORS

Christin E Burd, Jessica A Sorrentino, Kelly S Clark, David B Darr, Janakiraman Krishnamurthy, Allison M Deal, Nabeel Bardeesy, Diego H Castrillon, David H Beach, Norman E Sharpless

ABSTRACT

Monitoring cancer and aging in vivo remains experimentally challenging. Here, we describe a luciferase knockin mouse (p16(LUC)), which faithfully reports expression of p16(INK4a), a tumor suppressor and aging biomarker. Lifelong assessment of luminescence in p16(+/LUC) mice revealed an exponential increase with aging, which was highly variable in a cohort of contemporaneously housed, syngeneic mice. Expression of p16(INK4a) with aging did not predict cancer development, suggesting that the accumulation of senescent cells is not a principal determinant of cancer-related death. In 14 of 14 tested tumor models, expression of p16(LUC) was focally activated by early neoplastic events, enabling visualization of tumors with sensitivity exceeding other imaging modalities. Activation of p16(INK4a) was noted in the emerging neoplasm and surrounding stromal cells. This work suggests that p16(INK4a) activation is a characteristic of all emerging cancers, making the p16(LUC) allele a sensitive, unbiased reporter of neoplastic transformation.

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Complex oncogene dependence in miR-125a-induced myeloproliferative neoplasm
September 24, 2012
AUTHORS

Shangqin Guo, Haitao Bai, Cynthia M Megyola, Stephanie Halene, Diane S Krause, David T Scadden, Jun Lu

ABSTRACT

Deregulation of microRNA (miRNA) expression can lead to cancer initiation and progression. However, limited information exists on the function of miRNAs in cancer maintenance. We examined these issues in the case of myeloproliferative diseases and neoplasms (MPN), a collection of hematopoietic neoplasms regarded as preleukemic, thereby representing early neoplastic states. We report here that microRNA-125a (miR-125a)-induced MPN display a complex manner of oncogene dependence. Following a gain-of-function genomics screen, we overexpressed candidate miR-125a in vivo, which led to phenotypes consistent with an atypical MPN characterized by leukocytosis, monocytosis, splenomegaly, and progressive anemia. The diseased MPN state could be recapitulated in a doxycycline-inducible mouse model. Upon doxycycline withdrawal, the primary MPN phenotypes rapidly resolved after the discontinuation of miR-125a overexpression. However, reinduction of miR-125a led to complex phenotypes, with some animals rapidly developing lethal anemia with extensive damages in the spleen. Forced expression of miR-125a resulted in elevated cellular tyrosine phosphorylation and hypersensitivity toward hematopoietic cytokines. Furthermore, we demonstrate that miR-125a targets multiple protein phosphatases. Our data demonstrate that miR-125a-induced MPN is addicted to its sustained overexpression, and highlight the complex nature of oncogenic miRNA dependence in an early neoplastic state.

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Targeted Nanoparticles for Imaging Incipient Pancreatic Ductal Adenocarcinoma
April 15, 2008
AUTHORS

Kimberly A Kelly, Nabeel Bardeesy, Rajesh Anbazhagan, Sushma Gurumurthy, Justin Berger, Herlen Alencar, Ronald A Depinho, Umar Mahmood, Ralph Weissleder

ABSTRACT

Pancreatic ductal adenocarcinoma (PDAC) carries an extremely poor prognosis, typically presenting with metastasis at the time of diagnosis and exhibiting profound resistance to existing therapies. The development of molecular markers and imaging probes for incipient PDAC would enable earlier detection and guide the development of interventive therapies. Here we sought to identify novel molecular markers and to test their potential as targeted imaging agents.

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The Telomeric Protein TRF2 Binds the ATM Kinase and Can Inhibit the ATM-Dependent DNA Damage Response
August 2, 2004
AUTHORS

Jan Karlseder, Kristina Hoke, Olga K Mirzoeva, Christopher Bakkenist, Michael B Kastan, John H J Petrini, Titia de Lange

ABSTRACT

The telomeric protein TRF2 is required to prevent mammalian telomeres from activating DNA damage checkpoints. Here we show that overexpression of TRF2 affects the response of the ATM kinase to DNA damage. Overexpression of TRF2 abrogated the cell cycle arrest after ionizing radiation and diminished several other readouts of the DNA damage response, including phosphorylation of Nbs1, induction of p53, and upregulation of p53 targets. TRF2 inhibited autophosphorylation of ATM on S1981, an early step in the activation of this kinase. A region of ATM containing S1981 was found to directly interact with TRF2 in vitro, and ATM immunoprecipitates contained TRF2. We propose that TRF2 has the ability to inhibit ATM activation at telomeres. Because TRF2 is abundant at chromosome ends but not elsewhere in the nucleus, this mechanism of checkpoint control could specifically block a DNA damage response at telomeres without affecting the surveillance of chromosome internal damage.

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Revisions of the international criteria for neuroblastoma diagnosis, staging, and response to treatment
August 11, 1993
AUTHORS

GM Brodeur, J Pritchard, F Berthold, N L Carlsen, V Castel, R P Castelberry, B De Bernardi, A E Evans, M Favrot, F Hedborg, et al.

ABSTRACT

Based on preliminary experience, there was a need for modifications and clarifications in the International Neuroblastoma Staging System (INSS) and International Neuroblastoma Response Criteria (INRC). In 1988, a proposal was made to establish an internationally accepted staging system for neuroblastoma, as well as consistent criteria for confirming the diagnosis and determining response to therapy (Brodeur GM, et al: J Clin Oncol 6:1874-1881, 1988). A meeting was held to review experience with the INSS and INRC and to revise or clarify the language and intent of the originally proposed criteria. Substantial changes included a redefinition of the midline, restrictions on age and bone marrow involvement for stage 4S, and the recommendation that meta-iodobenzylguanidine (MIBG) scanning be implemented for evaluating the extent of disease. Other modifications and clarifications of the INSS and INRC are presented. In addition, the criteria for the diagnosis of neuroblastoma were modified. Finally, proposals were made for the development of risk groups that incorporate both clinical and biologic features in the prediction of prognosis. The biologic features that were deemed important to evaluate prospectively included serum ferritin, neuron-specific enolase (NSE), and lactic dehydrogenase (LDH); tumor histology; tumor-cell DNA content; assessment of N-myc copy number; assessment of 1p deletion by cytogenetic or molecular methods; and TRK-A expression.

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The vision of the William Guy Forbeck Research Foundation is to see cures for all cancers, especially neuroblastoma and other childhood malignancies.

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