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Reflecting on Key Scientific Accomplishments

Time for the Oscar edition of the blog! Not really, but for a change Harriet and I have seen many of the Best Picture candidates. I’m rooting for Lincoln, but suspect Argo will sneak in – either way the winner would be highly deserving. We had an otherwise quiet weekend dominated by working on an […]

Time for the Oscar edition of the blog! Not really, but for a change Harriet and I have seen many of the Best Picture candidates. I’m rooting for Lincoln, but suspect Argo will sneak in – either way the winner would be highly deserving. We had an otherwise quiet weekend dominated by working on an R01 renewal.

On Friday night I gave a talk at an event at the Greek Embassy, which was commemorating the career of George Papanicolaou, who created the field of cytology and pioneered the Pap test for cervical cancer. Dick Schlegel’s ears must be burning – I seized the opportunity to discuss the importance of his work in developing the HPV vaccine.

Speaking of Dick, our Program Leader’s meeting on Friday largely focused on a number of presentations focused on how Lombardi is utilizing Conditional Cellular Reprogramming.  So much is going on – we are collectively making a huge impact as we implement this powerful new technique for diagnostic, therapeutic and scientific purposes. I am exploring ways to engage all of our scientific community through a symposium that would explore all of the work being done in this area.

Those of you who regularly read this blog know that I have begun reviewing the Cancer Center’s status by sharing elements of the current version of my Director’s Overview for our upcoming CCSG renewal application. Last week I started with the section’s introductory comments. This week I start with some of our key scientific accomplishments over the past four years. It will take a few weeks to get through all of them, but I believe you will agree that this is a good start!

6.1.4 Scientific Accomplishments
LCCC’s broad and impactful scientific accomplishments during the current funding period demonstrate that the Center has flourished and benefited from our planning activities and their implementation. We have invested in key scientific platforms to energize and support translational, transdisciplinary science. These platforms include the development of cellular reprogramming technology, the creation of informatics tools to collect and analyze patient-specific information and data obtained from biospecimens, and the expansion of LCCC’s minority health and health disparities and health services research. These efforts have been supplemented by the development of regional collaborations, by building resources to access minority populations and increase trial accrual. Examples of successes in the current funding period are described below.

Fundamental Science with Translational Implications
·                Epithelial Cell Reprogramming Provides Opportunities for Personalized Diagnosis and Treatment as Well as Insight Into Cell Biology (Schlegel [MO]; Liu, Am J Pathol 2012; Proc Natl Acad Sci USA 2012). In research originating within the Molecular Oncology Program, Schlegel (MO) and colleagues have developed a cellular reprogramming protocol that routinely and rapidly immortalizes primary normal and malignant epithelial cells. They demonstrated the power of this technology by applying it to identify an effective therapy for a patient with a rare tumor (Liu New Engl J Med 2012). To maximize the impact of this discovery, LCCC has invested in pilot studies, with an expanding list of clinical trials. We have expanded the Tissue Culture Shared Resource to support these activities. We have established a GU-sponsored spin-off company that will permit scaling up of the activity to support LCCC research objectives. These activities have been coordinated at Program Leaders’ meetings to identify and prioritize research opportunities. Even though the discovery is recent, LCCC investigators have pursued biology-based studies in prostate, breast cancer (Furth [BC], Weiner [ET], Riegel [BC], thymoma (Giaccone [ET]) and head and neck cancer (Deeken [ET]).

Deeken is also using this technology to support two Phase I clinical trials. LCCC investigators have established collaborations with investigators at Yale, UNC and MSKCC to address the fidelity of this approach. Collaborations with the NCI Surgery Branch use this technique to grow tumor target cells to assist in the selection and testing of tumor specific T cells to be used in adoptive cellular therapy studies in patients with head and neck and GI malignancies.  In addition, investigator-initiated clinical trials, led by Herbolsheimer (BC) and Nunes (BC) employ conditionally reprogrammed cells to study drug sensitivities and pathway activation in patients with hormone receptor-positive and triple-negative breast cancers. These clinical trials engage patients from a diverse population that includes the MedStar Washington Hospital Center, which primarily serves minority populations in Lombardi’s catchment area. Impact: This new technology could provide a transformational, dynamic platform for personalized cancer therapy. Others share our view. “What could be more personalized than taking this person’s cell, growing it in culture, finding a drug to treat them and then treat them?” said Doug Melton, co-director of the Harvard Stem Cell Institute. The Georgetown method gives an answer quickly enough that it could save lives, he said (AP, 9/27/2012).

·       Mechanisms Underlying Genomic Instability in Glioblastoma and Bladder Cancer Are Elucidated (Waldman [MO]; Solomon, Science 2011). In groundbreaking research originating in the Molecular Oncology Program, Waldman led a collaboration including investigators at three other CCSG-funded cancer centers to demonstrate that cells lacking STAG2 display reduced sister chromatid cohesion, leading to chromosomal non-disjunction and aneuploidy. Most recently, Waldman’s laboratory has teamed with investigators from the MD Anderson Cancer Center Bladder Cancer SPORE to show that STAG2 is among the most commonly mutated genes in bladder cancer . Waldman is now teaming with investigators from the NCI intramural program to perform a synthetic lethality screen, with the ultimate goal of identifying lead compounds that are selectively cytotoxic towards aneuploid cancer cells. Impact: This work could offer the potential to specifically target a basic mechanism underlying the neoplastic phenotype.

·      Transcription Factor Drug Targets Are Identified in Childhood Sarcoma (Toretsky [MO]; Ezikian, Nature Med 2009). EWS-FLI1 was previously considered to be an “undruggable” protein due to its lack of enzymatic activity and because it is an intrinsically disordered protein. A small molecule blocking the interaction of the oncogenic protein EWS-FLI1 with RNA helicase A inhibits the growth of Ewing sarcoma. Working with Brown (ET) the drug YK-4-279 was created and shown to have promise in preclinical models. This small molecule is being developed for clinical use with the assistance of a spin-off pharmaceutical company and with support from the NCI NExT program.  Major funding included a $4.4 million ARRA RC4 grant awarded to Toretsky (MO) to support the development of an EWS-FLI1 inhibitor. Impact: This work offers a pathway to develop a new treatment for Ewing sarcoma, and provides evidence for the first time that transcription factors and intrinsically disordered proteins can be therapeutically targeted.

·      Arsenic Trioxide Inhibits Human Cancer Cell Growth and Tumor Development in Mice by Blocking the Hedgehog/GLI Pathway (Üren, Beauchamp J Clin Invest 2011). MO member Üren identified GLI1 as a direct transcriptional target of EWS-FLI1 in Ewing sarcoma cells (Beauchamp, J Biol Chem 2009). Since GLI1 activation is downstream of the hedgehog (Hh) pathway and Hh-GLI was also known to be a critical driving pathway of medulloblastoma a transgenic mouse model for medulloblastoma was created. The interdisciplinary work led to the discovery of arsenic trioxide (ATO) as a novel Hedgehog pathway inhibitor that binds directly to GLI1 and inhibits its transcriptional activity. ATO was effective in treating spontaneous medulloblastomas in the mouse model by inhibiting GLI1 transcriptional activity. Üren and colleagues are currently seeking support for a clinical trial in medulloblastomas. Impact: This work describes a new mechanism of action for an old drug that can readily translate into the clinic.

There is a lot more to follow, but I hope this has whetted your appetite. We may not get little gold statues when we do something memorable, but we do get the immeasurable satisfaction that comes with making a lasting difference in the world. And, no special effects are required!

Have a wonderful week.

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