From the Desk of Dr. Louis M. Weiner

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.

Hard to believe that, as I write this blog on a beautiful Sunday afternoon, after running a few errands and catching up on work, New England is still digging out from a snowpocalype.

Harriet and I actually ventured north to Baltimore and Philly yesterday, as we drove up to have dinner with our son Ken and his wife Sarah to celebrate his birthday. While Sarah is preoccupied with her studies as she heads into the homestretch of her first year of medical school (while being seven months pregnant!) Ken is working hard in two veterinary practices, while furiously renovating his new house so there is a kitchen and upstairs bathroom completed before the baby arrives. While we were out to dinner with the whole family including my dad at a lovely Italian restaurant called La Collina, I was recalling that the first time I went to that same restaurant I was a Grand Rounds speaker at Lankenau Cancer Institute and guest of the Institute’s director, George Pendergast (who is now editor of Cancer Research.) As I was telling the story I glanced to my left and to my utter amazement, there was George, having dinner with his wife. It was very nice to see him and chat. Small world!

The preceding week was very interesting. On Monday, I hosted a donor who had bid successfully for a lunch and tour of my lab at the Lombardi Gala in November. We had lunch in the French Embassy’s dining room, and the food beat my usual turkey and provolone sandwich from Subway by more than a few logs. Later that afternoon I participated in the thesis committee meeting for one of my students, Rishi Surana; he’ll be giving Data Meeting this Thursday, and I predict it will be very interesting. That evening Spiros Dimiltsas and I hosted some folks from Stevens Institute of Technology at dinner at Café Milano.

I was supposed to go on a Cancer Center site visit on Tuesday, but was informed that since I was recently appointed to the NCI Board of Scientific Counselors I needed to get a special waiver in order to do the grant review, and of course that process would take a month – so there was no time for me to be approved prior to the site visit. Accordingly, I had a few days to catch up on work (mostly related to the CCSG, of course) and develop and recover from a miserable cold. At the same time Harriet and I were watching Isaac for a few days, and we drove up to Baltimore on Wednesday to drop him off at home when his mom and dad returned from a brief trip. We did use his visit as an opportunity to take him to the Air and Space Museum – he in an aficionado of the Solar System and flight in general – and so, he was enthralled by most of what he saw (though the Planetarium show freaked him out a bit). But he knows a lot more about planets that I do! Admittedly, that is not a high bar…

I had a make-up clinic on Friday morning, since I expected to be out on Thursday. I hurried from clinic to attend the presentation of a medical oncology candidate, and had a series of meetings to conclude the week. I have a bunch of work to do tonight, and need to get my rest, because the coming week promises to be one the busiest I’ve had for quite some time. I hope your week is productive, but less hectic!

I am writing this week’s blog on Super Bowl Saturday, since I will be preoccupied tomorrow evening. We are set for tomorrow; my father is joining us to watch the game so we decided to prepare the food today. I made the chili, and think it will be a good batch when we reheat it tomorrow, I have decided to root for the Ravens (East Coast, etc.), though I generally am a NFC guy. However, my guess is that the 49ers will win by 10 (23-13). Most of all, I hope for a good game.

In reviewing the past week, all reminiscence starts and stops with our friend and colleague, Marko Moscovitch. As you know, Marko lost his battle with pancreatic cancer this past week. He was a longtime member of Lombardi, and my email inbox was clogged with heartfelt messages from his many friends here and around the world. He was a wonderful scientist, a fine, innovative teacher and a good man. He will be missed. Rest easy, my friend.

All other news pales in significance in comparison with the loss of a friend and colleague, but there were a few items to note. On Wednesday afternoon there was a ceremony celebrating Georgetown patent holders. Jeff Toretsky gave an inspiring and emotional keynote speech about his work with EWS-FLI-1 and the development of YK-279. I then scurried off to the Verizon Center to attend a donor event at the Georgetown-Seton Hall basketball game. Georgetown won handily, and the game was frankly a bit boring, but I was so busy speaking with our guests in the suite that it was just as well. Friday was exceptionally busy, starting with giving Grand Rounds at the University of Maryland Greenebaum Cancer Center. Our old friend Kevin Cullen had another obligation, but it was good to see Ed Sauseville and Curt Civin, among others. The remainder of the week was spent on the CCSG, as I am now revising my sections based on the most recent rounds of internal and external review.

That’s all for now. Have a Super Sunday and a wonderful week!